michael streiff, md rakhi naik, md mhs jody hooper, md ... · 07/07/2020 · 27% vte: 3.7%...

Michael Streiff, MDRakhi Naik, MD MHS

Jody Hooper, MDJuly 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

5.12 19239.7

12.8

4.7 0.7

16100139

2296

ALC 1.75 AST 21/ALT 12/ Alk Phos 69/ Bili 1.0Ferritin 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 Location Cohort characteristics Incidence of VTE

3 Dutch hospitals 184 ICU patients 27% VTE3.7% 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% PESame 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 patientsProspective 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 printMiddledorp 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.14830Lodigiani 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

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


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


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


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


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

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, MDProfessor of Medicine and Pathology

Medical Director, Johns Hopkins Anticoagulation ServiceCo-Director, Johns Hopkins Hemostatic Disorders Stewardship Program

Disclosures

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

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

The Pathogenesis of VTE

Rudolf Virchow (1821-1902)

Hypercoaguability

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

Pathogenesis of Venous Thromboembolism

Orthopedic surgery-triggered DVT in 50 year old

Thrombosis threshold

Age

Thro

mbo

sis R

isk

Rosendaal FR Lancet 1999

Thrombosis

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

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 ThrombRes 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)

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

The Pathogenesis of VTE

Rudolf Virchow (1821-1902)

Hypercoaguability

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

COVID Autopsies & Thromboemboli

Jody E. Hooper, MDDirector of Autopsy

Director, Legacy Gift Rapid Autopsy ProgramAssociate Professor of Pathology and Oncology

COV 2• 64 yo woman• Htn, hyperlipidemia, Prediabetes• 1 week post CV test• Acute respiratory distress • Code in ED, lived

less than 1 day

COV 4• 67 yo man• Asthma, hyperlipidemia • Brief admission w CV test• Returned 2 days later• 1.5 wk ICU• Comfort care

COV 18• 64 yo man• ETOH, COPD• To ED after 3 days• Hypotensive in ED• Bilateral PE• Pancreatitis• Died same day

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

Management of VTE in COVID-19

Rakhi Naik, MD MHSAssociate Director for Hematology, Hematology/Oncology Fellowship Program

Assistant Professor of Medicine

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 ThrombThrombolys 2020

Demeo-Rodriguez P Thromb Res 2020; Al-Samkari H et al. Blood 2020

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

41Al-Samkari H et al. Blood 2020

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



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

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

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

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

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

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

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

Clinical Questions

1. Are patients with COVID-19 at increased risk for VTE? Yes2. If so, what is the pathophysiology? Inflammatory and prothrombotic

state3. How should clinicians manage VTE in patients with COVID-19? High

intensity prophylaxis, case-by-case management of VTE

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michael streiff, md rakhi naik, md mhs jody hooper, md ... · 07/07/2020 · 27% vte: 3.7%...

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