14 Hemostasis Disorders Normal Hemostasis and Hemostasis Testing

Prevention of blood loss while maintaining maximal perfusion requires the interaction of the blood vessels, platelets, coagulation factors, and fibrinolytic agents.

Normal Hemostasis and Hemostasis Testing

Prevention of blood loss while maintaining maximal perfusion requires the interaction of the blood vessels, platelets, coagulation factors, and fibrinolytic agents.

Normal anticoagulation in small blood vessels Small blood vessels include capillaries, venules, arterioles.

1. Heparin-like molecules a. Enhance antithrombin III (ATIII) activity b. Neutralize serine protease coagulation factors

Factors XII, XI, IX, and X; prothrombin (factor II); and thrombin 2. Prostaglandin (PG) I2 (prostacyclin)

a. Synthesized by intact endothelial cells b. PGH2 is converted by prostacyclin synthase to PGI2. c. Vasodilator and inhibits platelet aggregation d. Aspirin does not inhibit synthesis of PGI2 by endothelial cells.

3. Protein C and S a. Vitamin K-dependent factors b. Inactivate factors V and VIII c. Enhance fibrinolysis

4. Tissue plasminogen activator (tPA) a. Synthesized by endothelial cells b. Activates plasminogen to release plasmin

c. Plasmin degrades coagulation factors and lyses fibrin clots (thrombi).

Procoagulants released in small vessel injury page 257

page 258Factor VIII:C is synthesized in the liver. When VIII:C is activated by thrombin, it dissociates from the VIII:vWF complex and performs its procoagulant function in the intrinsic coagulation cascade system.

1. Thromboxane A2 (TXA2) a. Synthesized by platelets

i. PGH2 is converted into TXA2 by thromboxane synthase. ii. Aspirin irreversibly inhibits platelet cyclooxygenase.

Prevents formation of PGH2, the precursor for TXA2

iii. Other nonsteroidal anti-inflammatory drugs reversibly inhibit platelet cyclooxygenase.

b. Functions of TXA2 in hemostasis

Vasoconstrictor, enhances platelet aggregation 22 Von Willebrand factor (vWF)

a. Synthesized by endothelial cells and megakaryocytes

i. Synthesized in Weibel-Palade bodies in endothelial cells ii. Platelets carry vWF in their α-granules.

b. Functions of vWF i. Platelet adhesion molecule

Binds platelets to exposed collagen Platelets have glycoprotein (Gp)Ib receptors for vWF.

ii. Complexes with factor VIII:C in the circulation VIII:vWF complexes prevent degradation of factor VIII:C

(procoagulant factor). Decrease in vWF secondarily decreases VIII:C activity.

2. Tissue thromboplastin (factor III)

c. Noncirculating ubiquitous substance

Released from injured tissue b. Activates factor VII in the extrinsic coagulation system

22 Extrinsic and intrinsic coagulation systems (see below)

Platelet structure and function page 258

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1. Derivation a. Cytoplasmic fragmentation of megakaryocytes b. Approximately 1000 to 3000 platelets are produced per megakaryocyte.

2. Locations a. Peripheral blood (live for ∼9-10 days) b. Approximately one third of the total platelet pool is stored in the spleen.

3. Platelet receptors a. Glycoprotein receptors for vWF are designated GpIb. b. Glycoprotein receptors for fibrinogen are designated GpIIb:IIIa.

i. Ticlopidine and clopidogrel Inhibit ADP-induced expression of platelet GpIIb:IIIa receptors Prevent fibrinogen binding and platelet aggregation

ii. Abciximab Monoclonal antibody that is directed against the GpIIb:IIIa receptor

4. Platelet factor 3 (PF3) a. Located on the platelet membrane b. Phospholipid substrate required for the clotting sequence

5. Platelet structure a. Contractile element

i. Called thrombosthenin

ii. Helps in clot retraction b. Dense bodies contain:

i. Adenosine diphosphate (ADP), an aggregating agent ii. Calcium, a binding agent for vitamin K-dependent factors

c. α-Granules contain: i. vWF, fibrinogen ii. Platelet factor 4 (PF4)

Heparin neutralizing factor 6. Platelet function

a. Fill gaps between endothelial cells in small vessels i. Prevents leakage of RBCs into the interstitium ii. Platelet dysfunction causes leakage of RBCs, producing petechia.

b. Formation of the hemostatic plug in small vessel injury c. Platelet-derived growth factor stimulates smooth muscle hyperplasia.

