Understanding Heparin-Induced Thrombocytopenia (HIT): Historical and Clinical Perspectives

1
Understanding Heparin-Induced Thrombocytopenia
(HIT) Historical and Clinical Perspectives
2
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

3
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)

4
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)

5
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

6
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
  lt1 LMW)
• (R) Schmitt, 1993 Schulman, 1997 1.1 to 2.9
• Some high rates are from studies that included
  patients with non-immune HAT.

7
Incidence of HIT and HIT Thrombosis Prospective
Studies of IV Therapeutic-Dose Heparin
No. of
Early (
4 days)
Late (
5 days)
?
?
Patients
Thrombosis
thrombo-
thrombo-
Arterial
Venous
cytopenia
cytopenia
Ansell, 1980
43
1
4
0
0
Ansell, 1985
104
5
5
0
0
Bailey, 1986
43
0
1
1
0
Ramirez-
Lassepas, 1984
211
2
9
2
1

Cipolle, 1983
Gallus, 1980
143
4
5
0
1
Green, 1984, 1986
89
0
2
1
1
Holm, 1980
90
0
1
0
0
Kakkasseril, 1985
142
--
9
2
2
Monreal, 1989
89
--
2
0
1
Nelson, 1978
37
6
3
0
0
Powers, 1979
120
2
2
1
1
Powers, 1984
131
2
3
0
0
Rao, 1989
94
3
3
0
0
Total
1,336
24 (1.8)
46 (3.4)
7
7
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 199475127. Some
information obtained by personal communication.
8
Differences Between HIT and Non-Immune HAT
Non-Immune HAT
HIT
Usually 514 days (may be
Onset
Within 4 days
sooner)
Platelet count
Typically 100,000150,000/
?
L
Typically 20,000150,000/
?
L
?

median nadir 50,000/
?
L in
most series rarely lt20,000/
?
L
?

sometimes falls gt30, but
remains gt150,000/
?
L
Complications
Thromboembolic lesions
None
530
1 at 1 week 3 at 2 weeks
Incidence
Recovery
13 days
57 days
Benign, tiny platelet
IgG-mediated strong platelet
Cause
aggregates
activation
9
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

10
Skin Necrosis

• Used with permission from Warkentin TE. Br J
  Haematol. 199692494497.

11
Acute Systemic Reactions Caused by IV Heparin
Bolus

• The following can occur in patients sensitized to
  heparin within 530 minutes
• Fever, chills
• Tachycardia, hypertension
• Flushing, headache
• Chest pain, dyspnea
• Nausea, vomiting, large-volume diarrhea
• Sudden anaphylactoid death
• Transient global amnesia

12
Molecular Structure of Heparin

• Member of heterogeneous family of
  glycosaminoglycans MW3,00030,000 daltons

CH2OH
O
O
OH
OH
OH
OH
HO
O
O
NHAc
NHSO3
COO
COO
OH
O
OH
O
OH
COO OH
OH
HO
OSO3
HO
HO
OH
OH
(1)
(2)
(3)
(4)
(5)
Adapted with permission from Physicians Desk
Reference. Montvale, NJ Medical Economics,
19983044.
13
Action of Heparin

• Primary action
• Binds to antithrombin (cofactor)
• After binding, increases antithrombins
  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

14
Pathophysiology of HIT and Thrombosis
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
15
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
16
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
17
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
18
Fourteen-Year Study of HIT

• Study design Retrospective cohort study
• Population 127 patients with serologically
  confirmed HIT in one medical community
• Group I (n65) HIT diagnosed after appearance of
  new thrombosis
• Group II (n62) 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.
  1996101502507.

19
Fourteen-Year Study of HITGroup II Results
After Heparin Discontinuation
100 90 80 70 60 50 40 30 20 10 0
52.8
Cumulative Thrombotic Event Rate ()
0
2
4
6
10
12
14
16
8
18
22
26
28
30
24
20
Days After Isolated HIT Recognized
Adapted with permission from Warkentin TE, Kelton
JG. Am J Med. 1996101502507.
20
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.
  1996101502507.

