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Chapter 133 Heparin-Induced Thrombocytopenia 1981

Caveats in Treatment of Heparin-Induced Diagnosis and Treatment of Heparin-Induced Thrombocytopenia
Thrombocytopenia Heparin-induced thrombocytopenia (HIT) should be clinically sus-
pected when thrombocytopenia occurs during (or soon after) heparin
Warfarin and other vitamin K antagonists (coumarins) should not be therapy and the temporal profile of the decrease in platelet count is
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used during the acute thrombocytopenic phase of HIT. A particu- consistent with immune sensitization to heparin. Four relevant ques-
larly high-risk situation is HIT associated with deep vein thrombosis, tions, the 4Ts, should be asked:
especially if there is overt (decompensated) DIC. If such patients are Thrombocytopenia: Does the patient have thrombocytopenia? A
treated with warfarin, there is a risk for progression to venous limb greater than 50% fall in the platelet count can indicate HIT even
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gangrene. 12,26,27 The laboratory marker for this unusual syndrome is if the platelet count has not fallen to below 150 × 10 /L. (Note:
a high INR (generally, greater than 4.0), which corresponds to the Severe thrombocytopenia, such as a platelet count below 10 ×
10 /L, is only rarely caused by HIT.)
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combination of a marked reduction in the level of protein C together Timing: Is the timing of the platelet count fall consistent with immune
with increased thrombin generation (as evidenced by elevated levels sensitization? In HIT the platelet count usually begins to fall 5–10
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of thrombin-antithrombin complexes) during warfarin therapy. days after starting heparin (first day of heparin is day 0); a more
Although warfarin (in theory) should be safe in a patient whose rapid fall in the platelet count can occur if the patient is already
thrombin generation is controlled (e.g., using a DTI), it is important sensitized from heparin exposure within the past 100 days.
to delay the initiation of warfarin until there is substantial resolution Thrombosis: Does the patient have thrombosis or other sequelae
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of the thrombocytopenia (to more than 150 × 10 /L). 26,27 Warfarin of HIT? (Note: In addition to venous and arterial thrombosis,
treatment should be delayed because its prolongation of the aPTT patients with HIT can develop necrotizing skin lesions at heparin
may result in underdosing of the DTI, and because stopping the DTI injection sites or systemic inflammatory or cardiorespiratory
reactions that begin 5–30 minutes after an IV heparin bolus.)
before resolution of the HIT during warfarin overlap can lead to limb OTher: Are there other explanations for the thrombocytopenia? HIT is
loss caused by fulminant venous limb gangrene. 4 less likely when there is compelling clinical evidence for another
Several case observations suggest that aPTT confounding of cause of the thrombocytopenia, such as positive blood cultures.
DTI therapy can be a factor explaining progression of thrombosis
in patients with severe HIT. 4,34 For example, patients can develop Steps in Management of Clinically Suspected Heparin-Induced
progressive thrombocytopenia and HIT-associated consumptive Thrombocytopenia
coagulopathy despite stopping heparin (Fig. 133.4). In such patients, 1. Confirm that thrombocytopenia is present (repeat complete blood
aPTT monitoring of DTI therapy can fail because a brief course count), test for DIC, and test for HIT antibodies, preferably using
a platelet activation test such as the serotonin-release assay.
of DTI can abruptly lead to supratherapeutic aPTT levels—not 2. Assess clinically and radiologically for thrombosis (e.g.,
because of anticoagulant overdosing but because of the combination compression ultrasound for lower-limb deep venous thrombosis).
of DTI and consumptive coagulopathy—and interruption/cessation 3. Stop all heparin, including heparin flushes and possibly use of
of DTI therapy can be associated with rapid progression of micro- heparin-coated intravascular catheters (catheters left in situ for
vascular thrombosis. In this setting, factor Xa inhibitors (danaparoid, several days may not have much residual heparin).
fondaparinux) may be more effective because they do not require 4. Initiate treatment with an alternative anticoagulant, generally
aPTT monitoring. Alternatively, DTI levels can be measured directly, in therapeutic doses if HIT is strongly suspected (options: a
a,c
a,b
d
but these assays are rarely performed in North American laboratories. danaparoid, fondaparinux, lepirudin, argatroban, bivalirudin ).
