A. The HIT Paradox: Thrombosis but not Hemorrhage

Table 1 summarizes the clinical spectrum and approximate frequency of clinical sequelae associated with HIT. Spontaneous hemorrhage is not characteristic of HIT, and petechiae are not typically observed, even in those occasional patients whose platelet count is less than 10 X 109/L. Bleeding complications were not increased over controls in two prospective studies of HIT (Cipolle et al., 1983; Warkentin et al., 1995).

Rule 4

Petechiae and other signs of spontaneous bleeding are not clinical features of HIT, even in patients with very severe thrombocytopenia.

The explanation for this clinical feature is unknown, but could be related to unique pathophysiological aspects of HIT, such as in vivo platelet activation, generation of procoagulant, platelet-derived microparticles, and procoagulant alterations of endothelium and monocytes (see Chapters 8 and 9).

B. HIT Is a Hypercoagulable State

A large controlled study (Warkentin et al., 1995, 2003) concluded that HIT is independently associated with thrombosis, even in a patient population at a high baseline risk for thrombosis (postoperative orthopedic patients). Moreover, both venous and arterial thrombosis was seen. Thus, HIT can be considered a hypercoagulable state (Table 3), a designation consistent with increased in vivo thrombin generation seen in almost all patients with HIT (Warkentin et al., 1997; Greinacher et al., 2000).

C. Timing of Thrombotic Complications

Thrombosis occurs in association with HIT in at least four ways. Only the last three situations are conventionally considered as HIT-associated thrombosis. First, thrombosis can precede heparin treatment, for which it usually represents the initial indication for heparin therapy. Second, HIT can be the presenting clinical manifestation of HIT, sometimes even occurring prior to the platelet count fall (Greinacher et al., 2005b) (Fig. 8). Indeed, new thrombosis is the initial clinical manifestation in about 40% to 50% of all HIT patients (Warkentin and Kelton, 1996; Greinacher et al., 1999, 2005b).

Third, thrombosis can occur during the period of thrombocytopenia or early platelet count recovery despite discontinuation of the heparin (discussed subsequently). Finally, thrombosis can occur following platelet count recovery (Gallus et al., 1987; Warkentin and Kelton, 1996). In these patients, it is possible that subclinical thrombosis occurred during the thrombocytopenia, but became clinically evident only later. The term heparin-induced thrombocytopenia-thrombosis (syndrome), also known as HITT or HITTS, is sometimes used to describe patients with HIT-associated thrombosis.

Natural History of "Isolated HIT"

There is a high probability of subsequent thrombosis even when heparin administration is stopped because of thrombocytopenia caused by HIT. A retrospective cohort study (Warkentin and Kelton, 1996) identified 62 patients with serologically confirmed HIT in whom the diagnosis was clinically suspected because of throm-bocytopenia alone, and not because of signs and symptoms indicative of possible new thrombosis. Thus, this cohort was identified without an apparent recognition

TABLE 3 The Prothrombotic Nature of HIT: Comparison with Other Hypercoagulable States

Hypercoagulable state Odds ratio for thrombosis

Heparin-induced thrombocytopenia: -

Platelet count <150 x 109/L 36.9

Platelet fall >50% beginning >5 days of heparin 12.4

Platelet fall >50%, but platelet count remains >150x 109/L 6.0

Factor V Leiden 6.6

Congenital protein C deficiency 14.4

Congenital protein S deficiency 10.9

Congenital antithrombin deficiency 24.1

Dysfibrinogenemia 11.3

Lupus anticoagulant 5.4

Source: Warkentin, 1995; Warkentin et al., 1995, 2003.

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