Transcript Understanding Heparin-Induced Thrombocytopenia (HIT

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 heparinassociated 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
No. of
Patients
Ansell, 1980
Ansell, 1985
Bailey, 1986
Ramirez-Lassepas, 1984*;
Cipolle, 1983*
Gallus, 1980
Green, 1984, 1986
Holm, 1980
Kakkasseril, 1985
Monreal, 1989
Nelson, 1978
Powers, 1979*
Powers, 1984
Rao, 1989
Total
43
104
43
211
143
89
90
142
89
37
120
131
94
1,336
Early ( 4 days)
thrombocytopenia
1
5
0
2
4
0
0
--6
2
2
3
24 (1.8%)
Late ( 5 days)
thrombocytopenia
4
5
1
9
5
2
1
9
2
3
2
3
3
46 (3.4%)
Thrombosis
Arterial
Venous
0
0
0
0
1
0
2
1
0
1
0
2
0
0
1
0
0
7
1
1
0
2
1
0
1
0
0
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; 1994:75–127.
* Some information obtained by personal communication.
Differences Between HIT and
Non-Immune HAT
Non-Immune HAT
HIT
Onset
Within 4 days
Usually 5–14 days (may be
sooner)
Platelet count
Typically 100,000–150,000/ L Typically 20,000–150,000/ L
 median nadir ~ 50,000/L in
most series; rarely <20,000/L
 sometimes falls >30%, but
remains >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 platelet
aggregates
IgG-mediated strong platelet
activation
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
CH2OSO3
CH2OH
O
OH
O
O
OH
OH
OH
HO
O
NHSO3
COO
NHAc
COO
O OH
O OH
OH
COO
OH
HO
OH
OSO3
HO
HO
OH
OH
(1)
(2)
(3)
(4)
(5)
Adapted with permission from Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 1998:3044.
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
Pathophysiology of HIT and
Thrombosis
7
4
6
3
1
5
2
Platelets
Heparin
Glycosaminoglycan molecule
PF4
Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
Pathophysiology of HIT and Thrombosis
(cont.)
7
4
6
3
1
5
2
Platelets
Heparin
Glycosaminoglycan molecule
PF4
Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
Pathophysiology of HIT and Thrombosis
(cont.)
7
4
6
3
1
5
2
Platelets
Heparin
Glycosaminoglycan molecule
PF4
Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
Pathophysiology of HIT and Thrombosis
(cont.)
7
4
6
3
1
5
2
Platelets
Heparin
Glycosaminoglycan molecule
PF4
Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
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.
Cumulative Thrombotic Event Rate (%)
Fourteen-Year Study of HIT:
Group II Results After Heparin Discontinuation
100
90
80
70
52.8%
60
50
40
30
20
10
0
0 2
4
6
8 10 12 14 16 18 20 22 24 26 28 30
Days After Isolated HIT Recognized
Adapted with permission from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.
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 Onset
Number of Patients
15
First Exposure
to Heparin
Subsequent Exposure
to Heparin
10
Thrombocytopenia
5
Thrombocytopenia
0
Thrombosis
Thrombosis
2
4
6
8 10 12 14 16 18 20
Day of Treatment
2
4
6
8 10
Day of Treatment
Adapted with permission from King DJ, Kelton JG. Ann Intern Med. 1984;100:536–540.
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-Serotonin
and Final Concentration of Heparin in HIT Patients
% 14C-Serotonin Release
100
1
2
3
80
4
60
40
20
0
0
0.001
0.01
0.1
1
10
Heparin Concentration (µ/mL)
Adapted with permission from Sheridan D, Carter C, Kelton JG. Blood. 1986;67:27–30.
100
1000
Diagnosis: Heparin/PF4 ELISA
Relative Sensitivity in 12 Patients with HIT
Positive Reactions, n
Assay
Undiluted
1:10
1:100
1:200
1:500
Serotonin
Release
12
12
2
Not
Tested
Not
Tested
ELISA
12
12
12
12
9
Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
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
No. of
Patients
Year
M
F
Age (year
range or SD)
Complications
n (%)
Mortality
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)
62
33
29
66.7 +/- 12.3
32 (51.6)
13 (21.0)
1996
†
*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/warfarinassociated 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 HIT
Treated with Danaparoid Sodium
Heparin
Platelets 109/L
500
Heparin
Dalteparin
Danaparoid
Danaparoid
300
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. 1992;64:40–42.
Clinical Report of HIT Patients
Treated with Ancrod
Age
(yr)
76
74
57
54
65
64
76
66
70
48
80
Indication for
Anticoagulant
Therapy
Nadir Platelet
Count
x10 9/L
Delay for
Platelet
Increase >150
9
x10 /L (d)
Bleeding
Episode
Recurrence
DV
History
of
T
DVT/PE
HIT
DVT/PE
Axillary
DV
DVT
DV
T
PE
T
DV
DV
T
DVT
T
History of HIT
DVT/PE
425
N/A
No
No
68
74
47
26
38
59
67
20
266
5
10
4
7
6
4
2
6
N/A
No
No
No
No
No
No
No
Yes ‡
No
Yes*
Yes †
No
No
No
No
No
No
No
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. 1991;78:2194–2197.