Important in the pathogenesis of atherosclerosis

Coagulation systempage 260

Warfarin is an anticoagulant that inhibits epoxide reductase, which prevents any further γ-carboxylation of the vitamin K-dependent coagulation factors. However, full anticoagulation does not immediately occur, because previously γ-carboxylated factors are still present. Prothrombin has the longest half-life; therefore, full anticoagulation requires at least 3 to 4 days before all functional prothrombin has disappeared. This explains why patients are initially placed on both heparin and warfarin, because heparin immediately anticoagulates the patient by enhancing ATIII activity.

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page 261When blood is drawn into a clot tube (no anticoagulant is added), a fibrin clot is formed. When the tube is spun down in a centrifuge, the supranate is called serum, which, unlike plasma, is missing fibrinogen, prothrombin (II), factor V, and factor VIII.

1. Coagulation cascade a. Extrinsic system (factor VII) b. Intrinsic system (factors XII, XI, IX, VIII)

2. Extrinsic system a. Factor VII is activated (factor VIIa) by tissue thromboplastin. b. Factor VIIa activates factor X in the final common pathway.

3. Intrinsic system a. Factor XII (Hageman factor) is activated by:

i. Exposed subendothelial collagen ii. High-molecular-weight kininogen (HMWK)

b. Functions of factor XIIa i. Activates factor XI ii. Activates plasminogen (produces plasmin) iii. Activates the kininogen system (produces kallikrein and bradykinin)

c. Factor XIa activates factor IX to form factor IXa i. Four-component complex is formed (IXa, VIII, platelet factor 3, calcium) ii. Complex activates factor X in the final common pathway.

iii. Calcium binds factor IXa, a vitamin K-dependent coagulation factor. 4. Final common pathway

a. Includes factors X, V, prothrombin (II), and fibrinogen (I) b. Prothrombin complex

i. Four-component system consisting of factor Xa, factor V, platelet factor 3, and calcium

ii. Calcium binds factor Xa, a vitamin K-dependent coagulation factor. iii. Complex cleaves prothrombin into thrombin (enzyme).

c. Functions of thrombin i. Acts on fibrinogen to produce fibrin monomers plus fibrinopeptides A and B ii. Activates fibrin stabilizing factor XIII

Factor XIIIa converts soluble fibrin monomers to insoluble fibrin. Enhances protein-protein cross-linking to strengthen the fibrin clot

iii. Activates VIII:C in the intrinsic system 5. Vitamin K-dependent factors

a. Factors II, VII, IX, X, protein C, and protein S b. Synthesized in the liver as nonfunctional precursor proteins c. Function of vitamin K

i. Vitamin K is activated in the liver by epoxide reductase. Majority of vitamin K is synthesized by colonic bacteria.

ii. Activated vitamin K γ-carboxylates each factor. Carboxylated factors can bind to calcium and PF3 in the cascade

sequence. 6. Certain coagulation factors are consumed in the formation of a fibrin clot.

o Consumed factors are fibrinogen (I), factor V, factor VIII, and prothrombin (II)

Fibrinolytic system 1. Activation

a. tPA activates plasminogen to release the enzyme plasmin. Alteplase and reteplase are recombinant forms of tPA used in thrombolytic

therapy. b. Other activators of plasminogen

2i Factor XIIa 2ii Streptokinase (derived from streptococci) 2iii Anistreplase (complex of streptokinase and plasminogen)

v2i Urokinase (derived from human urine) b. Aminocaproic acid

Competitively blocks plasminogen activation, thereby inhibiting fibrinolysis 22 Functions of plasmin

a. Cleaves insoluble fibrin monomers and fibrinogen into fibrin(ogen) degradation products (FDPs)

Fragments of cross-linked insoluble fibrin monomers are called D-dimers. b. Degrades factors V and VIII

c. α2-Antiplasmin (synthesized in the liver) inactivates plasmin.