21
Diagnosis of HIT

• Normal platelet count before commencement of
  heparin therapy
• Onset of thrombocytopenia typically 514 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

22
Diagnosis Based on Time of Onset
15
First Exposureto Heparin
Subsequent Exposureto Heparin
10
Thrombocytopenia
Number of Patients
5
Thrombocytopenia
0
Thrombosis
Thrombosis
2
4
6
8
10
12
14
16
18
20
2
4
6
8
10
Day of Treatment
Day of Treatment
Adapted with permission from King DJ, Kelton JG.
Ann Intern Med. 1984100536540.
23
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 3581 sensitivity higher
  using washed platelets
• Reactivity varies among donor platelets

24
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

25
Relationship Between Release of 14C-Serotonin and
Final Concentration of Heparin in HIT Patients
100 80 60 40 20 0
1
2
3
4
14C-Serotonin Release
0.001
0.01
0.1
1
10
100
1000
0
Heparin Concentration (µ/mL)
Adapted with permission from Sheridan D, Carter
C, Kelton JG. Blood. 1986672730.
26
Diagnosis Heparin/PF4 ELISA
Relative Sensitivity in 12 Patients with HIT
Positive Reactions,
n
Assay
Undiluted
110
1100
1200
1500
Serotonin
12
12
2
Not
Not
Release
Tested
Tested
ELISA
12
12
12
12
9
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
27
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 lt5
  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

28
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

29
Incidence of Complications and Mortality of HIT
No. of
Age (year
Complications
Mortality
Year
Patients
range or SD)
n
()
n
()
M
F
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. 1987102763-770
and Warkentin TE, Kelton JG. Am J Med.
1996101502507.
30
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
31
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

32
Conventional Strategies for HIT Variable Success

• Cessation of heparin alone
• Warfarin
• LMWH
• Danaparoid sodium
• Ancrod
• Prostacyclin analogues

33
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)
34
Venous Limb Gangrene

Used with permission from Warkentin TE, Elavathil
LJ, Hayward CPM, Johnston MA, Russett JI, Kelton
JG. Ann Intern Med. 1997127804812.
35
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

36
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

37
Typical Course of a Patient with HIT Treated with
Danaparoid Sodium
Heparin
500
Heparin
Dalteparin
Danaparoid
Danaparoid
300
Platelets ??109/L
200
Artificial respiration Dialysis
Thromboembolus
100
5
10
12
14
17
22
Days
Adapted with permission from Greinacher A, Drost
W, Michels I, et al. Ann Haematol. 1992644042.
38
Clinical Report of HIT Patients Treated with
Ancrod
Delay for
Nadir Platelet
Indication for
Platelet
Count
Increase gt150
Age
Anticoagulant
Bleeding
/L
(yr)
Therapy
Episode
Recurrence
76
DVT
425
N/A
No
No
History of HIT
74
DVT/PE
68
5
No
Yes

57
DVT/PE
74
10
No

Yes
54
Axillary DVT
47
4
No
No
65
DVT
26
7
No
No
64
DVT
38
6
No
No
76
PE
59
4
No
No
66
DVT
67
2
No
No

70
DVT
20
6
Yes
No
48
DVT
266
N/A
No
No
History of HIT
80
DVT/PE
52
7
No
No
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. 19917821942197.
39
Prostacyclin Analogues

• Act as natural vasodilators
• Inhibit platelet aggregation
• Advantages
• Platelet activation blocked in patients with HIT
• Short half-life (1530 minutes) permits ease of
  control
• Disadvantage
• Adverse reactions, such as hypotension, may limit
  usefulness

40
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
41
Action of Thrombin
Releases from endothelium NO PGI2 t-PA
von Willebrand ADP
Factor V Va Factor VIII VIIIa
Prothrombin thrombin
Thrombin
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 199718091842.
42
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) 19901993
Potential indications






Clin-Pharm investigations of lepirudin
19871989




Lepirudin developed 19861987

Amino
acid sequence determined
19841985


LTYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQS
HNDGDFEEIPEEYLQ
Hirudin primary structure determined
1976


