Stroke and Thromboprophylaxis in the Era of COVID-19

Abstract

In the rapidly evolving COVID-19 pandemic, many patients presenting with acute ischemic stroke may be potentially infected with the Severe Acute Respiratory Syndrome Coronavirus (SARS CoV-2) agent. As stroke patients are often unable to give an adequate history of preceding COVID-19 symptoms, all stroke patients in areas with high prevalence of community transmission should be considered potential cases. Observational studies have suggested an increased tendency for thrombotic events in patients infected with SARS CoV-2. These events include cryptogenic strokes with large vessel occlusion predominance,1Oxley T.J. Mocco J. Majidi S. et al.Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.New England Journal of Medicine. 2020; 382: e60Crossref PubMed Scopus (1355) Google Scholar,2Yaghi S, Ishida K, Torres J, et al. SARS2-CoV-2 and Stroke in a New York Healthcare System. Stroke;0:STROKEAHA.120.030335.Google Scholar deep-vein thrombosis (DVT) and pulmonary embolism (PE).3Poissy J. Goutay J. Caplan M. et al.Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence.Circulation. 2020; Crossref PubMed Scopus (711) Google Scholar, 4Klok F.A. Kruip M. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2726) Google Scholar, 5Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost. 2020; 18: 1023-1026Crossref PubMed Scopus (1124) Google Scholar Acute ischemic stroke is associated with rates of DVT as high as 50%,6Kelly J. Rudd A. Lewis R. Hunt B.J. Venous thromboembolism after acute stroke.Stroke. 2001; 32: 262-267Crossref PubMed Scopus (201) Google Scholar in the absence of COVID-19. Although acute stroke management algorithms in the COVID-19 pandemic have been proposed,7Nguyen T.N. Abdalkader M. Jovin T.G. et al.Mechanical Thrombectomy in the Era of the COVID-19 Pandemic: Emergency Preparedness for Neuroscience Teams.Stroke. 2020; 51: 1896-1901Crossref PubMed Scopus (77) Google Scholar, 8Cervantes-Arslanian A. Lau K.H.V. Anand P. et al.Rapid Dissemination of Protocols for Managing Neurology Inpatients with COVID-19.Ann Neurol. 2020; Crossref PubMed Scopus (4) Google Scholar, 9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar it is as important to review updated information on thromboprophylaxis during the COVID-19 pandemic for acute stroke patients and to develop practice guidance for the prevention of DVT and PE in this population. Acute ischemic stroke patients have a high risk of developing DVT and PE. Without prophylaxis, the risk of developing DVT is estimated at 50% within two weeks after the presenting stroke,6Kelly J. Rudd A. Lewis R. Hunt B.J. Venous thromboembolism after acute stroke.Stroke. 2001; 32: 262-267Crossref PubMed Scopus (201) Google Scholar This risk is greatest in the first week after the stroke and can lead to potentially fatal PE. Patients with hemiparesis or atrial fibrillation are at increased risk of developing DVT.6Kelly J. Rudd A. Lewis R. Hunt B.J. Venous thromboembolism after acute stroke.Stroke. 2001; 32: 262-267Crossref PubMed Scopus (201) Google Scholar Untreated symptomatic DVT can also result in post-thrombotic syndrome. International guidelines currently recommend pharmacologic prophylaxis for venous thromboembolism for acute stroke patients with restricted mobility9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar (see Table 1).Table 1Standard post stroke DVT ProphylaxisConditionModification of Treatment After intravenous thrombolysisIPC on admission,*IPC contraindicated in patients with dermatitis, established DVT, leg ulcer, severe edema, severe peripheral vascular disease and CHF anticoagulation delayed until 24 hours after intravenous thrombolysis No intravenous thrombolysisIPC on admission,*IPC contraindicated in patients with dermatitis, established DVT, leg ulcer, severe edema, severe peripheral vascular disease and CHF low-dose LMWH/heparin Already on anticoagulationIPC on admission,*IPC contraindicated in patients with dermatitis, established DVT, leg ulcer, severe edema, severe peripheral vascular disease and CHF low-dose LMWH/heparin added only if full-dose anticoagulation is stopped Contraindication to anticoagulationIPC alone*IPC contraindicated in patients with dermatitis, established DVT, leg ulcer, severe edema, severe peripheral vascular disease and CHF IPC contraindicated in patients with dermatitis, established DVT, leg ulcer, severe edema, severe peripheral vascular disease and CHF Open table in a new tab A thigh-length intermittent pneumatic compression (IPC) device is recommended for most patients.6Kelly J. Rudd A. Lewis R. Hunt B.J. Venous thromboembolism after acute stroke.Stroke. 2001; 32: 262-267Crossref PubMed Scopus (201) Google Scholar In the CLOTS 3 trial, the use of IPC compared to no IPC reduced the rate of DVT by 3.6% (95% CI 1.4–5.8)10Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial.The Lancet. 