Small vessel hemostasis response to injurypage 262

1. Sequence involves vascular, platelet, coagulation, and fibrinolytic phases. 2. Vascular phase

a. Transient vasoconstriction occurs directly after injury. b. Factor VII (extrinsic system) is activated by tissue thromboplastin. c. Exposed collagen activates factor XII (intrinsic system).

3. Platelet phase a. Platelet adhesion

Platelet GpIb receptors adhere to exposed vWF in damaged endothelial cells.

b. Platelet release reaction Release of adenosine diphosphate (ADP) causes platelet aggregation in

the lumens of injured vessels. c. Platelet synthesis and release of TXA2

2i Vessels constrict (reduce blood flow). 2ii Platelet aggregation is further enhanced.

b. Temporary platelet plug stops bleeding. 2i Aggregated platelets have fibrinogen attached to their GpIIb-IIIa receptors. 2ii It is an unstable plug that can easily be dislodged.

2. Coagulation phase a. Thrombin is produced by localized activation of the coagulation cascade.

Occurs in the vascular phase b. Fibrinogen attached to GpIIb/IIIa receptors is converted to insoluble fibrin

monomers. c. Stable platelet plug is formed.

22 Fibrinolytic phase a. Plasmin cleaves the insoluble fibrin monomers holding the platelet plug together.

b. Blood flow is reestablished.

Platelet tests

Table 14-1. Causes of Prolonged Bleeding TimeCause Nature of Defect CommentsAspirin or NSAIDs Platelet aggregation defect

Inhibition of platelet COX, which ultimately inhibits synthesis of TXA2

Normal platelet count

Bernard-Soulier syndrome

Platelet adhesion defectAutosomal recessive diseaseAbsent GpIb platelet receptors for vWF

Thrombocytopenia, giant plateletsLifelong bleeding problem

Glanzmann's disease Platelet aggregation defectAutosomal recessive diseaseAbsent GpIIb-IIIa fibrinogen receptorsAbsent thrombosthenin

Lifelong bleeding problem

Renal failure Platelet aggregation defectInhibition of platelet phospholipid by toxic products

Reversed with dialysis and desmopressin acetate

Scurvy Vascular defectCaused by vitamin C deficiency

May cause ecchymoses and hemarthroses

Defective collagen resulting from poor cross-linking

Thrombocytopenia Decreased platelet number Increased bleeding time when platelet count <90,000 cells/μL

Von Willebrand disease

Platelet adhesion defectAutosomal dominant disorderAbsent or defective vWFDecreased VIII:C

Combined platelet and coagulation factor disorder

COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; TXA2, thromboxane A2; vWF, von Willebrand factor. page 262

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1. Platelet count a. Normal count is 150,000 to 400,000 cells/μL. b. A normal count does not guarantee normal platelet function.

2. Bleeding time a. Evaluates platelet function up to the formation of the temporary platelet plug

Normal reference interval is 2 to 7 minutes. b. Disorders causing a prolonged bleeding time are listed in

3. Platelet aggregation test a. Evaluates platelet aggregation in response to aggregating reagents b. Aggregating agents include ADP, epinephrine, collagen, and ristocetin.

4. Tests for vWF a. Ristocetin cofactor assay

2i Evaluates vWF function 2ii Abnormal assay

Classic von Willebrand disease (deficiency of vWF) Bernard-Soulier disease (absent GpIb receptor)

b. vWF antigen assay 2i Measures the quantity of vWF regardless of function

2ii Decreased in classic von Willebrand disease

Coagulation testspage 264

Whether the patient is anticoagulated with heparin or warfarin, both the PT and PTT are prolonged, because both inhibit factors in the final common pathway. Experience has shown that the PT performs better in monitoring warfarin, while the PTT performs better in monitoring heparin.

1. Prothrombin time (PT) a. Evaluates the extrinsic system down to formation of the fibrin clot

Factors evaluated include VII, X, V, II, and I b. Normal reference interval for PT is 11 to 15 seconds.

