Michael Streiff, MD Rakhi Naik, MD MHS Jody Hooper, MD July 7th, - - PowerPoint PPT Presentation

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Michael Streiff, MD Rakhi Naik, MD MHS Jody Hooper, MD July 7th, - - PowerPoint PPT Presentation

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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

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Michael Streiff, MD Rakhi Naik, MD MHS Jody Hooper, MD July 7th, 2020

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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
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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
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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
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Clinical Case

5.12 192 39.7 12.8 4.7 0.7 16 100 139 22 96

ALC 1.75 AST 21/ALT 12/ Alk Phos 69/ Bili 1.0 Ferritin 98, D-dimer 1.3

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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
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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?

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Epidemiology of Venous Thrombosis in COVID-19

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Thrombosis Incidence: Examples From Literature

Location Cohort characteristics Incidence of VTE 3 Dutch hospitals 184 ICU patients 27% VTE 3.7% arterial thrombosis 2 Centers of a French tertiary hospital 150 patients with ARDS secondary to COVID-19 16.7% PE 1 French hospital 107 ICU patients 20.6% PE Same interval 2019: 6.1% 40 influenza patients 2019: 7.5% 1 hospital in Amsterdam 198 hospitalized patients At time of publication 8% still hospitalized 20% VTE, 13% symptomatic 1 hospital in Wuhan, China 81 ICU patients 25% VTE 1 hospital in Italy 388 ICU patients 21% venous and arterial thromboembolic events 1 hospital in France 34 ICU patients Prospective ultrasound of LE 79% DVT 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

  • Heterogeneous prevalence

in epidemiologic studies

  • Limitations of data
  • Primarily inpatient
  • ICU vs non-ICU
  • Majority retrospective
  • Screening vs evaluation

based on symptoms

  • Variable use of

VTE prophylaxis

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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.

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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.

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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)

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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.

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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.

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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.

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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.

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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.

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Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.

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Thrombotic Complications Summary

Al-Samkari H et al. Blood. 2020 Jun 3:blood.2020006520. doi: 10.1182/blood.2020006520. Online ahead of print.

  • 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

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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
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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

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Disclosures

  • Consulting
  • Bayer
  • Daiichi-Sankyo
  • BristolMyers Squibb
  • Dispersol
  • Janssen
  • Pfizer
  • Portola
  • Research support

– Boehringer-Ingelheim – Janssen – NIH/NHLBI – NovoNordisk – PCORI – Roche – Sanofi

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The Pathogenesis of VTE

Rudolf Virchow (1821-1902)

Hypercoaguability

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Risk Factors for Venous Thromboembolism

  • Age
  • Surgery/trauma
  • Cancer
  • Thrombophilia
  • Central venous catheters
  • Immobility
  • Heart Failure
  • Respiratory failure
  • Rheumatologic disease
  • Inflammatory bowel disease
  • Infections
  • Nephrotic syndrome
  • Sickle cell disease
  • Pregnancy/post-partum
  • Hormonal therapy
  • Central

Venous catheters

  • Obesity
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Pathogenesis of Venous Thromboembolism

Orthopedic surgery-triggered DVT in 50 year old Thrombosis threshold Age Thrombosis Risk Rosendaal FR Lancet 1999 Thrombosis

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A Modern View of Coagulation

X Fibrinogen Fibrin II Procoagulants Anticoagulants Intrinsic system

(surface contact)

Extrinsic system

(tissue damage)

TF/VIIa (Coagulation) APC VIIIa/IXa Xa PS TFPI Va IIa AT

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Coagulation abnormalities in COVID 19

  • Increased factor VIII and von Willebrand factor (Escher R Thromb Res 2020)
  • Complement activation (Magro C Transl Res 2020; Fletcher-Sandersjöö A Thromb

Res 2020

  • Platelet activation (Manne BK Blood 2020)
  • Increased fibrinogen (Panigada M J Thromb Haemost 2020)
  • Antiphospholipid antibodies (Helms J Intens Care Med 2020; Zhang Y N Engl J Med

