Understanding Heparin Induced Thrombocytopenia HIT Historical

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					 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
                                  No. of    Early ( 4 days)   Late ( 5 days)
                                 Patients     thrombo-           thrombo-           Thrombosis
                                              cytopenia          cytopenia       Arterial Venous
   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; 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         IgG-mediated strong platelet
                 aggregates                    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                                  O


                               OH                              OH
                                           OH                                 OH
                           O                            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




Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
   Pathophysiology of HIT and Thrombosis
                  (cont.)




Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
   Pathophysiology of HIT and Thrombosis
                  (cont.)




Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.
   Pathophysiology of HIT and Thrombosis
                  (cont.)




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


               Cumulative Thrombotic Event Rate (%)
                                                      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
                           15   First Exposure
      Number of Patients                                     Subsequent Exposure
                                  to Heparin                      to Heparin
                           10
                                             Thrombocytopenia


                            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. 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

                                100                        1
                                                           2
                                                           3
      % 14C-Serotonin Release



                                 80

                                                           4
                                 60


                                 40


                                 20


                                  0
                                      0   0.001   0.01    0.1      1          10        100   1000
                                                  Heparin Concentration (µ/mL)
  Adapted with permission from Sheridan D, Carter C, Kelton JG. Blood. 1986;67:27–30.
            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               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. 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                           Age (year         Complications        Mortality
      Year       Patients        M        F      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 HIT
                            Treated with Danaparoid Sodium

                            Heparin
                     500              Heparin
                                          Dalteparin    Danaparoid                                            Danaparoid
Platelets 109/L




                     300



                     200
                                                                                                      = Artificial respiration
                                                                                                      = Dialysis
                     100                                                                              = Thromboembolus



                                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
                                                           Delay for
                Indication for        Nadir Platelet       Platelet
   Age          Anticoagulant            Count          Increase >150       Bleeding
                                                               9
   (yr)            Therapy               x10 9/L            x10 /L (d)      Episode          Recurrence

    76          DV                         425               N/A                No                No
                History of
                T
    74          DVT/PE
                HIT                         68                 5               No                 Yes*
    57          DVT/PE                      74                10               No                 Yes †
    54          Axillary                    47                 4               No                 No
    65          DV
                DVT                         26                 7               No                 No
    64          DV
                T                           38                 6               No                 No
    76          PE
                T                           59                 4               No                 No
    66          DV                          67                 2               No                 No
    70          DV
                T                           20                 6               Yes ‡              No
    48          DVT
                T                          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. 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                                                                      Factor V             Va
 endothelium:                         Prothrombin            thrombin               Factor VIII          VIIIa
  NO
  PGI2
  t-PA
  von Willebrand
  ADP
                                        Thrombin

 Activation of platelets                 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                 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

 Coagulation System                           Antithrombin                 Endothelial Cells
  Clot formation:                                                          Synthesis and release:
    Fibrinogen  Fibrin                                                       Prostacyclin
    F XIII  F XIIIa
                                                                              EDRF, t-PA
  Amplification:
                                                                              Endothelin
    F V F Va
                                                                              Tissue factor
     F VIII F VIIIa                       Thrombin                       Activation:
                                                                              Protein C PC a
    Platelets                                  HIRUDIN                        Thrombomodulin
   Aggregation
 Release reaction
                                                                                Fibroblasts
                                                                                  Proliferation
  TxA2-synthesis
                                       Tumor cells       Neurons              Smooth Muscle
    Leukocytes                            Adhesion         Neurite                Contraction
     Chemotaxis                          Metastasis    growth regulation          Mitogenesis
 Cytokine production                     Cell growth

                        Macrophages                                              Heart
                         Chemotaxis                                         Positive inotrope



Adapted with permission from Markwardt F. Thromb Res. 1994;74:1–23.
     Structure of Lepirudin
                   65
          63                COO–         10
          Tyr
60



                                                               30
                                   Cys        Cys
                                                    14
                                    6

                                                         Cys
                                              Cys
      1 Leu
                                                         28
                                               16

                NH3+
                                                               22

                                                               Cys

     50                                        20                         Cys
                       47                                           Val
                                                                           39
                   Lys                                              40
   Properties of Unfractionated Heparin,
            LMWH, and Hirudin
                              Unfractionated Heparin      LMWH                      Hirudin

                               Inhibits thrombin and
    Thrombin inhibition        factor Xa equally, less    Some extent, mainly      Specific and potent
                               for IXa, XIa, and XIIa     factor Xa

     Antithrombin-
                               Yes                        Yes                      No
     dependent

     Neutralized by            Yes, also by several
                                                          Yes, weak
                               plasma proteins, PF4,                               No
     heparinase                                           endothelium binding
                               and endothelium
     Inactivates clot-                                                             Yes (clot-bound
     bound thrombin            No                         No
                                                                                   thrombin)
     and factor VII

                                                                                   No, except prevents
     Affects platelet                                     Yes
                               Yes                                                 thrombin-induced
     function
                                                                                   aggregation

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
                              Yes                        Yes                      No
    thrombocytopenia

    Bioavailability after
                              30%                        >90%                     ~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.; 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


                             Lepirudin             Historical Control
                   HAT-1                 HAT-2
                   (n =54)               (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       64    64     61         60   58    54      57   54   52   45 40
 500-

 400-

 300-

 200-

 100-

  0-
        Before Nadir Before 2            3       4    5         6   7    8    9    10   11
        heparin      lepirudin
                                                          Day
        Day 1 = Start of infusion of lepirudin
               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-
        Before Nadir Before 2            3        4   5         6    7    8    9    10    11
        heparin      lepirudin
                                                          Day
        Day 1 = Start of infusion of lepirudin
                                    Results of HAT-1:
                                    aPPT Prolongation
                      A1 n = 63       62      60     60       55    54    53    50      45   43   36
                      A2 n = 4         4       3      3        3     3     3     3       3    3    3
                      B n = 40        41      37     36       32    30    28    24      21   20   18
             4.5
aPPT Ratio




              3.0



              1.5


                                     Treatment regimen:              A1        A2        B

              0.0
                             Before 2         3      4        5      6    7         8   9    10   11
                            lepirudin
                                                                   Day
                     Day 1 = Start of infusion of lepirudin
         Results of HAT-1 and HAT-2:
   Cumulative Risk of Death, Limb Amputation,
      or Thromboembolic Complications
        Lepirudin*                                                                                          3
                                                  102    92        76         27         9       6
Historical control*                                55    38        28         20        12       11
               80                                                                                           6
          Cumulative Risk (%)




               70
               60                                        P = 0.004, log-rank test
               50
               40
               30
               20
               10
                 0
                                     0             7     14         21        28        35       42        49
                                                         Days After Start of Treatment

                                *Number at risk                  Lepirudin            (n = 113, censored = 88)
                                 Censored observations           Historical control   (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