Differentiating biochemical from clinical heparin resistance in COVID-19
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LETTER TO THE EDITOR
Differentiating biochemical from clinical heparin resistance in COVID‑19 Ton Lisman1 · Jecko Thachil2
© Springer Science+Business Media, LLC, part of Springer Nature 2020
With interest, we read the recent paper by White and coworkers in which heparin resistance in patients with COVID19 patients on the intensive care unit was described [1]. Accumulating evidence shows that patients with COVID-19 are at high risk for thrombotic events, even those that receive normal to increased doses of thromboprophylaxis with low molecular weight heparin or unfractionated heparin [2, 3]. The observation that thromboprophylaxis doesn’t prevent thrombotic events in a proportion of patients suggests that thromboprophylactic heparins insufficiently downregulate coagulation. White et al. demonstrate a failure to achieve heparin target levels as measured by APTT or anti-Xa assays. In addition, spiking of patient plasma with LMWH led to a lower than expected anti-Xa levels in plasma. These observations led the authors to conclude COVID-19 patients are heparin resistant. We wish to comment on the concept of heparin resistance, and offer an alternative explanation for the findings presented by White et al. Heparin resistance would ideally be defined as a decreased capacity of unfractionated or lowmolecular weight heparin to downregulate coagulation in a thrombotic environment. In a heparin-responsive patient, adequate downregulation of coagulation leads to a hemostatic state that, depending on the heparin dose, prevents or treats thrombotic events. In a heparin-resistant patient, inadequate downregulation of coagulation would lead to a sustained risk of thrombotic events in patients receiving thromboprophylaxis, or a lack of response in patients with an acute event. However, the biochemical response to heparins * Ton Lisman [email protected] 1
Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, BA33, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Department of Haematology, Manchester University Hospitals, Oxford road, Manchester, UK
2
is poorly defined in clinical practice. Functional tests to assess downregulation of coagulation by heparins are not yet available for clinical use. Such tests include thrombin generation tests that are able to assess functional efficacy of heparins by assessing thrombin generation in samples taken from patients prior to and while on heparin therapy. The proportional decrease of thrombin generation would be an indicator for the anticoagulant efficacy of heparin, and inadequate downregulation of coagulation would then qualify as ‘biochemical heparin resistance’. In clinical practice, however, heparin resistance is defined by unusually high heparin doses required to reach target APTT or anti-Xa levels in combination with a failure of heparins to prevent or treat thrombotic events. Heparin resistance is common, with a 22% incidence in patients undergoing cardiac surgery with
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