Only prolonged when a factor level is 30% to 40% of normal c. International normalized ratio (INR)

2i Standardizes the PT for use in warfarin therapy 2ii Results are the same regardless of the reagents used to perform the test.

b. Uses of PT

2i Follow patients who are taking warfarin for anticoagulation 2ii Evaluate liver synthetic function

Increased PT indicates severe liver dysfunction. 2iii Detect factor VII deficiency

2. Partial thromboplastin time (PTT) a. Evaluates the intrinsic system down to formation of a fibrin clot

Factors evaluated include XII, XI, IX, VIII, X, V, II, and I. b. Normal reference interval for PTT is 25 to 40 seconds.

Only prolonged when a factor level is 30% to 40% of normal c. Uses of PTT

2i Follow heparin therapy Heparin enhances ATIII activity. PTT is not required to follow low-molecular-weight heparin therapy.

2ii Detect factor deficiencies in the intrinsic system

Fibrinolytic system tests page 264

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1. Fibrin(ogen) degradation products (FDPs) o Detects fragments associated with plasmin degradation of fibrinogen or insoluble

fibrin in fibrin clots 2. D-Dimer assay

a. Only detects cross-linked insoluble fibrin monomers in a fibrin clot b. Does not detect fibrinogen degradation products (not cross-linked) c. Most specific test for evidence of degradation of a fibrin clot (thrombus); examples:

i. Thrombolytic therapy for coronary artery thrombosis Thrombus is composed of platelets held together by fibrin

ii. Screening test for pulmonary thromboembolism Thrombus is composed of RBCs, platelets, white blood cells

(WBCs) held together by fibrin iii. Screening test for disseminated intravascular coagulation (DIC)

Thrombus is composed of RBCs, platelets, and WBCs held together by fibrin (see Section III).

Platelet Disorders Classification of platelet disorders

1. Quantitative platelet disorders a. Thrombocytopenia b. Thrombocytosis

2. Qualitative (functional) platelet disorders

Classification of platelet disorders 1. Quantitative platelet disorders

a. Thrombocytopenia b. Thrombocytosis

2. Qualitative (functional) platelet disorders

Pathogenesis

Table 14-2. Disorders Producing ThrombocytopeniaDisorder Pathogenesis CommentsAcute idiopathic thrombocytopenic purpura (ITP)

IgG antibodies directed against GpIIb:IIIa receptors (type II hypersensitivity reaction)Macrophages phagocytose platelets

Most common childhood cause of thrombocytopeniaAbrupt onset after an upper respiratory tract infectionAbsence of lymphadenopathy and splenomegalyResponds to corticosteroids

Chronic idiopathic thrombocytopenic purpura

IgG antibodies directed against GpIIb:IIIa receptors (type II hypersensitivity reaction)

Most common cause of thrombocytopenia in adultsNewborn infants may have transient thrombocytopenia due to transplacental passage of IgG antibodiesSecondary causes: SLE, HIV

Heparin-induced thrombocytopenia

Type II variant: macrophage removal of platelets surfaced by IgG antibody directed against heparin attached to PF4 (type II hypersensitivity)

Occurs 5-14 days after heparin treatmentMust discontinue heparinRelease of PF4 after platelet destruction may cause vessel thrombosis

HIV thrombocytopenia Similar to ITP Most common hematologic abnormality in HIV (not AIDS-defining condition)

Thrombotic thrombocytopenic purpura (TTP)

Acquired or genetic deficiency in vWF-cleaving metalloprotease in endothelial cellsExcess of vWF increases platelet adhesion to areas of endothelial injury at arteriole-capillary junctionsPlatelets consumed in the formation of thrombi causes thrombocytopeniaEnhanced by factors that damage endothelial cells (e.g., ticlopidine, hypertension)

Occurs in adult femalesClinical pentad: fever, thrombocytopenia, renal failure, microangiopathic hemolytic anemia with schistocytes (damage by platelet thrombi), CNS deficitsTreated with plasmapheresisMortality rate is 10-20%

Hemolytic uremic syndrome (HUS)

Endothelial damage at arteriole-capillary junction caused by Shiga-like toxin of 0157:H7 serotype of Escherichia coliOrganisms proliferate in undercooked beef

Primarily occurs in childrenClinical findings similar to TTPCNS findings are less frequentMortality rate 3-5%

CNS, central nervous system; DIC, disseminated intravascular coagulation; PF4, platelet factor 4; SLE, systemic lupus erythematosus; vWF, von Willebrand factor.

