Understanding Heparin-Induced Thrombocytopenia (HIT):

Historical and Clinical Perspectives

Heparin-Induced Thrombocytopenia

• Heparin is a widely used anticoagulant drug for the treatment and prevention of thromboembolic disorders

• Heparin may cause immune thrombocytopenia (a reduction in platelet count), or HIT

• HIT can cause life- or limb-threatening thromboses

Clinical Conditions/Causes of Thrombocytopenia

• Increased platelet destruction– Non-immune

• Septicemia/Inflammation• Disseminated intravascular coagulation• Thrombotic thrombocytopenic purpura

– Immune• Autoimmune: idiopathic or secondary immune

thrombocytopenia• Alloimmune: post-transfusion purpura• Drug-induced: prothrombic (heparin), prohemorrhagic

(quinine, quinidine, gold, sulfa antibiotics, rifampin, vancomycin, NSAIDs, many others)

Clinical Conditions/Causes of Thrombocytopenia (cont.)

• Decreased platelet production– Alcohol, cytotoxic drugs– Aplastic anemia– Leukemia, myelodysplasia– Metastatic invasion of marrow– Certain infections

• Hypersplenism

• Hemodilution (infusion of blood products, colloids, or crystalloids)

Terminology Relating to HIT

• Heparin-induced thrombocytopenia (HIT) – Also known as HIT type II, white clot syndrome, and

heparin-associated thrombocytopenia (HAT)– Denotes demonstrable role of heparin in “inducing”

thrombocytopenia (ie, heparin-dependent antibodies are detectable)

• Non-immune heparin-associated thrombocytopenia (non-immune HAT) – Also known as HIT type I, HAT– Denotes absence of heparin-dependent antibodies and

the potential role for other factors in causing thrombocytopenia

Frequency of HIT

• Related to heparin source– Bovine lung: 1.9% to 30.8%*– Porcine intestine: 1.3% to 8%*– Full-dose IV heparin: 0% to 30%*

• Prospective studies (P) and review of literature (R) for HIT– (R) Warkentin and Kelton, 1994: 3.4%– (P) Warkentin et al, 1995: 2.7% (unfractionated; <1% LMW)– (R) Schmitt, 1993; Schulman, 1997: 1.1% to 2.9%

*Some high rates are from studies that included patients with non-immune HAT.

Incidence of HIT and HIT Thrombosis: Prospective Studies of IV Therapeutic-

Dose Heparin

From Warkentin TE, Kelton JG. In: Bounameaux H, ed. Low-Molecular-Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases. Fundamental and Clinical Cardiology. New York: Marcel Dekker, Inc; 1994:75–127. * Some information obtained by personal communication.

No. ofPatients

Early (4 days)thrombo-cytopenia

Late (5 days)thrombo-cytopenia

ThrombosisArterial Venous

Ansell, 1980 43 1 4 0 0Ansell, 1985 104 5 5 0 0Bailey, 1986 43 0 1 1 0Ramirez-Lassepas, 1984*; Cipolle, 1983*

211 2 9 2 1

Gallus, 1980 143 4 5 0 1Green, 1984, 1986 89 0 2 1 1Holm, 1980 90 0 1 0 0Kakkasseril, 1985 142 -- 9 2 2Monreal, 1989 89 -- 2 0 1Nelson, 1978 37 6 3 0 0Powers, 1979* 120 2 2 1 1Powers, 1984 131 2 3 0 0Rao, 1989 94 3 3 0 0Total 1,336 24 (1.8%) 46 (3.4%) 7 7

Differences Between HIT and Non-Immune HAT

Non-Immune HAT HIT

Onset Within 4 days Usually 5–14 days (may besooner)

Platelet count Typically 100,000–150,000/L Typically 20,000–150,000/L

median nadir ~ 50,000/L inmost series; rarely <20,000/L

sometimes falls >30%, butremains >150,000/L

Complications None Thromboembolic lesions

Incidence 5%–30% 1% at 1 week; 3% at 2 weeks

Recovery 1–3 days 5–7 days

Cause Benign, tiny plateletaggregates

IgG-mediated strong plateletactivation

Thromboembolic Disorders Associated

With HIT: Consequences• Venous thrombosis: DVT; venous limb gangrene;

pulmonary embolism; cerebral sinus thrombosis

• Arterial thrombosis: Limb gangrene; cerebrovascular accident; MI; miscellaneous end-organ thromboses

• Other complications: Adrenal hemorrhagic infarction; heparin-induced skin lesions (at injection sites); acute systemic reactions (post IV heparin bolus); disseminated intravascular coagulation

Skin Necrosis

Used with permission from Warkentin TE. Br J Haematol. 1996;92:494–497.

