copyrighted materialindex aat-deﬁcient patients, 233, 237. see also alpha-1 antitrypsin (aat)...

INDEX

AAT-deficient patients, 233, 237.

See also Alpha-1 antitrypsin (AAT)

deficiency

ABCAI-mediated efflux, 292, 293.

See also ATP-binding cassette

transporter AI (ABCAI)

ATP binding cassette transporter G1

(ABCGI), 292, 293

Accreditation Council for Continuing

Medical Education (ACCME), 418

Acid-citrate-dextrose (ACD) blood

collection solution, 4

Acid-stabilized plasmin, 268

as a direct-acting thrombolytic, 259–271

Acquired angioedema (AAE), 249

Acquired ATIII deficiency, 152

Acquired Factor X deficiency, 107, 108

Acquired human TSE infections, 369

Acquired immunodeficiency syndrome

(AIDS), convalescent plasma

treatment of, 209. See also HIV

entries; Human immunodeficiency

virus (HIV); National AIDS Control

Organization (NACO)

Acquired inhibitors, 57

Activated clotting factors, 66

Activated Factor VII (FVIIa), 51, 69, 75

Activated Factor IX (aFIX, FIXa), 75,

81–83

Activated Factor X (FXa), 81. See also

Activated purified Factor X

Activated Factor XI (FXIa), 94

Activated Factor XII (FXIIa), 242

in Factor XI activation, 94

Activated Factor XIII (aFXIII, FXIIIa),

102, 139, 140

Activated factors, in PCC products, 72

Activated Hageman factor (HFa),

193

Activated partial thromboplastin time

(aPTT), 95


(APTT) assay, 49, 50


(APTT) test, 111, 112, 118

Activated PCC, 76. See also Activated

prothrombin complex concentrates

(APCCs); Prothrombin complex

concentrates (PCCs)

Activated Protein C (APC), 67, 148

Activated prothrombin complex

concentrate (FEIBA1), 37

composition of, 53


concentrates (APCCs), 49, 50

clinical trials with, 52

mechanism of action of, 51–57

Activated purified Factor X, 112.

See also Activated Factor X (FXa)

Active coagulation enzymes, 51

Active lipids, 74

Acute coronary syndrome (ACS), 274,

288, 289

Acute hemorrhages, 57

Acute ischemic stroke, 268

Acute ITP, 220. See also Immune

thrombocytopenic purpura (ITP)

Acute lung injury (ALI), 352

Acute respiratory distress syndrome

(ARDS), 161, 341

ADAMTS-13 metalloprotease, 42

Adhesion molecules, expression of, 276

Adjunctive cancer therapy, ceruloplasmin

in, 341

Adsorption processes, for virus

removal, 364

Adsorption techniques, in plasma

fractionation, 441

Advanced glycation end products

(AGEs), 192

Advate1, 36

Adverse effects/events (AEs), 57, 58, 74

albumin-related, 176, 177

in ITP treatment, 220, 221

related to IVIG preparations, 198, 199

Adverse reactions

blood-cell-induced, 351

related to IVIG preparations, 198, 199

Aerosol alpha1-PI, 237, 238. See also

Alpha1-proteinase inhibitor

(Alpha1-PI)

Affinity chromatography, 33–35, 44,

84–86, 97, 105, 439, 440. See also

Double affinity chromatography

in albumin manufacture, 165

in FVIII manufacturing, 150

of FEIBA1 components, 51

of haptoglobin, 328

on heparin gels, 149

in plasma fractionation, 441

plasminogen purification by, 314, 315

in vWF purification, 45

Production of Plasma Proteins for Therapeutic Use, First Edition. Edited by Joseph Bertolini, Neil Goss, and John Curling.� 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

471

COPYRIG

HTED M

ATERIAL

Affinity ligand chromatography, 349, 350

Affinity purification method, for

alpha1-PI, 231

Aggregate formation, in IVIG prepara-

tions, 195. See also Aggregation

Aggregation

preventing, 340

of viruses, 191

Albondin, 163, 164

Albumin, 437. See also Human albumin

entries; Human serum albumin

(HSA)

accompanying IVIG preparations, 197

aluminum limits for, 169, 170

anticoagulant activity of, 164

appropriate and inappropriate use

of, 174, 175

binding properties of, 175

biochemistry of, 160, 161

burn patient benefits of, 174, 175

as carrier for nitric oxide, 164

centrifugation of, 167, 168

characteristics and specifications

of, 168–171

citrate concentrations in, 171

clinical issues related to, 171–176

color of, 169

demand for, 21, 464

demand in China for, 453

drug binding to, 163

effects of, 172, 173

esterase activity of, 164

fatty acids in, 162, 163

fluid balance and, 161

free thiol in, 171

future trends for, 177, 178

glycation of, 164

guidelines for therapeutic use of, 171

guidelines for use of, 159

haptoglobin precipitation and, 328

immunomodulatory properties of, 164

ionic properties of, 232

ligands binding to, 162–164

as a low-risk product, 176

manufacturing of, 164–171

manufacturing process development

for, 166, 167


molecular size distribution for, 171

pasteurization of, 165, 166

physiology and function of, 160

PKA activity in, 171

in plasma buffering, 164

preparation of, 159

prognostic value of, 174

properties of, 178

redox properties of, 164

role in critical illness, 160

roles of, 159, 171

as a safe plasma protein, 177

sepsis and, 176

transport and ligand binding of,

161–164

in treating liver disease, 175

Albumin concentration, 175

Albumin dialysis system, 175

Albumin fusion proteins, 178

Albumin microspheres, 178

Albumin preparations, purity of, 169, 170

Albumin production, 12

global, 159

Alkjaersig purification method, 313

Allergic PCC reactions, 75

Allergic reactions, 351–353

Alloantibodies, 37

inhibitory, 57

Alpha-1 antitrypsin (AAT)

deficiency, 227–229. See also AAT-

deficient patients

Alpha1-PI, 227, 228. See also Alpha1-

proteinase inhibitor (Alpha1-PI)

Augmentation therapy with, 229

elastase inhibition by, 229

future of, 237, 238

isolating, 230–232

new indications for, Inc., 238

structure of, 228, 229

trypsin-inhibitory activity of, 232

Alpha1-PI inactivation, 232

Alpha1-PI isoforms, 228

Alpha1-PI production methods,

comparison of, 236

Alpha1-PI purification methods

at industrial scale, 231–237

at laboratory scale, 229–231

Alpha1-proteinase inhibitor (Alpha1-PI),

227–240

Alphanate, 45

Alphanine1, 88

replacement therapy recommendations

for, 89

Alpha Therapeutics, 466

Aluminum limits, for albumin, 169, 170

Alzheimer’s disease, 195, 197, 200

American Association of Blood Banks

(AABB), 8, 423, 425

American market, 464

American Red Cross (ARC), 5, 7, 8, 10

in blood collection, 8

fractionation capability of, 9

Analytical comparability, strategies for

demonstrating, 408, 409

Analytical programs, successful, 410

Anamnestic responses, 58

Anaphylactic PCC reactions, 75

Anaphylactic reactions, 351, 352

Anaphylactoid reaction rate, for Octaplas

(LG), 352

Anastomosis, 3, 4

Angioedema

acquired, 249

hereditary, 241, 242, 248, 249

Angiogenic compounds, 152

Anhaptoglobinemia, 322

Animal bioassay, 375

Animal disease models, transferrin in,

306

Animal models

of blood loss and replacement, 326

in investigating hemophilia

therapies, 55

relevance of, 55–57

TSE-related, 371, 372

Animal parvoviruses, 328

Animal studies, haptoglobin in, 331

Animal thrombolysis studies, 265, 266

Anion(ic) exchange chromatography

(AEC), 44 , 187, 189

Anion exchange chromatography

procedure, 213

Anion exchangers, for PCC capture, 84

Anion exchange technology, 9

Annual Product Review, 399

Anthrax, as biological weapon, 210

Anthrax immune globulin (AIG), 212

Antibodies, 207

immobilized, 33

inhibitory, 37, 73, 74

inhibitory and noninhibitory, 57

monoclonal and polyclonal, 200

neutralizing, 191

reducing, 351

Antibody–antigen binding, 208

Antibody-based immunotherapy, 210

Antibody-based therapies, 207

Antibody concentrates, 7

Antibody degradation, 33

Antibody-dependent cellular cytotoxicity

(ADCC), 208

Antibody therapy, 208

Antibody titers, in IVIG

preparations, 195–197

Anticoagulant activity, of albumin, 164

Anticoagulant effect, reversal of, 73

Anticoagulants, 3

development of, 4

Anticoagulant solution, for source plasma

collection, 426

Anticoagulant system, 69

Anticomplementary active

aggregates, 198

Anticomplementary activity (ACA), 191,

193

of IVIG preparations, 192, 193

472 INDEX

Anti-D immune globulin, 9

Anti-D Mab, 222. See alsoMonoclonal

antibodies (Mabs)

Anti-D products, manufacturing process

of, 221

Antifibrinolytic agents, 249

Antifibrinolytic drugs, 96

Antihemophilic Factor B, 65

Antihemophilic globulin, in hemophilia

treatment, 33

Anti-HLA/HNA antibodies, 351, 352

Anti-inflammatory activity, of C1-

inhibitor, 249

Anti-inflammatory action, of

ceruloplasmin, 339

Antioxidant activity, of

ceruloplasmin, 338, 342

Antioxidant properties, of albumin, 164

Antiplasmin, 317

Anti-RBC antibodies, 220

Anti-Rh antibody, 218

Anti-Rh immunoglobulin, antenatal

administration of, 218

Antithrombin, 66, 67, 69, 70

in PCCs, 75

Antithrombin activity, 147, 148

Anti-thrombin–heparin complex, 52

Antithrombin III (ATIII). See also ATIII

entries

gene structure and function of,

147–149

manufacturing methods for, 149, 150

pasteurization of, 150

production and clinical use of, 147–157

protein structure and function of,

147–149

purification of, 149, 150

Antithrombin III deficiency, 151, 152

Antithrombin III therapy, 152

Antitoxins, virus neutralization and, 208

Antiviral products, 467

APCC composition, 53. See also


concentrates (APCCs)

APCC potency, 53

Apheresis, plasma collected by,

423–425

Aplastic anemia, ceruloplasmin treatment

of, 340–342

ApoA-1, 273–276. See also

Apolipoprotein AI entries

Apolipoprotein AI (ApoAI), 283

Apolipoprotein AIMilano (ApoAIMilano)

first characterization of, 286, 287

as a fusion protein, 290

low plasma levels of, 287

manufacture by seed-based expression

in plants, 289–295

plant-derived manufacturing of,

283–300

purification of, 291

safflower-derived, 290–292

Apolipoprotein AIMilano HDL

therapy, 289

Apolipoprotein AIMilano production, cost

estimates of, 289

Apotransferrin, 304, 306

Apple domains, 93–95

Applicant plasma, 431

Aprotinin, 141, 142

Aralast NP production method, 236,

238

Aralast purification process, 233, 234,

236, 237

Argentine hemorrhagic fever,

convalescent plasma treatment

of, 209

Armour & Company, 8

Armour Pharmaceutical, 21

Army Blood Transfusion Service, 5

Arterial plaque, control of, 283

Arterial/venous thrombosis models, 265

Arteriovenous anastomosis, 3, 4

Artificial aggregation, of viruses, 191

Artificial HDL particles, 273, 274

Ascites, 175

Asher, David M., xi, 369

Asia

fibrin glues in, 137

plasma collection in, 21

Assays, to detect TSE infectivity, 375

ATIII concentrates, treatment with, 152.

See also Antithrombin III (ATIII)

ATIII deficiency, 147

ATIII–HSPG interaction, 148

ATIII inherited deficiencies, 151, 152

classification of, 151

ATIII isoforms, 147

ATIII-protease complexes, 149

ATIII protease inhibition, regulators

of, 148, 149

Atheroma volume, 288

Atherosclerosis, 273

ERASE study of, 278

role of inflammation in, 275

Atherosclerotic lesions, 284

Atherosclerotic models, 294

ATP-binding cassette transporter AI

(ABCAI), 284–286. See also

ABCAI-mediated efflux

Attenuated androgens, 249

Audit execution, 398, 399

Audit management, 397–399

risk-based, 398

Auditor qualification, 398, 399

Audit reports, 397, 399

Audits

from external bodies, 398

frequency and scope of, 398

Audit schedule, 397

Audits/inspections, 398

Augmentation therapy, with alpha1-PI,

229

Australia, plasma fractionation in, 16, 17

Australian Red Cross, 17

Autodegradation, 260–262

Auto-FIX concentrates, 49

Autoplex, 49, 50

Aventis Behring, 15, 466

“Axial flow” type columns, in plasma

fractionation, 441, 442

B19 NAT, 349. See also Nucleic acid-

based testing (NAT); Parvovirus B19

(B19V)

Bacterial endotoxin test (BET), 194

“Bad cholesterol,” 274

Bags, peeling of plasma into, 439

Barga, 345

Batch adsorption, in plasma protein

collection, 439, 440

Batch mode manufacturing, solvent/

detergent plasma and, 345

Baxter Bioscience, 8, 9, 21, 451, 461

growth of, 16

manufacturing strategy of, 15

Baxter Healthcare, 233, 236, 247

Bayer AG, 15

B-domain deleted FVIII product, 36, 37

Bebulin VH, 71

Bees, William, xi, 217

Behringwerke AG, 10

Benesis, 18

Berinert1, 247

Beriplex P/N, 71

Berkovsky, Aron, xi, 337

Bertolini, Joseph, x, xi, 3, 423

b-amyloids, antibodies to, 197

b-glucans, in IVIG preparations, 194

b-glucocerebrosidase, 11

Beta-hydroxylation modifications, 108

b-thalassemia, 307

Biesert, Lothar, xi, 345

Bilateral membranous conjunctivitis, 317

Bilirubin, albumin binding to, 163

Binding affinities, haptide, 120, 121

Bioactive lipids, 351, 352

Biochemical IVIG parameters, 194–198.

See also

Biogenic amines, regulation of, 339

Biolex, 290

Biological IVIG parameters, 194–198.

See also Intravenous

immunoglobulin (IVIG)

INDEX 473

Biological products, pathogen safety

of, 72, 73

Biological products commercialization,

licensure requirements for, 405, 406

Biological variance, 193

Biological weapons, hyperimmunes as

defense against, 210–212

Biologic(al)(s) License Application

(BLA), 143, 405, 406

solvent/detergent plasma and, 346

Biomarkers, of haptoglobin efficacy, 331

Biomedical devices, fibrinogen in, 125

Biopharmaceutical industry, contribution

of, 468

Biopharmaceutical products,

development/commercialization

of, 403

Biopharmaceuticals, 283

Bio Products Laboratory (BPL), 327, 328

manufacturing process used by, 329

Bio Products Laboratory concentrate, 96

Bio Products Laboratory Factor X

properties of, 111

Biotest AG, 10, 461

Bleeding

FXI deficiency and, 94, 95

PCCs to stop massive, 73

termination of, 66

Bleeding control agents, 57

Bleeding disorders, treatment of, 73

Bleeding episodes, 58. See alsoMassive

bleeding

in hemophiliacs, 37

regulation of, 105

spontaneous, 58

Bleeding events, PCC dosage for, 74

Blood. See also Hemo- entries; Plasma

entries; Serum entries

infectious agents in, 361

for medical use, 4

storing, 4

TSE infectivity in, 371–373

Blood banking, early history of, 3–5

Blood banks

first, 5

in India, 19

Blood Betterment Association, 5

Blood-borne lipid-enveloped viruses

(LEVs), 72, 73

Blood-borne viruses, 366

Blood-cell-induced adverse reactions,

351

Blood cell separators, 4

Blood clotting, FX zymogen and, 52

Blood coagulation, 66–68. See also

Coagulation entries

Blood coagulation cascade, 122, 123.

