Discussion
HIT is an immune-mediated condition, characterized by platelet drop of 50% or greater, typically within 5 to 10 days of exposure to heparin, leading to hypercoagulability and presence of platelet-activating IgG antibodies.4-6 These antibodies target complexes of PF4 and heparin.6 The IgG-PF4-heparin immune complexes cross-link Fcy (γ) receptors on platelets and monocytes and activate them. Activation of platelets and monocytes increases thrombin generation, leading to thromboembolic complications.4
HIT affects 1 in 5000 hospitalized patients and paradoxically results in a prothrombotic state and usually does not induce bleeding.4 Thromboembolic phenomena are seen in half of the patients with confirmed HIT.4 The mortality rate is around 5% and 10%.6 In our patient with HIT, the diagnosis of venous thromboembolism preceded thrombocytopenia, which is not uncommon. In a series of 408 patients of HIT with thrombosis, 33.5% of patients developed thrombosis before the decrease in platelet counts.7
American Society of Hematology guidelines recommends the use of 4T score to estimate the pretest probability of HIT.6 In those with intermediate or high pretest probability, testing for the presence of HIT antibodies should be done, by using immunoassays or platelet activation assays.4,5
The first step in the management of highly suspected or confirmed HIT is to stop heparin (including heparin flushes), and to initiate a non-heparin anticoagulant, to prevent thrombotic events, in the setting of ongoing massive thrombin generation.4 Available options for anticoagulation include argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant.6 Argatroban is a reversible inhibitor of thrombin5 with a short half-life and is not renally cleared. It is commonly used in the United States for HIT.4 In 2 multicenter trials of patients with HIT, argatroban resulted in reduced composite endpoint of death, amputation, and thrombosis, when compared with historic controls.5 A major concern with argatroban is potential under-anticoagulation in patients with elevated partial thromboplastin time, secondary to additional coagulopathies (hepatic dysfunction, prior anticoagulation with warfarin, consumptive coagulopathy, and more recently, COVID-19).4 Partial thromboplastin time confounding may also occur in the presence of a nonspecific inhibitor (such as lupus anticoagulant).8 This would increase the risk of thrombosis and limb loss. Data supporting the efficacy of argatroban is limited to patients with suspected or confirmed HIT.8,9
A major problem of HIT is its overdiagnosis. Only around 50% of EIA+ sera have platelet-activating properties and, therefore, do not have true HIT.10 Antiphospholipid syndrome has been reported in COVID-19 patients,11 and these patients often test false positive with HIT serology.9 In the ICU setting, HIT explains about 1 out of 100 cases of thrombocytopenia.8 Critically ill patients have other plausible non-HIT mechanisms to explain their thrombocytopenia, including septicemia, consumptive coagulopathy in non-HIT-related pulmonary embolism, or catastrophic antiphospholipid syndrome.8
Many laboratories report EIA results qualitatively as positive or negative.10 Interpretation of this immunoassay is improved with quantitative reporting in the form of OD levels.1,10,12 Higher OD levels correspond to a higher likelihood of true HIT.10 Weak-positive EIA (OD 0.4 to 1 unit) points strongly against the diagnosis of HIT (≤5% have a strong-positive SRA). Patients with EIA OD ≥2 have a ~90% chance of strong-positive SRA.10,12 Accuracy of diagnosing HIT is significantly improved by combining an immunoassay with functional tests, such as platelet activation assays (eg, SRA).4 A negative functional assay essentially rules out HIT.4 Often, SRA is a “send-out test” and results are unavailable to assist with initial decision making.13
Liu et al14 suggested that anti-heparin-PF4 antibodies are induced in critical COVID-19 patients, resulting in HIT. However, OD analysis and SRA were not performed in these patients due to limited resources. Our 4 additional patients with COVID-19 were positive for anti-heparin PF4 antibodies. However, they had a negative confirmatory test. Perhaps, their intermediate to high pretest probabilities was partly related to complications from COVID-19 itself (venous thromboembolism, sepsis, multiorgan dysfunction, and DIC), which led to testing for HIT.
A misdiagnosis of HIT could potentially lead to exposure to alternate anticoagulants with risks of major hemorrhage, nonavailability of reversal agents, a potential increase in thrombosis from discontinuation of heparin, and increased medical expenditure when compared with heparin.13