Coagulopathy: What We Know So Far

95 views 5 05/03/2020 05/04/2020

  1. About coagulation and inflammation biochemical parameters:
    • Markedly decreased fibrinogen, high FDP (fibrin degradation product), high D-dimers and increased PT/PTT are observed in COVID-19 non survivors.1,2,3,4,5,6
    • Rapidly rising FDP may be correlated with disease progression and may be a better surrogate marker than D-dimers.1,4,5
    • Plasminogen levels tend to be higher in severe disease and may play a potential role in virulence.2 Patients with hypertension and diabetes tend to have higher baseline levels of plasminogen.2
    • CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), ferritin levels and IL-6 (interleukine-6) tend to be high in non-survivors, suggesting intense inflammation reaction.2,3
  2. About DIC (disseminated intravascular coagulopathy):
    • Data suggest that activation of the pulmonary vascular endothelium, platelets and leucocytes secondary to infection may result in dysregulated thrombin generation both locally in the lungs and systemically, resulting in subsequent microangiopathic pathology.6
    • Hyperfibrinolytic consumptive DIC with bleeding diathesis has not yet been reported, and the use of LMWH at prophylactic doses does not seem to be associated with a risk of bleeding3,4,5. If present, platelet count should be kept above 50 x 109/L (and above 20 x 109/L for non-bleeding patients).5
    • Severe disease is associated with multiorgan failure possibly due to microthrombosis.4,8
  3. About VTE (venous thromboembolisms) and microvascular thrombosis in lungs:
    • Pathology reports have identified both microvascular thrombosis and pulmonary embolisms in a small number of patients. Marked inflammatory changes in the lungs’ environment were seen: mononuclear cell infiltrates, virally infected cells and DAD (diffuse alveolar damage).1,3
    • Microvascular thrombosis in the pulmonary vessels may explain the right heart strain commonly seen on bedside echocardiograms in critically ill patients.8
    • Patients with VTE almost always had elevated D-dimer. Levels of D-dimer decreased gradually with therapeutic doses of heparin therapy.4,9
    • There is current concern that patients may harbour a higher rate of pulmonary embolisms that are missed on imaging studies due to primary lung injury from the virus.4,8
  4. About prophylactic and therapeutic heparin treatments:
    • Prophylactic anticoagulation seems to associated with lower mortality in patients with high D-dimer levels or SIC (sepsis induced coagulopathy criteria) ≥4 (see prophylactic anticoagulation in sepsis induced coagulopathy)
    • It is already known from previous studies on sepsis that high levels of fibrinogen are associated with an increased risk of thrombosis and resistance to heparin treatment.8 Moreover, studies suggest that VTE and microvascular thrombosis may occur despite prophylactic LMWH3. A small study found that most of the patients on prophylactic anticoagulation had VTE, and suggested VTE screening for all patients and prompt consideration for therapeutic anticoagulation.4,10
    • It is postulated that therapeutic anticoagulation may prevent to a certain extent the contribution of microvascular thrombosis to the progressive respiratory failure and allow more time for anti-inflammatory agents to decrease the damage done by ARDS.3 Interestingly, the British Society of Hematology recommends LMWH at therapeutic doses for thrombotic phenotype DIC.8
    • Therefore, it is postulated that therapeutic doses of heparin therapy may be beneficial to some patients. However, due to the lack of evidence and clinical trials, empiric therapeutic doses of LMWH cannot be suggested at the moment.
    • Current clinical trials are evaluating high dose vs. low dose anticoagulation, and more data should be available in the next weeks.
  5. Moreover, some evidence suggests that COVID-19 infection is associated with an increased risk of arterial thrombosis.11
  6. About other coagulopathies:
    • It is possible that COVID-19 infection during pregnancy may be associated with an increased risk of coagulopathy as reported by two case reports.12
    • Possible antiphospholipid syndrome secondary to COVID-19 has been documented in three case reports.13

 

For the moment, practical suggestions could include: 

  • Monitoring FDP and D-dimer;
  • Prophylactic anticoagulation for all patients with LMWH and consideration of higher doses for high body mass index;
  • Rapidly rising FDP or D-dimer should prompt the screening for VTE (doppler of lower limbs and/or PE imaging studies) and subsequent treatment with therapeutic anticoagulation if needed;
  • Keeping in mind that clinical trials are ongoing and evaluating therapeutic anticoagulation for COVID-19 related coagulopathy (without VTE evidence), and that therapeutic anticoagulation may be indicated earlier depending on their results. 

