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Clinical Picture of Heparin-Induced Thrombocytopenia

Theodore E. Warkentin

Michael G. DeGroote School of Medicine, McMaster University, and Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada


Heparin-induced thrombocytopenia (HIT) is a distinct clinicopathologic syndrome caused by platelet-activating antibodies that recognize complexes of platelet factor 4-heparin (PF4/H). Its strong association with venous and arterial thrombosis represents a striking paradox. However, thrombocytopenia itself is common in clinical medicine. Furthermore, heparin is usually given to patients who either have thrombosis, or who are judged to be at high risk for thrombosis. Thus, thrombocytopenia with or without thrombosis during heparin treatment does not necessarily indicate a diagnosis of HIT. Indeed, several disorders can closely resemble HIT (see Chapter 11).

On the other hand, HIT is associated with a wide spectrum of unusual thrombotic and other complications (Table 1). Unrecognized HIT may have been an important contributing factor in otherwise bizarre clinical events that have occurred in certain heparin-treated patients (Anderson et al., 1981; Solomon et al., 1988; Pfueller et al., 1990; Muntean et al., 1992). Laboratory documentation of HIT antibodies has been crucial in determining the clinical scope of the HIT syndrome. Accordingly, this chapter emphasizes clinical data obtained from large prospective and retrospective studies that have used diagnostic testing for HIT antibodies.

Estimated frequencies of the various complications of HIT are taken from reports with serological confirmation of the diagnosis (Warkentin et al., 1995, 1997; Warkentin and Kelton, 1996). "Rare" indicates an estimated frequency <3% of HIT patients.


Thrombocytopenia, using the standard definition of a platelet count of less than 150 X 10 /L, is the most common clinical effect of HIT, occurring in 85-90% of patients (Warkentin, 1998a). An even higher proportion develops "thrombo-cytopenia" if a definition appropriate for the clinical situation is used.

A. Timing

The characteristic delay of 5 or more days between initiation of heparin and onset of thrombocytopenia was the major clue that led early investigators to recognize the immune pathogenesis of HIT (Roberts et al., 1964; Rhodes et al., 1973). King and Kelton (1984) noted that thrombocytopenia occurred between days 6 and 15 for more than 90% of patients in whom HIT occurred during their first exposure to heparin. In contrast, for patients who developed HIT during a repeat course of heparin, the onset of thrombocytopenia was often more rapid, occurring within 2 days. These data have been interpreted as indicating an "anamnestic"

TABLE 1 Thrombotic and Other Sequelae of HIT

Venous thrombosis

Arterial thrombosis


DVT (50%): new, progressive, recurrent; lower limb (often bilateral); upper limb (at site of venous catheter); phlegmasia cerulea dolens Coumarin-induced venous limb gangrene (~5-10% of DVT treated with warfarin) Pulmonary embolism (25%): with or without right-sided cardiac intra-atrial or intraventricular thrombi Cerebral dural sinus thrombosis (rare) Adrenal hemorrhagic infarction (rare): bilateral (acute or chronic adrenal failure) or unilateral DIC, with hypofibrinogenemia deficiency, causing multiple

Aortic or iliofemoral thrombosis resulting in acute limb ischemia/infarction (5-10%) or spinal cord infarction (rare)

Acute thrombotic stroke (3-5%)

Myocardial infarction (3-5%) Cardiac intraventricular or intra-atrial thrombosis, in situ or via embolization of DVT (rare) Thrombosis involving miscellaneous arteries (rare): upper limb, renal, mesenteric, spinal, and other arteries Embolization of thrombus from heart or proximal aorta can also contribute to microvascular ischemic syndromes and acquired natural anticoagulant venous and arterial thromboses (rare)

Heparin-induced skin lesions at heparin injection sites (10-20%): Erythematous plaques Skin necrosis Coumarin-induced skin necrosis complicating HIT involving "central" sites (breast, abdomen, thigh, leg, etc.) (rare) Acute systemic reactions postintravenous heparin bolus (~25% of sensitized patients who receive an intravenous heparin bolus): Inflammatory: e.g., fever, chills, flushing Cardiorespiratory: e.g., tachycardia, hypertension, dyspnea; cardiopulmonary arrest (rare) Gastrointestinal: nausea, vomiting, diarrhea Neurological: transient global amnesia, headache

Abbreviations: DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis.

(Gr., memory) or "secondary" immune response in HIT; i.e., the immune system produces HIT antibodies more quickly on reencountering an antigen "remembered" within its memory cell repertoire. Recent data, however, suggest another explanation for these two temporal profiles of HIT, typical and rapid (discussed subsequently).

Typical Onset of HIT

A prospective study of serologically confirmed HIT showed that the platelet count typically begins to fall between days 5 and 10 (inclusive) of postoperative subcutaneous heparin prophylaxis (Warkentin et al., 1995, 2003) (Fig. 1). Note that the data refer to the day the platelet count begins to fall, and not the later day on which an arbitrary threshold defining thrombocytopenia is crossed. This study also showed that most patients who developed thrombocytopenia beginning after day 5 had HIT rather than another explanation for the thrombocytopenia. The data suggest the following clinical rule:

Rule 1

A thrombocytopenic patient whose platelet count fall began between days 5 and 10 of heparin treatment (inclusive) should be considered to have HIT unless proved otherwise (first day of heparin use is considered "day 0").

HIT-IgG antibodies generally are not detectable before day 5 of heparin treatment, but are readily detectable using sensitive assays when the platelet count first begins to fall due to HIT.

A recent study (Warkentin and Kelton, 2001a) that analyzed temporal aspects of the platelet count fall in 243 patients with serological confirmed HIT in

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