Acute Systemic Reactions Caused by

IV Heparin Bolus• The following can occur in patients sensitized

to heparin within 5–30 minutes:– Fever, chills– Tachycardia, hypertension– Flushing, headache– Chest pain, dyspnea– Nausea, vomiting, large-volume diarrhea– Sudden “anaphylactoid” death– Transient global amnesia

Molecular Structure of Heparin

Member of heterogeneous family of glycosaminoglycans; MW=3,000–30,000 daltons

Adapted with permission from Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 1998:3044.

O

COO

O

OH OH

O

OH

OO

OSO3

O

HO

OH

OH

HO

OH

HO

NHAc

OH

CH2OH

HO

OH

OH

(1) (2) (3) (4) (5)

CH2OSO3

NHSO3

OH

COO

COO

OH

Action of Heparin

• Primary action – Binds to antithrombin (cofactor)– After binding, increases antithrombin’s inhibition of

thrombin (factor IIa) and factors IXa, Xa, XIa, XIIa, and kallikrein

• Limited anticoagulant action– Prevents additional thrombus accretion– Unable to dissolve an existing thrombus directly

Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

Pathophysiology of HIT and Thrombosis

13

4

Glycosaminoglycan molecule

Platelets

7

2

5

6

Heparin PF4

Pathophysiology of HIT and Thrombosis (cont.)

Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

4

7

5

6

PF4

3

Glycosaminoglycan molecule

Platelets

Heparin

1

2

Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

Pathophysiology of HIT and Thrombosis (cont.)

7

PF4

3

Glycosaminoglycan moleculeHeparin

1

2

5

6

Platelets

4

Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

Pathophysiology of HIT and Thrombosis (cont.)

13

4

Glycosaminoglycan molecule

Platelets

2

5

6

Heparin PF4

7

Fourteen-Year Study of HIT

• Study design: Retrospective cohort study

• Population: 127 patients with serologically confirmed HIT in one medical community– Group I (n=65): HIT diagnosed after appearance of new

thrombosis– Group II (n=62): Initial diagnosis of isolated HIT (ie, no

new thrombosis at time of diagnosis)

• Reason for hospitalizations– Surgical: approximately 2/3 (mostly orthopedic)– Medical: approximately 1/3 (DVT or PE)

Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

Fourteen-Year Study of HIT:Group II Results After Heparin Discontinuation

Cu

mu

lati

ve T

hro

mb

oti

c E

ven

t R

ate

(%

)

Days After Isolated HIT Recognized

Adapted with permission from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

100

90

80

70

60

50

40

30

20

10

0

52.8%

0 2 4 6 10 12 14 168 18 22 26 28 302420

Fourteen-Year Study of HIT: Summary

• Relatively conservative, conventional management of patients with isolated HIT (ie, discontinuation of heparin with or without substitution with warfarin)

• Conservative treatment approaches can result in unacceptably high rates (~50%) of subsequent thrombosis

• Additional clinical studies needed to show whether more aggressive treatments using alternative anticoagulants would be useful for this patient population

Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

Diagnosis of HIT

• Normal platelet count before commencement of heparin therapy

• Onset of thrombocytopenia typically 5–14 days after initiation of heparin therapy but can occur earlier

• Exclusion of other causes of thrombocytopenia (eg, sepsis)

• Occurrence of thromboembolic complications during heparin therapy

Diagnosis Based on Time of OnsetN

um

ber

of

Pat

ien

ts

Adapted with permission from King DJ, Kelton JG. Ann Intern Med. 1984;100:536–540.

Day of Treatment

First Exposureto Heparin

Subsequent Exposureto Heparin

Thrombocytopenia

Thrombocytopenia

Thrombosis

Thrombosis

0

15

10

5

2 4 6 8 10 12 14 16 18 20 2 4 6 8 10Day of Treatment

Diagnosis: Platelet Aggregation Assay

• Measures platelet aggregation of IgG in serum or plasma of a HIT patient treated with heparin

• Donor platelets can be washed or suspended in citrated plasma

• Advantages– Easily performed in most laboratories – Specificity greater than 90%

• Disadvantages– Low sensitivity: 35%–81%; sensitivity higher using washed

platelets– Reactivity varies among donor platelets

Diagnosis: Serotonin Release Assay

• Measures the release of serotonin from aggregated platelets in serum of patient with HIT; relies on platelet aggregation in the presence of heparin

• Advantages – High specificity and sensitivity– Validated in blinded assessment of a clinical trial

• Disadvantages – Technically demanding and time-consuming– Requires the use of radioactive materials– Not widely available

Relationship Between Release of 14C-Serotoninand Final Concentration of Heparin in HIT Patients

Adapted with permission from Sheridan D, Carter C, Kelton JG. Blood. 1986;67:27–30.