See also Clotting cascade;

Coagulation cascade

Blood collecting agencies, 425

Blood collection unit, sterile vacuum-

type, 9

Blood components

TSE infectivity reduction studies

for, 374

use of, 4

Blood contaminants, inactivating, 35

Blood Derivatives Production Centers

Act, 12

Blood donation/transfusion centers, 11

Blood donor deferral policies, 374

Blood donor organizations, 10

Blood donor recruitment, 4, 5

Blood donors, paid, 12. See also

Nonremunerated plasma

Blood donor screening, 376

“Blood establishment” (BE), 384, 397,

398

Blood field depots, 4

Blood groups, discovery of, 3, 4

Blood plasma, use of, 4. See also Plasma

entries

Blood Plasma Corp. of Japan, 17

Blood processing industry, 5

Blood procurement, expanding, 5

Blood products, viral safety of, 189, 190

Blood Products Laboratory (BPL), 11

Blood-related viruses, removal of, 190

Blood safety programs, 20

Blood substitutes, 5

Blood testing, 427, 428

Blood transfusion, early history of, 3–5

Blood-typing globulins, 7

“Blue” proteins, 337

Blundell, James, 3

Bogdanov, Alexander, 4

Boothe, Joseph, xi, 283

Bottles, peeling of plasma in, 439

Botulism antitoxin (eBAT), 212

Botulism antitoxin product, 213

Bourgeois, Louise, 217

Bovine plasma, 6

Bovine spongiform encephalitis/

encephalopathy (BSE), 370–372

albumin and, 177

atypical forms of, 376, 377

Bovine thrombin solution, 137

Bowl-type centrifuges, 440

Boyd, W. C., 7

Bradykinin, 242, 248, 249

Brain-derived infectivity, 375

Brazil

contract fractionation arrangements

in, 458

plasma fractionation plant in, 13

BRIC (Brazil, Russia, India, China)

countries, new plant investments

among, 454

Buchacher, Andrea, xi, 185

Bulmer, Mark, xi, 159

Burn patients, benefits of albumin use

in, 174, 175

Burn treatment, ceruloplasmin and,

341, 342

Bypassing agents, 57, 74

PCCs as, 75, 76

C1-inhibitor, 241–258

biochemistry of, 241

clinical issues related to, 248, 249

in fibrolytic treatment, 250

future trends of, 250, 251

large-scale production of, 244

mechanism of action of, 243

physiology of, 242, 243

potential clinical application

of, 251

potential clinical indications for,

249, 250

in prophylactic regimens, 250

published purification methods

for, 245, 246

roles of, 242, 243

C1-inhibitor capture, 247

C1-inhibitor manufacturing 243–247

virus reduction steps in, 244

C1-inhibitor measurement, international

standards for, 247, 248

C1-inhibitor molecule, 248

C1-inhibitor mutations, 241

hereditary angioedema and, 248

C1-inhibitor products, characterization

of, 247, 248

C1-inhibitor purification, 244–247

C1-inhibitor purified concentrate, 249

Cadaver blood, 8

Call centers, 417, 418

Canada, fractionation facilities of, 9

Canadian Red Cross, 9, 10

Cancer therapy, ceruloplasmin in, 341

Cangene, 10

Canine coronary occlusion model, 261

Canine hemophilia model, 55

Capillary electrophoresis, 263

Capillary leak syndrome (CLS),

C1-inhibitor and, 250

Caprylate (octanoate) fractionation, 187

Caprylate (octanoate) treatment, 190

Caprylic (octanoic) acid treatment, 365

CarboPlatinum (CarboPt), 119, 120

Carboxylate reaction, 81

Cardiovascular disease models, 287, 288.

See also Heart entries

Cardiovascular diseases, 277, 283

Cascade plasma fractionation

processes, 38

Catheter-assisted thrombolysis, 264

474 INDEX

Catheter-assisted thrombolysis therapy,

261

Catheter-delivered plasmin, 265

Cation binding, 119

Cation(ic) exchange chromatography

(CEC), 142, 189

Cation exchange chromatography

procedure, 213, 214

Cations, albumin binding to, 163

Cattle-derived products, regulations

for, 374

CD163 macrophage receptor, 326, 327,

330

Celestial Biologics, 20

Cell-based assays, 375

of haptoglobin, 330

Cell culture

fibrinogen-based products for, 125, 126

recombinant FVIII production in,

36, 37

Cell-free hemoglobin (CFH), 321,

324–327, 330, 331

pathological consequences of, 325, 326

toxicity of, 325, 326, 331, 332

Cell membrane removal, 351

Cellular blood components, vCJD

transfusion transmission risk and,

373

Cellular cholesterol, 286

Centeon company, 15

Center for Biologics Evaluation and

Research (CBER), 404

Central Drugs Standard Control

Organization (CDSCO), 20

Central Laboratory of the Netherlands

Red Cross (CLB), 14

Central regulatory systems, role of,

67, 68

Centre National de Transfusion Sanguine

(CNTS), 11

Centre R�egional de Transfusion Sanguine(CRTS), 247

Centres of Excellence, 15

Centrifugation

in albumin manufacture, 167, 168

continuous-flow, 4

in ethanol fractionation, 440

intermittent flow, 4

Ceruloplasmin (CP), 337–344. See also

CP entries

as an acute inflammatory phase

protein, 339

as an adjunctive cancer therapy, 341


anti-inflammatory action of, 339

antioxidant activity of, 338, 342

in aplastic anemia treatment, 340–342

biogenic amine regulation by, 339

biological functions of, 337–339

clinical effectiveness of, 342

clinical uses of, 340–342

as copper carrier and copper cycle

regulator, 338

in emergency medicine, 341, 342

ferroxidase action of, 338

manufacture of, 339, 340

pharmaceutical indications for, 340

structure and function of, 337, 338

Ceruloplasmin deficiency, 337

Cetor1, 244

CFH removal, 332. See also Cell-free

hemoglobin (CFH)

cGMP compliant equipment, in plasma

fractionation, 441. See also Current

good manufacturing practice

(cGMP) guidelines

Chain-cleavage reactions, 123

Change, actions to execute, 397

Change control philosophy, 392

Change control process, 396, 397

Change control reports, 393

Change control system, 396, 397

objective of, 397

Change strategy, 396

Chart construction, 390, 391

Chart interpretation, 391

Chemical virus inactivation, 364, 365

Chemo-Sera Therapeutic Research

Institute, 18

China

demand for albumin in, 453

plasma fractionation in, 18, 19

China National Blood Products

Corporation, 18

Cholate-based method, 292

Cholesterol efflux, 292, 293

Cholesterol ester (CE), 284

Cholesterol ester transfer protein

(CETP), 284, 286

Cholesterol homeostasis, 283, 284

Cholesterol levels, safflower-derived

apolipoprotein AIMilano:POPC

and, 292, 293

Cholesterol metabolism, 275

Cholesterol transport, 274, 275, 283

Cholesteryl ester transfer protein

(CETP), 273, 274

Christmas factor, 65

Chromatographic fractionation, 188, 189

Chromatographic manufacturing, 9, 10

Chromatographic matrices, 84

Chromatographic procedures, 213, 214

for plasma fractionation, 437, 438

for virus removal, 364

Chromatographic processes, 17

albumin-related, 165

Chromatographic purification methods/

techniques, 105, 124

Chromatographic resins, in plasma

fractionation, 441

Chromatographic separation process, 221

Chromatographic technology, 11, 13

Chromatography

in human serum albumin manufacture,

166


Chromatography-based purification

method, for alpha1-PI, 230

Chromatography methods, for isolating

proteins, 38

Chromatography polishing, 188

Chronic intoxication, ceruloplasmin

and, 341

Chronic ITP, 219, 220. See also Immune


Chtourou, Sami, xi, 31, 41, 93

CIP fluids, 168. See also Clean in place

(CIP) centrifuge design

Circulatory volume, albumin and, 175

Cirrhotic ascites, 175

Citrate concentrations, in albumin, 171

Cleaning procedures, validation of, 394

Clean in place (CIP) centrifuge

design, 167. See also CIP fluids

Cleavage loop (CL), in plasminogen, 311

Clinical coagulation tests, 118

Clinical efficacy, of products, 406

Clinical-grade plasmin, manufacturing

of, 261–264

Clinical safety, of plasma-derived

products, 406

Clot formation, 139, 140. See also

Coagulation entries; Thromb- entries

Clot parameters, 119

Clotting cascade, FVIII during, 32.

See also Blood coagulation cascade;

Coagulation cascade

Clotting Factor VIII, 31–40. See also

Factor VIII (FVIII)

gene structure and function/regulation

of, 31, 32

immune tolerance to, 37, 38

nanofiltering, 36

production methods for, 33–35

Clotting factors, activated, 66

Clotting pathways, 82

Clotting-related proteins, 7

Clotting time (CT), simulating, 118,

119

Coagulant factor therapy, 35. See also

Clot- entries

Coagulation cascade, 94, 122, 123.

See also Clotting cascade

activators in, 59

INDEX 475

Coagulation disorders, replacement

therapy for, 46

Coagulation FVIII interaction, vWF

protein and, 42, 43

Coagulation Factor IX, 88. See also

Factor IX (IX)

Coagulation factor concentrates, 106

Coagulation factors, 59, 81

deficiencies of, 67, 68

elevated levels of, 68

mutations in, 75

of prothrombin complex, 65

Coagulation factor treatment, access

to, 37

Coagulation mechanisms, alternative,

123

Coagulation pathway physiology, 66–68

Coagulation products, safety of, 38

Coagulative system, C1-inhibitor role

in, 243

Coagulopathy, 152

Coan, Michael, 232

Cochrane Injuries Group Albumin

Reviewers Meta-analysis, 172, 173,

176

Code of Federal Regulations (CFR), 385,

423

Cofact, 71

Cohn, Edwin J., 4, 5–7, 423, 437

plasma fractionation industry and, 7, 8

Cohn I precipitate, 141. See also Cohn

Fraction I precipitate

Cohn IV-1 precipitation conditions, 232.

See also Cohn Fraction IVentries

steps in, 150

Cohn-Chromatography process, 17

Cohn Fraction I precipitate, 102. See also

Cohn I precipitate

Cohn Fraction IV, transferrin from, 303

Cohn Fraction IV-1, in ceruloplasmin

manufacture, 339

Cohn Fraction IV-1, 4 pastes, 230,

231–233, 235–237

Cohn fractionation method/process, 33,

43, 164, 186, 187, 437. See also

Cohn’s Method

transferrin from, 303

Kistler–Nitschmann fractionation

method vs., 165

Cohn/Oncley fractionation process, 191,

213, 262, 407

Cohn’s Method, 11, 221. See also Cohn

fractionation method/process

modifications to, 12

purification of hyperimmune

immunoglobulin and, 212

Cold ethanol fractionation, 363

Cold ethanol fractionation processes, 262

albumin-related, 164, 165

transferrin from, 303

Collagen binding assay (vWF:CB), 43

Collection centers, in United States, 21

Colloid osmotic pressure (COP)

of plasma, 161

Colloids, 172

Color, of albumin, 169

Column adsorption, in plasma protein


Columns, membranes vs., 445, 446

Commercial blood banks, in Japan, 17

Commercial fractionators

developments of, 16

processing capacity of, 14, 15

Commercial plasma fractionation

facilities, total number of, 15

Commercial product strategy, Medical

Affairs and, 416, 417

Commercial sector, 461

Commonwealth Serum Laboratories

(CSL), in Australia, 16, 17. See also

CSL entries

Communication centers, 417

Communication channels, cross-

functional, 421

Community-based Donor standard, 427

Company–government

relationships, 466, 467

Comparability concept, 407–410

Comparability Master Plan, 407, 408

Comparability program, successful, 409,

410

Comparability strategy, 409

Comparability study, 409

Comparability testing, 408, 409

Complement activation, 208

Complement activation pathways,

regulation of, 242, 243

Complement control protein (CCP)

domain, in haptoglobin, 323

Complement system, C1-inhibitor role

in, 243

Compliance

with GMP and GLP, 388

with key regulatory standards, 416

“Compliance Program Guidance for

Pharmaceutical

Manufacturers,” 414

Component plasma, 431

Comprehensive change strategy, 396

Concanavalin A chromatography step, in

alpha1-PI purification, 230

Concentrates

differences among, 70

formation of, 69, 70

Concurrent plasma, 431

Conestat alpha, 250

Confidence interval (CI), 58

Congenital emphysema, 229

Connaught Laboratories, 9

Contact centers, 417

Contact system, C1-inhibitor role in, 243

Contaminant removal, 214

Contaminated plasma, solvent/detergent

plasma and, 345

Continuous centrifuges, 440

Continuous-flow centrifugation, 4

Continuous process verification, 393

Continuous small volume mixing

(CSVM) process, 11

Contract fractionation, 90, 458

Contract manufacturing, 465, 466

Control chart, 390, 391

Convalescent plasma, 209

passive immunotherapy with, 209, 210

Convalescent serum (sera), 210

for infectious diseases, 209

Copley, A., 117

Copper, 337, 338

Copper binding areas, of

ceruloplasmin, 337

Copper deficiency, 338

Core Summary of Product Characteristics

(cSmPC), 173, 174

CorifactTM, 105

Coronary atherosclerosis, ERASE study

of, 278

Coronary heart disease, ApoAI and, 284

Corporate restructuring, 413

Corrective Action/Preventive Action

(CAPA) principle, 387, 389, 395,

396

Corrective actions, 395, 396

Corticosteroids, 316

Corticoteroid treatment, 219

Courtland Laboratories, 9

Covalent complex, 244

CP isoforms, 337. See also

Ceruloplasmin (CP)

CP-mediated copper excretion

cycle, 338

CP properties, role in disease

treatment, 342

CP proteolysis, 340

CP synthesis, 337

Creutzfeldt-Jakob disease. See Sporadic

CJD (sCJD); Variant Creutzfeldt-

Jakob disease entries

Critical process parameters (CPP), 389

Critical quality attributes (CQA), 389

Critical therapeutics, control and

oversight of, 446

Cross-contamination, 429

“Cross flow” filtration, in plasma

fractionation, 443

476 INDEX

Cross-functional communication

channels, 421

Cryo-poor plasma, 431, 432, 439

Cryoprecipitate(s), 44, 102, 141, 375

fibrinogen from, 123, 124

in hemophilia treatment, 33

Cryoprecipitation, in plasma protein


Cryo-rich plasma, 432, 439

Cryosupernatant, 456

Crystalloids, 172

CSL-112 formulation, 278. See also

Commonwealth Serum Laboratories

(CSL)

CSL Behring, 15, 234, 236, 237, 451,

461, 466

CSL Ltd., 17, 21

growth of, 16

CSL process, 234

“Cup and saucer” architecture, 94

Curling, John, x, xi, 3, 451

Current good manufacturing practice

(cGMP) guidelines, 429, 444, 445.