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
Activation of platelets
Prothrombin
thrombin
Factor V
Factor VIII
Va
VIIIa
Thrombin
Fibrinogen
fibrin
Factor XIII
XIIIa
cross-linked fibrin
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.
Development of Lepirudin (rDNA)
for Injection (Refludan)
Lepirudin (recombinant hirudin) approved for anticoagulation in patients
with heparin-induced thrombocytopenia (HIT) and thromboembolic disease
in order to prevent further thromboembolic complications
Lepirudin phase I-II trials (safety, PK)
Potential indications
1998 ====
====
====
====
====
1990–1993 ====
====
====
====
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
Coagulation
System
Clot formation:
Antithrombin
Fibrinogen  Fibrin
F XIII  F XIIIa
Amplification:
F V F Va
Thrombin
F VIII F VIIIa
HIRUDIN
Platelets
Aggregation
Release reaction
TxA2-synthesis
Endothelial Cells
Synthesis and release:
Prostacyclin
EDRF, t-PA
Endothelin
Tissue factor
Activation:
Protein C PC a
Thrombomodulin
Fibroblasts
Proliferation
Leukocytes
Chemotaxis
Cytokine production
Tumor cells
Neurons
Adhesion
Metastasis
Cell growth
Neurite
growth regulation
Macrophages
Chemotaxis
Adapted with permission from Markwardt F. Thromb Res. 1994;74:1–23.
Smooth Muscle
Contraction
Mitogenesis
Heart
Positive inotrope
Structure of Lepirudin
63
65
COO–
10
Tyr
60
30
Cys
Cys
14
6
Cys
1 Leu
16
NH3+
Cys
28
22
Cys
20
50
Cys
47
Val
Lys
40
39
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
Antithrombindependent
Yes
Yes
No
Neutralized by
heparinase
Yes, also by several
plasma proteins, PF4,
and endothelium
Yes, weak
endothelium binding
No
Inactivates clotbound thrombin
and factor VII
No
No
Yes (clot-bound
thrombin)
Affects platelet
function
Yes
Yes
No, except prevents
thrombin-induced
aggregation
Thrombin inhibition
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.
Properties of Unfractionated Heparin,
LMWH, and Hirudin (cont.)
Unfractionated Heparin
LMWH
Hirudin
Can cause immune
thrombocytopenia
Yes
Yes
No
Bioavailability after
SC injection
30%
>90%
~85%
Dose effect response
Poor
Fair
Fair
Immunogenicity
Yes (HIT)
Yes (HIT)
Possible in ~ 40%
of patients
Liver toxicity
Transient increase
of liver enzymes
common
Transient increase
of liver enzymes
possible
No
Increases vascular
permeability
Yes
No
No
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.
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
Historical Control
Lepirudin
HAT-1
(n=54)
HAT-2
(n=59)
(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%
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, 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 (cont.)
•
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
Results of HAT-1:
Platelet Count Recovery Profile
Platelets x 109/L
n = 63 64
500-
64
64
61
60
58
54
57
54
52
4
5
6
7
8
9
45 40
4003002001000Before Nadir Before 2
heparin
lepirudin
3
Day 1 = Start of infusion of lepirudin
Day
10
11
Results of HAT-2:
Platelet Count Recovery Profile
Platelets x 109/L
n = 60 63
500-
62
60
57
60
Before Nadir Before 2
heparin
lepirudin
3
4
54
57
58
51
5
6
7
8
51
51
37
400300-
2001000-
Day 1 = Start of infusion of lepirudin
Day
9
10
11
Results of HAT-1:
aPPT Prolongation
A1 n = 63
A2 n = 4
B n = 40
62
4
41
60
3
37
60
3
36
55
3
32
54
3
30
53
3
28
50
3
24
45
3
21
43
3
20
36
3
18
10
11
aPPT Ratio
4.5
3.0
1.5
Treatment regimen:
0.0
Before 2
lepirudin
3
4
A1
5
6
Day
Day 1 = Start of infusion of lepirudin
A2
7
B
8
9
Results of HAT-1 and HAT-2:
Cumulative Risk of Death, Limb Amputation,
or Thromboembolic Complications
Lepirudin*
Historical control*
80
70
60
50
40
30
20
10
0
Cumulative Risk (%)
102
55
92
38
76
28
27
20
9
12
6
11
3
6
35
42
49
P = 0.004, log-rank test
0
7
14
21
28
Days After Start of Treatment
*Number at risk
Censored observations
Lepirudin
Historical control
(n = 113, censored = 88)
(n = 75, censored = 45)
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