Using sensitive assays for HIT antibodies, LMWH reacts 5. Although initial treatment decisions are made on clinical grounds,
similarly to UFH in vitro. Furthermore, because LMWH can lead results of testing for HIT antibodies can influence subsequent
treatment, including the decision to resume heparin if HIT has
to worsening of clinical HIT, these agents should not be used to treat been ruled out.
HIT. 26,27
Although primary treatment for HIT should include an anti- Caveats
coagulant that inhibits thrombin or reduces its generation, certain • Do not use low-molecular-weight heparin to treat HIT.
treatment adjuncts can be used in special situations. These include • Do not start (or continue) warfarin or other coumarins until the
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surgical thromboembolectomy, high-dose intravenous immuno- platelet count has returned to normal (greater than 150 × 10 /L),
and give only in low initial doses (warfarin, 5 mg or less) and
globulin, antiplatelet drugs such as aspirin, and therapeutic plasma overlap with a parenteral anticoagulant for at least 5 days.
exchange. • Do give vitamin K (e.g., 5–10 mg IV over 30–60 minutes) if
These caveats, along with recommendations for management of HIT is diagnosed after warfarin has already been given, so as
patients with suspected HIT, are summarized in the box on Diagnosis to reduce risk for coumarin necrosis and to avoid underdosing
and Treatment of Heparin-Induced Thrombocytopenia. of DTI because of activated partial thromboplastin time (aPTT)
prolongation by warfarin.
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• Beware of confounding of aPTT-monitored DTI therapy
PLATELET COUNT MONITORING FOR HEPARIN-INDUCED in patients with severe HIT complicated by HIT-associated
THROMBOCYTOPENIA consumptive coagulopathy (DIC) or who have other explanations
for an elevated aPTT, such as warfarin therapy, liver disease, or
antiphospholipid syndrome.
The frequency of platelet count monitoring in patients receiving • Do not give prophylactic platelet transfusions (platelet
heparin should reflect the overall risk of HIT (i.e., the preparation, transfusions are appropriate if the patient is bleeding or if there is
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the dose, and the clinical situation). At least alternate-day platelet diagnostic uncertainty).
count monitoring should be considered in patients at relatively high a
Not approved for treatment of HIT in the United States (except, in the case of
risk for developing HIT (e.g., after orthopedic or cardiac surgery). bivalirudin, for anticoagulation during percutaneous coronary intervention).
Monitoring at least two or three times a week should be considered b Withdrawn from the US market but available in many other countries.
for patients at moderate risk for developing HIT (e.g., medical c Fondaparinux is not approved for treatment of HIT, but case series suggest
patients receiving UFH, postoperative patients receiving UFH that it is at least as effective as DTI therapy; moreover, the risk for bleeding with
1,6
flushes or LMWH). The frequency of HIT is low with LMWH, fondaparinux is likely to be lower than that with DTI therapy, and fondaparinux
costs less than the other agents. Also, there is greater experience with fondaparinux
particularly in medical patients or during pregnancy, and routine than DTIs for prevention and treatment of thrombosis in non-HIT situations,
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platelet count monitoring may not be required in such settings. and only approximately 10% of patients with suspected HIT actually have the
In addition, HIT rarely begins 14 or more days after initiation of a disorder. Fondaparinux also avoids the risk for confounding of aPTT-monitored
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course of heparin, so routine monitoring beyond this period is not DTI therapy. The author is a proponent of the use of fondaparinux to treat HIT.
Lepirudin was discontinued by the manufacturer, April 2012.
d
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required. A more recent consensus conference recommended some-
what less intensive platelet count monitoring than advised in this
paragraph.