See also cGMP compliant equipment

Cutter, Robert, 5, 8

Cutter Laboratories, 8

Cutter purification process, 232, 233

Cyclic adenosine monophosphate

(cAMP), 293

Cyclic Fenton reaction, 123

Cysteine residues, in haptoglobin, 323

Cysteine

in albumin, 161

in FXI molecular structure, 93

Cysteine residues, in vWF protein

structure, 42

Cystic fibrosis, 238

Dalton, Joan, xi, 321

“Dead-end” filtration, in plasma

fractionation, 443

DEAE-Cellulose, 84, 244

DEAE-Sephadex1, 83, 84, 108, 213,

244, 247, 313, 439, 445

DEAE-Sepharose1 FF, 70, 83, 84


Dempster, F. J., 16

Denatured FVIII, 37. See also Factor VIII

(FVIII)

Denmark State Serum Institute, 14

De novo donors, 221

Depth filters, 440

des-1,2-ApoAIMilano, 291, 292. See also

Apolipoprotein AIMilano

(ApoAIMilano)

Desiccated plasma, 5

Design of experiments (DoE), 389, 390,

407

Design qualification (DQ), 391

Design space, 389, 390

Desmopressin (DDAVP), 43, 96

Deutsches Rotes Kreuz (DRK)

Blutspendedienst Nordrhein-

Westfalen, 345. See also German

Red Cross (DRK)

Developing countries/nations

blood collection improvements

within, 454

dependency on plasma products, 458

providing plasma products to, 453,

454

Developing country needs,

addressing, 465, 466

Developing markets, growth potential

of, 468

Deviations

dealing with, 393–396

process flow for handling, 395

Dextran sulfate affinity resins, 85

Diabetes, therapeutics for, 283. See also

Type 1 diabetes

Diafiltration

in alpha1-PI purification, 230, 231


Diatomaceous earths, filter aids based

on, 168

Dichtelm€uller, Herbert, xi, 361

Diphtheria, antibodies to, 195, 196

Direct-acting thrombolytics, acid-

stabilized plasmin as, 259–271

Direct transfusion, 3, 4

Diseases. See also Alzheimer’s disease;

Atherosclerosis; Cardiovascular

diseases; Diabetes; Emphysema;

Graft-versus-host disease (GVHD);

Hemolytic disease of the fetus and

newborn (HDFN); Hemolytic

disease of the new born (HDN);

Hepatitis entries; Infectious diseases;

Infectious inflammatory diseases;

Ischemic heart disease; Ligneous

conjunctivitis; Liver disease;

Pancreatitis; Polio; Prion diseases;

Pseudomembraneous disease; TSE

diseases; Variant Creutzfeldt-Jakob

disease (vCJD); Viral diseases;

Wilson–Konovalov disease

as biological weapons, 210–212

pulmonary, 228

rare, 101, 462, 463

reconstituted HDL replacement therapy

for, 277

transmission of, 151

Disease state plasma, 212

Disposables, 445

Disruptive processes, 445

Disseminated intravascular coagulation

(DIC), 152

Disulfide bonds, in haptoglobin, 323

Disulfide bridges, in alpha1-PI, 230, 231

Divalent cations, albumin binding to, 163

Domains. See also Apple domains; Factor

IX catalytic domain; Kringle

domains; Serpin C1-inhibitor

domain

albumin, 160

for coagulation factors, 82

fibrinogen, 138, 139

in haptoglobin, 323

plasminogen, 312

thrombin, 139

in vWF protein structure, 42

Domain structure, of fibrinogen, 117, 118

Donation centers, 426

Donations, testing of, 427, 428

Donor deferral, 374, 428

Donor Education Standard, 427

Donor history questionnaire, 426, 427

Donor screening, 426, 427

Donor selection, 361, 366

“Donor stim” program, 213

Dosage optimization, for PCCs, 74

Dose-efficacy relationship, 89

Double affinity chromatography, 85, 86

Drew, Charles, 5, 10

Dried human plasma, 6

Drugs

albumin binding to, 163

binding and transport of, 163

binding to fibrinogen, 119, 120

HDL-increasing, 273

Dry fibrin glue formulations, 143

Dry heat treatment, 35, 87

DTT treatment, 234

Duran-Jord�a, F., 10Dysplasminogenemia, 315

Early generation PCCs, thrombotic events

with, 66

ECH-Lysine Sepharose resin, 314

Economic growth, 18

Economics, of plasma

fractionation, 451–460

Edsall, John T., 7

Educational grants, 418

Efficacy, preclinical evidence of,

264–267

Efficacy studies, 264–266

Egyptian Organization for Biological and

Vaccine Production (Vacsera), 20

Ehrlich, Hartmut, xi, 413

Ehrlich, Paul, 5

VIIISelect affinity matrix, 38

Elastase, alpha1-PI inhibition of, 229

INDEX 477

Elastase, 227, 228

Electrophoresis, of haptoglobin, 330

Electrospun fibrinogen fibers, 125

Electrostatic interactions, haptoglobin

quaternary structure and, 323

Elsinger, Fritz, 50, 51

EMABling1, 221, 222

EMA regulatory documents, 385

Emergency medicine, ceruloplasmin

in, 341, 342

Emerging markets, 464, 465

Emphysema, 227–229

Enders, J. F., 7

Endogenous blood infectivity, reduction

studies with, 375

Endothelial glycocalyx layer (EGL), 161

Endotoxemia, C1-inhibitor and, 249,

250

Endotoxins, in IVIG preparations,

193, 194

Enveloped viruses, inactivating, 190

Epidemiological data, 384

Epidermal growth factor (EGF)-like

domains, 82

Epitope masking, 218

Epitopes, fibrinogen, 120–122

Equine IgG, 213, 214

Equine serum, 6

Equipment, 444

ERASE study, 278

Erythroblastosis fetalis, 217

Esterase activity, of albumin, 164

Etablissement FranScais du SangAquitaine-Limousin, 345

ETC216 (1-palmitoyl-2-oleoyl

phosphatidylcholine), 288, 289, 292

Ethanol-based precipitation methods, 7

Ethanol fractionation, 186, 187, 440.

See also Cold ethanol fractionation

entries

in human serum albumin

manufacture, 166

Ethicon, 20

EU GMP regulations, 386. See also

European Union (EU)

Europe

AAT deficiency in, 228


for-profit fractionation in, 12, 13

legal plasma-regulatory documents

in, 385

multinational fractionation industry

in, 14–16

not-for-profit fractionation in, 11–13

not-for-profit sector consolidation

in, 14


plasma fractionation in, 13

plasma manufacture in, 384, 385

European Directorate for the Quality of

Medicines and HealthCare (EDQM),

429

European fractionation industry, 10–13

European governments, Red Cross

and, 11–13

European guidelines, for plasma

collection, 424

European market, 463, 464

European Medicines Agency

(EMA), 318, 362, 384, 467

European Medicines Agency Committee

for Medicinal Products for Human

Use (EMEA/CHMP), 66

European Pharmacopoeia (EP), IVIG

parameters defined by, 191–194

European Pharmacopoeia Monograph

1223, 87, 88

European Union (EU). See also EU GMP

regulations

plasma standards in, 425

rare disorders in, 101

Exogenous infectivity, reduction studies

with, 375, 376

Exosites, 139

Expanded bed chromatography, 446

External audits, 399

Extracellular matrix (ECM), 119

Extrinsic clotting pathway, 82

Eye drop plasminogen concentrate, 311

in case study, 317, 318

FI-C precipitate, 102–104. See also

Fibrinogen (Factor I)

FII-FXa complexes, 56. See also

Factor II (FII, prothrombin); Factor

Xa (FXa); Prothrombin entries

FV-deficient plasma, 54. See also Factor

V (FV)

FVIIa concentration, 72. See also Factor

VII (FVII, proconvertin)

FVII activation, 59

FVIII antibodies, 73, 74. See also Factor

VIII (FVIII); Plasma-derived FVIII

FVIII coagulant activity, 51

FVIII concentrates, 37

FVIII-deficient hemophilic dog, 55

FVIII gene, 31

FVIII immunogenicity, 37

FVIII-inactivating inhibitors, rescue

therapy for patients with, 37, 38

FVIII infusions, 37

FVIII inhibitor plasma, 53, 54

FVIII inhibitors, therapeutic approaches

for, 57

FVIII molecule, improving expression

levels of, 36, 37

FVIII mutations, 31

FVIII products, improvement of, 44

FVIII protein, structure and function

of, 31, 32

FVIII protein synthesis, 31

FVIII replacement, 33

FVIII variants, 38

FVIII/vWF–heparin interaction, 45

FVIII/vWF-rich plasma fraction, 43

FIX activation, 85. See also Factor IX

(FIX, antihemophilic Factor B,

Christmas factor)

FIX concentrates, 52, 73

clinical efficacy of, 89

FIX deficiency, 49, 73

FIX dosing, 88

FIX manufacture, processes used in, 87

FIX product yield, 87

FIX units, 74

FX activation, 32. See also Factor X (FX,

Stuart–Prower factor)

FX separation, 85

FXIa inhibition, 243. See also Factor XI

(FXI)

FXIa procoagulant activity, 199

FXI binding, 59

FXI cleavage, 94

FXI coagulation activity, 95, 96

FXI concentrates, 97

FXI zymogen crystal structure, 94

FXIII-A subunit, 102. See also Factor

XIII (FXIII, fibrin stabilizing factor)

deficiency of, 105

FXIII-B subunit, 102

FXIII concentration, 142

Facility design, 443, 444

Facnyne, 71

Factane1, principal steps in

manufacturing, 36

Factor I. See Fibrinogen (Factor I)

Factor II (FII, prothrombin), 65, 69. See

also FII–FXa complexes

biochemical characteristics of, 68

Factor II concentration, 66

Factor V (FV), 55. See also FV-deficient

plasma

Factor VII (FVII, proconvertin), 65, 69.

See also FVII entries


reduction of, 52

Factor VIIa (FVIIa), 37. See also Plasma-

derived FVIIa

Factor VII concentration, 66

Factor VIII (FVIII), 439. See also

Clotting Factor VIII; FVIII entries;

Human plasma coagulant

Factor VIII; Plasma-derived FVIII;

Plasma-derived FVIII; Purified

FVIII; Recombinant Factor VIII

(rFVIII)

inhibitors and, 57

478 INDEX

prophylactic therapy with, 58

risk of contamination of, 375

sales of, 452

Factor VIII inhibitor bypassing activity

(FEIBA1), 49–63, 65

active principle of, 51–57

clinical use/experience with, 57, 58

in FVIII-deficient plasma with

inhibitors, 59

inhibitor bypassing potency of, 52, 53

as multicomponent therapeutic agent,

59, 60

pharmacokinetic properties of, 57

Factor VIII products, 34, 467

Factor IX (FIX, antihemophilic Factor B,

Christmas factor), 65, 69, 81–92.

See also FIX entries


biochemistry and physiology of, 81–83

clinical aspects of, 88, 89

posttranslational modifications of, 83

prophylactic therapy with, 58

sales of, 452

Factor IXa-a, 82

Factor IX catalytic domain, 82

Factor IX concentrates

developing high-purity, 87

flow diagram for, 85

highly purified plasma-derived, 86

production processes for, 83–87

Factor IX concentration, 66

Factor IX gene, 81

Factor IX isolation, techniques used

for, 84

Factor IX products, 82, 83, 467

process comparison for, 86

purification methods of, 85

Factor IX purification, 84

Factor X (FX, Stuart–Prower factor), 65,

101, 107–111. See also FX entries





indications for, 112

in prothrombin complex

concentrates, 108



Factor Xa (FXa), 51, 53, 69. See also

FII-FXa complexes

prothrombin protection by, 59

role of, 53–55

Factor X activation, 107

Factor Xa inactivation, 107

Factor X concentrate

functionality of, 111

safety profile of, 111

therapeutic, 108

toxicity of, 111

Factor X concentration, 66, 110

Factor X deficiency, 107

bleeding patterns of, 107

substitution therapy for, 110

Factor X gene, 107

Factor X manufacturing process,

characteristics of, 111

Factor X potency, 110

Factor X products, development of, 108

Factor X safety concerns, 110, 111

Factor X-specific activity, 108, 110

Factor X zymogen, 52

Factor XI (FXI), 93–99. See also FXI

entries


fibrinolysis and, 95

mechanism of action of, 94, 95

pathophysiology of, 95

Factor XI activation, 94

Factor XI concentrates, 96

Factor XI deficiency

management of, 95, 96

understanding, 97

Factor XI dimerization, 93

Factor XI gene structure, 95

Factor XI inhibition, by plasma

inhibitors, 95

Factor XI mutations, 95

Factor XII (FXII), in Factor XI

activation, 94

Factor XII activation, 242

Factor XIII (FXIII, fibrin stabilizing

factor), 101–107, 139. See also

FXIII entries

binding sites for, 138, 139



freeze-dried, 104



physiological roles of, 102


Factor XIII activity, 107

functional assays for, 107

Factor XIII concentrate pasteurization,

virus inactivation by, 106

Factor XIII concentrates

characterization of, 106, 107


manufacture of therapeutic, 103

Factor XIII deficiency, 102

Factor XIII process, characteristics

of, 105

Factor XIII product, properties of, 105

Factor XIII purification procedures,

modification of, 104, 105

Factor XIII purity, 107

Factor XIII replacement therapy, efficacy

of, 106

Factor XIII subunits, 101, 102

Falksveden fractionation scheme,

187, 188

False Claims Act, 414

Fantus, Bernard, 5

Farhood, Ramin, xi, 413

Fatty acid binding, to fibrinogen, 124

Fatty acids, in albumin, 162, 163

Favism, haptoglobin in treating, 330

Fc function, in IVIG preparations, 195

Fc section, 207, 213

FDA Blood Products Advisory

Committee, 424. See also Food and

Drug Administration (FDA)

FDA meeting, recommendations for,

404, 405

Feasibility Study, for SAPG, 21

Feed bans, 374

FEIBA1 components, affinity

chromatography of, 51. See also

Factor VIII inhibitor bypassing

activity (FEIBA1)

FEIBA1 NF, manufacture of, 50

FEIBA1 NF prophylactic treatment, 58

FEIBA1/NovoSeven1 Comparison

(FENOC) study, 58

FEIBA1 products, efficacy and safety

of, 57, 58

FEIBA1 unit, 49, 50

FEIBA1 VH, 58

Feldman, Peter, xi, 101

Fenton reactions, 123

Fibrin, 312, 313

classic blood coagulation cascade

leading to, 122, 123

interaction with plasminogen, 140

interaction with tissues, 140

Fibrin associations, haptide contribution

to, 121, 122

Fibrin bandages, 143

Fibrin clot, 81

as hydrogel, 137

Fibrin clot dissolution, plasmin in, 259,

260

Fibrin clot formation, 66, 81, 139, 140

Fibrin degradation, 139

Fibrin degradation products, 140

Fibrin glue producers, 137, 138

Fibrin glues, 137–145


clinical use of, 144

downstream steps in

manufacturing, 141

fibrinogen component of, 137, 141, 142

future perspective on, 144

INDEX 479

Fibrin glues (Continued)

history of, 137, 138

manufacture of, 137

physiology of, 138

production of, 141–143

recombinant, 144

safety of, 144

thrombin component of, 137, 142, 143

Fibringluraas1, 137

Fibrin microbeads (FMBs), 125

Fibrinogen (Factor I), 102, 117–135, 138,

139. See also FI-C precipitate

binding of molecules to, 119, 120

cell attachment activity of, 120

exposure to free radicals, 123

fatty acid binding to, 124

haptide epitopes in, 120

heat stability of, 117–119

hydrophobicity of, 120, 124

hygroscopic nature of, 118

intracellular biosynthesis of, 117

metabolites and drugs that bind to, 119

minimal concentration of, 118

new forms and composites of, 125

production of, 123, 124

spray-dried, 143

structure and composition of, 117

variants of, 117

Fibrinogen associations, haptide

contribution to, 121, 122

Fibrinogen-based products

for cell culture, 125, 126

future prospects for, 126

Fibrinogen binding, 119

Fibrinogen component, 137


Fibrinogen concentrates, 142

Fibrinogen concentration, clotting time

and, 118, 119

Fibrinogen domains, 117, 118, 138, 139

Fibrinogen epitopes, 120–122

Fibrinogen molecule, 117, 138, 139

Fibrinogen packaging/applicators, 126

Fibrinogen polymerization

induced by thrombin activation,

118, 119

turbidity and phase change during, 118

Fibrinogen preparations, 124

viral inactivation in, 124

Fibrinogen removal, 104

Fibrinogen stabilization, 141

Fibrinogen standard, 124

Fibrinolysis, 140

Factor XI and, 95

role of plasminogen in, 312

Fibrinolysis inhibitors, 141, 142

Fibrinolytic system

C1-inhibitor role in, 243

main purpose of, 260

regulation of, 242

Fibrinopeptide A (FPA), 139

Fibrinopeptide B (FPB), 139

Fibrin polymerization reactions, 122

Fibrin protofibrils, 119

Fibrin stabilizing factor, 139. See also

Factor XIII (FXIII, fibrin stabilizing

factor)

Fibrin tubes/stents, 125

Fibrogammin1, 105

Fibrolytic treatment, C1-inhibitor in, 250

Filling process, in plasma fractionation,

443

Filter aids, based on diatomaceous earths,

168

Filter presses, 440

Filtration, 354


in the plasma fractionation industry, 168

for virus removal, 363, 364

Filtration technology, 440

Finnish Red Cross Blood Transfusion

Service, 11

Finnish Red Cross fractionation plant, 14

Firazyr1, 251

Five Layer Safety Net, 426, 429

Flebogamma 5% DIF preparation, 187,

189

“Fl�ebula,” 10

Flexbumin, 169

Flood Review, 17

Fluorescence intensity, 53

Food and Drug Administration (FDA),

404, 414, 423, 467

guidance on comparability from, 408

qualification/validation guidelines

by, 391, 392

TSE clearance studies and, 375, 376

Food-borne vCJD cases, 370, 371

Formalin-stabilized human serum, 11

Formulation process, in plasma

fractionation, 443

For-profit fractionation, in Europe, 12, 13

Foster, P. R., 11

Fractionated placental serum, 11

Fractionation. See also Caprylate

fractionation; Cascade plasma

fractionation processes;

