(> {sent the mame uti summary by edtor inch snc, THE PRESENT AND FUTURE JAC STATE-OF-THE-ART REVIEW COVID-19 and Thrombotic or ® Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up JACC State-of-the-Art Review Behnood Bikdeti, MD, MS,"*"* Mahesh V. Madhavan, MD,*** David Jimenez, MD, PuD,* Taylor Chuich, Pua." Isaac Dreyfus, MD," Elissa Drigin, MD,’ Caroline Der Nigoghossian, PuanuD,” Walter Ageno, MD," Mohammad Magjid, MD, MS,’ Yutao Guo, MD, PxD,* Liang V. Tang, MD," Yu Hu, MD," Jay Gir, MD, MPH," Mary Cushman, MD, MSc, Isabelle Quéré, MD, PriD,” Evangelos P. Dimakakos, MD,” C. Michael Gibson, MD.” Giuseppe Lippi, MD,’ Emmanuel J. Favaloro, PuD,' Jawed Fareed, PuD,' Joseph A. Caprini, MD, MS," Alfonso J. Tafur, MD, MS, John R. Burton, MD," Dominic P. Francese, MPH, Elizabeth Y. Wang, MD.* ‘Anna Falanga, MD," Claire McLintock, MD,” Beverley J. Hunt, MD,” Alex C. Spyropoulos, MD,” Geoffrey D. Barnes, MD, MSc," John W. Eikelboom, MBBS, Ido Weinberg, MD," Sam Schulman, MD, Pub,"™"=" Mare Carrier, MD, MSc," Gregory Piazza, MD, MS," Joshua A. Beckman, MD," P. Gabriel Steg, MD,!!™™ GGtegg W. Stone, MD,°"" Stephan Rosenkranz, MD," Samuel 2. Goldhaber, MD," Sahil A. Parikh, MD," Manuel Monreal, MD, PiD,”” Harlan M. Krumbolz, MD, SM," Stavros V. Konstantinides, MD, PriD,” Jeftey 1. Weitz, MD.'** Gregory V.H. Lip, MD," for the Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function Coronavirus disease-2019 (COVID-1S), a viral respratory ilness caused by the severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial crculations, because of excessive inflammation, platelet activation, endothelial dysfunction, ad stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, ‘dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during atime with much focus on COVID-19, iis critical to consider how to optimize the available technology to care fr patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and ‘outcomes of patients with COVID-19 wha develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention ar care for their thrombotic disease during the COVID-19, pandemic. (J Am Coll Cardiol 2020;75:2950-73) © 2020 by the American Collage of Cardiology Foundation. From the ‘NewYork: Presbyterian HoeptalClumbi Universty ving Medical Center, New Yor, New Yorks Center fr Out comes Research and Walutoa (CORD, Yate Schon of Medine, New Haven, Connect Cn Teas Center, Crdavacale [Research Foundation, New York, New Yorks “Resprtry Departmen, Hospital Rann y Cajal and Medicine Department, Un seria de Aas nso de Rann y aa de Inestiacion Sitar), Centro de Investig Biome en Re de fer ‘medadesRespiatonn, Madsid Spain, “Dgpartment of Medicine and Surgery, University of nub, Vatee, Maly MeCavern Modal School, university of Teas Heath eonce Center t Houston, Houston, Texas "Department of Cardo, Chinese PLA General Hopital, eg, China nstute of Hematology, Union Hepa, Tog Mica! Clee, Huazhong Univesity ofS ence and Technology, Waban, Cina; Cardiovascular Divison, Hosp of the Unversity of Peansyvana, Philadelphia, Pen sylvan tenn ardovasur Outcomes, Quality, apd yaks Resrrch Conte, Leonard Zavisinsttute of Hcl Economic, University of Penasyvana, Phladelphia, Pennsylvania; *Cxperal Michael 1. Cescenz VA Medal Centr, Place, Pennsylvania: "Univers of Vermont Medial Cntr, avington, Vermont; "Department of Vasuar Mein, University of ISSN 0735:1007/836.00 tps:/eoLorg/0.016/sec2020.08031oronavirus disease-2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and now has been deemed a pandemic by the World Health Organization (1-3). COVID-19 has a number of important cardiovascular implications (4-6). Patients with prior cardiovascular disease are at higher risk for adverse events