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CHAPTER 118 complex. In the early 1990s, this complex was identified as heparin
bound to the platelet-specific chemokine, platelet factor 4 (PF4). Over
6
HEPARIN-INDUCED the past 20 years, additional insights into the mechanism(s) underlying
this immune complex disorder have emerged that have advanced our
THROMBOCYTOPENIA understanding of why this disorder is particularly prothrombotic and
occurs in a only a small subset of patients. Additionally, advances have
been made on the clinical side with respect to prevention, diagnosis,
and treatment.
Adam Cuker and Mortimer Poncz
EPIDEMIOLOGY

The frequency of HIT in heparin-treated patients ranges from less than
SUMMARY 0.1 percent to 5.0 percent, depending on patient- and heparin-specific
risk factors. These include the patient population, gender, nature of the
Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication heparin used, and duration of heparin exposure (Table 118–1).
of treatment with heparin. It is associated with mild-to-moderate throm- The most important determinant of risk is the patient population.
bocytopenia, although the main clinical concern is the high frequency of In a meta-analysis of seven prospective studies, the incidence of HIT
both arterial and venous thromboembolism, which may be limb- or life- was greater among surgical than medical patients (odds ratio [OR]:
7
threatening. HIT is an immune complex-based disorder involving platelet 3.25; 95 percent confidence interval [CI]: 1.98 to 5.35). The incidence of
factor 4 complexed to negatively charged multimeric molecules, especially HIT approaches 5 percent in patients who receive unfractionated hepa-
8
surface heparan side chains. It is initiated by exposure to heparin, particularly rin (UFH) after major orthopedic surgery. Patients undergoing surgery
with cardiopulmonary bypass have a very high frequency of anti-PF4/
unfractionated heparin. There is growing understanding of the unusual nature heparin antibody seroconversion (50 to 75 percent by postoperative day
of the underlying immune response in HIT, why certain individuals develop 10), but a lesser incidence of HIT (0.5 to 1.0 percent). 8–10 HIT occurs
this disorder, and why HIT is prothrombotic. Diagnosis is based upon an assess- in 0.5 to 1.0 percent of medical patients and in less than 0.1 percent
7
ment of clinical probability and specialized laboratory testing. Management of pregnant women 11,12 and children. In a randomized trial of trauma
13
involves immediate cessation of heparin and initiation of parenteral inhibitors patients, major trauma was associated with a significantly greater inci-
of thrombin or factor Xa. dence of HIT than minor trauma (2.2 percent vs. 0.0 percent, p = 0.01)
despite identical heparin exposure. 14
Female sex is also a risk factor for HIT. A meta-analysis found an
approximately twofold greater risk of HIT in women than men (OR:
DEFINITION AND HISTORY 2.37; 95 percent CI: 1.37 to 4.09). Analyses of a German database
and a randomized trial of UFH versus low-molecular-weight heparin
Heparin-induced thrombocytopenia (HIT) is a complication of heparin (LMWH) after orthopedic surgery yielded similar findings. 7
therapy in which there is a fall in platelet count and an unusually high HIT is more common with UFH than LMWH in surgical patients.
incidence of arterial and/or venous thromboembolic complications in In a meta-analysis of 15 studies, primarily involving orthopedic surgery
association with heparin therapy. patients, the incidence of HIT with UFH and LMWH was 2.6 percent
Although clinical usage of heparin as an anticoagulant began in and 0.2 percent, respectively. Data are conflicting on whether the risk
15
the late 1950s, it was not until the early 1970s that a small percentage of HIT is reduced with LMWH in medical patients. 7,16,17 Fondapari-
of treated patients were noted to develop a complication consisting of nux, a synthetic pentasaccharide anticoagulant, is associated with a
thrombocytopenia with paradoxical, life-threatening thromboemboli nearly negligible risk of HIT, although several cases of fondaparinux-
(for a historical review see Ref. 1). In the 1980s, it became clear that HIT associated HIT have been reported. 18
was caused by immunoglobulin (Ig) G antibodies that activate platelets. Duration of heparin exposure also influences the risk of HIT. In a
It was also recognized that HIT could be divided into two types, the meta-analysis of 3529 patients receiving UFH thromboprophylaxis for
classic immune-mediated prothrombotic disease that is the focus of this 6 or more days, the incidence of HIT was 2.6 percent. Review of a hos-
15
chapter (formerly called HIT type II), and a benign nonimmune con- pital database indicated that briefer courses induce a substantially lower
dition associated with a mild, immediate, and transient drop in platelet incidence of HIT (0.2 percent). 19
count and no increased risk of thrombosis (formerly called HIT type I). High-quality data on the impact of dose and route of administra-
2
In this chapter, “HIT” means the immune-mediated form of the disease. tion of heparin on the risk of HIT are lacking. Some studies suggest a
In the 1970s and 1980s, it became clear that HIT antibodies acti- lower rate of HIT with prophylactic dose subcutaneous UFH than ther-
19
vated both platelets and endothelial cells. Further analysis showed apeutic dose intravenous UFH, but these analyses are confounded by
3,4
that blocking platelet FcγRIIA inhibited platelet activation by HIT differences in the patients that receive these treatments including the
sera in vitro, suggesting that platelet activation involved an immune clinical indication for heparin. Rarely, HIT has been reported with very
5
low doses of heparin such as with use of heparin flushes or heparin-
bonded catheters. 20,21
Acronyms and Abbreviations: CI, confidence interval; DIC, disseminated intra- ETIOLOGY AND PATHOGENESIS
vascular coagulation; GAG, glycosaminoglycan; HIT, heparin-induced thrombocyto-
penia; INR, international normalized ratio; LMWH, low-molecular-weight heparin; The development of HIT antibodies is nonclassical in that these anti-
MTHFR, methylenetetrahydrofolate reductase; PF4, platelet factor 4; UFH, unfrac- bodies typically begin as IgG and not IgM, may disappear after a few
22
tionated heparin. months, and may not reappear with heparin reexposure. It has been
23
proposed that the initial antigen exposure involves PF4 complexed with

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