Chromatographic fractionation;

Cohn fractionation process; Cohn/

Oncley fractionation process; Cold

ethanol fractionation processes;

Commercial plasma fractionation

facilities; Contract fractionation;

Ethanol fractionation; European

fractionation industry; Falksveden

fractionation scheme; Finnish Red

Cross fractionation plant; For-profit

fractionation; Ion exchange

chromatographic fractionation

technology; Kistler–Nitschmann

fractionation method; Multinational

fractionation industry; Not-for-profit

fractionation; Octanoic acid

fractionation; Plasma fractionation

entries; Plasma protein fractionation

entries; Regional fractionation

centers; Small-scale fractionation;

Subfractionation methods; Toll

fractionation

in North Africa, 20, 21

in the Middle East, 20, 21

not-for-profit, 11–13

plasma for, 423–436

Fractionation centers

difficulties in maintaining, 14

in Japan, 17

Fractionation economics, 452

Fractionation facilities, in China, 18

Fractionation industry, 101

companies dominating, 21

Fractionation intermediates,

exchanging, 408

Fractionation processes, 50

Fractionation products, clinical use of, 7

Fractionators

in China, 19

commercial, 7, 8

Fraction facilities, decrease in, 14

Fraction I paste, 123

Free cholesterol (FC), 284

Free radicals, 164

fibrinogen exposure to, 123

Free thiol, in albumin, 171

Freeze-dried Factor XIII, 104

Freeze-dried PCCs, 70

Freeze-dried plasma, 5, 9, 11

Freeze-drying technology, 10

Frenzel, Wolfgang, xi, 345

Fresh frozen plasma (FFP), 4, 96, 110,

350–353, 430

European guidelines for

collecting, 424

Frozen plasma, 438, 439

Fusion protein, 290, 291

Fusion protein therapeutics, albumin in,

178

Gamma-carboxylated factors, 68

Gammagard liquid process steps, 189

Gamunex process steps, 187

Gelatin plasma expander, 10

Gel filtration


in vWF purification, 44, 45

480 INDEX

Gel filtration chromatography, 33

Gelmont, David, xi, 413

Genereux, Maurice, xi, 207, 217

Gene therapy, 97

Genetic ATIII deficiency, 147. See also

Antithrombin III (ATIII)

German Red Cross (DRK), 14. See also

Deutsches Rotes Kreuz (DRK)

Blutspendedienst Nordrhein-

Westfalen

German Red Cross centers, 12

Glaser purification method, 230, 231

GlassiaTM purification process,

235–237

Global fractionation capacity, 21

Global hemostatic function, assessment

of, 111

Global Medical Affairs departments

emerging roles of, 413–422

internal communication and, 420, 421

outsourcing by, 417, 418

publication strategy and, 417

Global Medical Affairs function, 415

Global plasma industry, 466

Global regulatory environment, 403

b-Glucans, in IVIG preparations, 194

b-Glucocerebrosidase, 11

Glucose 6 phosphate dehydrogenase

deficiency (G6PD), haptoglobin in

treating, 330

Glutamic acid (GLA) domain, 81

Glutamic acid (Gla) residues, 108

Glycation, of albumin, 164

O-Glycosylation, 151

N-Glycosylation sites, 93

Glycosylation variants, 303

GMP compliance, 437. See also Good

manufacturing practices (GMP)

state of, 397

GMP guidelines, 429

GMP information, 387

Golgi apparatus, proteolytic processing

in, 41

“Good cholesterol,” 274

Good development practice (GDP), 386

Good laboratory practice (GLP),

386–389

Good manufacturing practices (GMP),

386–389, 399, 423

in plasma collection/manufacture, 383


Goss, Neil, xi, 3, 451

Government–company

relationships, 466, 467

Graft-versus-host disease (GVHD), 307

Grancha, Salvador, xi, 81

Green Cross Corporation, 17, 18, 327

manufacturing process used by, 329

Gregori, Luisa, xi, 369

Grifols Bioscience, 451, 461, 466.

See also Laboratorios Grifols

Grifols Lucas, J. A., 10

Grifols plasmin production process,

262, 263

Grifols Roig, J. A., 10

Grifols SA, 233

Guidance documents, 404

“Guidance on Qualification of Existing

Equipment,” 393

Guideline of Plasma-derived Medicinal

Products, 444, 445

Gulle, Heinz, xi, 137

H5N1 influenza, convalescent plasma

treatment of, 210

Haemate P, 44

Hagen, P. J., 12

Haptide aggregation, 120, 121

Haptide epitopes

in fibrinogen and other proteins, 120

in protein chains, 122

Haptide–haptide (Hap–Hap)

interactions, 121, 122

Haptides

contribution to fibrin(ogen)

associations, 121, 122

hydrophobicity of, 120

Haptoglobin (Hp), 169, 321–336. See

also Hp entries

active sites of, 323, 324

as an acute phase protein, 325


in animal studies, 331

biological properties of, 327

characterization of, 328–330


future trends in, 331, 332

genetics and biochemistry of, 321–324

hemoglobin binding by, 326


multiple infusions of, 331

physiology of, 324–327

potency of, 330

primary function of, 325

primary structure of, 322, 323

prophylactic, 330

quantitation of, 329, 330

quaternary structure of, 323

secondary structure of, 323

as a sequestrator of free

hemoglobin, 325, 326

tertiary structure of, 323

toxicity of, 331

usage of, 330–332

Haptoglobin efficacy, 331

biomarkers of, 331

Haptoglobin–hemoglobin (Hp–Hb)

complex, 321, 324, 326, 327

Haptoglobin multimers, identification and

characterization of, 329

Haptoglobin precursor, 322

HAS products, 169. See also Human

albumin solutions (HAS)

HAVantibody levels, 197. See also

Hepatitis A virus (HAV)

Hayes, Timothy, xi, 423

HDL-cholesterol, secretion of, 287, 288.

See also High-density lipoprotein

(HDL)

HDL-increasing therapies, 273, 279

HDL manufacturing process, 276

HDL metabolism, 284–286

HDL particle size, 291, 292

HDL therapy, 286–289

in cardiovascular disease risk

reduction, 287

efficacy of, 287, 288

HDN Mab candidates, 222. See also

Hemolytic disease of the newborn

(HDN); Monoclonal antibodies

(Mabs)

Health Canada, 9

Healthcare, evolving landscape of, 415

Healthcare environment, transparency

in, 413

Health economics outcomes research

(HEOR), 419, 421

Heart damage, iron depositions and, 301.

See also Cardiovascular disease

entries; Myocardial infarction

Heat treatment, of IVIG solutions, 190

Hedrich, Hans Christian, xi, 137

Heger, Andrea, xi, 345

Hemagglutinins, IVIG preparations

and, 193

Hemasure, 14

Hemin, 326

Hemodialysis catheter occlusions

(HCOs), 267, 268. See also Blood

entries; Plasma entries

Hemoglobin (Hb)

haptoglobin and, 321

oxidation of, 326

Hemoglobin-based oxygen carriers

(HBOCs), 325, 326

Hemoglobin clearance mechanism,

326, 327

HEMOLEVEN1, 96, 97

Hemolysis, 3, 4, 331, 332

Hemolytic disease of the fetus and

newborn (HDFN), 9, 217

treatment of, 217, 218

Hemolytic disease of the newborn (HDN),

351. See also HDN Mab candidates

INDEX 481

Hemophilia, 31

temporary, 55

transformation of, 38

Hemophilia A, 31

inhibitor development in, 57

replacement therapy for, 57

Hemophilia A treatment, 33

complications of, 37, 38

Hemophilia B, 49, 73, 88

Hemophilia B treatment, 89, 90

Hemophilia C, 93

Hemophiliacs, bleeding episodes in, 37

Hemophilia therapies, animal models in

investigating, 55

Hemophilia treatment

milestones in, 32

morbidity and mortality in, 37

Hemorrhages, intracranial, 219

Hemorrhagic events, therapeutic

approaches for, 57

Hemostasis

pathophysiology of, 59

regulation of, 66–68

thrombin solutions for, 142, 143

vWF protein role in, 42

Hemostasis evaluations, 351

Hemostasis regulators, 65

Hemostatic balance, 68, 75

Hemostatic products, need for, 143

Hemostatic regulatory proteins, 69

in PCC products, 70

Hemostatic safety studies, 266

Hemostatic system, 74

Hemovigilance, 384, 385

Heparin, 52, 69, 70

in PCCs, 75

thrombin inhibition and, 139

Heparin-based resins, 85

Heparin binding site, of antithrombin III,

148

Heparin gels, 149

Heparin induced thrombocytopenia

(HIT), 75

Heparin Sepharose-FF1, 85

Heparin-Sepharose1 (HS), 96

Heparin sulfate proteoglycans (HSPGs),

148

Heparin therapy, 152

Hepatitis A virus (HAV), 72, 73, 349.

See also Liver disease

antibodies to, 196, 197

in virus validation studies, 362

Hepatitis B immune globulin/

immunoglobulin (HBIG), 20, 209

Hepatitis B infection, 12

Hepatitis B surface antigen (anti-HBs),

209

Hepatitis B vaccine, plasma-derived, 9

Hepatitis B virus (HBV)

antibodies to, 196

transmission risk for, 348

Hepatitis C infections, 12

Hepatitis C virus (HCV), 35


Hepatology, albumin in, 175

Hereditary angioedema (HAE), 241, 242,

248, 249

diagnosis of, 249

products for treating, 250, 251

Herring, Steven, xi, 81

Hetzl, Ernst, xi, 437

Hexyl-Sepharose1, 244

High barrier-to-entry/investment

cost, 461, 462

High-density lipoprotein (HDL). See also

HDL entries; Reconstituted HDL

(rHDL)

antiatherogenic activities of, 275

antiatherogenic function of, 286

apolipoprotein components in, 275

biogenesis of, 274

heterogeneity of, 286

physiological function of, 284

physiology, biochemistry, and


pleiotropic effects of, 275, 276

reconstituted, plasma-derived, 273–282

High development countries, 465

Highly purified Factor X, 108–110.

See also High-purity entries

Highly purified plasma-derived FIX

concentrates, 86

High molecular weight kininogen

(HMWK), 242

High molecular weight kininogen

binding, 93, 94

High performance liquid chromatography

(HPLC), 263

High purity alpha1-PI, 235

High-purity FIX, 83

High-purity Factor IX, self-sufficiency

and, 89, 90

High-purity Factor IX pharmacological

monographs, 87, 88

High-purity IgG preparations, 188. See

also Immunoglobulin G (IgG)

High-purity products, 33, 408, 409

High-purity vWF concentrate, 44–46

High quality plasma, availability of, 454

High specificity, of antibody-based

therapies, 207, 208

HIV infections, 12. See also Acquired

immunodeficiency syndrome

(AIDS); Human immunodeficiency

virus (HIV)

ITP secondary to, 219

HO-1 expression, 327

Hoechst AG, 15

Holotransferrin, 304, 306

Homosolvex Factor IX, 71

Hoppe, Hans, 221

Hp genes, 321, 322. See also

Haptoglobin (Hp)

Hp phenotypes, 321, 322

differences among, 327

monomer units for, 324

Hp precipitation, 328

Hp synthesis, 321, 324

impact of hemolysis on, 324, 325

Hp turnover, 324, 325

in animals, 325

HSA infusion, 175. See also Human

serum albumin (HSA)

HSA products, 169

HT DEFIX, 71

Human albumin, 6, 7

Human albumin solutions (HAS)

specifications for, 169–171

tests and limits for, 169, 170

in therapeutic plasma exchange,

175, 176

Human blood transfusion, early history

of, 3

Human development index (HDI), 465

Human Factor X (FX) zymogen, 52

Human immune serum globulin, 7

Human immunodeficiency virus

(HIV), 35, 72. See also HIV

infections


in virus validation studies, 362

Human plasma

dried, 6

fractionation of, 6

intravenous immunoglobulin G

from, 185–205

Human plasma-based hyperimmune

products, 210–212

Human plasma coagulant Factor VIII,

production and clinical profile

of, 31–40

Human plasma-derived products, outlook

for, 468

Human plasma-derived von Willebrand

Factor, production and clinical

profile of, 41–48

Human plasma fibrinogen, 138

Human plasma proteins, recombinant

plasma proteins vs., 467, 468

Human plasma substitute, 6

Human plasminogen gene, 311

Human sCJD, 373. See also Sporadic

CJD (sCJD); Variant Creutzfeldt-


482 INDEX

Human serum, formalin-stabilized, 11

Human serum albumin (HSA), 159–183

characteristics and specifications

of, 168–171



guidance for use of, 174

ligands binding to, 162

managing critically ill with, 172

manufacturing processes for, 166

molecular structure of, 160, 161

as a NO carrier, 177

physiology and function of, 160

safety of, 176–178

in therapeutic plasma exchange,

175, 176

Human serum albumin (HSA)–fatty acid

complexes, 162, 163

Human transferrin, characterization

of, 305

Human vCJD, 372, 373. See also

Sporadic CJD (sCJD); Variant

Creutzfeldt-Jakob disease entries

Hustin, Albert, 4

HVAC units, 444

Hydrophobic interaction chromatography

(HIC), 234, 263, 328


Hydrophobicity, of fibrinogen, 120, 124

Hydrops fetalis, 217

Hydroxyethyl starch (HES), 172

Hydroxylation modifications, 108

Hyland Laboratories, 9, 49, 50

Hyperfibrinolysis, 351

Hyperimmune globulins, 209

Hyperimmune immunoglobulin G,

207–216

complement activation and, 208

Hyperimmune immunoglobulin

products, 211

development of, 209

worldwide market in, 215

Hyperimmune immunoglobulins, 210–212


Hyperimmune initiatives, past, 214

Hyperimmune passive

immunotherapy, 209, 210

Hyperimmune plasma, 433

Hyperimmune products, 10, 22

human plasma-based, 210–212

production of, 9

Hyperimmunes, 214

as defense against biological

weapons, 210–212

Hyperimmune therapy, 210

Hyperoncotic albumin, 172

Hypoplasminogenemia, 315

Hypotransferrinemia, 306

Iatrogenic CJD, 369. See also Variant

Creutzfeldt-Jakob disease entries

ICH 09, 396, 398. See also International

Conference on Harmonization of

Technical Requirements for

Registration of Pharmaceuticals for

Human Use (ICH) project

ICH Guidances, 392

ICH Q5E, 410

ICH Q7A, 388

ICH Q10, 387, 388

Icterus gravis, 217

Identification, of IVIG preparations, 192

IgG–Fc receptor interactions, 208. See

also Immunoglobulin G (IgG)

IgG fragments, accompanying IVIG

preparations, 197, 198

IgG production process, 199, 200

IgG purification process, 187

Immobilized antibodies, 33

Immune neutralizing antibodies, solvent

detergent treatment and, 348, 349

Immune response, 57, 106

“Immune sera,” 207

Immune serum globulin, 16, 214

Immune suppressive action,

ceruloplasmin and, 341

Immune thrombocytopenic purpura

(ITP), 218–221. See also

Thrombotic thrombocytopenic

purpura (TTP)

Immune tolerance, to FVIII, 37, 38

Immunization, passive, 7

Immunoaffinity chromatography, 33, 34,

85

Immuno AG, 13, 49, 50, 247

Immunoassays, 375

Immunodeficiencies, secondary, 185

Immunogenicity, 89, 251, 406

Immunogenic potential, 111

Immunoglobulin(s)