from COVID-19. Individuals without @ history of cardiovascular disease are at risk for incident cardiovascular complications (5) ‘There are several ways in which the COVID-19 pandemic may affect the prevention and manage: ment of thrombotic and thromboembolic disease (hereafter collectively referred to as thrombotic dis- cease for brevity). First, the direct effects of COVID-19 or the indirect effects of infection, such as through severe illness and hypoxia, may predispose patients to thrombotic events. Preliminary reports suggest that hemostatic abnormalities, including dissemi- nated intravascular coagulation (DIC), occur in pa- tients affected by COVID-19 (7,8). Additionally, the severe inflammatory response, ctitical illness, and underlying traditional risk factors may all predispose kde eta 2051 COWD-19 and Thrombotic Dasa to thrombotic events, similar to prior virulent zoonotic coronavirus outbreaks (Table 1) (9,10). Second, investigational therapies for ‘eating COVID-19 may have adverse drug- drug interactions with antiplatelet agents and anticoagulants. Third, the pandemic, because of resource allocations or social distancing recommendations, may adversely affect the care of patients without COVID-19 but who present with thrombotic events. For example, (mis)perception that antith- rombotic agents confer increased risk for contracting COVID-19 may lead to untoward interruption of anticoagulation by some patients, ‘The current paper, authored by an inter- national collaborative of clinicians and in- vestigators, summarizes the pathogenesis, epidemiology, treatment, and available ‘outcome data related to thrombotic disease in Patients with COVID-19, as well as manage- ment of thrombotic events in patients without COVID-19 during this pandemic. ‘Montpler, Centre Hosptaler Universe Montplle,InoVTEF-CREN Retwork, Montpller, France; “Oncology Unit GP, Sota General Hospital Athens Schoo of Medicine, Athens. Greece "Harvard Medial School Beton, Massachusetts "eth Isl Desconess Medical Gene, Boston, Masacnsets, Laborstry of Cink Chemisty and Hematology, Univesity Hosp of ‘erons, Veron, Ray "Haematology Laboratory, Institute of Cla atelogy and Midcal Research, NSW Health Patol, Westra Hopital Westra, New South Wales, Anta “Sydney Centres fr Thromboss ane Haemostasis, Westmead, New South Wales, Ausvaia'oyela Unwersty Medial Cate, Chicago lols: Paaker Sool of Medicine, Univer of Chg, {chicago ios: "son of Vascular Medicine, Department of Medicine NohShore Unversity Healhsystem, Skok tlinas; Depattmect of lnsmunshemstology and Transfon Maine, Honpital Pps Giana XX, Univers of Milan Bice, ‘Bergamo, aly "Auckland Cy Hospital, Auclan, New Zealand; "St Thomas Hospi, London, United Kinglom; Donald and ‘Barbara Zucker Scho! of Medicine t HofstaMowvel, Hata University, Hempstead, New York; “Cente for Bethe and Socal cence In Medicine, Univers of Michgan, ann Aer, Michigan; *anklCrdovasculr Cntr, iver of Michigan, ‘Ann Aer, chigans “Population Heath Research Inst, Hamifon Hest Sciences, McMoster University, Hato, Onan, ‘canada, “asachnets General Hospital, Boston, Masacusets; “partment of Obtetics and Gynecogy, LM, Sechenoe Fist soscow State Meal Univesity, Moscow, Fuss; "MeMaster Universit, Hanlon, Ontario, Canals; Thombs and heros Rescate Inst, Hamilton, Ontario Gnas; naw Hostal Research Isnt, Otaw, Ontario, Canc; Farnam and Women's Hogptal, Boston, Masachsets;SVandetin Univeray Schl of Madi, Nastvil, Tennessee, ‘SnnseRot Uns Hp Biche, Assance Publique HSptaux de Pars, FACT enc Aiance for Cardovasuar Tals), Fans France "Univers Fais Pars, France "Royal Brompton Hosta mera Colege Landon London, United Kino snd Michac A. Winer Cardiovascular institut, lea School