1. Thrombocytopenia

o Decreased number of platelets

a. Decreased production Examples-aplastic anemia, leukemia

b. Increased destruction

2i Immune Examples-idiopathic thrombocytopenic purpura, drugs

2ii Nonimmune Examples-thrombotic thrombocytopenic purpura, DIC

b. Sequestration in the spleen

Hypersplenism in portal hypertension 2. Thrombocytosis

o Increased platelet count o Primary thrombocytosis

Examples-essential thrombocythemia, polycythemia vera o Secondary (reactive) thrombocytosis

Examples-chronic iron deficiency, infections, splenectomy, malignancy 2. Qualitative platelet disorders

o Acquired (e.g., aspirin) or hereditary (e.g., Glanzmann's disease)

Clinical findings associated with platelet dysfunctionEcchymoses (purpura) can be caused by a variety of disorders unrelated to platelet dysfunction. Palpable purpura (purpura that can be felt) is a sign of a small vessel vasculitis . Because vasculitis is a type of acute inflammation, the lesions are palpable due to increased vessel permeability and not a platelet disorder. Senile purpura is a normal finding in elderly patients and is due to vessel instability . Ecchymoses develop in areas of trauma (e.g., back of the hands, shins).

1. Epistaxis (nosebleeds) is the most common symptom. 2. Petechia and multiple small ecchymoses (purpura)

a. Petechia are pinpoint areas of hemorrhage in subcutaneous tissue . RBCs leak through gaps in the endothelium of venules and capillaries.

b. Ecchymoses are the size of a quarter. 3. Bleeding from superficial scratches

o No temporary platelet plug is present to stop bleeding from injury to small vessels. 2. Other findings

a. Menorrhagia, hematuria b. Bleeding from tooth extraction sites c. Gastrointestinal and intracranial bleeding

Coagulation Disorders Classification of coagulation disorders

1. Acquired o Single or multiple coagulation factor deficiencies

2. Hereditary

o Usually a single coagulation factor deficiency

Classification of coagulation disorders 1. Acquired

o Single or multiple coagulation factor deficiencies 2. Hereditary

o Usually a single coagulation factor deficiency

Pathogenesis page 267

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1. Decreased production o Examples-hemophilia A, cirrhosis

2. Pathologic inhibition o Example-acquired circulating antibodies (inhibitors) against coagulation factors

3. Excessive consumption

o Example-disseminated intravascular coagulation

Clinical findings in coagulation disorders 1. Late rebleeding after surgery or wisdom tooth extraction

a. Temporary platelet plug is the only mechanical block preventing bleeding. b. Lack of thrombin prevents formation of a stable platelet plug held together by fibrin.

2. Findings in severe factor deficiencies a. Hemarthroses b. Retroperitoneal and deep muscular bleeding

3. Findings similar to platelet disorders a. Ecchymoses, epistaxis b. Menorrhagia, hematuria c. Bleeding from tooth extraction sites

d. Gastrointestinal and intracranial bleeding

Hemophilia A page 268

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Hemophilia B (Christmas disease) is an X-linked recessive disorder involving a deficiency of factor IX. It is clinically indistinguishable from hemophilia A.

1. Epidemiology a. X-linked recessive

i. Females are asymptomatic carriers. ii. Females transmit the abnormal X chromosome to 50% of their sons.

b. Absent family history of hemophilia

Most likely due to a new mutation (30% of cases) b. Female carriers with symptomatic disease

i. Due to inactivation of more maternal than paternal X chromosomes ii. Females become "homozygous" for the abnormal X chromosome

2. Pathogenesis

o Decreased synthesis of factor VIII:C in the intrinsic system 2. Clinical findings in hemophilia A

a. Signs and symptoms correlate with the level of factor VIII:C activity i. Activity below 1% correlates with severe disease (e.g., spontaneous

hemarthroses). b. Bleeding problems may occur in newborns (10-15% of cases).

i. Excessive bleeding may occur after circumcision or umbilical cord separation.

c. Laboratory findings in hemophilia A i. Increased PTT and a normal PT ii. Decreased factor VIII:C activity iii. Decreased factor VIII:antigen (VIII:Ag)