Hepatitis B, 20

inactivation of, 365

intravenous, 17, 20

in ITP treatment, 219, 220

purification of, 7


Immunoglobulin A (IgA), IVIG

preparations and, 193

Immunoglobulin G (IgG). See also IgG

entries

characteristics of, 207

demand for, 462

hyperimmune, 207–216

recovery of, 7

Immunoglobulin G loss, 1868

Immunoglobulin molecule

integrity of, 191

structure of, 20

Immunoglobulin preparations, 7

procoagulant activity in, 199

Immunoglobulin production, 12, 21, 22

Immunoglobulin products, 199

treatment of, 364

Immunoglobulin protein removal, 187

Immunohistochemical techniques, 316

Immunological incompatibility, 6

Immunomodulatory properties, of

albumin, 164

Immunoprotection, ceruloplasmin

and, 341

Immunotherapy

passive, 207, 209, 210

Imported plasma products, 18

Impurities

accompanying IVIG preparations, 194,

197, 198

control of, 409

Independent medical education

(IME), 418

India, plasma fractionation in, 19, 20

Industrialized countries, as strategic

partners, 465

Industrial-scale alpha1-PI

purification, 231–237

Industry consolidation, overview

of, 466

Industry standards, 385

Infection, caused by inflammation, 325

Infectious agents, in blood, 361

Infectious diseases, convalescent serum

for, 209

Infectious inflammatory diseases,


Inflammation

atherosclerosis and, 275

infection caused by, 325

Inflammatory cascade, 330. See also

Clotting cascade

Infusion solutions, 8

Inhalable alpha1-PI, 238

Inhibitor development, 89

in hemophilia A, 57

Inhibitor dogs, 55

Inhibitor patients, controlled bleeding

in, 52

Inhibitor plasma, clotting time of, 53

Inhibitor rabbits, 55, 56

Inhibitors

FVIII-inactivating, 37, 38

in previously treated proteins, 37

in previously untreated patients, 37

Inhibitory alloantibodies, 57

Inhibitory antibodies, 37, 57, 73, 74

Inhibitory factors, 66

Innovation, industry success and, 468

INDEX 483

Innovative plant biotechnology, future

of, 295

Innovative products, development of, 462

Installation qualification (IQ), 391

Institut M�erieux, 11

Integrated medical action plan (IMAP),

420

Interleukin 6 (IL-6), 326

Intermittent flow centrifugation, 4

Internal audits, 399

Internal communication/

coordination, 420, 421

International Conference on

Harmonization of Technical

Requirements for Registration of

Pharmaceuticals for Human Use

(ICH) project, 385, 429. See also

ICH entries

International normalized ratio (INR), 74

introduction of, 66

International Organization for

Standardization (ISO), 386

International Plasma Fractionation

Association (IPFA), 467

International Quality Plasma Program

(IQPP), 424, 427

International Society for Pharmaceutical

Engineering (ISPE), 392, 393

International suppliers, 398

Intoxication, ceruloplasmin and, 341

Intracellular Factor XIII (cFXIII), 102.

See also Factor XIII (FXIII)

Intracranial hemorrhages, 219

Intratect manufacturing process, 187, 188

Intrauterine exchange transfusion, 217,

218

Intravenous hyperimmune products, 207

Intravenous immunoglobulin (IVIG), 17,

20, 185, 219–221. See also IVIG

entries

global sales of, 462

safety of, 220, 221

Intravenous immunoglobulin G (IgG),

from human plasma, 185–205

Intravenous immunoglobulin products,

sales of, 451–453

Intravenous lys-plasminogen, 316, 317

Intrinsic clotting pathway, 82

Inventory Hold standard, 427, 428

Investigations, actions related to, 395

Investigator-initiated trials (IITs),

418, 419

In vitro cholesterol efflux, 294

In vitro efficacy studies, 264, 265

In vitro studies, 53–55

In vivo efficacy studies, 265, 266

In vivo recovery (ivr) concept, 88, 89

In vivo studies, 55–57

Ion exchange chromatographic

fractionation technology, 11

Ion exchange chromatographic steps, 188

Ion exchange chromatography (IEC), 33,

34, 213, 214




Ion exchange/gel filtration combination,


Iranian Blood Transfusion

Organization, 21, 458

Iron-binding proteins, 301, 306

Iron depositions, heart damage and, 301

Iron metabolism, regulation of, 306, 307

Irradiation, for virus inactivation, 364

Ischemia, C1-inhibitor and, 250

Ischemic heart disease, 273

Israel, plasma fractionation facilities

in, 20

Israeli Red Cross, 20

Italian Medicines Agency (AIFA), 314,

317

Italian plasma, fractionating, 12

Italian Voluntary Blood Association

(AVIS), 12

ITP phases, 219. See also Immune


ITP treatment

immunoglobulin in, 219, 220

Rh (D) immunoglobulin in, 220

IVIG concentrates, quality criteria

for, 185, 186. See also Intravenous

immunoglobulin (IVIG)

IVIG preparations

aggregate formation in, 195

antibody titers in, 195–197

anticomplementary activity of,

192, 193

Fc function in, 195

formulation of, 198

hemagglutinins and, 193

identification of, 192

immunoglobulin A and, 193

molecular size distribution of, 192

osmolality of, 192

pH of, 192

plasma proteins accompanying,

197, 198

prekallikrein activator in, 193

process-related impurities in, 194

protein composition of, 192

purification schemes for, 199

pyrogens and endotoxins in, 193, 194

safety and adverse events related

to, 198, 199

sterility of, 193

subclass distribution in, 194, 195

total proteins of, 192

visual appearance of, 191, 192

IVIG products, differences among, 199

IVIG quality parameters, 191–195

IVIG-related thrombotic events, 199

IVIG solutions, heat treatment of, 190

IV pastes. See Cohn Fraction IV-1, 4

pastes

Janeway, Charles, 6

Japan

blood transfusion in, 17

haptoglobin studies in, 331

plasma fractionation in, 17, 18

Japanese monograph, 87, 88

Japanese Red Cross (JRC), 14, 17

Jesse, Jens, xi, 383

Joint bleeding, 58

Jorquera, Juan Ignacio, xi, 81

JTT-705, 273

Kaar, Waltraud, xii, 185

Kabi, 11

Kaketsuken, 18

Kalbitor, 251

Kallikrein, 242

hereditary angioedema and, 248

Kamada Ltd., 20, 238

Kamada Ltd GlassiaTM purification

process, 235–237

KASKADIL, 71

Kedrion, 15, 461

Kedrion clinical development

program, 317, 318

Kedrion evaluation of plasminogen

product, 318

Kedrion plasminogen case study, 317

Kedrion plasminogen manufacturing

process, 311, 314, 315

Kendrick, D. B., 6

Kernicterus, 217

Key opinion leaders (KOLs),

relationships with, 418

Key regulatory standards, compliance

with, 416

Kininogen binding, 93, 94

KIOVIG process steps, 189

Kirschbaum, Nancy, xii, 403

Kistler, P., 12

Kistler–Nitschmann fractionation

method, 12, 186, 213, 327

Cohn fractionation process vs., 165

Kitasate, Shibasaburo, 207

Kline purification method, 313

Koenderman, Anky, xii, 241, 301

Kogenate1, 36

Korean Red Cross (KRC), 18, 19

Kramer, Christine, xii, 241

484 INDEX

Kringle domains, 259

in plasminogen, 311, 312

Labeling, for source plasma, 426

Laboratoire FranScaise du Fractionnement

et des Biotechnologies (LFB)

concentrate, 96

Laboratorios Grifols, 10, 21. See also

Grifols entries

growth of, 16

internationalization of, 15

Laboratory deviations, 396

Laboratory-scale alpha1-PI

purification, 229–231

Laboratory-scale purification

methods, 229–231

Landsteiner, Karl, 3

Large buffer volumes, in plasma

fractionation, 442

Large-scale manufacturing, of

transferrin, 303, 304

“Last liter economics,” 452

Law on Securing a Stable Supply of Safe

Blood Products and the Revised

Pharmaceutical Affairs Law (Blood

Law) of 2003, 18

Lebing, Wytold, xii, 227

Lecithin-cholesterol acyltransferase

(LCAT), 273, 274, 284, 286

Lee, Timothy, xii, 403

Lerch, Peter, xii, 273

Less than 6 h plasma, 432

Less than 24 h plasma, 432

Leukoreduction filters, 374

Licensure requirements, 405, 406

Ligneous conjunctivitis

early treatment methods for, 316, 317

etiology of, 315, 316

inheritance of, 315, 316

surgery for, 316

Ligneous conjunctivitis therapy,

plasminogen in, 311–320

Limulus polyphemus Amoebocyte Lysate-

test (LAL test), 194

Lipid-enveloped viruses (LEVs), 72, 73

Lipid peroxidation (LPO), 338

Lipids

active, 74

bioactive, 351, 352

Lipoprotein lipase (LPL), 284

Lister Institute, 11

Liver, ceruloplasmin synthesis in, 337,

338

Liver disease, albumin treatment

for, 175. See also Cirrhotic ascites;

Hepatitis entries

Logistical operations, efficient, 462

Long chain fatty acid (LCFA)

binding, 162, 163

Low-density lipoprotein (LDL), 273,

274, 284

oxidized, 326

Low pH, immunoglobulin preparation

treatment at, 191

Low pH plasmin formulation, 261, 262

Low plasma albumin, 171, 172

Low-purity products, 409

LPO level, effects of, 338

Lucas, Victor Grifols, 5

Lyophilization steps, in alpha1-PI

purification, 230

Lyophilized CP, 340

Lyophilized plasma, 5, 11

Lyophilized products, 364

Lyophilized reconstituted HDL, 276.

See also High-density lipoprotein

(HDL)

Lyophilizing fibrinogen solutions, 118

LYOplasLG, 346, 353

Lys-Glu polymorphism, in

haptoglobin, 322, 323

Lys-plasminogen, 261

Lys-plasminogen application, 315

Lys-plasminogen intravenous infusions,

316, 317

Lys-plasminogen preparations, 314

Lys-plasmin structure, 312

Macrophages, 324

Maillard reaction, 192

Major inflammatory events, 152

“Make-or-buy” decisions, 458

Management leadership, 429

Mannan binding lectin-associated

protease (MASP), 243. See also

MASP-2

Manufacturing failures, 446

Manufacturing processes

for apolipoprotein AIMilano, 283–300

optimization of, 66

Manufacturing technologies, new, 445, 446

Marcucci, Paolo, xii, 461

Marcucci Group, 15

Marketing departments, independence

from Medical Affairs, 413

Market performance, 462–464

Marx, Gerard, xii, 117

MASP-2, inactivation mechanism

of, 244. See alsoMannan binding

lectin-associated protease (MASP)

Massachusetts Biologic Laboratories

(MBL), 9

Massive bleeding, PCCs to stop, 73

Master Batch Record, 444

Matrix-assisted laser-desorption

ionization (MALDI) analysis, 263

Mature markets, 463, 464

Measles, antibodies to, 195, 196

Medical Affairs departments, 413, 414

diverse functions of, 415–420

emerging role of, 413–415

globalization of, 414

goals of, 415

IIT issues and, 419

independence from Marketing, 413

independent medical education

and, 418

key bridging function of, 419

partnership with R&D and

Marketing, 414

Phase 4 studies and, 420

strategic planning and, 417

“Medical Affairs: Effective Global

Resource Allocation,: 415, 416

Medical Affairs partnership, 416

Medical Affairs personnel, 421

Medical Affairs policy, 418

Medical Affairs reporting structure,

changes in, 415

Medical and Scientific Advisory Council

(MASAC), 58

Medical information centers, 417, 418

effectively managed, 418

Medical science liaisons (MSLs), role

of, 418

Meeting briefing document, 405

Meeting questions, 405

Membrane attack complex (MAC), 243

Membrane chromatography, 445, 446

Membranes, columns vs., 445, 446

Mercaptoalbumin (MA), 171

Messenger RNA (mRNA) splicing, 95

Metal-chelating chromatography, 85

Michaelis complex, 244

Microbiological purity, 194

Microfiltration, in plasma

fractionation, 442

Microfluidic devices, 119

Microgen, CP manufacture by, 339, 340

Middle East, fractionation in, 20, 21

Mimetic ligand affinity, 97

Minimal concentration of fibrinogen, 118

Minimum Requirements for Biological

Products 2006, 87, 88

Minipool testing, 428

“Missense” mutation, 95

“Mixed mode” resins, in plasma

fractionation, 441

Model viruses, 362, 363

Molecular adsorbent recirculating system

(MARS), 175

Molecular integrity, 107

Molecular size distribution

for albumin, 171

of IVIG preparations, 192

Molecules, binding to fibrinogen,

119, 120

INDEX 485

Moloney, Maurice, xii, 283

Monoclonal antibodies (Mabs), 200, 214,

215, 221, 467

More, John, xii, 159

Morelli, Andrea, xii, 147

More than 24 h plasma, 432

“Mousetrap” effect, 243

Multichamber centrifuges, in albumin

manufacture, 167

Multimeric protein structure, 43

Multimerization, 41

Multinational fractionation industry,

14–16

Murine models, of Hp expression, 324

Murray, Elizabeth, xii, 283

Mutations, of Factor XI, 95

Myocardial infarction, 261

Nanofiltration, 35, 36, 70, 87, 142,

190, 191, 247, 264


terminal, 87

for virus removal, 363, 364

Nanofiltration techniques, 73

Nardini, Claudia, xii, 311

Natal Bioproducts Institute, 345

Natal Blood Transfusion Service (NBTS),

13, 14

National AIDS Control Organization

(NACO), 20. See also Acquired

immunodeficiency syndrome

(AIDS)

National Bioproducts Institute (NBI), 14

National Blood Authority (NBA), 17

National Blood Center (NBC), 20

National Donor Deferral Registry

(NDDR), 427

National Hemophilia Foundation, 58

National Organization for Rare Disorders

(NORD), 101

National Plasma Fractionation Center,

19, 20

National policies, 13, 14

National transfusion infrastructures, 4, 5

NAT testing, 427, 428, 453. See also

Nucleic acid-based testing (NAT)

Negative column chromatography, 188

Negatively charged platelet micro-

particles, removal of, 351, 352

Neisser-Svae, Andrea, xii, 345

neoFib, 123

Netherlands Red Cross, 14

Neurodegenerative illnesses, 369

Neutralizing antibodies, 191

Neutrophil elastase, 228

New manufacturing technologies,

445, 446

New York Blood Center (NYBC), 9

New York Blood Transfusion Betterment

Association, 10

Nexin 2, 95

N-glycosylation sites, 93

Niche products, 214

Nitric oxide (NO), albumin as carrier

for, 164. See also NO signaling

Nitschmann, H., 12

Nomenclature, plasma-related, 424

Noncholate-based methods, 292

Nonclinical pharmacology/toxicology,

406

Nonenveloped viruses (NEVs), 72, 73,

190, 191

solvent detergent treatment and, 348

Nongovernmental organizations (NGOs),

454

Noninhibitory antibodies, 57

Nonreducing SDS-PAGE, 329

Nonremunerated plasma, 384

“Nonsense” mutation, 95

No observed adverse effect level

(NOAEL), 266

“Norfolk Incident,” 6

Normalized water permeability (NWP),

168

North Africa, fractionation in, 20, 21

North America

immunoglobulin consumption in, 186


plasma fractionation industry in,

7–10

North American market, 463, 464

NO signaling, 326. See also Nitric oxide

(NO)

Not-for-profit fractionation, in Europe,

11–13

Not-for-profit fractionators, processing

capacity of, 14

Not-for-profit manufacturers, 21

Not-for-profit sector, 461

consolidation in, 14

Novel viruses, 65

Novokhatny, Valery, xii, 259

Nucleic acid-based testing (NAT), 72,

361–363, 384. See also NAT

testing

Nykiforuk, Cory, xii, 283

Octagam batches, 197

Octagam process steps, 190

Octanoic (caprylic) acid fractionation, 187

Octanoic (caprylic) acid treatment, 190

Octapharma AG, 13–15, 190, 451, 453,

461

growth of, 16

as solvent/detergent plasma producer,

345, 346, 348

Octaplas1, 345, 346

biochemical characterization of, 351

Octaplas(LG), 347, 351, 352, 354

anaphylactoid reaction rate for, 352

biochemical profile of, 350



manufacturing of, 346

single-donor FFP vs., 352, 353

virus neutralization and prior removal

from, 349

Octaplex1, 70, 71

Octaplex1 manufacturing process, 72

Oilbody (OB) biogenesis, 290

Okemefuna, Azubuike, xii, 321

Oliver, Percy, 4

Omni Bio Pharmaceuticals, Inc., 238

On-demand treatment, 58

Oniplas, 353

OOS handling system, main requirements

for, 395. See also Out of

specification (OOS) occurrences

OOS results, 396

Operational costs, of a developing-nation

plasma fractionation facility,

456, 457

Operation qualification (OQ), 391

Operations, in the production

process, 444, 445

Opsonization, 208

Orphan drugs, 238, 468

Orphan drug system, 101

Osmolality, of IVIG preparations, 192

Outcomes research, 419

Out of specification (OOS) occurrences,

393–395. See also OOS entries

Over, Jan, xii, 301

Oxidation, of hemoglobin, 326

Oxidation damage, 326

Oxidative process reduction,


Oxidative stress, albumin and, 164

Oxidized LDL, 326. See also Low-

density lipoprotein (LDL)

P�aez, Antonio, xii, 81Paid blood donors, 12

in India, 19

Pancreatitis, C1-inhibitor and, 250

Parasites, pathogen transmission via, 347

Parkkinen, Jaakko, xii, 301

Partial prothrombinase complex, 57

Partial thromboplastin time (PTT) test,

118

Parvovirus B19 (B19V), 72, 191.