2020; Bowles L N Engl J Med 2020

  • Neutrophil extracellular traps (NETs) (Middleton E Blood 2020)
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Impact of COVID 19 on Coagulation

X Fibrinogen Fibrin II Procoagulants Anticoagulants Intrinsic system

(surface contact)

Extrinsic system

(tissue damage)

TF/VIIa (Coagulation) APC VIIIa/IXa Xa PS TFPI Va IIa AT

Complement NETs Cytokines (IL1β, IL6) Antiphospholipid antibodies

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The Pathogenesis of VTE

Rudolf Virchow (1821-1902)

Hypercoaguability

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COVID19 and Heparin Resistance

  • Heparin resistance defined as > 25 units/kg/hr CIV or 35,000 units/day
  • Causes-
  • AT deficiency- Congenital deficiency, DIC, acute thrombosis, nephrotic syndrome,

liver disease, ECMO, L-asparinginase

  • Heparin-binding proteins: platelet factor 4, histidine-rich glycoprotein, vitronectin,

fibronectin

  • Elevated factor VIII and fibrinogen: affect aPTT
  • COVID19 causes heparin resistance (White D et al. J ThrombThrombolys 2020)
  • Clinical resistance in 15 patients
  • Reduced anticoagulant effect by 17-52% in vitro

Durrani J et al. J Comm Hosp Intern Med Persp 2018;Anderson JAM and Saenko E Brit J Aanaesthes 2002; Hirsh J Raschke R Chest 2004

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COVID Autopsies & Thromboemboli

Jody E. Hooper, MD Director of Autopsy Director, Legacy Gift Rapid Autopsy Program Associate Professor of Pathology and Oncology

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COV 2

  • 64 yo woman
  • Htn, hyperlipidemia,

Prediabetes

  • 1 week post CV test
  • Acute respiratory distress
  • Code in ED, lived

less than 1 day

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COV 4

  • 67 yo man
  • Asthma, hyperlipidemia
  • Brief admission w CV test
  • Returned 2 days later
  • 1.5 wk ICU
  • Comfort care
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COV 18

  • 64 yo man
  • ETOH, COPD
  • To ED after 3 days
  • Hypotensive in ED
  • Bilateral PE
  • Pancreatitis
  • Died same day
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JHH Autopsies with thromboemboli

  • 2/25 with gross pulmonary thromboemboli
  • 1 with probable aortic clotting, not verified at autopsy
  • 10/19 with microscopic thrombi (6 cases with histology pending)
  • Most cases with thrombi also have acute lung injury
  • 3 autopsies with thrombi without acute lung injury (30%)
  • 5 autopsies with acute lung injury without thrombi
  • No thrombi seen in other organs
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Management of VTE in COVID-19

Rakhi Naik, MD MHS

Associate Director for Hematology, Hematology/Oncology Fellowship Program Assistant Professor of Medicine

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Strategy for VTE Prevention in COVID Patients

  • VTE prophylaxis guidelines must account for both thrombotic and bleeding risk
  • Adapt prophylaxis strategy to COVID patient characteristics due to heparin

resistance

  • For non-ICU patients, limit high-intensity prophylaxis to patients at highest risk
  • Clinical characteristics (ICU, active cancer, previous

VTE, thrombophilia including sickle cell disease)

  • Laboratory characteristics- D dimers > 1.5 mg/L (cutoff based on best available data for

VTE risk in COVID)

Bikdeli B JACC 2020; Escher R Thromb Res 2020; Panigada M J Thromb Haemost 2020; White D et al J Thromb Thrombolys 2020 Demeo-Rodriguez P Thromb Res 2020; Al-Samkari H et al. Blood 2020

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Bleeding Risk in COVID+ Patients

  • Study of 400 COVID+ patients
  • 4.8%

VTE, 9.5% overall thrombotic rates

  • 4.8% overall bleeding rate, 2.3%

major bleeding (predominantly GI bleeds)

  • 2/3 of major bleed cases on

standard dose prophylaxis or less

41

Al-Samkari H et al. Blood 2020

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JHHS VTE Prophylaxis Recommendations

