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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%
     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

                                                                            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.
         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 limb
Note: VenousDVTgangrene 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
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                              Factor VIII            VIIIa
  NO
                                  thrombin
  PGI2
  t-PA
  von
 Willebrand
  ADP
                                    Thrombin

 Activation of platelets             Fibrinogen                             Factor XIII
                                     fibrin                                 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
       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

				
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