See also B19 NAT

Parvoviruses, 328

Passive antibody administration, 210

486 INDEX

Passive immunization, 7

protective factor of, 349

Passive immunotherapy, 207

with convalescent plasma, 209, 210

hyperimmune, 209, 210

Pasteurization, 35, 104, 190, 247

of albumin, 165, 166

of ATIII, 150

enhanced, 176, 177

in plasma fractionation, 442, 443

for virus inactivation, 364

Past hyperimmune initiatives, 214

Pathogen inactivation/removal proce-

dures, product safety via, 150, 151

Pathogen reduction, 65

Pathogen removal, 354

Pathogen safety, ix, 65, 72, 73, 233, 251,

263, 264

in plasma fractionation industry, 231

solvent/detergent plasma and, 346, 347

Pathogen safety-related measures, 86, 87

Pathogen transmission, risk of, 106

Patients, with FVIII-inactivating

inhibitors, 37, 38

PCC capture, 83, 84. See also

Prothrombin complex concentrates

(PCCs)

PCC dosage optimization, 74

PCC factor deficiencies, 73

PCC factor domain structures, 68

PCC factor function, 67

PCC factors, 74

PCC manufacturing procedures, 71

PCC manufacturing process, state-of-the-

art, 70, 72PCC packaging, 72

PCC product characteristics, 66

PCC production processes, state-of-the-

art, 73PCC reactions, 75

PCC starting material, 83

PCC starting material isolation, facility

requirements for, 87

Peeling. See Plasma peeling process

Peer-to-peer scientific exchange, with

physicians, 415

Performance qualification (PQ), 391

Peripheral arterial occlusion (PAO), 268

Peripheral vascular disease, 277

Perry, David, xii, 413

Persistent ITP, 219. See also Immune


Petteway, Stephen, Jr., xii, 259

pFXIII tetramer, 102. See also Factor

XIII (FXIII)pH

immunoglobulin preparation treatment

at low, 191

of IVIG preparations, 192

Phagocytes, 208

Pharmaceutical industry

nanofiltration in, 190, 191

quality by design in, 389

Pharmaceutical Inspection Convention

(PIC/S) Code, 388

Pharmaceutical manufacturing

environment, 437, 448

Pharmaceutical products

commercially successful, 417

implementation of GMP for, 388

Pharmaceutical sector, quality systems

in, 387

Pharmacodynamic studies, 406

Pharmacological monographs, high-

purity Factor IX, 87, 88

Pharmacological Research and

Manufacturers of America (PhRMA)

Code, 414

Pharmacology

nonclinical, 406

safety and plasmin-related, 266,

267

Pharmacovigilance studies, 176

Phase 4 clinical trials, 419, 420

Phospholipid micelles, 59

Phospholipids (PLs), 284

Phospholipid transfer protein (PLTP),

284, 286

Physical virus inactivation procedures,

364Physicians, peer-to-peer scientific

exchange with, 415

Placenta, plasma derivatives from, 11

Placental extracts, 8

Placental serum, fractionated, 11

Plaminogen, 260

Plant-based production platform, 295

Plant biotechnology, future of, 295

Plant capacity increase, plasma to

feed, 453

Plant construction costs, in the developing

world, 456

Plant-derived manufacturing, of

apolipoprotein AIMilano, 283–300

Plant design, for the developing world,

455Plant location, in the developing

world, 455

Plant production, 283

Plants

seed-based expression in, 289–295

transgenic, 283, 295

Plaque lipids, reduction of, 293

Plasma

as a source of C1-inhibitor, 249Plasma

bovine, 6

colloid osmotic pressure of, 161

convalescent, 209

desiccated, 5

donation of, 361

for fractionation, 423–436

freeze-dried, 5, 9, 11

fresh frozen, 110

frozen, 438, 439

intravenous immunoglobulin G from,

185–205

lyophilized, 5, 11

main fractions of, 8


quality and safety of, 408

recovered, 423, 424

regulations governing the control

of, 385

as a source of therapeutic

proteins, 1013

sourcing of, 212, 213, 384

thrombolytic efficacy of, 265

for transfusion and further

manufacture, 423–425

from U.S.-based collection

facilities, 42

Plasma antithrombin III (ATIII),

production and clinical use of,

147–157. See also Antithrombin III

(ATIII)

Plasma bags, peeling of plasma in,

439

Plasma-borne pathogens, 35

Plasma bottles, peeling of plasma in,

439Plasma buffering, albumin in, 164

Plasma clarification processes, 194

Plasma collection, 8, 383, 425, 426

in Asia, 21

assessment of, 397, 398

in China, 18

in Europe, 21

increased scrutiny of, 429

methods for, 423, 424

in North America, 21

Plasma collection centers, 424

Plasma component, vCJD transfusion

transmission risk and, 373, 374

Plasma component solubility, 187

Plasma concentration, increase in,

88, 89Plasma derivatives, 8, 410


in emerging market countries,

464, 465

regulation of, 404

viruses of concern for, 362

Plasma derivatives business, importance

of, 467Plasma derivatives industry, 461

goals of, 468

INDEX 487

Plasma-derived (pd) FII-FXa

complex, 56. See also Factor II (FII,

prothrombin); Factor Xa (FXa);

Prothrombin entries

Plasma-derived coagulation products,

viral contamination of, 36

Plasma-derived FVIIa, 56. See also

Factor VIIa (FVIIa)

Plasma-derived FVIII, 55. See also

Factor VIII (FVIII)

purification of, 33–35

Plasma-derived FVIII concentrates, 37

Plasma-derived FIX concentrate, 89.

See also Factor IX (FIX)

Plasma-derived Factor IX products,

82, 83

Plasma-derived Factor XIII

concentrate, 105, 106. See also

Factor XIII (FXIII)

manufacturing processes for, 102

Plasma-derived fibrin glues, safety

of, 144

Plasma-derived HDL, 273–282

Plasma-derived hepatitis B vaccine, 9

Plasma-derived hyperimmune products,


Plasma-derived Medicinal Products

guideline, 444, 445

Plasma-derived pharmaceuticals, per

capita consumption of, 464

Plasma-derived plasmin, as a direct-

acting thrombolytic agent, 268

Plasma-derived products, 251

availability of, 465

demand and supply of, 468

in vivo recovery of, 89

manufacture of, 429

regulatory environment of, 383–385

safety of, 35

Plasma-derived proteins, 55

producing, 7

Plasma-derived therapeutic products, ix,

461

Plasma-derived vWF concentrates, 43,

45

Plasma donations, screening, 361, 362

Plasma donors, screening, 264. See also

Blood donor entries

Plasma enzymes, accompanying IVIG

preparations, 197

Plasma Factor XIII (pFXIII)

activity, 102. See also Factor XIII

(FXIII)

Plasma for fractionation, 434

“Plasma for Great Britain Project,” 10

Plasma for stable products, 432

Plasma fractionation, 9, 11, 237

in Australia, 16, 17

in China and South-East Asia, 18, 19

commercial environment and

economics of, x

current technologies used in, 437–443

development of, 5–7

economics of, 451–460

in Europe, 13

first practical process for, 437

history of, 5–7

in India, 19, 20

in Japan, 17, 18

key validation activities for, 394

quality system specific to, 386

steps in, 438

Plasma fractionation companies,

worldwide, 466

Plasma fractionation facilities

in China, 18

construction cost of, 454–456

in developing nations, 453, 454

in Israel, 20

operating costs of, 456, 457

Plasma fractionation industry, 461

changes in, 111, 112

in Europe, 10–13

future of, 22

in North America, 7–10

multinational, 14–16

pathogen safety in, 231

process technology development

in, 167, 168

strengths of, 451

in 2010, 2011, 21, 22

2010 economic environment of,

451–454

Plasma fractionation industry screening

systems, 237

Plasma fractionation plants, in Brazil, 13

Plasma fractionation process,

specifications for, 389

Plasma fractionators, worldwide, 13

Plasma frozen within 24 h after

phlebotomy, 434

Plasma FXIII, 139. See also Factor XIII

(FXIII)

Plasma half-lives, 75

Plasma HDL increase, therapeutic

approaches for, 274. See also

High-density lipoprotein (HDL)

Plasma Hp, turnover of, 324, 325.

See also Haptoglobin (Hp)

Plasma human serum albumin (pHSA),

development of, 177, 178

Plasma imports, independence from, 18

Plasma inhibitors, Factor XI inhibition

by, 95

Plasma investigation, 429

Plasma kallikrein, 242

Plasma manufacturing processes, 385

Plasma Master File (PMF), 362, 384. See

also PMF concept

Plasma peeling process,438, 439

Plasmapheresis, 4, 8, 10

Plasmapheresis centers, 362

Plasmapheresis donors, repetitive

donation pattern of, 427

Plasma pooling, 428, 437

Plasma pools, 366, 374

Plasma processing, 8

for the developing world, 455, 456

Plasma processing industry, 12

Plasma product classes, international

sales of, 452

Plasma production market, future trends

in, 461–470

Plasma product life cycle, 392

Plasma product manufacture, quality

assurance requirements in, 383–401

Plasma product manufacturing industry,

governance of, 383, 384

Plasma product revenues, 457, 458

Plasma products, 22

global demand for, 453

global market for, 429

global sales of, 451

manufacture of, 446

providing to developing

countries, 453, 454

safety and quality of, 399

supply and demand for, 14


for, 374–376

TSEs and, 369–380

viral transmission risk from, 176, 177

virus safety of, 361–368

Plasma product safety issues, 106

Plasma products market, barriers to entry

into, 461, 462

Plasma products sector, trading conditions

in, 464

Plasma product substitutes, preparing

for, 467, 468

Plasma protein fractionation, history and

evolution of, ix

Plasma protein fractionation industry, ix

history and development of, 3–28

Plasma protein fractions (PPFs), 159, 186

Plasma protein products, qualification and

validation aspects for, 393

Plasma Protein Purification System

(PPPS), 165, 167

Plasma proteins

accompanying IVIG preparations, 197,

198

biology of, ix

deficiencies in, 101

488 INDEX

manufacture of, 437

production of, ix


recombinant, 36

Plasma protein therapeutics, future

of, 410

Plasma Protein Therapeutics Association

(PPTA), 385, 398, 424, 426, 457,

467. See also PPTAvoluntary

standards

Plasma protein therapeutics production/

commercialization, regulatory

activities associated with, 403–411

Plasma purification, 440, 441

Plasma quarantine, 428

Plasma safety, 426–429

Plasma safety net, 426

Plasma serine protease inhibitors, 95

Plasma sources, voluntary, 12

Plasma specifications, 424

Plasma standards, U.S. and European,

425

Plasma storage, 9, 426

Plasma suppliers, monitoring, 400

Plasma supply problems, 8

Plasma transfusion, 73

Plasma transfusion therapy, 43

Plasma types/specifications, 430–434

Plasmin

acid-stabilized, 268

catheter-delivered, 265

clinical experience with, 267, 268

clinical-grade, 261–264

as a direct-acting thrombolytic,

259–271

general properties of, 259

historical perspective on, 260, 261

main physiological function of,

259, 260

manufacturing of clinical-grade,

261–264


structure and physiological function

of, 259, 260

thrombolytic efficacy of, 267, 268

toxicology/safety pharmacology

summary, 266, 267

Plasmin development, as a direct-acting

thrombolytic agent, 260, 261

Plasmin efficacy, relationship to safety,

268, density

Plasmin formulation, low pH, 261, 262

Plasmin inhibitors, 141

activity of, 350

Plasmin manufacturing process, 262, 263

Plasminogen, 139, 140, 262

activation of, 259



mutant form of, 314


purification of, 313–315

role in ligneous conjunctivitis

therapy, 311–320


Plasminogen activation, 263, 313

by tPA, 259, 260

Plasminogen activators (PAs), 261

failure of, 261

Plasminogen concentrate, 311, 317

Plasminogen concentrate preparation, key

development in, 313, 314

Plasminogen deficiencies, 311, 315,

316

Plasminogen eye drops case studies, 317

Plasminogen–plasmin system, 260

Plasminogen process, 263

Plasminogen products

future of, 318

Kedrion evaluation of, 318

Plasminogen purification, by affinity

chromatography, 314, 315

Plasminogen reduction, 141

Plasminogen synthesis, 311, 312

Plasmin process, 263

Plasmin products, characterization

of, 263

Plasmin Revascularization for the

Ischemic lOwer extRemITY

(PRIORITY) trial, 268

Plasmin storage, 260

Plasmin structures, 260

Plasmin therapeutic index, 269

Plasmin tolerance, 266

PLAS þ SD (S/D-treated plasma), 9

Plastic bag blood collection system, 4

Plate filter designs, 168

Platelet adhesion, vWF protein and, 42

Platelet agglutination, 43

Platelet counts, 220

Platelet Factor XI, 94, 95. See also

Factor XI (FXI)

Platelet poor plasma, 431

Platelet rich plasma (PRP), 431

PMF concept, 397, 398. See also Plasma

Master File (PMF)

Pneumonic anthrax infection, as

biological weapon, 210

Pock, Katharina, xii, 65

Polio, antibodies to, 195, 196

Polyacrylamide gel electrophoresis

(PAGE), 306, 321, 322

Polyclonal antibodies, recombinant, 467

Polyclonal antibody preparations, 200

Polyether sulfone (PES) membranes, in

albumin manufacture, 168

Polyethylene glycol (PEG)

precipitation, 149, 187, 188

Polymerase chain reaction (PCA),

427, 428

Polyvinyl chloride (PVC) bags, 346

Pooled plasma, 433. See also Plasma

pool entries

Porcine FVIII, 55, 57. See also Factor

VIII (FVIII)

Portfolio management, 404

Postmarketing surveillance study, 58

Postoperative complications,


Posttranslational modifications, of

Factor IX, 83

Poulle, Michel, xii, 41, 93

PPSB-human SD/Nano 300/600, 71

PPTAvoluntary standards, 427. See also

Plasma Protein Therapeutics

Association (PPTA)

