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Principal Developers: D. Lee Heparin Induced Thrombocytopenia 1. DEFINITION Heparin-induced thrombocytopenia
(HIT) is a drug-induced immune-mediated syndrome characterized by thrombocytopenia and
thrombotic events that may be life- or limb threatening.
HIT occurs in up to 5% of certain types of patients receiving unfractionated
heparin (e.g., postoperative orthopedic patients), and less than 1% of patients receiving
low-molecular weight heparin. The diagnosis of HIT is based on
three criteria: 1. The patient is currently receiving or has had recent exposure to
heparin, 2. the presence of at least one clinical feature of the syndrome (usually
thrombocytopenia with or without thrombosis), and 3. laboratory evidence of HIT
antibodies. HIT must be distinguished from other
causes of thrombocytopenia. 2. PATHOGENESIS OF HIT HIT is caused by antibodies (HIT-Ig) that generally
recognize a target antigen complex of platelet factor 4 (PF4) and heparin. The resulting
antibody/antigen complexes activate platelets, generating procoagulant platelet-derived
microparticles, and activate endothelial cells and monocytes. These diverse effects likely
explain the thrombocytopenia and thrombotic events observed in HIT. 3. CLINICAL FEATURES OF HIT HIT typically presents with a fall in
platelet count with or without thrombosis. a. Thrombocytopenia. A
platelet count fall of greater than 50%, or an absolute thrombocytopenia, beginning 5 to
10 days after heparin exposure in the absence of other causes of thrombocytopenia should
be considered to be HIT, unless proven otherwise. HIT can also present with a more rapid
fall of the platelet count soon after starting heparin in patients who have had previous
exposure to heparin, usually within the preceding 100 days. The severity of
thrombocytopenia in HIT is usually moderate: most patients have a platelet count between
30-100 x 109/L, with only 20% having a platelet count of 30 x 109/L
or less. In about 20% of patients, the platelet count never falls below 100 x 109/L. Despite thrombocytopenia that can
occasionally be severe, bleeding complications are infrequent in HIT. b. Thrombosis. Paradoxically,
patients with HIT are at higher risk of thrombosis than bleeding, even when
thrombocytopenia is severe. HIT is associated with a high risk (30 to 50%) of new
thrombosis or extension of existing thrombosis. Thrombosis may be the presenting clinical
manifestation of HIT and can occur during the period of thrombocytopenia or several days
after platelet count recovery, even despite discontinuation of heparin. Most thrombotic
events are venous, although both venous and arterial thrombotic events can occur.
Thrombotic events typically include deep vein thrombosis, pulmonary embolism, limb
arterial thrombosis, venous limb gangrene, thrombotic stroke, and myocardial infarction;
however, thromboses in unusual locations can also occur. HIT should be considered in the
differential diagnosis of patients with new or recurrent venous or arterial
thromboembolism that develops during or shortly after exposure to heparin. c. Other clinical manifestations
of HIT. Less frequently observed manifestations of HIT include heparin-induced skin
lesions, adrenal hemorrhagic infarction, and acute systemic reactions (e.g., chills,
dyspnea, cardiac or respiratory arrest following intravenous heparin bolus therapy). 4. LABORATORY TESTING Therapeutic decisions should not be delayed for the
results of laboratory testing if the clinical suspicion of HIT is strong. Serum should be
sent for HIT-Ig testing using a sensitive and specific functional assay (e.g., the
platelet serotonin release assay), or antigen assay (e.g., PF4/heparin ELISA). 5. MANAGEMENT OF PATIENTS WITH HIT There are few prospective randomized
studies on which to base recommendations regarding the management of HIT. Patients with
HIT are best managed by, or in consultation with, a specialist experienced in managing
HIT. a. All heparin should be discontinued
in patients with HIT or suspected HIT. This includes unfractionated and low-molecular
weight heparins by any route, heparin flushes, and vascular catheters that are
heparin-coated. b. In patients with HIT or suspected
HIT, with or without thrombosis, anticoagulation with an alternative non-heparin
anticoagulant (danaparoid, lepirudin, or argatroban, listed in historical order of
availability) is recommended (see #6. Anticoagulants for HIT). c. Warfarin should be avoided in
acute HIT unless it is used in combination with therapeutic-dose danaparoid, lepirudin, or
argatroban. Warfarin has been associated with worsening venous thrombosis, venous limb
gangrene, and/or skin necrosis when used alone or in combination with ancrod in acute HIT.