 

Pregnancy related coagulopathy case reports: 1- A 40 year old woman, known for congenital neutropenia and pregnancy complicated by gestational diabetes, neutropenia (0.1-0.3 x 10^9/L) and mild respiratory infections treated with antibiotics. She started G-CSF 4 weeks prior admission. Admitted at 35+3 weeks with cough and temperature (39°C), with normal air sat. SARS-CoV-2 was confirmed by PCR on nasopharyngeal swab. Over 48 hours, she developed progressive thrombocytopenia, declining fibrinogen and rising of coagulation parameters. Neutrophil count increased, but doctors did not know if it was secondary to G-CSF or bacterial infection. Therefore, she was put on piperacillin-tazobactam. No hypertension, hemolysis or proteinuria was noted and HELLP syndrome was unlikely. She underwent c-section under spinal anesthesia. LMWH was initiated 12h later and coagulopathy improved on postoperative day two. 2- A 23 year old woman with no past medical history. She was admitted at 35+2 for cough and pyrexia (38.6°C) and tested positive for SARS-CoV-2 by nasopharyngeal swab. She was found to have new onset of thrombocytopenia, prolonged APTT and transaminitis. She was transferred to a tertiary center in France. Progressive deterioration of coagulation parameters was noted coupled to non-reassuring fetal hart rate. Emergency C-section under general anesthesia was performed. Fibrinogen 3g and tranexamic acid 1g were administered prior to delivery. Coagulopathy resolved on post-op day 1 and no bleeding or clotting diathesis was noted. Prophylactic LMWH was administered on post-op day 1.

Antiphospholipid syndrome case reports: A series of case reports in Wuhan described 3 critically ill patients with SARS-CoV-2 and detection of new antiphospholipid antibodies (Anticardiolipin IgA, anti-β2-glucoprotein 1 IgA and IgG). Clinically, they showed evidence of ischemia in the lower limbs bilaterally as well as in the digits, and bilateral cerebral infarcts in multiple vascular territories on CT. It is unsure if antiphospholipid syndrome was responsible for the multifocal thrombosis.

Sources :

  1. Ji H-L., Zhao R.Z., Matalon S., Matthay M.A. (April 03, 2020). Elevated plasminogen as a common risk factor for COVID-19 susceptibility. Physiological Reviews. https://doi.org/10.1152/physrev.00013.2020
  2. Guan W.J., Ni Z.Y., Liang W.H., Ou C.Q., He J.X., Liu L., Shan H., Lei C.L., Hui D.S.C., Du B., Li L-J. et al. (February 28, 2020). Clinical Charateresticis of Coronavirus Disease 2019 in China. New England Journal of Medicine. DOI: 10.1056/NEJMoa2002032, https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  3. Connors J. (April 17, 2020). Thromboinflammation and the hypercoagulability of COVID-19. Journal of Thrombosis and Haemostasis (JTH). https://doi.org/10.1111/jth.14849
  4. Abutalib A.S.A., Connors J.M. (April 27, 2020). Hypercoagulability in Critically Ill Patients With COVID-19:Where Do We Stand?. The Asco Post. https://www.ascopost.com/news/april-2020/hypercoagulability-in-critically-ill-patients-with-covid-19/b
  5. Thachil J et al. (March 25, 2020) ISTH interim guidance on recognition and management of coagulopathy in COVID19. J Thromb Haemost (https://doi.org/10.1111/JTH.14810)
  6. Han H., Yang L., Liu R., Wu K.L., Liu X.H. (March 16, 2020). Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clinical Chemistry and Laboratory Medicine (CCLM). https://doi.org/10.1515/cclm-2020-0188
  7. Lillicrap D. (March 24, 2020). Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia. Journal of thrombosis and haemostasis. https://doi.org/10.1111/jth.14781
  8. Barrett C. (April 17, 2020). ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment. Journal of Thrombosis and Haemostasis (JTH) https://doi.org/10.1111/jth.14860
  9. Cui S., Chen S., Li X., Wang F. (April 09, 2020). Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. https://doi.org/10.1111/jth.14830
  10. Llitjos KF., Leclerc M., Chochois C., Monsallier JM., Remakers M., Auvray M., Merouani K. (April 22, 2020). High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. Journal of thrombosis and haemostasis. https://doi.org/10.1111/jth.14869
  11. Oxley T.J., Mocco J., Majidi S., Kellner C.P., Shoirah H., Singh I.P., De Leacy R.A., Shigematsu T., Ladner T., Yaeger K.A., Skliut M., Weinberger J., Dangayach N.S., Bederson J.B., Tuhrim S., Fifi J.T. (April 28, 2020). Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. The New England Journal of Medicine NEJM. DOI: 10.1056/NEJMc2009787. https://www.nejm.org/doi/full/10.1056/NEJMc2009787
  12. Koumoutsea E.V., Vivanti A.J., Shehata N., Benchi A., Le Gouez A., Desconclois C., Whittle W., Snelgrove J., Malinowski A.K.  (April 17, 2020). COVID-19 and acute coagulopathy in pregnancy. Journal of Thrombosis and Haemostasis (JTH). DOI: 10.1111/jth.14856
  13. Zhang Y., Xiao M., Zhang S., et al. (April 8, 2020). Coagulopathy and Antiphospholipid Antibodies in Patients with COVID-19. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMc2007575
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