Factor VIII protein iv. Detection of female carriers

DNA techniques are most sensitive. 2. Treatment of hemophilia A

a. Mild cases respond to desmopressin acetate i. Increases VIII:C activity

b. Severe cases require infusion of recombinant factor VIII

i. No risk for HIV

Classic von Willebrand disease (vWD) 1. Epidemiology

a. Autosomal dominant disorder b. Most common hereditary coagulation disorder

2. Pathogenesis

o Decreased vWF and factor VIII:C activity 2. Clinical findings in vWD

a. Menorrhagia, epistaxis, easy bruisability b. Association with angiodysplasia of the right colon

3. Laboratory findings in vWD

c. Increased PTT and a normal PT d. Increased bleeding time

Due a platelet adhesion defect e. Abnormal ristocetin cofactor assay f. Decreased vWF antigen g. Decreased VIII:Ag and VIII:C activity

4. Treatment of vWD

h. Desmopressin acetate (increases vWF and VIII:C activity)

i. Oral contraceptive (estrogen has a similar action as desmopressin)

Circulating anticoagulants (inhibitors) 1. Pathogenesis

a. Coagulation factor is destroyed by antibodies. b. Most common type is antibodies against factor VIII:C (e.g., post-partum).

2. Clinical findings

o Similar to those with coagulation factor deficiencies due to decreased production 2. Laboratory findings

a. Prolonged PT and/or PTT, depending on the factor deficiency Does not differentiate immune destruction versus decreased production

b. Mixing studies Normal plasma is mixed with patient plasma in a test tube.

2i No correction of PT and/or PTT indicates immune destruction.

2ii Correction of PT and/or PTT indicates decreased production.

Vitamin K deficiency page 270

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1. Function of vitamin K o γ-Carboxylates vitamin K-dependent factors II, VII, IX, X and proteins C and S

2. Causes of vitamin K deficiency

a. Decreased synthesis of vitamin K by colonic bacteria i. Newborns lack bacterial colonization of the bowel.

Vitamin K levels normally decrease between days 2 and 5. Danger of severe bleeding (e.g., intracerebral hemorrhage)

Newborns require an intramuscular injection of vitamin K at birth. Breast milk contains very little vitamin K.

ii. Prolonged treatment with antibiotics Antibiotics sterilize the bowel causing decreased production of

vitamin K. Most common cause of vitamin K deficiency in a hospitalized

patient b. Decreased small bowel reabsorption of vitamin K

i. Malabsorption of fat causes malabsorption of fat-soluble vitamins. ii. Example-celiac disease

c. Decreased activation of vitamin K by epoxide reductase in the liver i. Warfarin inhibits epoxide reductase.

Vitamin K-dependent factors are nonfunctional. Rat poison contains warfarin. Children may have exposure to warfarin from elders living in the

household. ii. Cirrhosis

Decreased activation of vitamin K and synthesis of vitamin K-dependent coagulation factors

Prolonged PT is not corrected with intramuscular injection of vitamin K.

2. Clinical findings of vitamin K deficiency a. Gastrointestinal bleeding b. Bleeding into subcutaneous tissue c. Bleeding at the time of circumcision d. Intracranial hemorrhage

3. Treatment of vitamin K deficiency a. If bleeding is not severe, treatment is an intramuscular injection of vitamin K.

Corrects bleeding in a few hours 2b If bleeding is severe, treatment is with fresh frozen plasma.

i. Immediate correction

ii. Vitamin K-dependent factors are γ-carboxylated.

Hemostasis disorders in liver disease 1. Pathogenesis

a. Decreased synthesis of coagulation factors i. Multiple coagulation factor deficiencies ii. Decreased γ-carboxylation of vitamin K-dependent factors

b. Decreased synthesis of anticoagulants

Examples-ATIII, proteins C and S b. Decreased synthesis of fibrinolytic agents (e.g., plasminogen) c. Decreased clearance of FDPs and D-dimers

Interfere with platelet aggregation and polymerization of fibrin d. Decreased clearance of tPA and decreased synthesis of α2-antiplasmin

May produce primary fibrinolysis (see section IV) 22 Laboratory findings in liver disease

a. Increased PT and PTT

b. Increased FDPs and D-dimers

c. Increased bleeding time

Disseminated intravascular coagulation (DIC) page 271

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1. Causes of DIC a. Sepsis

Common pathogens include E. coli (most common) and Neisseria meningitidis

b. Disseminated malignancy

2i Acute promyelocytic leukemia 2ii Pancreatic cancer with release of procoagulants in mucin

b. Other causes

Crush injuries, rattlesnake envenomation, amniotic fluid embolism 22 Pathogenesis

a. Activation of the coagulation cascade Due to release of tissue thromboplastin and/or endothelial cell injury

b. Fibrin thrombi develop in the microcirculation.

