What’s the evidence that patients with Covid-19 are at high risk of blood clots?

Although we often think of it as a respiratory disease, emerging evidence suggests that Covid-19, particularly when severe,  is also associated with high risk of thrombotic events, including pulmonary embolism, venous thrombosis, and arterial thrombotic events.1

A Chinese study found that ICU patients with severe Covid-19 had a venous thromboembolism (VTE) incidence of 25%, with disseminated intravascular coagulopathy (DIC) found in the majority of fatal cases.2

A prospective Dutch study involving critically ill ICU patients with Covid-19 reported VTE in 27% and arterial thrombotic events in another 3.7%, despite standard VTE prophylaxis.3 The authors suggested the use of “high prophylactic doses” of anticoagulants in these patients due to concern over hypercoagulability.

An ICU French study also found high frequency of thrombotic complications in Covid-19 patients with ARDS, with 11.7% of patients having pulmonary embolism vs 2.1% in non-Covid-19 patients with ARDS. As with the Dutch study, thrombotic complications occurred despite standard prophylactic anticoagulation.4

Postmortem studies have also shown marked changes in lung microvasculature with the presence of microthrombi, with some calling it “pulmonary intravascular coagulopathy” to distinguish it from DIC.1

A NEJM letter reported 5 Covid-19 patients less than 50 years of age who presented with large vessel stroke symptoms without an alternative explanation.5 Of interest, 2 of these patients had no other symptoms suggestive of Covid-19.  A pre-print article from China reported an acute stroke incidence of 5% in hospitalized patients with Covid-19.6

The finding of a hypercoagulable state in patients with severe Covid-19 is not surprising given the frequent association of this infection with a high inflammatory state and the well-known capability of SARS-CoV-2 to attack the endothelial surfaces of blood vessels. High inflammatory state can promote activation of blood coagulation through release of inflammatory cytokines (eg, IL-6, IL-8, and TNF-alpha).1

Perhaps even more intriguing is the finding of extremely high levels of factor VIII found in some Covid-19 patients which could make them hypercoagulable.7 This phenomenon should be suspected when a patient appears to be resistant to anticoagulation by heparin based on aPTT but not based on anti-Xa assay.7

 Bonus pearl: Did you know that the overall incidence of VTE is lowest among Asians-Pacific islanders, followed by Hispanics and Caucasians, with highest rate among African-Americans? 1 ,8

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  1. Fogarty H, Townsend L, Cheallaigh CN, et al. COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020, https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16749
  2. Cui S, Chen S, Li X, et al. Huang C, Wang Y, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haematol 2020, April 9. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14830
  3. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. https://www.sciencedirect.com/science/article/pii/S0049384820301201?via%3Dihub
  4. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf
  5. Oxley TJ, Mocco J, Majidie S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020, April 28. https://www.nejm.org/doi/full/10.1056/NEJMc2009787?query=featured_home
  6. Li Y, Wang M. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. 2020. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3550025
  7. Beun R, Kusadasi N, Sikma M, et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020, April 20. https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.13230
  8. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res 2009;123 Suppl 4:S11-S17. doi:10.1016/S0049-3848(09)70136-7

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the evidence that patients with Covid-19 are at high risk of blood clots?

Should I use aPTT or anti-Xa levels to monitor my patient on IV heparin infusion?

Despite more than half a century of use unfractionated heparin (UFH), the optimal method to monitor its anticoagulation effect remains unclear, with arguments for and against continued use of activated partial thromboplastin time, aPTT) vs switching to antifactor Xa heparin assay (anti-Xa HA). 1-4

The advantage of aPTT include decades of use and familiarity by providers, and its relative accessibility, ease of automation and cost.1 Its disadvantages include variation among the sensitivities of different aPTT reagents as well as susceptibility to factors that do not reflect intrinsic heparin activity (eg, liver dysfunction, hypercoagulable states). 1,2 Thus patients may receive unnecessarily high or low heparin doses because of physiologic and non-physiologic influences on aPTT.

In contrast, since anti-XA HA measures the inhibition of a single enzyme (factor Xa)1, it is a more direct measurement of heparin activity, with less variability and minimal interference by certain biological factors (eg, lupus anticoagulants). Anti-Xa monitoring may also improve the time to therapeutic anticoagulation and lead to fewer dose adjustments compared to aPTT monitoring.2

The disadvantages of anti-Xa HA include inaccuracy in the setting of hypertriglyceridemia (>360 mg/dL), hyperbilirubinemia (total bilirubin >6.6 mg/dL), recent use of low molecular weight heparin, fondaparinux and direct oral factor Xa inhibitors. Its relative expense and generally less laboratory availability among healthcare facilities may also limit its use in monitoring patients on therapeutic UFH. 1-3

Somewhat unsettling is the frequent discordance between aPTT and anti-Xa values having been reported in 46% to 60% of instances that may result in either thromboembolic or bleeding complications. 1,4 One study reported that aPTT may be therapeutic only 35% of the time that anti-Xa is also therapeutic! 2

What’s clearly missing are definitive studies that can shed light on the clinical impact of these intriguing findings on patient outcomes. So stay tuned!

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  1. Guervil DJ, Rosenberg AF, Winterstein AG, et al. Activated partial thromboplastin time versus antifactory Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother 2011;45:861-68. https://www.ncbi.nlm.nih.gov/pubmed/21712506
  2. Whitman-Purves E, Coons, JC, Miller T, et al. Performance of Anti-factor Xa versus activated partial thromboplastin time for heparin monitoring using multiple nomograms. Clinical and Applied Thromosis/Hemostasis 2018;24:310-16. https://www.ncbi.nlm.nih.gov/pubmed/29212374
  3. Fruge KS, Lee YR. Comparison of unfractionated heparin protocols using antifactory XA monitoring or activated partial thrombin time monitoring. Am J Health-System Pharmacy. 2015; 72: S90-S97, https://doi.org/10.2146/sp150016
  4. Samuel S, Allison TA, Sharaf S, et al. Antifactor XA levels vs activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther 2016;41:499-502.
  5. doi:10.1111/jcpt.12415. https://www.ncbi.nlm.nih.gov/pubmed/27381025
Should I use aPTT or anti-Xa levels to monitor my patient on IV heparin infusion?