of Medea Mount Sina New York, New Yok: Calazne Car iovascalr Research Cntr, Heart Canter, Department of Carlo, University of Clogae, Cologe, Gemany, Departmen of ‘“pepartment of Health Poly and Admstaton, Yale Sool of Pubic Health, New Haven, Conneticut "section of Caco ‘cular Medicine, Deparment of itera Mecns, Yale School of Meine, New Haven, Connecticut “Center fr Thrombosis and Hemost Johannes Gutenberg Univesity of Mainz, Mainz, Germany "Uverpol Centre fr Crdhovasua Science, LW ‘poo! Heart and Chest Hospital, Univers of Liverpo, Liverpool United Kingfor: and the “Aatorg Universit, Aor. ‘Denna “Dis kdl and Machavancoatbuted equal to ths wor. This wrk vas endorsed hy the Iterations Soc ob ‘ThrombisandHaerostas, Nom American Tomboss Forum, European Sodety of Vascular Medi, apdintrationa Union ‘oF angoiogy: and sapere bythe European Scie of Crogy Working Group on the Pulmonary Cicltion and Right Ver ‘cur Function (o Ds Haselzanz and Konstantin.) De. Madhavan wis ayported by a gant ra the Naina sites of ‘ealthNationa Hear Lung, and Blood institute to Columbia Unversity Irving Meicl Center 2 HLOV754) Dr. kde has served acoalingespert on bhai pai, for igaton elated oa speciic type ofinferiorvenaeavaiten: Diener ‘msaurved as nadir or consultat fo ayer fealtCae Pharmaceutials, Dodger ingle, Bist Mer qu, Dich Soniye, Leo Para, Phzer, ROVL and Sano; hs served 3s a speaker o 2 member oa Speakers Bara for Bayer Heanare urmaceutials,Docsinge Ingen, rst Myers Sq, Dac Sankyo, Leo Phas, ROW, and Sano and a eee ant for cna sear om Dich Sankyo, Sad and ROVL. Dr. Ageno hs eee a teseach gant ran Bayer: and has {eave honoraria for ptcpation in Advisory Beds toms Rotringe Ingest, ayer Parmaceute, Bist Myers qu) zr ae Sanyo, Aspe, Sano, Pro Leo Pharma, and Jansen Dr. Gil has eve onthe Advisory Bead for ASazenes: rive amet DVT dep win tronbere emo = exracapeet ‘wea es P= pamonaryenboton ‘etry syne: STEM «STsegnent lation = waco nepaal eo COVD-19 ae Thrombotic Datos Although the focus is on the prevention and man- agement of venous thromboembolism (VTE) and antithrombotic therapy for acute coronary syndromes other conditions requiring antithtombotic therapy. We provide clinical guidance, when feasible, and also identify areas that require urgent attention for future (ACS), many of the recommendations are relevant to research. ha seve the Tal Sting Comat fr ay Metical has recived istunna research grant suppor om Recor Medica ‘ndt ude Media: and has eeved personal es for ajuda rm the New England Research site De. Qui has recived lecture fes fom Pac, Bayer Phanmaceutcs, Aspen, and Lee Pharma, Dr. Dimalakos has recived consulting fees "om Sao an eo Pha. Dr Capra has served a the steering comme for anise RAD; has Served the bled disor oa or hrs has served on the Aso Bad for Bist Myers Squib and Alexion Pimaceutics herve asa constant for Recovery Force and ns received honerania fom Sane Dr Tafurhas eved a5 a constant for Recovery ores as conducted research or Janssen, so Myers Squib, Doasense and Mars and has received eduatona grant support om Sanssen, Dr. Flan has recived Speaker honoraia fot Raye, Pies, and Sapo Dr: Hunt has served as haf the teeing soup of Word Thrombosis Day and Medica Dceta of Tombods UK, 2 not for rot organs fom which she take no fees Dr. Spyropulo as served 52 constant fer Boohrnger ingen Janssen, Bristol myers Squibb, yer, Pots, andthe [ATLAS Goupy and ha recived reseanh grant suppot fom Boltinges Inge aa ase De. Bares as served 2 4 constant for Phzr/Suisto- Myers Squib, Jansen Pool, and AMAG Phamaccutals, Dares as saved asa consular esto Myers Squibb, Janssen, Fortla and AMAG Pharmaccutials; and has recived pant funding fom zeta Myer Squib, and