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C H A P T E R 133

HEPARIN-INDUCED THROMBOCYTOPENIA

Theodore E. Warkentin

2,3
Heparin-induced thrombocytopenia (HIT) is the most important in vitro. However, patient-dependent susceptibility factors are also
drug-induced immune-mediated cytopenia for several reasons. First, important, because at most only half of all patients who form platelet-
heparin is a widely used anticoagulant (see Chapter 149). Second, activating antibodies develop HIT.
HIT is relatively common, occurring in approximately 1% to 3% of
postoperative patients, and 0.2% to 0.5% of medical patients, who
receive unfractionated heparin (UFH) derived from porcine intestine PATHOBIOLOGY
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for 7–14 days. Third, HIT frequently causes life- and limb-
threatening venous or arterial thrombosis. Finally, there are several Fig. 133.1 illustrates several features of HIT pathogenesis. Heparin
pitfalls of HIT management, including the potential for thrombocy- binds reversibly and saturably to platelets and can weakly activate
topenia and/or thrombosis to worsen despite stopping heparin, the platelets in vitro through potentiation of α IIb β 3 -mediated outside-in
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high risk for warfarin-associated microthrombosis (most often mani- signaling. In general, the direct platelet-activating effects of heparin,
festing as venous limb gangrene), and the potential for failure of as well as its immunogenicity, are proportional to its molecular mass
approved direct thrombin inhibitor (DTI) therapy because of the and degree of sulfation; consequently, LMWH is less likely to cause
confounding of activated partial thromboplastin time (aPTT)-mon- HIT than UFH. 1,2,6
itored dosing that results from HIT-associated coagulopathies. Platelet activation by HIT antibodies occurs because platelet-
1–3
HIT is caused by platelet-activating immunoglobulin G (IgG) activating HIT-IgG cross-link platelet FcγIIa receptors. The HIT
antibodies that bind to multimolecular complexes of platelet factor antigens reside on large multimolecular complexes formed between
2,3
4 (PF4) bound to heparin. Although anti-PF4/heparin antibodies cationic PF4—a member of the CXC subfamily of chemokines—and
are frequently triggered by heparin therapy, relatively few patients anionic heparin. A unique laboratory characteristic of HIT is that
develop clinically evident HIT. Indeed, a major current problem with high heparin concentrations (10–100 units/mL) inhibit platelet
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4
HIT is its “overdiagnosis” : only 5% to 10% of patients who are activation by the pathogenic IgG ; this laboratory feature is exploited
referred for antibody testing have a serologic profile that supports a in diagnostic testing for HIT (see Diagnosis).
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diagnosis of HIT. The challenge for the clinician is to discern which There is a characteristic timeline that underlies the HIT immune
3
of the (many) patients who develop thrombocytopenia in association response (Fig. 133.2). Formation of pathogenic IgG antibodies is
with heparin therapy really have HIT, a conundrum magnified by surprisingly fast, even in patients who have never previously been
the observation that at most 50% of anti-PF4/heparin antibody– exposed to heparin. Bacterial cell walls, which are negatively charged,
positive patients have “true” HIT, as indicated by the presence of bind PF4, and there is evidence that bacterial infection could be
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platelet-activating IgG antibodies. 1,5 responsible for preimmunization against PF4-dependent antigens.
This could explain both the high frequency of anti-PF4/heparin
immunization and of clinical HIT (i.e., HIT could represent a mis-
EPIDEMIOLOGY directed antibacterial immune response). Although heparin-treated
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patients can form heparin-dependent antibodies of the IgM or IgA
Table 133.1 lists risk factors for HIT. The highest risk for HIT is seen subclass, these are unlikely to cause HIT. 1–3
in patients with multiple interacting risk factors (e.g., females given Excess thrombin generation contributes to the pathogenesis of
postoperative thromboprophylaxis with UFH for 2 weeks [frequency some of the unusual sequelae of HIT, which can include venous
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12
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approximately 5%]). Even higher frequencies (approximately 10%) thromboembolism, warfarin-associated venous limb gangrene,
are reported in patients with ventricular assist devices who are receiv- and overt (decompensated) disseminated intravascular coagulation
ing therapeutic doses of UFH. Ironically, even though the risk for (DIC). Increased thrombin generation in HIT is triggered by the
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HIT appears to be somewhat higher in women (odds ratio, 1.5–2.0), shedding of procoagulant microparticles from platelets activated
HIT is rare in pregnancy, particularly with the use of low-molecular- by HIT antibodies, as well as by the expression of tissue factor
weight heparin (LMWH). The synthetic antithrombin-binding sul- by endothelial cells or monocytes activated by HIT antibodies (see
fated pentasaccharide, fondaparinux, although similarly immunizing Fig. 133.1). 13
as LMWH, is much less likely than LMWH to cause HIT, likely As noted, thrombocytopenia develops in only a minority of
1
because fondaparinux does not usually increase the platelet-activating patients who form HIT antibodies. The variable risk for HIT in
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potential of HIT antibodies. Indeed, fondaparinux appears to be an different patient populations may reflect variations in the susceptibil-
effective treatment for HIT (discussed later). ity of platelets to activation by HIT-IgG and/or differences in the
2,3
Only a minority of patients who form anti-PF4/heparin antibod- levels and immunoglobulin class composition of HIT antibodies.
2,3
ies following heparin treatment develop clinically evident HIT. The Poorly defined clinical factors also influence the risk for HIT, which
proportion of antibody-positive patients who develop HIT ranges occurs more often in surgical patients than in medical or obstetric
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from as high as one-third (e.g., postorthopedic surgery thrombo- patients. Major trauma was more likely than minor trauma to be
prophylaxis with UFH) to as few as 1 in 50 (postcardiac surgery associated with HIT antibody formation and clinical HIT in one
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1,2
patients). Notably, the risk for HIT in postcardiac surgery patients study. There is indirect evidence that formation of stoichiometrically
who receive UFH thromboprophylaxis is only approximately 1% optimal complexes of PF4/heparin influences the risk for immuniza-
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even though as many as 50% to 80% of patients develop detectable tion. The clinical situation influences the type of HIT-associated
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anti-PF4/heparin antibodies within 2 weeks of surgery. In general, thrombosis: venous thromboembolism typically develops in orthope-
those at highest risk for HIT are the subgroup of patients whose anti- dic patients with HIT, whereas thrombosis develops equally often in
PF4/heparin antibodies evince strong platelet-activating properties arteries and in veins in cardiovascular patients with HIT. 1
1973