However, warfarin is appropriate for longer term anticoagulation in patients with HIT and
thrombosis. Warfarin should be delayed until therapeutic anticoagulation with danaparoid,
lepirudin or danaparoid is achieved, and ideally, until there is substantial resolution of
the thrombocytopenia. Warfarin-associated thrombotic complications have been described in
patients in whom the alternative anticoagulant was stopped prior to resolution of
thrombocytopenia. The optimal duration of anticoagulation in patients with HIT with or
without thrombosis is not known. d. Surgical thromboembolectomy, or
systemic/local thrombolysis may be appropriate for selected patients with large vessel
arterial thromboembolism or severe pulmonary embolism, respectively. e. Low-molecular-weight heparin
(LMWH) should not be used in patients with HIT. LMWH is associated with treatment failure
in several reports, and on occasion, has been associated with disastrous complications in
patients with HIT. f. Prophylactic platelet transfusions
are not recommended in HIT. This is because petechiae and other clinical evidence for
thrombocytopenic bleeding is uncommon in HIT. In addition, thrombotic events occurring
soon after the transfusion of platelets have been reported. However, platelet transfusion
can be justified in thrombocytopenic patients who develop serious hemorrhagic
complications. g. Unfractionated and LMWH should be
avoided in patients with a previous history of HIT. Under special circumstances,
exceptions to this recommendation may be considered. For example, use of unfractionated
heparin for cardiac surgery is an appropriate option for a patient with previous HIT in
whom HIT antibodies are no longer detectable by sensitive and specific laboratory
assay(s). h. Although there
are promising reports describing the use of fondaparinux and bivalirudin for the treatment
of HIT, the safety and efficacy of these agents in patients with HIT has not yet been
established. 6. ANTICOAGULANTS FOR HIT a. Danaparoid. Danaparoid is a heparinoid that
inhibits factor Xa, and to a lesser extent, inhibits thrombin. It is renally excreted and
there is no specific antidote. The anti-Xa half-life in plasma is approximately 25 hours.
In patients with significant renal failure, the half-life is prolonged and dosage
reduction is recommended. Clinically
significant cross-reactivity with the HIT antibodies has been reported, but appears to be
uncommon. Patients should be monitored for unexplained platelet count fall, and new,
progressive or recurrent thromboembolism. Dosing
regimens for therapeutic anticoagulation and prophylaxis in adult patients with normal
renal function are shown below. There is evidence that therapeutic-dose danaparoid may be
more appropriate for treating most patients with HIT than prophylactic-dose danaparoid,
even when the indication for anticoagulation is prevention of thrombosis in a patient with
isolated HIT.
b. Lepirudin (recombinant hirudin). Hirudin is a
direct thrombin inhibitor that is produced by the salivary glands of the medicinal leech.
Lepirudin is a recombinant hirudin that has a structure that is almost identical to the
natural leech-derived protein. Lepirudin is eliminated renally, and has a half-life of
approximately 1.3 hours. In patients with renal failure, the half-life is greatly
prolonged and substantial dosage reduction is recommended. There is no known antidote.
Rare cases of anaphylaxis have been associated with IV bolus infusion of lepirudin,
occurring in patients with and without previous exposure to lepirudin. Monitoring of
therapeutic-dose lepirudin by activated partial thromboplastin time (aPTT) is required.
Dosages for adult patients (up to 100 kg) with normal renal function are shown below.
c. Argatroban. Argatroban is a synthetic,
small-molecule direct thrombin inhibitor with an even shorter half-life (40-50 min.) than
lepirudin. In further contrast to lepirudin, argatroban is excreted normally in patients
with renal insufficiency; however, the dose of argatroban must be reduced in patients with
hepatic failure. Like lepirudin, argatroban is usually monitored using the aPTT. Concurrent use of argatroban and warfarin increases
the INR beyond that produced by warfarin alone. A
guideline for the transition to warfarin monotherapy can be found in the product
monograph. Dosages for adult patients with
normal hepatic function are shown below.
7. REFERENCES
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