lve Clos Oe Shield f Michigan. Dr ikelboor has eee contig fees andlor one fran Astrazeneca, Bayer, BoelvingetIngelbein, Busta Myers Squibb, DaichiSankyo, Hl Lily, GlxeSmKline, Pat, nssen, Sono and Serve; and has eeived pant andor in kind support rom Arazenec, Baer, Boehringer Ingle, Bristol Myers ‘qui, Gaxosaittise, Phat, ase, nd Sal De Weber as evel consuling foes fom Magneto Thome ny Solutions. De. Selman has received esearch grant support fam Octapharma and Boehringer tgeeim; and has ected honoraria rm Anya, Bayer, Boehringer Inglis Myers Squib, Duc Sankyo, and Snot. Backman as served om the advisory Hoard for Amgen, astrazneca Glxssmittine, and Jansen as served on the Data Safty Monitoring Hoard Saf Dr Case has esived reser funding fom Dito yrs Squib, Leo Pharma, and Pe, and hs ecived consulting honoraria fom Bristol-Myers Squbb Bayer, Pier, Lo Pharma, Srvc, and Sano. Dr. Mazza as rected esearch gant support foo EKOSIBG Interationl, rate Myers Sub, Dic Sanyo, Dyer, Poros, ad Janes; ae ha recived onsalting fees rom Pizer and Thomo Dr Steg has wecelved esearch grant oe Ami, Bayer, Sane and Servi: has served onthe tering Commitee, Data Safety Montring Boar, crcl Enépoint Goto for cna al oe Amarin, ‘Astrazeneca, Bayer, Roetringer ng, Bristol Myers Squib, tons, Nowa, ize, Sano and Server and tae ecived speaker r consulting Fes rem Anata Astrazeneca, Byer, Boevinge Ingelein, Bstl Myers Squib, Mos, Novas, Mie, Sano and Server. Dr, Stone tas received speaker or other Honora rom Cook, Terumo, QOOL Therapetes, and Orchestra Biomed served 6 consi Vali, TherOx, Vase Dynamics, Roba, Henntlow, Gre Abate Suton, Mic, Novas, V-Wave, Abome, Ancora, MAIA Pharmaceutics, Vetcois, Rea, and Matizyne: and has equlyoptions from ‘Ancora, Goo! Terapeutes agent Aplied Therapeutics, Bos Friyof funds, SpecraWave, Orchestra Biomed, Ai, Carine ‘Stcoes, MedFoc arly of finds, an Yai Ex. Rosenkranz has esived concn andor ltr es fom abot, Aca son, Actelion, rae, ayer, Bett Myers Squibb, lanai, Merck Shap ad Dobe, Novas, Per and United Ther apeutis; and as reeeved lnsttulonal search glans fom Actelion, Asrazeneca, ayer, Novartis, Deutsche Forschungsgemeinscha, se Bundesminstrum fr Bung und Forschung. and Kroner Peseniue ting, eldhaber has recived esearch support an Rayer, Boovinges Inge, Brito Myers, TG EKOS, Dich Sane, lanes, the US. atonal Heat lod, and Ling tsi and the Tombosis Research Institute; and has eeled consulting fes fom Bayer and Boohringe Inglis. Dr. Parikh has received insttional grntsesnch suppor fom Abbott Vasu, Shockwave Medial, Tame Medi, and Surmedis; and has received consul fos om Terumo and Abiomed; as parispated ca ‘dviory Bonds for Abbot, Boston Set St, Jansen, Medtronic, and Pips and has served cn the Tata Safety and Montring Boar fo Sik Road Nedial-r. Monreal asserted as an advisor constant for ano, Leo Pama, and Dah Sonja ha esived a nonrstced educational grat by Saal and Bayer to sponsar the RIETE ety. De Kram has worked under contact with the Centers for Medicae& Medical Servcstospor quay messurement programs; hasrecived Inettaonal esac gant auppot fiom Medonie and the US. Food and Dnug Adminstration, dotsoa & loan, and Shenzhen Genter fr Heath informavons has served as 3 constant forthe Nationa Center for Cadiovascul Diseases Being: hax eceved contig fees from Arold& Porte aw es (Sano opie! itgton, Ben. Marin awn Cac Cet VC ‘er Ligation), and Steged and Jensen law fm (Vion ization; has served as CtdaeScntie Advsary Bou ha or Unitoceathy has served aba member ofthe IM Watson Health fe SincesBoud;has served onthe Advisory Hoard ec ement Since and Pacshook; served on the Physician Adviser Bod fr Asta; ads the cofounder of Hgelealih nd Refactor Health