key: cord-0833240-q1975uhv
authors: Riker, Richard R.; May, Teresa L.; Fraser, Gilles L.; Gagnon, David J.; Bandara, Mahesh; Zemrak, Wes; Seder, David B.
title: Response to The challenges of diagnosing heparin‐induced thrombocytopenia in patients with COVID‐19
date: 2020-07-09
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12417
sha: 632b8b8dd32975d8cf61b17f04344635fdcc0aec
doc_id: 833240
cord_uid: q1975uhv

We thank May et al for their comments, expanding the number of reported cases of suspected and confirmed heparin‐induced thrombocytopenia (HIT) associated with COVID‐19, and reemphasizing the complexity of the prothrombotic state observed (1). We agree that false‐positive enzyme immunoassay (EIA) detection of anti‐platelet factor 4 (PF4)/heparin antibodies could explain the results we observed in patients #2 and #3 (2), and this has been the conventional interpretation when functional testing (such as the serotonin‐release assay [SRA]) returns negative. We suggested that a false negative SRA result could have explained our findings, as opposed to the contention by May et al that we concluded they were falsely positive, to broaden our discussion about SRA‐negative HIT, a relatively new and evolving clinical condition (3‐6).

This article is protected by copyright. All rights reserved We thank May et al for their comments, expanding the number of reported cases of suspected and confirmed heparin-induced thrombocytopenia (HIT) associated with COVID-19, and reemphasizing the complexity of the prothrombotic state observed (1) . We agree that false-positive enzyme immunoassay (EIA) detection of anti-platelet factor 4 (PF4)/heparin antibodies could explain the results we observed in patients #2 and #3 (2) , and this has been the conventional interpretation when functional testing (such as the serotonin-release assay [SRA]) returns negative. We suggested that a false negative SRA result could have explained our findings, as opposed to the contention by May et al that we concluded they were falsely positive, to broaden our discussion about SRAnegative HIT, a relatively new and evolving clinical condition (3-6).

Though not yet standardized, SRA-negative HIT may be considered when clinical suspicion for HIT is high (4T score ≥6) with an EIA optical density >1.00, or intermediate (4T score 4 or 5) with an optical density ≥2.00 (3, 6) , especially if the clinical course is highly suggestive of HIT (e.g. an appropriate rise in platelet count after stopping heparin or thromboses occurring while receiving heparin). Neither our patient #3 nor the seven patients presented by May et al met these definitions, and we did not perform any of the proposed adaptations of functional testing to confirm SRAnegative HIT, so our contention remains possible, but not confirmed. Testing to confirm SRAnegative HIT might include adding exogenous human PF4 (4), or using a flow cytometry PF4dependent P-selectin expression assay (6).

May et al also cite the review by Connors and Levy, which does not mention HIT as a potential contributor to the prothrombotic state associated with COVID-19 (7); we would highlight two additional concerns regarding this otherwise comprehensive review. They propose that inflammation, rather than any specific property of the virus, explains the coagulation abnormalities seen with SARS-CoV-2 (7). Although inflammation undoubtedly contributes, additional mechanisms must be considered. Cross-reactivity of specific anti-viral antibodies with PF4, leading to a catastrophic thrombotic environment, has been proposed (8) . This was previously documented during clinical trials with a humanized monoclonal IgG1 antibody for Alzheimer's disease (ABT-736), halting its development (9) . If this mechanism is confirmed, supplementing anti-viral antibodies with convalescent plasma may have unexpected adverse consequences. Additionally, Connors and Levy propose empiric escalation of heparin to treatment levels when sudden respiratory decompensation, right ventricular strain, or peripheral thrombosis is noted and imaging to test for pulmonary embolism Accepted Article cannot be obtained (7) . If HIT is not considered and excluded in this situation, continuing heparin may have life-threatening consequences.

We agree with May et al that functional platelet assays should be included when assessing for HIT, and would modify their proposal with two additional recommendations:

1. HIT must be considered and assessed in patients treated with prophylactic or therapeutic doses of heparin or low molecular weight heparin when thrombocytopenia or new thromboses occur.

2. SRA-negative HIT is an uncommon but real entity that should be considered in patients with high clinical suspicion and a negative standard functional assay for HIT.

The authors declare nothing to report.

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