Response to The challenges of diagnosing heparin‐induced thrombocytopenia in patients with COVID‐19

We thank May et al1.May J. Siniard R.C. Marques M. The challenges of diagnosing heparin‐induced thrombocytopenia in patients with COVID‐19. Letter to Editor.Res Pract Thromb Haemost. 2020; Abstract Full Text Full Text PDF Scopus (10) Google Scholar for their comments, expanding the number of reported cases of suspected and confirmed heparin‐induced thrombocytopenia (HIT) associated with coronavirus disease 2019 (COVID‐19), and reemphasizing the complexity of the prothrombotic state observed. 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.Riker R.R. May T.L. Fraser G.L. Gagnon D.J. Bandara M. Zemrak W. et al.Heparin‐induced thrombocytopenia with thrombosis associated with COVID‐19 adult respiratory distress syndrome.Res Pract Thromb Haemost. 2020; 4: 936-941Crossref PubMed Scopus (35) Google Scholar 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.Warkentin T.E. Nazy I. Sheppard J.I. Smith J.W. Kelton J.G. Arnold D.M. Serotonin‐release assay‐negative heparin‐induced thrombocytopenia.Am J Hematol. 2020; 95: 38-47Crossref PubMed Scopus (30) Google Scholar, 4.Vayne C. Guery E.A. Kizlik‐Masson C. Rollin J. Bauters A. Gruel Y. et al.Beneficial effect of exogenous platelet factor 4 for detecting pathogenic heparin‐induced thrombocytopenia antibodies.Br J Haematol. 2017; 179: 811-9Crossref PubMed Scopus (40) Google Scholar, 5.Pandya K.A. Johnson E.G. Davis G.A. Padmanabhan A. Serotonin release assay (SRA)‐negative HIT, a newly recognized entity: implications for diagnosis and management (Letter).Thromb Res. 2018; 172: 169-71Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 6.Padmanabhan A.n.a.n.d. Jones C.u.r.t.i.s. .G. Curtis B.r.i.a.n. .R. Bougie D.a.n.i.e.l. .W. Sullivan M.i.a. .J. Peswani N.a.m.r.a.t.a. et al.A novel PF4‐dependent platelet activation assay identifies patients likely to have heparin‐induced thrombocytopenia/thrombosis.Chest. 2016; 150: 506-15Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Though not yet standardized, SRA‐negative HIT may be considered when clinical suspicion for HIT is high (4Ts score ≥ 6) with an EIA optical density > 1.00, or intermediate (4Ts score 4 or 5) with an optical density ≥ 2.00,3.Warkentin T.E. Nazy I. Sheppard J.I. Smith J.W. Kelton J.G. Arnold D.M. Serotonin‐release assay‐negative heparin‐induced thrombocytopenia.Am J Hematol. 2020; 95: 38-47Crossref PubMed Scopus (30) Google Scholar, 6.Padmanabhan A.n.a.n.d. Jones C.u.r.t.i.s. .G. Curtis B.r.i.a.n. .R. Bougie D.a.n.i.e.l. .W. Sullivan M.i.a. .J. Peswani N.a.m.r.a.t.a. et al.A novel PF4‐dependent platelet activation assay identifies patients likely to have heparin‐induced thrombocytopenia/thrombosis.Chest. 2016; 150: 506-15Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar especially if the clinical course is highly suggestive of HIT (eg, 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 SRA‐negative HIT, so our contention remains possible, but not confirmed. Testing to confirm SRA‐negative HIT might include adding exogenous human PF4,4.Vayne C. Guery E.A. Kizlik‐Masson C. Rollin J. Bauters A. Gruel Y. et al.Beneficial effect of exogenous platelet factor 4 for detecting pathogenic heparin‐induced thrombocytopenia antibodies.Br J Haematol. 2017; 179: 811-9Crossref PubMed Scopus (40) Google Scholar or using a flow cytometry PF4‐dependent P‐selectin expression assay.6.Padmanabhan A.n.a.n.d. Jones C.u.r.t.i.s. .G. Curtis B.r.i.a.n. .R. Bougie D.a.n.i.e.l. .W. Sullivan M.i.a. .J. Peswani N.a.m.r.a.t.a. et al.A novel PF4‐dependent platelet activation assay identifies patients likely to have heparin‐induced thrombocytopenia/thrombosis.Chest. 2016; 150: 506-15Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar May et al also cite the review by Connors and Levy,7.Connors J.M. Levy J.H. COVID‐19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-40Crossref PubMed Scopus (0) Google Scholar which does not mention HIT as a potential contributor to the prothrombotic state associated with COVID‐19; 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 severe acute respiratory syndrome coronavirus 2.7.Connors J.M. Levy J.H. COVID‐19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-40Crossref PubMed Scopus (0) Google Scholar Although inflammation undoubtedly contributes, additional mechanisms must be considered. Cross‐reactivity of specific antiviral antibodies with PF4, leading to a catastrophic thrombotic environment, has been proposed (Hillen H, personal communication, June 5, 2020 [[email protected]]). This was previously documented during clinical trials with a humanized monoclonal IgG1 antibody for Alzheimer disease (ABT‐736), halting its development.8.Almagro J.C. Gilliland G.L. Breden F. Scott J.K. Sok D. Pauthner M. et al.Antibody engineering and therapeutics, The Annual Meeting of the Antibody Society: December 8–12, 2013, Huntington Beach, CA.MAbs. 2014; 6: 577-618Crossref PubMed Scopus (4) Google Scholar If this mechanism is confirmed, supplementing antiviral 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 cannot be obtained.7.Connors J.M. Levy J.H. COVID‐19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-40Crossref PubMed Scopus (0) Google Scholar 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.