% 14

C-S

ero

ton

in R

elea

se

Heparin Concentration (µ/mL)

123

4

100

80

60

40

20

00.0010 0.01 0.1 1 10 100 1000

Diagnosis: Heparin/PF4 ELISA

Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

Relative Sensitivity in 12 Patients with HIT

Positive Reactions, n

Assay Undiluted 1:10 1:100 1:200 1:500

SerotoninRelease

12 12 2 NotTested

NotTested

ELISA 12 12 12 12 9

Prevention of HIT

• Obtain medical history regarding previous sensitization to heparin; earlier monitoring may be required if patient previously received heparin

• Limit heparin duration whenever possible to <5 days

• Avoid heparin flushes

• Use warfarin early to minimize the length of heparin administration in patients requiring longer-term anticoagulation, except when HIT is diagnosed

• Routinely initiate oral anticoagulation at start of heparin therapy in patients who need longer-term oral anticoagulation

• Use LMWH if possible

Prevention of Thrombotic Complications of HIT

• When HIT is recognized, promptly discontinue use of heparin

• Avoid warfarin unless there is adequate anticoagulant control with a drug such as danaparoid sodium or recombinant hirudin

• Monitor platelet count throughout hospitalization

• Use alternative antithrombotic therapy, such as danaparoid sodium or recombinant hirudin, for patients with HIT and thrombosis

Incidence of Complications and Mortality of HIT

Year

No. of

M F

Age (year Complications Mortality

Patients range or SD) n (%) n (%)

1983 62 34 28 19-93 38 (61.0) 14 (23.0)

1986 169 97 72 2-94 38 (22.5) 20 (12.0)

1996* 127 60 67 67.0 +/- 11.4 99 (78.0) 26 (20.5)

1996†62 33 29 66.7 +/- 12.3 32 (51.6) 13 (21.0)

*Includes patients initially presenting with thrombosis†Subgroup of the 127 patients presenting with thrombosis From Laster J, Cikrit D, Walker N, Silver D. Surgery. 1987;102:763-770 and Warkentin TE, Kelton JG. Am J Med. 1996;101;502–507.

Treatment of Non-Immune HAT

• Heparin should be continued if still indicated

• Patients with non-immune HAT are asymptomatic; platelet counts should return to normal during continuation of heparin therapy

• No additional risk of thrombosis

Note: It may sometimes be difficult to distinguish between immune HIT and non-immune HAT on clinical grounds alone

Treatment of Suspected HIT

• Discontinue all heparin immediately, including– Heparin flushes– Heparin-coated pulmonary catheters– Heparinized dialysate and any other medications or

devices containing heparin

• Confirm diagnosis of HIT with the appropriate laboratory test

• Consider alternative anticoagulation • Monitor carefully for thrombosis• Monitor platelet counts until recovery• Avoid prophylactic platelet transfusions

Conventional Strategies for HIT: Variable Success

• Cessation of heparin alone

• Warfarin

• LMWH

• Danaparoid sodium

• Ancrod

• Prostacyclin analogues

Treatment of HIT Complicated by DVT: Risk for Warfarin-Induced

Venous Limb Gangrene

• Vitamin K antagonists such as warfarin may also be used for continuing anticoagulant therapy– Mechanism of action: Inhibits vitamin K dependent

coagulant factors

• Disadvantages– Requires 5 days to achieve full therapeutic effect– Warfarin has been associated with venous limb

gangrene when used alone (especially at high doses) or with ancrod during acute HIT, particularly in patients with DVT

Note: Venous limb gangrene arises from a disturbance in procoagulant/anticoagulant hemostatic balance (HIT-associated increase in thrombin generation/warfarin-associated depletion of the natural anticoagulant protein C)

Venous Limb Gangrene

Used with permission from Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. Ann Intern Med. 1997;127:804–812.

