A hit to current “hit” wisdom: A century later, it's time for a change
Authors: Francesco Rodeghiero
Journal: American Journal of Hematology (2017)

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 Howell1 and 70 years after its first use in humans by Professor Charles Best in Toronto in 1937,2 unfractionated heparin (UFH) and low molecular weight heparin (LMWH) continue to be the subject of active research. In 1973, Rhodes et al.3 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.4 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 Hematology5 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.6 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 thrombocytopenia7, 8]. 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 anticoagulation was started. Argatroban was used in 60% of cases, followed by bivaluridin (25%), fondaparinux (15%), and lepirudin (9%). After an average of 10 days of inpatient administration, most patients, particularly those with HIT-T, were discharged on non-heparin treatment, mainly warfarin. Gloomy results were recorded during a 45-day observation period. The composite endpoint of death, limb amputation/gangrene, and new thrombosis (mainly venous), occurred in 48%, 36%, and 17% of HIT-T, isolated HIT and no HIT, respectively. Most events occurred within 14 days for the 2 HIT groups and, in a substantial proportion of cases, while patients were still on non-heparin anticoagulation. Platelet transfusion (9% in HIT-T, 16% in isolated HIT)—a practice that should be avoided—was associated with an increased risk of vascular events. The overall mortality rate was 20%, without significant differences between the three groups but with an increased risk ratio of HIT-T and HIT vs. no HIT. The prevalence of limb amputation/gangrene and new thrombosis was also higher in HIT patients. An exceedingly and unexpectedly high frequency of major bleeding events (defined as any 24 hours in which ≥ 2 red blood cells units were transfused) was observed while patients were on nonheparin anticoagulation, 47%, 29%, and 29% in HIT-T, isolated HIT and no HIT, respectively. Time-to-event variables analysis showed a concentration of events in the first 2–3 weeks. There was no statistically significant effect of non-heparin anticoagulation on death, limb amputation/gangrene, or major bleeding; surprisingly, a significant positive association with composite endpoint and its new thrombosis component was instead observed. By restricting the analysis to those patients with a high or intermediate “4T score” (that could be assigned to 60 HIT-T and to 166 isolated HIT), the overall results did not change. As discussed by the Authors, their study suffers from several limitations, including the retrospective nature and the non-randomized treatment allocation, together with unavailability of data on factors influencing treatment decisions and the lack of a golden standard laboratory test to confirm HIT. However, the course and clinical manifestations of patients included in the study reflect those of historical studies on HIT.9, 10 Patients classified as no HIT were possibly overtreated with non-heparin anticoagulation, which was instituted in 45% of cases, perhaps for the fear of real HIT and/or a perceived high risk of thrombosis. Unfortunately, no data are provided to justify this policy. Overall, however, HIT treatment was consistent with current guidelines or—more precisely—with how these guidelines are applied in real clinical practice.11 To summarize, some crude facts stand out: major bleeding was confined to patients under non-heparin anticoagulation; thromboembolic events remain frequent; platelet transfusion is still practiced with an increased risk; non-heparin anticoagulation is not associated with a reduction of composite endpoint events in HIT and HIT-T groups and is associated, paradoxically, with a high rate of new thrombosis and bleeding. It remains to be established if, as suggested by the Authors, the high rate of new thrombosis in these patients is due to the decision of preferentially treating with non-heparin anticoagulation those patients perceived at an increased risk of thrombosis. The current clinical practice in the USA reveals a failure in managing HIT, which continues to be plagued by a high bleeding risk, with no apparent benefit from non-heparin anticoagulation. The Authors' suggestion is that an assessment of the relative risk of thrombosis and bleeding in each individual patient should guide the best management strategy. In my opinion, however, a stronger message can be derived from their paper, one that urges a global re-evaluation of the general policy on HIT. While research should continue to more completely unravel its pathogenic mechanisms and to make sensitive and specific tests for its diagnosis more available, the time seems ripe for a more radical paradigm change, mandating the elimination of UFH as much as possible, as is already the case in Europe. We know that LMWH, at least at prophylactic doses, is around 5 to almost 10 times less likely to cause HIT and HIT-associated thromboembolism, with virtual absence of amputations or deaths.12, 13 So, almost 25 years after LMWH was made available in the USA, there are good medical reasons to use it as a first choice for prophylaxis in post-surgery or in medical patients. An “avoid-heparin” protocol was adopted in 2006 at a 450-bed tertiary care hospital in Canada.14 It proved successful in substituting LMWH for UFH for most indications, confining its use to hemodialysis, cardiac surgery, and acute coronary syndrome. Dramatic results were observed after 5 years in comparison to the pre-intervention period. The incidence of confirmed HIT was reduced by 79% and costs associated with its management were reduced by around 80%. No doubt, the recent availability of new oral anticoagulants will benefit more clinical situations in which the treatment or prevention of thrombosis is required. A future free from UFH (apart from limited situations, such as cardiac surgery or to maintain the patency of lines of intravascular devices) seems on the horizon, with the specter of HIT progressively vanishing. Until then, however, hematologists should maintain a high grade of competence in suspecting and managing this deadly syndrome.