42

Renal Function Weight 40-59 kg Weight 60-199kg Weight ≥120 kg or BMI 40 kg/M2 CrCl ≥ 30 ml/min UFH 5000 Units q12h Enoxaparin 40 mg daily Enoxaparin 40 mg q12h CrCl < 30 ml/min UFH 5000 units q12h UFH 5000 units q8h UFH 7500 units q8h Renal Function Weight 40-59 kg Weight 60-199kg Weight ≥120 kg or BMI 40 kg/M2 CrCl ≥ 30 ml/min Enoxaparin 40 mg daily Enoxaparin 30 mg q12h Enoxaparin 40 mg q12h CrCl < 30 ml/min UFH 5000 units q8h UFH 7500 units q8h UFH 10000 units q8h

Standard Intensity Prophylaxis High Intensity Prophylaxis

Adjust to UFH level 0.1-0.3 or LMWH level 0.2-0.5 units/ml

Dane K, Lindsley J, Rowden A, Naik R and Streiff MB

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VTE Prophylaxis Recommendations

  • Adjust prophylaxis to target range
  • UFH anti-Xa 0.1-0.3 units/ml
  • LMWH anti-Xa 0.2-0.5 units/ml
  • Check UFH/LMWH peak level 4 hours after at least 3 doses
  • Monitor UFH/LMWH levels weekly
  • Use pneumatic compression devices in all immobilized ICU patients and all

patients with contraindications to anticoagulant prophylaxis

July 7, 2020 43

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Challenges with VTE Diagnosis in COVID

  • Difficulty in coordinating doppler or CTA studies in COVID+ patients, especially

in the ICU

  • If suspicion of a symptomatic PE is high (unexplained hypoxemia, increasing A/A

gradient, decreased P/F ratio, new RV strain on bedside echo)

  • Empiric escalation to therapeutic AC can be considered
  • Definitive imaging to be obtained as soon as feasible to guide duration of

treatment

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Challenges with VTE Diagnosis in COVID

  • For DVT suspicion (new leg/arm swelling) without access to imaging, empiric

escalation can be considered in patients without bleeding risk factors

  • If bleeding risk factors, obtain imaging prior to escalation
  • Bleeding risk factors:
  • Platelets <50k, INR >1.5, fibrinogen <100
  • Cirrhosis or liver failure
  • Recent major bleed <3 months
  • For DVT confirmed by unofficial bedside ultrasound only, definitive imaging should

be obtained when feasible

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Management of Confirmed VTE in COVID+ patients

  • Duration of AC for confirmed VTE at least 3-6 months with

reassessment of risk factors (i.e. immobility) at that time

July 7, 2020 46

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Post-discharge prophylaxis in COVID+ patients

  • No data to inform risk of

VTE in non-hospitalized COVID patients

  • Increased risk of VTE for 90 days post-discharge in non-COVID patients

hospitalized for an acute medical illness

  • Extended post-discharge prophylaxis can be considered in high-risk COVID

patients at discharge

  • High risk features include active cancer, previous

VTE, thrombophilia, sickle cell disease, D dimer at discharge > 1.0 mg/L

  • Post-discharge prophylaxis regimens include enoxaparin 40 mg daily, rivaroxaban 10 mg daily

and apixaban 2.5 mg BID

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Key Points

  • 1. COVID-19 infection is associated with profound inflammatory

prothrombotic state

  • 2. High-intensity

VTE Prophylaxis should be used in high-risk COVID- 19 patients

  • 3. Objective confirmation of suspected

VTE should be sought in all patients but should not delay treatment

  • 4. Management of VTE may require case-by-case assessment of risks

and benefits of treatment

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Clinical Questions

  • 1. Are patients with COVID-19 at increased risk for VTE?

Yes

  • 2. If so, what is the pathophysiology? Inflammatory and prothrombotic

state

  • 3. How should clinicians manage VTE in patients with COVID-19? High

intensity prophylaxis, case-by-case management of VTE

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Join Us in T wo Weeks: Schools Reopening with

  • Dr. Jennifer Nuzzo
  • Dr. Josh Sharfstein
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SLIDES & RECORDINGS ARCHIVED ONLINE

https://bit.ly/2Y2DIDj