Low-Molecular-Weight Heparins

• Advantages– Binding to plasma proteins and endothelial cells not as

strong compared with unfractionated heparin– Reduced binding associated with greater bioavailability and

more predictable dose response than unfractionated heparin

• Disadvantages– High in vitro cross-reactivity rates with heparin-dependent

antibody (approaching 100% using sensitive assays) – Potential cause of HIT, but less often than unfractionated

heparin– Significant risk of recurrent or progressive thrombocytopenia

and/or thrombosis

Danaparoid Sodium - a LMW Heparinoid

• Mixture of anticoagulant glucosaminoglycans with a low degree of sulfation (50% fewer sulfate groups than heparin)

• Favorable results in ~90% of patients• Half-life of anti-factor Xa activity is ~25 hours; a

potential disadvantage for patients who may need surgical procedures

• Cross-reactivity with heparin-dependent antibody in vitro is 10% to 20%– Defined as increased platelet activation over background

in presence of patient serum and danaparoid– Uncertain clinical significance of in vitro cross-reactivity

Typical Course of a Patient with HITTreated with Danaparoid Sodium

5 10 12 14 17 22

Danaparoid

= Artificial respiration= Dialysis= Thromboembolus

DanaparoidDalteparinHeparin

Pla

tele

ts

1

09/L

200

100

300

500Heparin

DaysAdapted with permission from Greinacher A, Drost W, Michels I, et al. Ann Haematol. 1992;64:40–42.

Clinical Report of HIT Patients Treated with Ancrod

DVT, deep venous thrombosis; PE, pulmonary embolism; N/A not applicable.*Extension of DVT, 10 days after stopping ancrod while receiving adequate warfarin (INR between 2 and 3).†Terminal carcinoma, phlegmasia cerulea dolens 10 days after stopping ancrod therapy.

‡Increase in thigh volume and 16 g/L decrease in hemoglobin concentration.Adapted with permission from Demers C, Ginsberg JS, Brill-Edwards P, et al. Blood. 1991;78:2194–2197.

Age(yr)

Indication forAnticoagulant

Therapy

Nadir PlateletCount

9x10 /L

Delay forPlatelet

Increase >150x109/L (d)

BleedingEpisode Recurrence

76 DVT 425 N/A No NoHistory of HIT

74 DVT/PE 68 5 No Yes*57 DVT/PE 74 10 No Yes†

54 Axillary DVT 47 4 No No65 DVT 26 7 No No64 DVT 38 6 No No76 PE 59 4 No No66 DVT 67 2 No No70 DVT 20 6 Yes‡ No48 DVT 266 N/A No No

History of HIT80 DVT/PE 52 7 No No

Prostacyclin Analogues

• Act as natural vasodilators

• Inhibit platelet aggregation

• Advantages– Platelet activation blocked in patients with HIT– Short half-life (15–30 minutes) permits ease of

control

• Disadvantage– Adverse reactions, such as hypotension, may limit

usefulness

Alternative Treatments of HIT

• IV immunoglobulin preparations of the IgG class: success reported in a few cases

• Platelet transfusions: usually unnecessary (low bleeding risk in HIT); may increase risk of new thromboembolic lesions

• Plasmapheresis: anecdotal experience only

Note: Consider alternative treatments only as adjuncts to a major alternative anticoagulant agent such as danaparoid sodium or recombinant hirudin

Action of Thrombin

Releases from endothelium: NO PGI2 t-PA von Willebrand ADP

Prothrombin thrombin

Fibrinogen fibrin

Activation of platelets

Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Company; 1997:1809–1842.

Factor XIII XIIIa cross-linked fibrin

Factor V Va Factor VIII VIIIa

Thrombin

Development of Lepirudin (rDNA)

for Injection (Refludan)Lepirudin (recombinant hirudin) approved for anticoagulation in patients 1998 ====with heparin-induced thrombocytopenia (HIT) and thromboembolic disease ====in order to prevent further thromboembolic complications ====

==== ====

Lepirudin phase I-II trials (safety, PK) 1990–1993 ====Potential indications ====

==== ====Clin-Pharm investigations of lepirudin 1987–1989 ==== ==== ====Lepirudin developed 1986–1987 ====

==== ====

Amino acid sequence determined 1984–1985 ==== ====

LTYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQSHNDGDFEEIPEEYLQ ====

Hirudin primary structure determined 1976 ==== ====

====Hirudin defined as thrombin inhibitor 1955–1957 ====

==== ====Use of hirudin from H. medicinalis 1903–1904 ====

==== ====Anticoagulant activity of medicinal leech identified 1884 ====

Hirudin Inhibition

Adapted with permission from Markwardt F. Thromb Res. 1994;74:1–23.