Preactivation peptide, 139

Precipitate A, 186

Precipitate separation, by centrifugation

and filtration, 440

Precipitation


sequential, 437

virus removal via, 191, 363

Precipitation agents, 141

Precipitation processes, 214

Precipitation purification procedure, for

alpha1-PI, 230

Precipitation techniques, in plasma

fractionation, 441

Precision Pharma, 15

Prekallikrein, 94, 242

Prekallikrein activator (PKA)

activity, 104

in albumin, 171

in IVIG preparations, 193

Premarket regulatory processes, 403

Preventive actions, 395, 396

Previously treated proteins (PTPs),

inhibitors in, 37

Previously untreated patients (PUPs),

inhibitors in, 37

Price, Hugh, xii, 207

Primary ITP, 219. See also Immune


Principal component analysis (PCA), 389

Prins-de Nijs, Ingrid, xii, 301

Prion (PrPsc) affinity ligands, 36

Prion-based disease, 65

Prion diseases, 369

Prion disease transmission, 354

Prion protein (PrP), 151. See also PrPc

protein; PrPTSE protein

Prion protein removal, 264

INDEX 489

Prion removal, 349, 350

Prions, inactivation of, 73

Privigen manufacturing process, 187, 188

PRNP gene, 376

PRNP genotypes, 373

ProApoAI proprotein, 285

Procedures, in the production process,

444, 445

Process analytical technology (PAT),

387, 390

Process charting, 390, 391

Process comparability strategy, 409

Processes, control of, 406, 407

Process-induced aggregation, 195

Process quality, 386

Process-related impurities, in IVIG

preparations, 194

Process technology development, in the

plasma fractionation industry,

167, 168

Procoagulant activity, in immunoglobulin

preparations, 199

Procoagulant process, maintaining, 60

Procoagulants, 59

Proconvertin, 65

Product characterization, 408

Product development, 112

Production facilities, design of, 443, 444

Production management, 444, 445

Production methods, for purified FVIII,

33–35

Production processes, for Factor IX

concentrates, 83–87

Product life cycle management, quality by

design in, 407, 408

Product quality, 408

Product Quality Review, 399

Product range, for the developing

world, 455

Products, control of, 406, 407

Product safety, 398, 399

ensuring, 35, 36

ensuring by pathogen inactivation/

removal, 150, 151

Product testing, 263

PRO-FEIBA1 study, 58

Profilnine SD, 71

Project management, 404

Prolastin1, 227, 233

Prolastin-C purification process, 234, 235,

236, 237

Prolastin purification process, 232, 233,

236

Prophylactic regimens, C1-inhibitor

in, 250

Prophylactic therapy, with FVIII and

FIX, 58

Proplex-T, 71

Protalix, 290

Protease inhibition, 148

Protein augmentation therapy, with

alpha1-PI, 229

Protein C, 70, 75, 148


HDL and, 275

Protein chains, haptide epitopes in, 122

Protein composition, of IVIG

preparations, 192

Protein C pathway, 67

Protein formulation, 328

Protein Fractionation Center, 11

Protein misfolding cyclic amplification

(PMCA), 376

Protein multimerization, 41

“Protein only” hypothesis, 370

Protein S, 69, 70, 75


HDL and, 275

reduced levels of, 351

Proteins

chromatography methods for

isolating, 38

clotting-related, 7

hemostasis regulators among, 65

plasma as a source of therapeutic, 101

types of, ix

vitamin K-dependent, 68

Protein stabilization, 261

Protein therapeutics, 399, 400. See also

Plasma protein therapeutics

production/commercialization

Protein Z, 69, 70, 75


Protein Z-dependent protease inhibitor,

107

Proteolytic processing, in Golgi

apparatus, 41

ProthoRAAS, 71

Prothrombin, 65, 139. See also Factor II

(FII, prothrombin)

FXa and, 59

role of, 53–55

Prothrombinase complex, 59

Prothrombin complex (PCC), 65–79,

142, 439

characteristics of, 70–72


(PCCs), 49, 51–53, 65, 110, 353,

439

as bypassing agents, 75, 76

for bypassing therapy, 52


clinical trials with, 52

clinical use of, 66

effectiveness of, 52

Factor X in, 108

freeze-dried, 70

heparin and antithrombin in, 75

history of, 65, 66

importance of, 66

in intensive care medicine, 75)

manufacturing of, 69, 70

quality of, 66

safety considerations related to, 74, 75

to stop massive bleeding, 73

therapeutic indications for, 66

thrombotic events with early

generation, 66

Prothrombin complex zymogens, roles

of, 51–53. See also Prothrombin

zymogen

Prothrombinex-VF, 71

Prothrombin–FXa complex, 54, 58, 59

pharmacokinetic properties of, 57

potency of, 55, 56

results obtained with, 57

Prothrombin time (PT), 74

Prothrombin time (PT) test, 111, 112, 118

Prothrombin zymogen, role of, 59

Prothrombotic reactions, 74, 75

Prothromplex-T, 71

PrPc protein, 269, 370. See also Prion

protein (PrP)

PrPTSE protein, 369, 370, 371, 372, 373,

375, 376

Pseudomembraneous disease, 315

Pseudomembranes, recurrence of, 317

Publication planning/execution, 417

Public health, regulatory authority

and, 410

Public/private collection systems, 467

Pulmonary diseases, 228

Pure rFXa, 54

Purification, in plasma fractionation, 440,

441

Purification concepts, 186–189

Purification methods

for alpha1-PI, 229–231

in development, 38

Purification principles, 185

Purification schemes/techniques, 142

for IVIG preparations, 199

Purification technologies, 33–35

development of, 46

Purified FVIII, production methods

for, 33–35. See also Factor VIII

(FVIII)

Purified Factor IX, European and

Japanese requirements for, 87, 88

Purified plasma-derived porcine

FVIII, 37

Purified prothrombin, 53

Pyrogens, in IVIG preparations, 193, 194

Pyrogen testing, 194

490 INDEX

QAE-Sephadex1, 70

QA system, 397. See also Quality

assurance system

QC laboratories, 388, 389. See also

Quality control (QC)

“Quaking-induced conversion”

(QuIC), 376

Qualification, 391–393

Qualified donors, 361

Qualified Donor standard, 427

Quality Agreement, 399

Quality assurance (QA), 383, 395, 397

Quality assurance requirements, in

plasma product manufacture,

383–401

Quality assurance system, 386, 387.

See also QA system; Quality systems

responsibilities of, 386

Quality by design (QbD), 387, 389, 407,

410

applying to product life cycle

management, 407, 408

Quality control (QC), 386, 387. See also

QC laboratories

Quality maintenance, 444, 445

Quality management reviews, 387

Quality Risk Management guideline, 398

Quality Standards of Excellence,

Assurance and Leadership (QSEA),

424

Quality systems, 429. See also Quality

assurance system

interfaces to, 399

Quality Systems Regulation, 403

Quarantine, of plasma, 428

Quarantine plasma, 433

Quarantine residual plasma, 433

Quick, J., 74

Quick value, 74

Rabbit stroke model, 265, 266

Rabies immunoglobulin products, 20

“Radial flow” type columns, in plasma

fractionation, 442

Rare diseases, 101, 462, 463

Ravdin, Isador, 6, 7

Reactive nitrogen species (RNS), 164

Reactive oxygen species (ROS),

164, 326

Rebbeor, James, xii, 259

Recombinant activated Factor VII

(rFVIIa), 96

Recombinant ApoA-1 preparations, 274

Recombinant apolipoprotein AIMilano,

manufacturing large quantities

of, 289

Recombinant DNA products, 17

Recombinant-DNA technology, 250, 451

Recombinant (r) FII-FXa complex, 56.

See also Factor II (FII, prothrombin);

Factor Xa (FXa); Recombinant

prothrombin–FXa complex

Recombinant FVIIa (rFVIIa), 65

Recombinant FVIIa (rFVIIa) treatment,

57

response to, 56

Recombinant FVIII, 55. See also

Recombinant Factor VIII entries

Recombinant FVIII preparations, von

Willebrand factor in, 37

Recombinant FVIII production, in

transgenic animals, 38

Recombinant FIX concentrate, 89. See

also Recombinant Factor IX entries

Recombinant FXa (rFXa), 53

pure, 54

Recombinant Factor VIII (rFVIII), 22.

See also Recombinant FVIII entries

production in cell culture, 36, 37

Recombinant Factor VIII products, 36, 37

Recombinant Factor IX (rFIX), 83. See

also Recombinant FIX concentrate

Recombinant Factor IX products, 82, 83

Recombinant Factor XIII-A (rFXIII-A),

105, 106

Recombinant fibrin glues, 144

Recombinant hepatitis B vaccine, 209

Recombinant human alpha1-PI, 237

Recombinant human antithrombin III

(rhATIII), 151

Recombinant human serum albumin

(rHSA), development of, 177, 178

Recombinant plasma proteins, 36

human plasma proteins vs., 467, 468

Recombinant polyclonal antibodies, 467

Recombinant products, 251, 467

Recombinant protein therapeutics,

transgenically produced, 38

Recombinant prothrombin–FXa

complex, 54. See also Recombinant

(r) FII-FXa complex

Recombinant techniques, 112

Recombinant technology, 467

Recombinant transferrin products,

304, 305

Recombinant vWF, plasma- and albumin-

free, 46

Recombinate1, 36

Reconstituted HDL (rHDL), 273–282. See

alsoHigh-density lipoprotein (HDL)

beneficial effects of, 278

clinical experienced related to, 277, 278

efficacy of, 277, 278


manufacture and characterization

of, 276, 277

Reconstituted HDL disks, 277

Reconstituted HDL infusions, effects

of, 278

Reconstituted HDL preparations, 274

tolerability of, 277

Reconstituted HDL therapies, 295

Recovered plasma, 423, 424, 430

Recovered-plasma products, 195, 196

Red blood cells (RBCs), 120, 326

vCJD transfusion transmission risk

and, 373

Red Cross, European governments

and, 11–13. See also American Red

Cross (ARC); Australian Red Cross;

Canadian Red Cross; Central

Laboratory of the Netherlands Red

Cross (CLB); Deutsches Rotes

Kreuz (DRK) Blutspendedienst

Nordrhein-Westfalen; Finnish Red

Cross entries; German Red Cross

entries; Israeli Red Cross; Japanese

Red Cross (JRC); Korean Red Cross

(KRC); Netherlands Red Cross;

Swiss Red Cross

Red Cross transfusion services, 11, 12

Redox properties, of albumin, 164

Reduced vitamin K, 81

Reducing SDS-PAGE, 329

Reduction studies

with endogenous blood infectivity, 375

with exogenous infectivity, 375, 376

ReFacto1, 37

ReFactoR1, 36

Regional fractionation centers, 11

Regulations

plasma-related, 385

standardized, 414

Regulatory affairs (RA) departments, role

of, 403, 404

Regulatory affairs (RA)

professionals, 403, 404

Regulatory agencies, role in

biopharmaceutical development/

commercialization, 404, 405

Regulatory application, preparation

of, 407

Regulatory authorities

interaction with, 404

public health and, 410

Regulatory compliance, 112

Regulatory environment

changes in, 413

of plasma-derived products, 383–385

Regulatory processes, differences

among, 403

Regulatory standards, compliance

with, 416

“Reischauer Affair,” 17

INDEX 491

Reliseal1, 137

REMS programs, 420. See also Risk

evaluation and mitigation strategies

(REMS)

Renal adverse reaction, related to IVIG

preparations, 199

Renal failure, during ITP treatment,

220, 221

Reperfusion injury, C1-inhibitor

and, 250

Replacement therapy, 89, 316. See also

vWF replacement therapy

for coagulation disorders, 46

for hemophilia A, 57

for hemophilia B, 88

Reprecipitation, 104

Rescue therapy, for patients with FVIII-

inactivating inhibitors, 37, 38

Research and development (R&D), 413.

See also Scientific/medical

knowledge

Resin density, 446

Resource management, 404

RETAIN trial, 238

Reverse cholesterol transport (RCT),

273–275, 283, 284, 291, 292

Rh-antigen, 217

Rh blood group system, 217

Rh (D) antibodies, 218

inhibition of, 218

Rh (D) immunoglobulin, 17, 217–225

advantages of, 220

in ITP treatment, 220

safety of, 220, 221

Rh (D) immunoglobulin doses, 220

Rh (D) immunoglobulin products, 20

Rh (D) isoimmunization, 218

Rh Institute, 9, 10

Rh-isoimmunization, prevention of, 218

Rhone-Poulenc Rorer, 15

Rh Pharmaceuticals Inc., 10

Risk assessment, in virus inactivation,

365, 366

Risk-based auditing schedules, 398

Risk-based audit management, 398

Risk evaluation and mitigation strategies

(REMS), 419–421, 414

Ristol, Pere, xii, 81

Robertson, Oswald, 4

R€omisch, J€urgen, xii, 65

Rotating horizontal leaf filter, 168

Rouleaux formation, 120

Rous-Turner solution, 4

Rozrolimupab, 221

Ruconest, 250, 251

Russia

blood donors in, 12

CP manufacture in, 339, 340, 342

Safety. See also Blood safety programs;

Pathogen safety entries; Product

safety; Virus safety; Virus safety

system

of blood products, 189, 190

of coagulation products, 38

ensuring by pathogen inactivation/

removal, 150, 151

Factor X-related, 110, 111

of FEIBA1 products, 57, 58

of human albumin, 176–178

of IVIG preparations, 198, 199

of PCCs, 74, 75

of plasma, 408

of plasma-derived fibrin glues, 144

of plasma-derived products, 35, 406

of plasma products, 106

plasmin efficacy relationship to, 268,

269

preclinical evidence of, 264–267

of Rh (D) immunoglobulin and IVIG,

220, 221

of solvent/detergent plasma, 351–353

viral, 86, 96

Safety assessments, 267

Safety pharmacology studies, plasmin-

related, 266, 267

Safflower-derived apolipoprotein

AIMilano, 290–292

biological activity of, 292–295

preclinical efficacy of, 294

Saline versus Albumin Fluid Evaluation

(SAFE) study, 172, 173

Salvaged plasma, 433

Sanquin-CAF-DCF organization, 14

Sanquin Plasma Products, 304

SARS-Corona virus, 363. See also Severe

acute respiratory syndrome (SARS)

Saturated ammonium sulfate (SAS), 244

Saudi Arabia (KSA), fractionation facility

in, 20, 21

Saudi Arabian Plasma Group (SAPG), 21

Saudi Pharmaceutical and Appliances

Corporation (SPIMACO), 20, 21

Schultze–Heimburger purification

method, 230

Schwarz, Hans Peter, xii, 49

Scientific/medical knowledge,

disseminating, 421. See also

Research and development (R&D)

Scope of a project, 454

Scott, Dorothy, xii, 369

Scottish National Blood Transfusion

Service (SNBTS), 11, 20

Scrapie, atypical forms of, 376

Scuderi, Philip, xii, 259

S/D plasma, 433. See also Solvent

detergent (S/D) plasma

S/D plasma production methods, 346

S/D plasma products, coagulation factors

and inhibitors in, 350

S/D reagents, 348

Secondary immunodeficiencies, 185

Secondary ITP, 219. See also Immune


Seed-based expression, in plants, 289–295

Seed overexpression, 290

Self-sufficiency, high-purity Factor IX

and, 89, 90

Self-sufficiency plan, 21

Self-sufficiency policies, 13, 14, 16, 17,

18

SemBioSys Genetics Inc., 290, 295

SemBioSys production platform, 290

Separation resins, 33

Sepharose1 beads (SBs), 120, 122, 125.

See also DEAE-Sepharose1 FF;

ECH-Lysine Sepharose resin;

Heparin-Sepharose1 entries;

Hexyl-Sepharose1

Sepsis

albumin and, 176

C1-inhibitor and, 249, 250

Sequential ethanol precipitation, 440

Sequential precipitation, 437

Serine protease inhibitors

(“serpins”), 227, 228, 241. See also

Serpin entries

Serious adverse events (SAEs), 268

Serpin C1-inhibitor, 244

Serpin C1-inhibitor domain, 3D models

of, 241, 242

SERPING1 gene, 241

Serum, 3. See also Blood entries; Plasma

entries

equine, 6

Serum albumin, clinical issues related

to, 171–176

Serum Institute of India, 19

Serum levels, albumin and, 171, 172

Serum therapy, 207, 214

Severe acute respiratory syndrome

(SARS), convalescent plasma

treatment of, 209, 210. See also

SARS-Corona virus

Severe ITP, 219. See also Immune


Shearer process, 232

Shen, Yin, xii, 283

Short consensus report (SCR) domain, in

haptoglobin, 323

Short Supply Agreement, 406

Sinclair, Christopher, xii, 207, 217

Single-donor FFP, Octaplas(LG) vs., 352,

353. See also Fresh frozen plasma

(FFP)

492 INDEX

Single donor plasma, 433

6–12 h plasma, 432

Six Sigma concept, 387

Size exclusion chromatography

(SEC), 33, 34, 192, 263


Small-scale fractionation, 13

Smith, Jodi, xii, 217

Sodium dodecyl sulfate (SDS)

electrophoresis, 43

Sodium dodecyl sulfate polyacrylamide

gel electrophoresis (SDS-PAGE)

analysis, 241, 263, 329

Soluble fibrinogen, transformation into a

clot, 118, 119

Solvent detergent (S/D) method/

treatment, 33, 35, 190, 328

in FIX manufacture, 87


superiority of, 347

for virus inactivation, 365


Solvent/detergent (S/D) plasma, 345–357.

