Michael Streiff, MD Rakhi Naik, MD MHS Jody Hooper, MD July 7th, 2020
Session Overview • Case presentation • Clinical questions • Epidemiology of venous thrombosis in COVID-19 • VTE pathophysiology • Thromboemboli in autopsies done at JHH • Prophylaxis, diagnosis, and management of VTE in COVID-19
Clinical Case • 45 year old woman presents to ED with 7 days of progressive shortness of breath, subjective fevers/chills, headache • Past Medical History • IDDM: last HbA1C 9.0% • Hypothyroidism, controlled • HTN, controlled • Hyperlipidemia, controlled
Clinical Case • Social History • Lives with her spouse in Maryland • Works in service industry • Wears a mask while working, but others do not • Sick contact through a coworker • Physical exam • Tm 39°C, HR 100, RR 24, BP 138/90, O2 saturation 92% on 4L • Appears short of breath • Otherwise normal exam
Clinical Case 12.8 16 139 100 192 5.12 96 4.7 22 0.7 39.7 ALC 1.75 AST 21/ALT 12/ Alk Phos 69/ Bili 1.0 Ferritin 98, D-dimer 1.3
Clinical Case • SARS-CoV-2 nasopharyngeal swab returns positive in ED • Admitted to floor • On day 2 increasing oxygenation requirement requires ICU transfer • LE ultrasound shows B DVT • CTA B segmental pulmonary emboli • TTE without right heart strain • Placed on therapeutic anticoagulation; no other complications • Discharged 14 days after admission
Clinical Questions 1) Are patients with COVID-19 at increased risk for VTE? 2) If so, what is the pathophysiology? 3) How should clinicians manage VTE in patients with COVID-19?
Epidemiology of Venous Thrombosis in COVID-19
Thrombosis Incidence: Examples From Literature • Heterogeneous prevalence Location Cohort characteristics Incidence of VTE in epidemiologic studies 3 Dutch hospitals 184 ICU patients 27% VTE 3.7% arterial thrombosis • Limitations of data 2 Centers of a French 150 patients with ARDS secondary 16.7% PE • Primarily inpatient tertiary hospital to COVID-19 • ICU vs non-ICU 1 French hospital 107 ICU patients 20.6% PE Same interval 2019: 6.1% • Majority retrospective 40 influenza patients 2019: 7.5% • Screening vs evaluation 1 hospital in Amsterdam 198 hospitalized patients 20% VTE, 13% symptomatic based on symptoms At time of publication 8% still hospitalized • Variable use of VTE 1 hospital in Wuhan, China 81 ICU patients 25% VTE prophylaxis 1 hospital in Italy 388 ICU patients 21% venous and arterial thromboembolic events 1 hospital in France 34 ICU patients 79% DVT Prospective ultrasound of LE 1 hospital in France 71 hospitalized, non-ICU patients 22.5% VTE Klok FA, et al. Thromb Res . doi:10.1016/j.thromres.2020.04.013. published online ahead of print. Helms J, et al. Intensive Care Med. 2020 Jun;46(6):1089-1098. Poissy J et al. Circulation. 2020 Apr 24. doi: 10.1161/CIRCULATIONAHA.120.047430. Online ahead of print Middledorp S, et al. J Thromb Haemost. 2020 May 5. doi: 10.1111/jth.14888. Online ahead of print. Cui S, et al. J Thromb Haemost 2020; Apr 9. doi: 10.1111/jth.14830 Lodigiani C, at al. Thromb Res . 2020 Jul;191:9-14. doi: 10.1016/j.thromres.2020.04.024. Epub 2020 Apr 23. Artifoni M et al J Thromb Thrombolysis 2020;50(1):211
Thrombosis Incidence: China • Cross-sectional survey of 159 patients at the West Branch of Union Hospital in Wuhan, China • Major referral hospital for critically ill adult patients with COVID-19 • Performed lower extremity US on all 143 patients • 16 not studied died or were transferred prior to study enrollment • If clinical suspicion for PE CTA performed Zhang L, et al. Circulation . 2020 May 18. doi: 10.1161/CIRCULATIONAHA.120.046702. Online ahead of print.
Thrombosis Incidence: China • Mean age 63 ± 14 years • 74 (51.7%) patients men • 74.1% (106/143) severe or critical • At time of publication 92 (64.3%) patients discharged and 32 (22.4 %) died • 53 (37.1%) patients given DVT prophylaxis • Prevalence of DVT = 46.1% (66/143) • Duration from first appearance of symptoms to hospitalization 11 ± 6 days Zhang L, et al. Circulation . 2020 May 18. doi: 10.1161/CIRCULATIONAHA.120.046702. Online ahead of print.