Positive inotropeHeart

Thrombin

Antithrombin

Tumor cellsAdhesion

MetastasisCell growth

HIRUDIN

Clot formation:Fibrinogen FibrinF XIII F XIIIa

Amplification:F V F Va

F VIII F VIIIa

Coagulation System

AggregationRelease reaction

TxA2-synthesis

Platelets

LeukocytesChemotaxis

Cytokine production

ChemotaxisMacrophages

Synthesis and release:ProstacyclinEDRF, t-PAEndothelinTissue factor

Activation:Protein C PC a Thrombomodulin

Endothelial Cells

FibroblastsProliferation

Neuritegrowth

regulation

NeuronsContractionMitogenesis

Smooth Muscle

Structure of Lepirudin

47

COO–65

60

63

50

40

6

10

16

14

30

28

20

1

NH3+

Leu

Val

Lys

Tyr

Cys Cys

CysCys

39

22

Cys

Cys

Properties of Unfractionated Heparin, LMWH, and Hirudin

Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Co.; 1997:1809-1842.

Unfractionated Heparin LMWH Hirudin

Thrombin inhibitionInhibits thrombin and factor Xa equally, less for IXa, XIa, and XIIa

Some extent, mainly factor Xa

Specific and potent

Antithrombin-dependent

Yes Yes No

Neutralized by heparinase

Yes, also by several plasma proteins, PF4, and endothelium

Yes, weak endothelium binding

No

Inactivates clot-bound thrombin and factor VII

No NoYes (clot-bound thrombin)

Affects plateletfunction

Yes YesNo, except prevents thrombin-induced aggregation

Properties of Unfractionated Heparin, LMWH, and Hirudin

(cont.)

Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Co.; 1997:1809-1842.

Unfractionated Heparin LMWH Hirudin

Can cause immunethrombocytopenia

Yes Yes No

Bioavailability afterSC injection

30% >90% ~85%

Dose effect response Poor Fair Fair

Immunogenicity Yes (HIT) Yes (HIT) Possible in ~ 40%of patients

Liver toxicityTransient increaseof liver enzymescommon

Transient increaseof liver enzymespossible

No

Increases vascularpermeability

Yes No No

Clinical Trials of Lepirudin: HAT-1 and HAT-2 Studies on HIT

• Design: Prospective, historically controlled trials

• Primary objective: Demonstrate that treatment of HIT with lepirudin increases platelet counts or maintains normal baseline values while providing effective anticoagulation (prolongation of aPTT to 1.5 to 3 times baseline value)

• Secondary objective: Evaluate incidences of new arterial or venous thromboembolic complications, major bleeding complications, surgical interventions/limb amputations, and deaths

Baseline Characteristics of Patients Presenting with Thromboembolic

Complications in HAT-1 and HAT-2

LepirudinHAT-1(n=54)

HAT-2(n=59)

Historical Control

(n=91)

Males 27.8% 44.1% 35.2%

Females 72.2% 55.9% 64.8%

Age < 65 years 63.0% 67.8% 44.0%

Age > 65 years 37.0% 32.2% 56.0%

• Treatment regimen A1– HIT patients with arterial or venous

thromboembolism without thrombolytic therapy • initial IV bolus = 0.4 mg/kg BW*

• continuous IV infusion = 0.15 mg/kg BW/h, 2–10 days†

• Treatment regimen A2– HIT patients with arterial or venous

thromboembolism with concomitant thrombolytic therapy

• initial IV bolus = 0.2 mg/kg BW*

• continuous IV infusion = 0.1 mg/kg BW/h, 2–10 days†BW, body weight

*Not to exceed body weight of 110 kg†Typically 2–10 days duration; longer if clinically warranted

Lepirudin Treatment Regimens for HAT-1 and HAT-2

• Treatment regimen B– Prophylaxis of arterial or venous thromboembolism

• continuous IV infusion = 0.1 mg/kg BW/h*, 2–10 days†

• Treatment regimen C– Anticoagulation during cardiopulmonary bypass

• priming of HLM = 0.2 mg/kg BW*• initial IV bolus = 0.25 mg/kg BW*• additional boluses = 5 mg (to maintain ECT > 40 s)

BW, body weight; ECT, ecarin clotting time*Not to exceed body weight of 110 kg†Typically 2–10 days duration; longer if clinically warranted

Lepirudin Treatment Regimens for HAT-1 and HAT-2 (cont.)