See also S/D entries

biochemical profile of, 350, 351


clinical safety and tolerability of,

351–353

producers of, 345, 346

Solvent/detergent (S/D) technology, 9

Sorbitol concentration, 104

Source material, control of, 406

Source plasma, 21, 424, 430

control of, 406

donation of, 361

labeling for, 426

Source plasma centers, 427

Source plasma collection, anticoagulant

solution for, 426

Source plasma regulations, 424

South African Blood Transfusion Service

(SABTS), 13, 14

South American market, 463

South-East Asia, plasma fractionation

in, 18, 19

Spanish flu H1N1 pandemic, 209

Specific activity (SA), 83, 84

Spiked infectivity, reducing, 375, 376

Spiked viruses, inactivation of, 364

Spiking preparations, 375

Splenectomy, 219

Spongiform encephalitis/

encephalopathy, 35

Spontaneous bleeding episodes, 58

Sporadic CJD (sCJD), 369, 371. See also

Human sCJD; Variant Creutzfeldt-


Spray-dried fibrinogen/thrombin, 143

SRBI receptor, 292, 293

“Standardized” filtered blood, 10

Standardized regulations, 414

Standard operating procedures (SOPs),

388, 389, 399, 429, 444

Standard procedures, violation of,

393–395

Standard purification principles, 185

Standards, in donor screening, 426, 427

Starling’s Law, 161

Starting material plasma, composition

of, 200

State-of-the-art PCC manufacturing

process, 70, 72. See also


(PCCs)

State-of-the-art PCC production

processes, 73

Statin therapy, 273

Statistical data/charts, 396

Steam in place (SIP) centrifuge

design, 167

Stem cell harvesting, 125

Sterile filtration, solvent/detergent plasma

and, 347

Sterile vacuum-type blood collection

unit, 9

Sterility, of IVIG preparations, 193

Steroid hormones, albumin binding

to, 163

S-TIM4 vapor heat treatment, 49

Stokes, Joseph, 7

Strategic National Stockpile (SNS),

210–212

Strategic planning, Medical Affairs

departments and, 417

Streptokinase, 260

Stroke, 268

Stuart–Prower factor, 65

Subclass distribution, in IVIG

preparations, 194, 195

Subfractionation methods, 7

Substitution therapy, 306

for Factor X deficiency, 110

Substrate concentrations, increasing, 59

Sudlow sites, 161

Suicide inhibitor, 243

Summary of product characteristics

(SPC), 66

Superoxide dismutases (SODs), 338

Supplier audit program, 399

Supplier audits/inspections, 398

Suppliers, audits/inspections of, 398.

See also Plasma suppliers

Surgical glues, 137

Sustainability, 16, 17

Svae, Tor-Einar, xii, 345

Svedberg, Theodore, 6

Swine flu, convalescent plasma treatment

of, 210

Swiss Red Cross, 20

SympressTM expression system, 221

Synthetic colloids, 172

Synthetic plasma expanders, 172

Talecris Biotherapeutics, Inc., 15, 21,

234, 235, 236, 262, 451, 461, 466

growth of, 16

Target antigen binding, 208

Task Force on Clinical Use of FIX

Concentrates, 52

Technology types, for the developing

world, 455

Temporary hemophilia, 55

Tenascins, 122

“Tenase” complex, 81, 82

ter Hart, Hennie, xii, 301

Terminal incubation, in albumin

manufacture, 166

Terminal nanofiltration, 87

TF/Factor VIIa complex, 81

b-Thalassemia, 307

Thawing process, in plasma protein


Therapeutic C1-inhibitor products,

247, 248

Therapeutic exchange plasma (TEP),

433

Therapeutic FVIII production,

development strategies for, 38.

See also Factor VIII (FVIII)

Therapeutic Factor X concentrate, 108

manufacture of, 108–110

Therapeutic Factor XIII concentrate,

manufacture of, 103

Therapeutic plasma exchange (tPEx),

175, 176

Therapeutic plasma proteins, availability

of, 465

Therapeutic products, plasma-derived,

461

Therapeutic proteins

extraction and purification of, 290

plasma as a source of, 101

from transgenic plants, 295

Therapeutics, control and oversight of

critical, 446

Thiol, in albumin, 171

Thrombin, 139

FXI activation by, 94

spray-dried, 143

Thrombin activatable fibrinolysis

inhibitor (TAFI), 95

Thrombin activation, 42, 43

fibrinogen polymerization induced

by, 118, 119

INDEX 493

Thrombin component, 137


Thrombin concentration, 81

Thrombin generation, 57, 59

Thrombin generation assay, 53

Thrombin generation curves, 53, 54

Thrombin inhibition, heparin and, 139

Thrombin inhibitors, 141

Thrombin polypeptide chains, 139

Thrombin regulation, 147

Thrombin solutions, for hemostasis,

142, 143

Thrombocytopenias, 218, 219

Thromboembolic events, 74, 199

Thromboembolic risk factors, 75

Thromboembolism, risk of, 176

Thrombogenicity, 84, 106

Thrombogenicity risks, 89

Thrombogenicity tests, 111

Thrombogenic material, separating, 110

Thrombolysis therapy, 261

Thrombolysis treatment testing, 266

Thrombolytic agents

limitations of, 261

plasma-derived plasmin as, 268

Thrombolytic conditions, human plasmin

for, 266

Thrombolytics, acid-stabilized plasmin

as, 259–271

Thrombosis, 73, 221, 351

Thrombosis model system, 264, 265

Thrombotic events, 58, 96

with early generation PCCs, 66

Thrombotic stroke, 277

Thrombotic thrombocytopenic purpura

(TTP), 42, 353. See also Immune


Tiselius, Arne, 6

Tissue factor (TF), 81

Tissue factor pathway inhibitor (TFPI),

148

Tissue plasmin activator (tPA), 259, 260,

261, 265

Tissue-type plasminogen activator (tPA),

312

Titmuss, Richard, 12

Toll arrangement, 458

Toll fractionation, 17

Toll manufacturing, 458

Topical plasminogen drops, 317

Torcetrapib, 273

Total proteins, of IVIG preparations,

192

Toxicity

of cell-free hemoglobin, 325, 326

of early plasmin preparations, 260

of Factor X concentrate, 111

of haptoglobin, 331

Toxicological studies, plasmin-related, 266

Toxicology

nonclinical, 406

plasmin-related, 266, 267

Toxin neutralization, 208

Tranexamic acid, 142

Transferrin, 301–310

accompanying IVIG preparations,

197

binding capacity of, 303


characterization of, 305, 306

clinical applications for, 306

clinical development of, 306, 307


iron-binding capacity of, 301, 306

manufacture of, 303–305


physiology of, 301

as a targeting molecule, 307

Transferrin-dependent iron uptake, 302

Transferrin formulations, 304

Transferrin preparations, 304, 306

Transferrin purification, 304, 305

Transferrin-receptor complex, 302

Transferrin receptors, 302

Transferrin substitution therapy, 306

Transferrin synthesis, 301

Transfusion

early history of, 3–5

plasma collected for, 423–425

Transfusion complications, 353

Transfusion Medicine Epidemiological

Review (TMER), 372, 373

Transfusion related acute lung injury

(TRALI), 221, 351, 352

risk of, 352, 353

Transfusion Sanguine d’Urgence (TSU),

11

Transfusion substitutes, developing, 5–7

Transfusion-transmitted (TT) sCJD

(TTsCJD) infections, 373

Transfusion-transmitted (TT) vCJD

(TTvCJD) infections, 372, 373

Transgenic animals, recombinant FVIII

production in, 38

Transgenic plants, 283

therapeutic proteins from, 295

Transgenic rhATIIIs, 151

Transmembrane pressure (TMP), 442

Transmissible spongiform encephalitis/

encephalopathies (TSEs), 35.

See also TSE entries

albumin and, 177

future issues related to, 376, 377

histopathological changes of, 369, 370

new developments concerning, 376,

377

plasma products and, 369–380

Transplacental blood transfer, 218

Treatment-emergent adverse events

(TEAEs), 268

Triacylglycerol (TAG), 284

Triglycerides, 284

Trinuclear cluster, of ceruloplasmin, 337

Trypsin-inhibitory activity, of alpha1-

PI, 232

Trypsone1, 233

TSE clearance studies, 375, 376. See

also Transmissible spongiform

encephalitis/encephalopathies (TSEs)

TSE diseases, classification of human, 370

TSE infections, transmissibility of, 369

TSE infectivity, in blood, 371–373


for blood components, 374

for plasma products, 374–376

TSE infectivity removal, 375

TSE removal methods, 36, 151

TSE screening tests, 376

Tubular-bowl centrifuge designs, 167

Tubular bowl centrifuges, 167

Tubular centrifuges, 440

Tumor necrosis factor (TNF), 321

Turbidity monitoring, in centrifuge

design, 167

Turecek, Peter L., xii, 49

12–24 h plasma, 432

Type 1 diabetes, 238. See also Diabetes

Tzanck, Arnault, 11

Ultrafiltration, 234, 328



Ultrafiltration membranes, 442

Ultrasound, in HDFN treatment, 217, 218

Ultraviolet light inactivation, 36. See also

UV-irradiation

UMAN Complex D.I., 71

Uniplas, 346

UniProt, 322

United States. See also American entries;

Code of Federal Regulations (CFR);

Food and Drug Administration

(FDA); Government–company

relationships; National entries; U.S.

entries

AAT deficiency in, 228


immune globulin product sales in, 185

legal plasma-regulatory documents

in, 385

licensure requirements in, 405, 406

plasma collection/recovery in, 21, 423,

424

plasma manufacture in, 384

plasma standards in, 425

quality control systems in, 387

rare disorders in, 101

494 INDEX

United States Pharmacopoeia (USP)

Factor IX complex monograph, 87

Urokinase-type plasminogen activator

(uPA), 312

U.S.-based collection facilities, plasma

from, 423

U.S. collection centers, 21

US Food and Drug Administration

Amendments Act of 2007, 414

Utilities, 444

UV-irradiation, for virus

inactivation, 364. See also

Ultraviolet light inactivation

V.I. Technologies, Inc. (VITEX), 9,

345, 346

Vaccines, development of, 209

Vaccinia immune globulin (VIG), 212

Vaccinia virus (VACV), 347, 348

Vacuum-type blood collection unit, 9

Validation, 391–393, 429

of cleaning procedures, 394

Validation Master Plan (VMP),

392, 393

items included in, 393

Vapor heat treatment, 247, 443

Variant Creutzfeldt-Jakob disease (vCJD),

35, 65, 73, 347. See also vCJD

entries

albumin and, 177

epidemiology of, 369, 370, 371

precautionary measures against, 374

risk for developing, 372

Variant Creutzfeldt-Jakob disease

outbreak, 11

Vaschenko, Vladimir, xii, 337

Vascular cell adhesion molecule-1

(VCAM-1), 275, 278

Vasoactive mediators, 249

vCJD blood test, 376. See also Variant

Creutzfeldt-Jakob disease (vCJD)

vCJD exposure, reducing, 374

vCJD-infected blood components, risk of

transfusion transmission from, 373,

374

vCJD infectivity removal, 374

vCJD risks, 373, 374

reduction of, 374–376

vCJD spreading, controlling, 374

vCJD transmission, 349, 350

Vendor assessment, 399

Vendor contracts, 399

Venous/arterial thrombosis models, 265

Venous thromboembolism, risk of, 176

Venous thrombosis, 199

Very low-density lipoproteins (VLDLs),

284, 286

VIIISelect affinity matrix, 38

Viral clearance, in plasma fractionation,

440, 441

Viral “clearance” studies, 375

Viral contamination, of plasma-derived

coagulation products, 36

Viral diseases, transmission of, 151

Viral (virus) filtration, 35, 36, 328

for ATIII, 150

Viral inactivation/removal processes, 37


Viral (virus) inactivation/removal, 104,

142, 150, 187, 190, 214, 232, 235,

237, 247, 305, 362

by Factor XIII concentrate

pasteurization, 106

in fibrinogen preparations, 124

in Octaplas(LG) treatment

method, 347, 348, 349

in plasma fractionation, 442, 443

via precipitation, 191, 363

Virus removal procedures, 363, 364

Viral (virus) inactivation/removal

methods/procedures, 33–36, 65, 86,

141, 142, 364, 365

Viral inactivation/removal

technologies, 35, 36

Viral marker testing, 385

Viral safety, 86, 96

of blood products, 189, 190

Viral segregation, 444

Viral zones, 444

Viremic donations, excluding, 349

Viruses

artificial aggregation of, 191

blood-borne, 366

identification of, 65

nonenveloped, 190

novel, 65

Virus-inactivated ATIII concentrates, 152

Virus inactivation/removal

combination, 365

Virus inactivation reagents, in IVIG

preparations, 194

Virus marker testing, 176

Virus neutralization, 208

Virus reduction, 72, 361–366

Virus reduction methods, 189, 190

Virus reduction steps, in C1-inhibitor

manufacturing, 244

Virus reduction studies, 264

Virus removal steps, 363

Virus-safe plasma derivatives, production

of, 366

Virus safety, of plasma products, 361–368

Virus safety system, 363

Virus transmission, risk from, 176, 177

Virus validation studies, 362, 363

examples from, 364

Visual appearance, of IVIG preparations,

191, 192

Vitamin K, reduced, 81

Vitamin K antagonists (VKAs), 66, 73

INR and, 74

Vitamin K-dependent factors

function of, 68, 69

structure of, 68

Vitamin K-dependent proteins,


Vitamin K system, 68

Volume expansion, 172

Voluntary blood donation, 12

Voluntary plasma sources, 12

Voluntary viral marker standard, 426

von Behring, Emil, 207. See also

Behringwerke AG; CSL Behring

von Bonsdorff, Leni, xii, 301

von Willebrand, Erik, 41

von Willebrand antigen II, 41

von Willebrand disease (VWD), 41.

See also VWD entries

von Willebrand factor (VWF), 31, 32,

439. See also VWF entries

production and clinical profile of

human plasma-derived, 41–48

in recombinant FVIII preparations, 37

structure, synthesis, and function

of, 41–43

von Willebrand Factor deficiency, 41

VWD categories, 41. See also von

Willebrand disease (VWD)

VWD therapy, 43

VWD treatment products, 44

VWD types, 43

VWF concentrates. See also von

Willebrand factor (VWF)

high-purity, 44–46

plasma-derived, 43, 45

production of, 43–45

VWF deficiency (VWD), 43

VWF/FVIII complex, 42. See also

Factor VIII (FVIII)

VWF:FVIIIB binding, 43

VWF gene mutations, 41

VWF protein


coagulation FVIII interaction and,

42, 43

in hemostasis, 42

initial glycosylation of, 42

platelet adhesion and, 42

VWF purification

ion exchange chromatography in, 44, 45

size exclusion chromatography/gel

filtration in, 44

VWF replacement therapy, 41

VWF synthesis, 41

INDEX 495

Ward, Gordon R., 4

Warfarin reversal, 68

Water

albumin and, 161

fibrinogen and, 118

Watt, J. G., 11

Weibel–Palade bodies, 42

Welfide Corporation, 17, 18

West Nile virus (WNV), 363

White blood cells (WBC), depletion of,

374

WHO guidance document, 386. See also

World Health Organization (WHO)

Whole blood-derived plasma, 423, 424

Whole-blood transfusion, risks associated

with, 4

Wilate, 45

Wilfactin1, 45

Willfact1, 45

Wilson–Konovalov disease, 337, 338

Winnipeg process, 221

World Health Organization (WHO), 467.

See alsoWHO guidance document

Worldwide plasma market, 462

Wound healing, fibrinogen and, 117

Wouters, Diana, xii, 241

Zeerleder, Sacha, xii, 241

Zemaira1, 227, 231, 234

Zemaira purification process, 234,

236

Zentrallaboratorium, Blutspendedienst

SRK (ZLB), 11, 12

Zymogen Factor X activation, 107

Zymogens, 51–53, 59

496 INDEX

copyrighted materialindex aat-deﬁcient patients, 233, 237. see also alpha-1 antitrypsin (aat)...

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