2i Thrombi obstruct blood flow. 2ii Thrombi consume coagulation factors (I, II, V, VIII) and trap platelets.

b. Activation of the fibrinolytic system

Secondary fibrinolysis due to activation of plasminogen by factor XII 22 Clinical findings in DIC

a. Thrombohemorrhagic disorder

2i Ischemia from occlusive fibrin thrombi 2ii Bleeding from anticoagulation

Factors I, II, V, and VIII are consumed in the fibrin thrombi c. Shock due to blood loss d. Diffuse oozing of blood from all breaks in the skin and mucous membranes e. Petechiae and ecchymoses

2. Laboratory findings in DIC a. Coagulation abnormalities

2i Increased PT and PTT 2ii Decreased fibrinogen

b. Platelet abnormalities 2i Thrombocytopenia 2ii Increased bleeding time

c. Fibrinolysis abnormalities

Presence of FDPs and D-dimers b. Normocytic anemia with schistocytes and reticulocytosis

RBCs are damaged by fibrin thrombi (microangiopathic hemolytic anemia).

22 Treatment a. Treating the underlying disease is most important. b. Transfuse blood components

2i Fresh frozen plasma for multiple coagulation factor deficiencies 2ii Packed RBCs for anemia

2iii Platelet concentrates for thrombocytopenia

Fibrinolytic Disorders Primary fibrinolysis

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1. Causes a. Open heart surgery

Cardiopulmonary bypass causes a decrease in α2-antiplasmin and increase in tPA.

b. Radical prostatectomy Causes increased release of urokinase

c. Diffuse liver disease Causes a decrease in the synthesis of α2-antiplasmin

2. Pathogenesis a. FDPs interfere with platelet aggregation. b. Plasmin degrades coagulation factors causing multiple factor deficiencies.

3. Clinical findings

o Severe bleeding 2. Laboratory findings

a. Increased PT and PTT Due to multiple factor deficiencies

b. Increased bleeding time Due to interference with platelet aggregation

c. Positive test for FDPs d. Negative D-dimer assay

No fibrin thrombi are present.

e. Normal platelet count

Primary fibrinolysis page 272

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1. Causes a. Open heart surgery

Cardiopulmonary bypass causes a decrease in α2-antiplasmin and increase in tPA.

b. Radical prostatectomy Causes increased release of urokinase

c. Diffuse liver disease Causes a decrease in the synthesis of α2-antiplasmin

2. Pathogenesis a. FDPs interfere with platelet aggregation. b. Plasmin degrades coagulation factors causing multiple factor deficiencies.

3. Clinical findings

o Severe bleeding 2. Laboratory findings

a. Increased PT and PTT Due to multiple factor deficiencies

b. Increased bleeding time Due to interference with platelet aggregation

c. Positive test for FDPs d. Negative D-dimer assay

No fibrin thrombi are present.

e. Normal platelet count

Secondary fibrinolysis 1. Compensatory reaction in the presence of intravascular coagulation

2. Increase in both FDPs and D-dimers

Summary of Laboratory Test Results in Hemostasis Disorders

Table 14-3. Laboratory Findings in Common Hemostasis DisordersDisorder or Condition Platelet Count Bleeding Time PT PTTThrombocytopenia ITP, TTP, HUS ↓ ↑ Normal NormalVon Willebrand disease Normal ↑ Normal ↑Hemophilia A Normal Normal Normal ↑DIC ↓ ↑ ↑ ↑Primary fibrinolysis Normal ↑ ↑ ↑Aspirin or NSAID use Normal ↑ Normal NormalWarfarin or heparin use Normal Normal ↑ ↑

DIC, disseminated intravascular coagulation; HUS; hemolytic uremic syndrome; ITP, idiopathic thrombocytopenic purpura; NSAID, nonsteroidal antiinflammatory drug; PT, prothrombin time; PTT, partial thromboplastin time; TTP, thrombotic thrombocytopenic purpura.