Regression Analyses Subgroup of patients with a Padua prediction score ≥ 4 and US performed ˃ 72 • hours after admission • DVT present in 18 (34.0%) of the subgroup receiving prophylaxis vs 35 (63.3%) in nonprophylaxis group ( P = 0.010)
Thrombosis Incidence and Epidemiology: U.S. • 400 patients ≥18y with positive SARS -CoV-2 rtPCR test • 3/1/20 through 4/5/20 • Five hospitals within the Partners Healthcare system • D-dimer on initial presentation to care with COVID-19 • Thrombotic and bleeding complications assessed Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Thrombosis Definitions • Radiographically confirmed VTE • Probable VTE • Consistent evidence by vital signs, physical exam, hemodynamics, ECG, plus • Strong clinical suspicion, plus • Therapeutic anticoagulation initiated as a result of suspicion • Clinically significant non-vessel thrombotic complications • ≥2 central or a-line clotting episodes • ≥2 CVVH circuit clots prompting systemic anticoagulation within 24h Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Rates of Venous Thromboembolism • Radiographically-confirmed VTE rate 4.8% (19 events in 19 patients) • 3.1% in non-critically ill patients • 7.6% in critically-ill patients • Overall VTE rate 6% (24 events in 24 patients) • 3.5% in non-critically ill patients • 10.4% in critically-ill patients • All patients but one were receiving standard-dose anticoagulation with unfractionated or low molecular weight (LMW) heparin • One was receiving therapeutic-dose apixaban • Two of these patients also had arterial thrombotic events Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Other Thrombotic Complications • Arterial Thrombosis rate 2.8% (11 events in 11 patients) • 1.2% in non-critically ill patients • 5.6% in critically-ill patients • All were receiving prophylaxis with unfractionated or LMW heparin • Clinically Significant Non-Vessel Thrombotic Complications • 8/12 patients on CVVH had recurrent clotting of the circuit while receiving prophylactic anticoagulation • 5 of these 8 also had venous or arterial thromboses • 3/4 who did not have circuit clotting were on therapeutic heparin infusions • Two additional critically ill patients had recurrent line-associated thromboses Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Bleeding Rates • Overall bleeding rate 4.8% • 3.1% in non-critically ill patients • 7.6% in critically-ill patients • Major bleeding rate 2.3% • 5.6% in critically-ill patients (all but one such event) • Similar to large, prospective study of critically ill patients without COVID-19 • Three patients diagnosed with DIC by clinical & lab parameters • All had grade 3 or 4 bleeding events Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Thrombotic Complications Summary • Overall thrombotic complication rate 9.5% • 4.7% in non-critically ill patients • 18.1% in critically-ill patients • 41 patients (10%) were transitioned from prophylactic to therapeutic anticoagulation to manage thrombi and/or new atrial fibrillation • 4 of these patients also had bleeding complications • Thrombosis primarily associated with inflammatory markers rather than coagulation parameters Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.
Epidemiology of Venous Thrombosis in COVID-19: Key Points • Data are heterogeneous • Consistently high rates of VTE, despite prophylaxis • US data: Overall thrombotic complication rate 9.5% • 4.7% in non-critically ill patients • 18.1% in critically-ill patients
Pathophysiology of VTE in COVID-19 Michael B. Streiff, MD Professor of Medicine and Pathology Medical Director, Johns Hopkins Anticoagulation Service Co-Director, Johns Hopkins Hemostatic Disorders Stewardship Program
Disclosures • Consulting • Research support • Bayer – Boehringer-Ingelheim • Daiichi-Sankyo – Janssen • BristolMyers Squibb – NIH/NHLBI • Dispersol – NovoNordisk • Janssen – PCORI • Pfizer – Roche • Portola – Sanofi
The Pathogenesis of VTE Rudolf Virchow (1821-1902) Hypercoaguability
Risk Factors for Venous Thromboembolism • Age • Inflammatory bowel disease • Surgery/trauma • Infections • Cancer • Nephrotic syndrome • Thrombophilia • Sickle cell disease • Central venous catheters • Pregnancy/post-partum • Immobility • Hormonal therapy • Heart Failure • Central Venous catheters • Respiratory failure • Obesity • Rheumatologic disease
Pathogenesis of Venous Thromboembolism Orthopedic surgery-triggered DVT in 50 year old Thrombosis Thrombosis Risk Thrombosis threshold Rosendaal FR Lancet 1999 Age
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