A hit to current “hit” wisdom: A century later, it's time for a change

A century after extraction from liver by the medical student Jay McLean of an heparphosphatid anticoagulant–a substance later named “heparin” by his mentor, Professor William Henry Howell and 70 years after its first use in humans by Professor Charles Best in Toronto in 1937, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) continue to be the subject of active research. In 1973, Rhodes et al. first identified heparin-induced thrombocytopenia (HIT) as a syndrome presenting with paradoxical life-threatening thrombotic manifestations and thrombocytopenia, characteristically occurring 5 to 10 days after heparin exposure. The fight against the ominous consequences of HIT, with a mortality rate as high as 20% in the absence of early intervention, has been at the heart of decades of intensive, basic, translational, and clinical research worldwide. Now, we know that HIT is caused by an immune reaction mediated by autoantibodies directed against endogenous platelet factor 4 (PF4) in complex with heparin. HIT antibodies cause dual activation of platelets and monocytes by binding to FCyRIIA, thus inducing platelet intravascular aggregation and intense thrombin generation that may cause catastrophic arterial and venous thrombosis. The current knowledge on this adverse effect caused by heparin and, to a much lower extent, by LMWH has been crystallized in a plethora of guidelines and reviews. It is a tenet of current wisdom that in patients with a reasonable suspicion of HIT, exposure to UFH or LMWH should be immediately eliminated and a non-heparin anticoagulant should be administered even before a definite diagnosis can be made. It is widely assumed that this approach greatly reduces complications. The dissonant paper of Kuter et al. in this issue of the American Journal of Hematology sounds as a dreadful alarm, signaling that exposure to UFH and LMWH still continues to be plagued by an unacceptable burden of thrombotic and bleeding complications, including death. To assess the outcome of HIT in current clinical practice, the Authors undertook, in 19 major medical centers, an 8-month retrospective chart review of all consecutive patients with a clinical suspicion of HIT testing positive to heparin-PF4 ELISA. This test has a very low specificity and positive predictive value, but is extremely sensitive, so that, in the presence of a negative test, HIT can be excluded in 98%-99% of cases. For this reason and for its easy implementation, this test is widely used and was available in all centers participating in this study. More specific tests able to detect the presence of truly pathogenic platelet activating antibodies, like those measuring serotonin release from normal platelets in the presence of a patient’s serum and heparin, unfortunately present technical difficulties and are used only in a few reference centers, making them of scarce utility in current practice. A total of 668 patients with a heparin-PF4 ELISA positive test were tracked, but 226 were excluded from analysis mainly because they had no heparin exposure during all admissions or in the 5 days preceding the test (day 0). Thus, 442 cases with a possible diagnosis of HIT were retained (admitting service: cardiovascular surgery 21%-28%; orthopedic surgery 3%-5%; other surgery 9%-21%; medicine 51%65%). Over 90% of them received UFH and under 25% LMWH, some receiving both. Patients were classified as HIT-T (thrombotic event associated with heparin exposure within the preceding 5 days with/ without thrombocytopenia, N 71); isolated HIT (thrombocytopenia with heparin exposure in the 5 preceding days without new thrombotic events in this period, N 284); no HIT (heparin exposure in the preceding 5 days but not meeting criteria for HIT-T or isolated HIT, N 87). These criteria do not entirely fit the commonly accepted criteria suggested by main guidelines which require, in addition to the positivity of a sensitive test for HIT antibodies, also an intermediate (10%-20%) or high (40%-80%) pre-test clinical probability as calculated with “4T score” or similar scales. “4T score” is based on the typical clinical features of HIT [Thrombocytopenia, Timing of platelet count fall, Thrombosis and exclusion of other causes of thrombocytopenia]. However, by reanalyzing all their cases according to the current consensus criteria including “4T score”, a high correlation was found between the Authors’ and the “4T score” classification. A high or intermediate score could be assigned to 85% of HIT-T, to 58% of isolated HIT, and to 8% of no HIT, respectively. Patients with a low “4T score” were not present in this study. Among patients still on heparin on day 0, heparin was stopped within 3 days in more than 84% of cases and non-heparin