Thrombosis Syndromes Acquired thrombosis syndromes

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1. Antiphospholipid syndrome (APLS) a. Epidemiology

Associations include SLE and HIV b. Pathogenesis

2i Presence of antiphospholipid antibodies (APAs) Directed against phospholipids bound to plasma proteins

2ii APAs include anticardiolipin antibody and lupus anticoagulant. Anticardiolipin antibody reacts with the cardiolipin reagent in the

rapid plasma reagin test for syphilis. b. Clinical findings in APLS

2i Produce arterial and venous thrombosis syndromes 2ii Repeated abortions due to thrombosis of placental bed vessels 2iii Strokes, thromboembolism

2. Other acquired causes of thrombosis a. Postoperative state with stasis of blood flow b. Malignancy

2i Increase in coagulation factors 2ii Thrombocytosis 2iii Release of procoagulants from tumors, particularly pancreatic cancers

c. Folate or vitamin B12 deficiency

Due to increased plasma homocysteine levels b. Oral contraceptives

Estrogen increases the synthesis of coagulation factors and decreases ATIII

c. Hyperviscosity

2i Polycythemia syndromes

2ii Waldenström's macroglobulinemia

Acquired thrombosis syndromes page 273

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1. Antiphospholipid syndrome (APLS) a. Epidemiology

Associations include SLE and HIV b. Pathogenesis

2i Presence of antiphospholipid antibodies (APAs) Directed against phospholipids bound to plasma proteins

2ii APAs include anticardiolipin antibody and lupus anticoagulant. Anticardiolipin antibody reacts with the cardiolipin reagent in the

rapid plasma reagin test for syphilis.

b. Clinical findings in APLS 2i Produce arterial and venous thrombosis syndromes 2ii Repeated abortions due to thrombosis of placental bed vessels 2iii Strokes, thromboembolism

2. Other acquired causes of thrombosis a. Postoperative state with stasis of blood flow b. Malignancy

2i Increase in coagulation factors 2ii Thrombocytosis 2iii Release of procoagulants from tumors, particularly pancreatic cancers

c. Folate or vitamin B12 deficiency

Due to increased plasma homocysteine levels b. Oral contraceptives

Estrogen increases the synthesis of coagulation factors and decreases ATIII

c. Hyperviscosity

2i Polycythemia syndromes

2ii Waldenström's macroglobulinemia

Hereditary thrombosis syndromes There is a potential for heterozygote carriers of protein C deficiency to develop hemorrhagic skin necrosis when placed on warfarin. Heterozygote carriers have ∼50% protein C activity. Protein C has a short half-life (∼6 hours). When patients are placed on warfarin, protein C activity falls to zero activity in 6 hours, causing a hypercoagulable state due to increased activity of factors V and VIII. This causes cutaneous vessel thrombosis and concomitant skin necrosis.

1. Epidemiology a. Autosomal dominant syndromes b. Deep venous thrombosis and pulmonary emboli occur at an early age. c. Venous thromboses often occur in unusual places.

Examples-hepatic vein, dural sinus 2. Factor VLeiden

a. Most common hereditary thrombosis syndrome. b. Mutant form of factor V cannot be degraded by protein C and protein S.

3. Antithrombin III (ATIII) deficiency a. Functions of ATIII

2i Activity is enhanced by heparin. 2ii Neutralizes serine proteases (e.g., factors XII, XI, IX, X, II, thrombin)

b. No prolongation of PTT after injecting a standard dose of heparin c. Treatment

2i Infuse a greater dose of heparin than normal PTT eventually increases due to enhancement of whatever ATIII is

present. 2ii Send the patient home on warfarin.

2. Proteins C and S deficiency

a. Pathogenesis

Cannot inactivate factors V and VIII b. Treatment

2i Begin with heparin and a very low dose of warfarin to reduce the risk for developing hemorrhagic skin necrosis.

2ii Send the patient home on warfarin.