Note-. Where there was uncertainty over the numbers of patients with HIT, the higher estimated value was indicated in the table, to minimize the bias toward a high frequency of HIT-associated thrombosis (contrast analysis shown in Table 2).

aDetailed clinical data on thrombosis were available only on the subset of patients with cerebrovascular disease (n= 137).

bThromboses diagnosed only at autopsy were not included; one stroke due to paradoxical embolism through patent foramen ovale classified as venous thrombosis. "Another five patients developed venous thrombosis in association with a positive HIPA assay, but the platelet count did not fall by >50%. ineffective testing was used (platelet aggregation without heparin).

Abbreviations: ATE, arterial thromboembolism; EIA, PF4-heparin enzyme-linked immunosorbent assay; HIPA, heparin-induced platelet activation test (aggregation of washed platelets); HIT, heparin-induced thrombocytopenia; LMWH, low molecular weight heparin; MI/ACS, myocardial infarction or acute coronary syndromes; PRP, HIT assay using citrated platelet-rich plasma (PRP/SR, with serotonin release); SRA, serotonin release assay using washed platelets; UFH, unfractionated heparin; VTE, venous thromboembolism.

This risk did not differ whether the heparin had been discontinued, or whether warfarin had been substituted for the heparin. Similar findings were reported from a much smaller earlier study performed in Europe (Boon et al., 1994). This high risk for thrombosis in HIT is also supported by a prospective study (Warkentin et al., 1995), in which five of six HIT patients developed thrombosis either on the first day that their platelet count fell below 150 X 109/L or within the next few days despite the discontinuation of heparin.

Subsequent to the Hamilton study, a report by Wallis and colleagues (1999) from Loyola University confirmed the high risk for thrombosis among patients in whom HIT is identified by platelet count monitoring, even with discontinuation of heparin (Table 7). Overall, the 30-day thrombotic event rate was 43/113 (38%), with a ratio of venous to arterial thrombosis of just 1.4. The relatively low predominance of venous thrombosis could be explained by the large number of patients (59%) in this study who developed HIT following cardiac surgery (i.e., a patient population had relatively high risk for arterial thrombosis).

An intriguing finding of the Wallis report is that early cessation of heparin did not appear to improve clinical outcomes. For 40 of the 113 patients with HIT (35%), heparin was discontinued within 48 h of onset of thrombocytopenia (defined as a platelet count fall to less than 100 X 109/L, or a greater than 50% fall from the peak platelet count after initiating heparin). Indeed, there was a trend to a higher rate of thrombosis in the patients with early heparin cessation, compared with the remaining 65% of patients in whom heparin was stopped later (45% vs. 34%; p = 0.26) (Table 7).

Further evidence supporting an unfavorable natural history of untreated HIT was provided by a large prospective cohort study (Greinacher et al., 2000). These investigators found that the thrombotic event rate was 6.1% per day during the mean 1.7-day interval between diagnosis of HIT (and cessation of heparin) and initiation of lepirudin therapy. This event rate (6.1 X 1.7 = 10.4%) corresponds closely to the 10% rate of thrombosis observed in the Hamilton study in the first 48 h following diagnosis of isolated HIT (Warkentin and Kelton, 1996) (Fig. 2).

Most recently, Zwicker and colleagues (2004) noted a high frequency of thrombosis (~36%) among patients with isolated HIT and a "strong" anti-PF4/ polyanion EIA result (>1.0 OD units).

Taken together, these studies of the natural history of isolated HIT provide the basis for the recent recommendation that prophylactic anticoagulant therapy (in therapeutic doses) is appropriate for most patients strongly suspected (or confirmed) to have isolated HIT (Hirsh et al., 2001; Warkentin and Greinacher, 2004) (see Chapters 1 and 12-15). Other data to support this concept include the high probability of detecting subclinical deep-vein thrombosis by duplex ultrasonography in patients with isolated HIT (Tardy et al., 1999), as well as the persistence of marked in vivo thrombin generation for several days in patients with acute HIT even following discontinuation of heparin (Warkentin et al., 1997; Greinacher et al., 2000).

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