Hirudin defined as
thrombin inhibitor
19551957


Use of hirudin from H. medicinalis
19031904


Anticoagulant activity of
medicinal leech identified 1884
43
Hirudin Inhibition
Antithrombin
Endothelial Cells
Synthesis and release Prostacyclin EDRF,
t-PA Endothelin Tissue factor Activation Prote
in C ??PC a Thrombomodulin
Thrombin
HIRUDIN
Smooth Muscle
Contraction Mitogenesis
Adapted with permission from Markwardt F. Thromb
Res. 199474123.
44
Structure of Lepirudin
65
63
COO
10
Tyr
60
30
Cys
Cys
14
6
Cys
Cys
Leu
1
28
16
NH3
22
Cys
20
50
Cys
47
Val
39
Lys
40
45
Properties of Unfractionated Heparin, LMWH, and
Hirudin
Unfractionated Heparin
LMWH
Hirudin
Inhibits thrombin and factor Xa equally, less
for IXa, XIa, and XIIa
Some extent, mainly factor Xa
Specific and potent
Thrombin inhibition
Antithrombin-dependent
Yes
No
Yes
Yes, also by several plasma proteins, PF4, and
endothelium
Neutralized by heparinase
Yes, weak endothelium binding
No
Inactivates clot-bound thrombin and factor VII
Yes (clot-bound thrombin)
No
No
No, except prevents thrombin-induced aggregation
Affects platelet
Yes
Yes
function
Adapted with permission from Fuster V, Verstraete
M. In Braunwald E, ed. Heart Disease A Textbook
of Cardiovascular Medicine. Philadelphia WB
Saunders Co. 19971809-1842.
46
Properties of Unfractionated Heparin, LMWH, and
Hirudin (cont.)
Unfractionated Heparin
LMWH
Hirudin
Can cause immune
Yes
Yes
No
thrombocytopenia
Bioavailability after
30
gt90
85
SC injection
Dose effect response
Poor
Fair
Fair
Possible in 40
Immunogenicity
Yes (HIT)
Yes (HIT)
of patients
Transient increase
Transient increase
Liver toxicity
of liver enzymes
of liver enzymes
No
common
possible
Increases vascular
Yes
No
No
permeability
Adapted with permission from Fuster V, Verstraete
M. In Braunwald E, ed. Heart Disease A
Textbook of Cardiovascular Medicine.
Philadelphia WB Saunders Co. 19971809-1842.
47
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

48
Baseline Characteristics of Patients Presenting
with Thromboembolic Complications in HAT-1 and
HAT-2
Historical Control
Lepirudin
HAT-1
HAT-2
(
n
91)
(
n
54)
(
n
59)
Males
27.8
44.1
35.2
Females
72.2
55.9
64.8
Age lt 65 years
63.0
67.8
44.0
Age gt 65 years
37.0
32.2
56.0
49
Lepirudin Treatment Regimens for HAT-1 and HAT-2

• 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, 210
  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, 210
  days

BW, body weight Not to exceed body weight of 110
kg Typically 210 days duration longer if
clinically warranted
50
Lepirudin Treatment Regimens for HAT-1 and HAT-2
(cont.)

• Treatment regimen B
• Prophylaxis of arterial or venous thromboembolism
• continuous IV infusion 0.1 mg/kg BW/h, 210
  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 gt 40 s)

BW, body weight ECT, ecarin clotting time Not
to exceed body weight of 110 kg Typically 210
days duration longer if clinically warranted
51
Results of HAT-1 Platelet Count Recovery Profile
Platelets x 109/L
n 63 64 64 64 61 60 58
54 57 54 52 45 40
500- 400- 300- 200- 100- 0-
Nadir
Before heparin
Before lepirudin
2
4
5
6
7
3
8
9
10
11
Day
Day 1 Start of infusion of lepirudin
52
Results of HAT-2 Platelet Count Recovery Profile
Platelets x 109/L
n 60 63 62 60 57 60 54
57 58 51 51 51 37
500- 400- 300- 200- 100- 0-
Nadir
Before heparin
Before lepirudin
2
4
5
6
7
3
8
9
10
11
Day
Day 1 Start of infusion of lepirudin
53
Results of HAT-1 aPPT Prolongation
A1 n 63 62 60 60 55 54 53 50 45 43 36A2 n
4 4 3 3 3 3 3 3 3 3 3B n 40 41 37 36 32 30 2
8 24 21 20 18
??4.5
3.0
aPPT Ratio
1.5
Treatment regimen A1 A2 B
0.0
2
4
5
6
7
3
8
9
10
11
Before lepirudin
Day
Day 1 Start of infusion of lepirudin
54
Results of HAT-1 and HAT-2 Cumulative Risk of
Death, Limb Amputation, or Thromboembolic
Complications
Lepirudin
10255
9238
7628
2720
912
611
36
Historical control
80
70
60
P 0.004, log-rank test
50
Cumulative Risk ()
40
30
20
10
0
0
7
14
21
28
35
42
49
Days After Start of Treatment
Lepirudin (n 113, censored 88) Historical
control (n 75, censored 45)
Number at risk Censored observations
55
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

56
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

57
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

58
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