2013; 382: 516-524Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar , including both symptomatic and asymptomatic DVT. While the patients treated with IPC had a higher rate of skin breaks, no major adverse effects were seen.10Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial.The Lancet. 2013; 382: 516-524Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar Contraindications to IPC include patients with dermatitis, leg ulcers, severe edema, severe peripheral vascular disease and congestive heart failure10. They should not be used in patients with an established DVT. The risk of DVT is reduced even further with the combination of pharmacological prophylaxis and IPC.11Kakkos S.K. Caprini J.A. Geroulakos G. et al.Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism.Cochrane Database Syst Rev. 2016; 9CD005258PubMed Google Scholar For patients with no contraindications, pharmacological prevention options include low molecular weight heparin (LMWH) or subcutaneous low-dose unfractionated heparin (UFH).12Hirsh J. Bauer K.A. Donati M.B. Gould M. Samama M.M. Weitz J.I. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008; 133: 141S-159SAbstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar, 13Harenberg J. Kallenbach B. Martin U. et al.Randomized controlled study of heparin and low molecular weight heparin for prevention of deep-vein thrombosis in medical patients.Thrombosis Research. 1990; 59: 639-650Abstract Full Text PDF PubMed Scopus (115) Google Scholar, 14Sherman D.G. Albers G.W. Bladin C. et al.The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.The Lancet. 2007; 369: 1347-1355Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar LMWH has a longer duration of action and more predictable pharmacodynamics when compared to UFH.12Hirsh J. Bauer K.A. Donati M.B. Gould M. Samama M.M. Weitz J.I. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008; 133: 141S-159SAbstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar Additionally UFH carries higher risk of heparin-induced thrombocytopenia15Shorr A.F. Jackson W.L. Sherner J.H. Moores L.K. Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest. 2008; 133: 149-155Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar compared to LMWH. In a meta-analysis by Shorr et al, the use of LMWH compared to UFH was associated with a significant risk reduction for VTE, with an odds ratio (OR) of 0.54 (95% CI 0.41–0.70, p < 0.001) and PE (OR, 0.26; 95% CI 0.07–0.95; p = 0.042).15Shorr A.F. Jackson W.L. Sherner J.H. Moores L.K. Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest. 2008; 133: 149-155Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Despite these studies the overall benefit of pharmacological thromboprophylaxis in stroke patients is inconclusive as a mortality or functional status improvement is not seen on follow up.9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar While there is a lower risk of DVT with LMWH or UFH, this is offset by an increased risk of symptomatic bleeding.9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar,16Dennis M. Caso V. Kappelle L.J. Pavlovic A. Sandercock P. European Stroke O. European Stroke Organisation (ESO) guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke.Eur Stroke J. 2016; 1: 6-19Crossref PubMed Scopus (32) Google Scholar In a meta-analysis by Whiteley et al. reduction in mortality was not documented with LMWH or UFH prophylaxis in stroke patients.17Whiteley W.N. Adams Jr., H.P. Bath P.M. et al.Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials.Lancet Neurol. 2013; 12: 539-545Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Guidelines recommend that where pharmacological prophylaxis is used, it should be delayed for 24 hours after the administration of thrombolytic therapy.18Lansberg M.G. O'Donnell M.J. Khatri P. et al.Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 141 (e601S-e36S)Abstract Full Text Full Text PDF Scopus (365) Google Scholar COVID-19 has been associated with prominent features of widespread inflammation and a prothrombotic coagulopathy.5Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost. 2020; 18: 1023-1026Crossref PubMed Scopus (1124) Google Scholar,19Klok F.A. Kruip M. van der Meer N.J.M. et al.Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.Thromb Res. 2020; 191: 148-150Abstract Full Text Full Text PDF PubMed Scopus (1172) Google Scholar The rate of thrombotic complications in patients with severe COVID-19-related pneumonia admitted to an ICU was reported to be as high as 49%.4Klok F.A. Kruip M. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2726) Google Scholar,19Klok F.A. Kruip M. van der Meer N.J.M. et al.Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.Thromb Res. 2020; 191: 148-150Abstract Full Text Full Text PDF PubMed Scopus (1172) Google Scholar These events include both venous (96.3%) and arterial (3.7%) events. Other centers have reported rates of DVT of 25%20Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1101) Google Scholar and PE of 20.6%.3Poissy J. Goutay J. Caplan M. et al.Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence.Circulation. 2020; Crossref PubMed Scopus (711) Google Scholar These rates may be underreported due to incomplete follow-up in patients that were still hospitalized at the time of these publications. Poissy et al. reported that over 90% of patients who later developed PE were already on thromboprophylaxis.3Poissy J. Goutay J. Caplan M. et al.Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence.Circulation. 2020; Crossref PubMed Scopus (711) Google Scholar COVID-19 has been associated with several coagulation abnormalities. The most common are elevated rates of D-dimer, which is indicative of increased thrombin generation and has been correlated with mortality.5Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost. 2020; 18: 1023-1026Crossref PubMed Scopus (1124) Google Scholar, 21Thachil J. The versatile heparin in COVID-19.J Thromb Haemost. 2020; 18: 1020-1022Crossref PubMed Scopus (275) Google Scholar Prothrombin time has been found to be modestly prolonged in COVID-19 patients and again associated with higher mortality.22Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar Thrombocytopenia is inconsistently associated with COVID-19 severity.22Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar Limited data are available on disseminated intravascular coagulation (DIC): in one report low fibrinogen levels as a marker of DIC were present in 71.4% of patients who later died, compared to 0.6% of survivors.22Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar This is in contrast with other studies showing elevated fibrinogen levels and overt DIC being relatively rare.23Guan W.J. Ni Z.Y. Hu Y. et al.Clinical Characteristics of Coronavirus Disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (17227) Google Scholar,24Pavoni V. Gianesello L. Pazzi M. Stera C. Meconi T. Frigieri F.C. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia.J Thromb Thrombolysis. 2020; Crossref PubMed Scopus (130) Google Scholar Thromboelastometry studies have suggested a severe underlying inflammatory prothrombotic state that is driven by fibrinogen, and platelet activation to a lesser extent, rather than a consumptive coagulopathy.24Pavoni V. Gianesello L. Pazzi M. Stera C. Meconi T. Frigieri F.C. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia.J Thromb Thrombolysis. 2020; Crossref PubMed Scopus (130) Google Scholar Nevertheless, there has been considerable interest in the prognostic implications of an elevated fibrinogen and its use as a marker of illness severity.25Bi X. Su Z. Yan H. et al.Prediction of severe illness due to COVID-19 based on an analysis of initial Fibrinogen to Albumin Ratio and Platelet count.Platelets. 2020; : 1-6Google Scholar Recent data published by Tang et al. suggest that COVID-19 patients with a D-dimer level greater than 6 times normal or elevated sepsis-induced coagulopathy (SIC) scores > 4 may derive a mortality benefit from thromboprophylaxis at doses of 40–60 mg of enoxaparin or 10000–15000 units of heparin daily.22Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar Additionally, patients who weigh greater than 100 kg may benefit from higher doses of thromboprophylaxis.4Klok F.A. Kruip M. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2726) Google Scholar Patients who are hospitalized with COVID-19 infection are also at increased risk of stroke and rates have been reported ranging from 0.9%2Yaghi S, Ishida K, Torres J, et al. SARS2-CoV-2 and Stroke in a New York Healthcare System. Stroke;0:STROKEAHA.120.030335.Google Scholar amongst all hospitalized patients in the US to 4.5% in intensive care unit patients in China.26Mao L. Jin H. Wang M. et al.Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China.JAMA Neurology. 2020; Crossref PubMed Scopus (3941) Google Scholar In the critically ill, the PREVENT trial demonstrated no reduction in the incidence of proximal DVT from adjunctive use of IPC in patients already prescribed drug prophylaxis with UFH or LMWH.27Arabi Y.M. Al-Hameed F. Burns K.E.A. et al.Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.New England Journal of Medicine. 