Results of HAT-1: Platelet Count Recovery Profile

500-

400-

300-

200-

100-

0-

n = 63 64 64 64 61 60 58 54 57 54 52 45 40

Nadir Beforelepirudin

2 4 5 6 73 8 9 10 11

Platelets x 109/L

Before heparin

Day 1 = Start of infusion of lepirudinDay

Results of HAT-2: Platelet Count Recovery Profile

500-

400-

300-

200-

100-

0-

n = 60 63 62 60 57 60 54 57 58 51 51 51 37

Nadir Beforelepirudin

2 4 5 6 73 8 9 10 11

Platelets x 109/L

Before heparin

Day 1 = Start of infusion of lepirudinDay

Results of HAT-1: Results of HAT-1: aPPT ProlongationaPPT Prolongation

0.00.0

A1 A1 n n = 63= 63 6262 6060 6060 5555 5454 5353 5050 4545 4343 3636A2 A2 n = n = 44 44 33 33 33 33 33 33 33 33 33B B n n = 40= 40 4141 3737 3636 3232 3030 2828 2424 21 21 2020 1818

BeforeBeforelepirudinlepirudin

22 44 55 66 7733 88 99 1010 1111

aPP

T R

ati

oaP

PT

Ra

tio

Day 1 = Start of infusion of lepirudinDayDay

1.51.5

3.03.0

4.4.55

Treatment regimen: Treatment regimen: A1A1 A2A2 BB

Results of HAT-1 and HAT-2: Results of HAT-1 and HAT-2: Cumulative Risk of Death, Limb Cumulative Risk of Death, Limb

Amputation, Amputation, or Thromboembolic or Thromboembolic

ComplicationsComplications

00 77 1414 2121 2828 3535 4242 494900

10102020303040405050606070708080

Historical control*Historical control*Lepirudin*Lepirudin* 102102

555592923838

76762828

27272020

991212

661111

33

66

PP = 0.004, log-rank test = 0.004, log-rank test

Days After Start of TreatmentDays After Start of Treatment

Cu

mu

lati

ve R

isk

(%

)C

um

ula

tive

Ris

k (

%)

LepirudinLepirudin (n = 113, censored = 88)(n = 113, censored = 88)

Historical controlHistorical control (n = 75, censored = 45)(n = 75, censored = 45)

*Number at risk

Censored observations

Adverse Events in HAT-1 and HAT-2

• Study group: 198 pts treated with lepirudin; historical controls• Bleeding was most frequent adverse event• Bleeding events in 113 pts with thromboembolic complications

compared with historical control group:– Anemia or an isolated drop in hemoglobin: pts, 12.4%; control, 1.1%– Bleeding from puncture sites and wounds: pts, 10.6%; control, 4.4%– Other hematomas and unclassified bleeding: pts, 10.6%; control, 4.4%

• No intracerebral or fatal bleeding seen in any pt receiving lepirudin; major bleeding occurred only slightly more often (statistically non-significant) in study group

• Fever, pneumonia, sepsis, and unspecified infections, taken as a whole, were most frequently reported nonhemorrhagic events in lepirudin pts

Development of Anti-Hirudin Antibodies in HAT-1 and HAT-2

• Possible immunologic preselection as HIT patients already developed drug-induced antibodies

• Positive anti-hirudin antibodies (IgG) developed in ~40% of pts• No association of reduced hirudin plasma levels with formation

of anti-hirudin antibodies• No association between antibody levels and clinical endpoints

(death, limb amputation, new thromboembolic complications, major bleedings, and allergic reactions)

• May increase anticoagulant effect of hirudin possibly due to delayed renal elimination of active lepirudin-antihirudin complex

• Because anti-hirudin antibodies can increase the anticoagulant effect of lepirudin, strict ongoing monitoring of aPTT is necessary even during prolonged therapy

Conclusions from HAT-1 and HAT-2

• Lepirudin is a safe and effective anticoagulant that allows rapid recovery of platelet counts in patients with HIT

• Lepirudin does not cross-react with heparin-induced antibodies, as demonstrated by rapid and sustained platelet recovery

• In comparison to a historical control group, lepirudin substantially reduced the risk of serious complications associated with HIT

• Lepirudin is well-tolerated; major bleeding was not significantly more common in the lepirudin-treated group

Conclusions

• Heparin, although an important anticoagulant, has several drawbacks, most notably its ability to cause HIT

• HIT can lead to severe and even life-threatening thromboembolic disorders

• Treatment of HIT should be initiated before laboratory confirmation

• A new generation of drugs such as the thrombin inhibitors, including the hirudins, may provide important new options for the treatment and possible prevention of HIT