2019; 380: 1305-1315Crossref PubMed Scopus (107) Google Scholar This large trial however was not limited to high-risk stroke patients and was conducted prior to the SARS CoV-2 pandemic. Given the prothrombotic nature of coronavirus and limited evidence of harm, IPC should be considered in all critically ill COVID-19 patients. Pharmacological thromboprophylaxis should be prescribed for hospitalized COVID-19 patients, but currently there appears to be little evidence to support routine therapeutic anticoagulation for this population. The use of D-dimer guided anticoagulation in COVID-19 patients is currently being investigated in the PROTECT COVID trial.2Yaghi S, Ishida K, Torres J, et al. SARS2-CoV-2 and Stroke in a New York Healthcare System. Stroke;0:STROKEAHA.120.030335.Google Scholar Strokes, particularly those resulting from large vessel occlusion, are associated with certain prothrombotic states and the ensuing immobility and/or acute hospital care can compound the risk for thrombotic complications. There may also be an increased risk of stroke due to the inflammatory prothrombotic state in both symptomatic and indolent SARS-CoV-2 infection.1Oxley T.J. Mocco J. Majidi S. et al.Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.New England Journal of Medicine. 2020; 382: e60Crossref PubMed Scopus (1355) Google Scholar Therefore, particular attention should be given to thromboprophylaxis in this population. In patients who have undergone intravenous thrombolytic therapy, thromboprophylaxis should be initiated as soon as the post-thrombolysis 24 h interval has elapsed, and repeat CT demonstrates no haemorrhage or indication for craniectomy.9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar In patients who have not undergone intravenous thrombolytic therapy, thromboprophylaxis can be initiated upon admission, in the absence of high-grade hemorrhagic transformation (i.e. parenchymal hematoma 1 or 2).9Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2397) Google Scholar IPC should be used for all patients without contraindications, and pharmacological VTE prophylaxis should be strongly considered for all COVID-19 patients. Patients who are already anticoagulated should not receive additional doses of pharmacological VTE prophylaxis. The choice of drug will largely depend on local guidelines or institutional preference, however altered pharmacokinetics in the critically ill should be considered in addition to the potential prothrombotic state generated by COVID-19. Some centers have initiated regular assessment of coagulation factors with measurement of fibrinogen and d-dimer, and introduced higher intensity thromboprophylaxis regimes and therapeutic anticoagulation in selected patients (Table 2).28Cattaneo M. Bertinato E.M. Birocchi S. et al.Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified?.Thromb Haemost. 2020; Google ScholarTable 2Suggested pharmacological thromboprophylaxis regimes in stroke patients with suspected or confirmed COVID – 19 infectionIndicationLMWH,Cr CL ≤ 30mL/minHeparin, CrCL ≤ 30mL/min Standard doseNo additional identifiable risk factorsEnoxaparin 40mg once dailyHeparin 5000 U twice daily Consider high intensity doseWeight > 100kgSIC > 4 D-dimer > 6 fold normalEnoxaparin^ 40mg twice dailyNo bolus and low aPTT goal Consider full anticoagulation#Confirmed DVT or PEEstablished indication for anticoagulationDialysis filter thrombosisHigh clinical concern and unable to perform confirmatory testing1mg/kg enoxaparin^ twice dailyBolus and standard aPTT goal 55-90 seconds# Progress CT should dictate timing of thromboprophylaxis in patients with large established infarcts. ^Consider anti-Xa monitoring in patients with extremes of body size and renal dysfunction. Open table in a new tab # Progress CT should dictate timing of thromboprophylaxis in patients with large established infarcts. ^Consider anti-Xa monitoring in patients with extremes of body size and renal dysfunction. A situation that warrants consideration is that of patients hospitalized because of COVID-19 infection who have had VTE prophylaxis initiated on admission, and subsequently developed a large vessel ischemic stroke, an occurrence with a reported frequency up to 4.5%.23Guan W.J. Ni Z.Y. Hu Y. et al.Clinical Characteristics of Coronavirus Disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (17227) Google Scholar Such an event may suggest that the routine VTE prophylaxis was unable to mitigate the prothrombotic state of COVID-19, raising the issue of whether escalation to full therapeutic anticoagulation is indicated in this instance. Although there are no current data to inform such decision, it may be reasonable to consider therapeutic anticoagulation in the event of the ischemic stroke(s) involving multiple vascular territories (thus suggesting an embolic phenomenon), provided there is no imaging evidence of large territory infarct or hemorrhagic transformation of the new infarct(s). Similar considerations would likely apply to the occurrence of a single large-vessel ischemic stroke while on VTE prophylaxis, with the caveat that the risk/benefit balance of escalation to therapeutic anticoagulation should take into consideration not only the presence of hemorrhagic transformation, but also the size of the infarct, a factor known to correlate with risk of hemorrhagic transformation whilst anticoagulated.29Paciaroni M. Agnelli G. Falocci N. et al.Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study.Stroke. 2015; 46: 2175-2182Crossref PubMed Scopus (182) Google Scholar As COVID-19 patients with stroke have been reported to have elevated antiphospholipid antibodies, it may be appropriate to screen for them prior to deciding on the optimal antithrombotic agent in an individual case.30Zhang Y. Xiao M. Zhang S. et al.Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.New England Journal of Medicine. 2020; 382: e38Crossref PubMed Scopus (1408) Google Scholar It is unclear whether these antibodies represent definite antiphospholipid syndrome and repeat testing should be performed. In patients who have a stroke and pre-existing indication for direct oral anticoagulant therapy, such as atrial fibrillation, it may be reasonable to consider a vitamin K antagonist or therapeutic heparin in the presence of elevated antiphospholipid antibodies due to the reported inferiority of rivaroxaban compared with warfarin in a recent randomized trial.31Pengo V. Denas G. Zoppellaro G. et al.Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.Blood. 2018; 132: 1365-1371Crossref PubMed Scopus (402) Google Scholar The role and efficacy of DOAC therapy in the COVID-19 population has not been established. Furthermore in the presence of renal impairment a vitamin K antagonist may be preferred. Given the evidence that high D-dimer rates are associated with mortality and thrombosis,5Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost. 2020; 18: 1023-1026Crossref PubMed Scopus (1124) Google Scholar monitoring COVID-19 patients with D-dimer, platelet count, fibrinogen, and PT can be considered. Routine therapeutic anticoagulation for patients with acute stroke in COVID-19 infection is not indicated at this time due to the concerns for hemorrhagic transformation.32Dogra S. Jain R. Cao M. et al.Hemorrhagic stroke and anticoagulation in COVID-19.Journal of Stroke and Cerebrovascular Diseases. 2020; Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Surveillance for thrombotic events such as DVT and PE is encouraged for patients at high risk of VTE. Critically ill patients with COVID-19, who require mechanical ventilation are at particularly high-risk for developing DVT/PE.4Klok F.A. Kruip M. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2726) Google Scholar,20Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1101) Google Scholar As thromboprophylaxis has been shown to be associated with reduced mortality in patients with elevated D-dimer,22Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar several anticoagulation algorithms have been proposed in critically ill COVID-19 patients and adjusted for eGFR. In patients with altered mental status or focal neurological signs, it is appropriate to obtain a head CT prior to initiating anticoagulation to ensure there is no large infarction or hemorrhage.32Dogra S. Jain R. Cao M. et al.Hemorrhagic stroke and anticoagulation in COVID-19.Journal of Stroke and Cerebrovascular Diseases. 2020; Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar There are reports of an increase in cerebral microhemorrhages in COVID – 19 patients but the clinical significance of this is unclear.33Radmanesh A. Derman A. Lui Y.W. et al.COVID-19 –associated Diffuse Leukoencephalopathy and Microhemorrhages.Radiology. 2020; 40Google Scholar Close monitoring of PTT or anti-factor Xa levels may be necessary to ensure patients are not supratherapeutic. Neurological surveillance is also important in this population due to the risk of intracranial hemorrhage whilst on anticoagulation, with high associated mortality rates.32Dogra S. Jain R. Cao M. et al.Hemorrhagic stroke and anticoagulation in COVID-19.Journal of Stroke and Cerebrovascular Diseases. 2020; Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar DVT prophylaxis is standard of care for acute stroke patients. In the context of suspected or confirmed SARS-CoV-2 infection, there is an increased risk of VTE. As such, routine mechanical DVT prophylaxis and pharmacological thromboprophylaxis is recommended. Special consideration should be given to drug pharmacokinetics and pharmacodynamics, with increased dosing in patients with COVID-19, in the critically ill, or those with increased body habitus or documented coagulopathy. Currently there is insufficient evidence to routinely commence therapeutic doses of anticoagulation in this stroke population. Future studies may provide further guidance on targeted anticoagulation regimens in this patient group.