Dr. Konstantdes has recelved esearch rant sport fam Baye A, Bocinger Ingen, Actin nse; has recived educational grant suppor fom Biocompatible Group UK/Bston Scent and Dah Sankyo; and has recived lecture is re Bayer AG Paes Myers Su and Merc Sharp and Dole Dr, Weitz hie vered av acon ad rected honor fom yer, lansen,Snson& oso, Bisa Myers Squib Mizer, Bodine ngelein, Nova Dah Sky, Merck, Serve, Amos, Ions. and Phas. Dr. Lip has served as. onslant for Bayeanssen, rst Myers Squbhy ae, Meni, Deter igetein, Novas, Vtsce and De Sankyo andbasservedsaspeate or ver Besta Myers Suh fier,Aeitons Boelsinge ingen, and ich Sanyo. letherautorskave reported try haven relationships relevant tothe contents af his pape to disclose. Thomas M Maddox MD, MSc, served a Ges aor Chie for this paper. ‘Thoauthorsatesttheyaeincompince with human stdiescommiteesand animal welfare regulations ofthe authors stations thar instructions page. Manusexp eee Ap, 2025 ceed Ap 15,2020.METHODOLOGICAL CONSIDERATIONS Every effort was made to provide a comprehensive assessment of the published evidence (MEDLINE with PubMed interface; date of last search: April 12, 2020). ‘To accommodate the rapidly evolving nature of in: formation and concer for the delay between completion of studies and their publication, we also reviewed manuscripts on 2 preprint servers (medRxiv and SSRN; date of last search: April 12, 2020). We acknowledge that the manuscripts from the latter 2 sources are not peer-reviewed. ‘There is international variability in preventive measures and testing strategies by local authorities, diagnostic tests’ availability, access to care, and treatment strategies, as well as variability in outcome reporting for COVID-19. These issues influence the reported diagnosed cases, casualties, and in turn, case-fatality rates. Moreover, to date, we lack large prospective cohorts. The existing evidence, including data on thrombotic complications, is derived primarily from small and retrospective analyses (Figure 1) ‘The current document represents an effort to pro- vide general guidance for patient care related to thrombosis and antithrombotic therapy. Given the limitations of the evidence base, the steering com- mittee (B.B.y MVM, Jd.Wey SV-Key S.ZsGey AIT MM, HAM-K., G.Y.HLL.) chose several questions that seemed more challenging but relevant to patient care (12). These questions were sent to the entire group of authors twice. The Delphi method was implemented to provide consensus-based guidance. The questions included considerations for prophylactic or thera- peutic anticoagulant regimens among various sub- groups of patients. with COVID-19, and antithrombotic therapy in the setting of suspected or confirmed DIC, PATHOGENESIS AND TRANSMISSION SARS-CoV-2 is a single-strand RNA coronavirus, which enters human cells mainly by binding the angiotensin-converting enzyme 2 (12), which is highly expressed in lung alveolar cells, cardiac myocytes, the vascular endothelium, and other cells (13). SARS-CoV-2 Is transmitted primarily after viral par- ticles are inhaled and enter the respiratory tract (1). In addition, the virus can survive for 24 to 72 h on sur- faces, depending on the type of surface, which en- ables fomite transmission (1), Initial symptoms of COVID-19 overlap with other viral syndromes, and include fever, fatigue, head- ache, cough, shortness of breath, diarrhea, head- aches, and myalgias (15-17). As with other virulent COWD-19 and Thrombotic Dasa HIGHLIGHTS: + COVID-19 may predispose patients to arterial and venous thrombosis ‘ Initial series suggest the common occur- rence of venous thromboembolic disease in patients with severe COVID-19. The optimal preventive strategy warrants + Drug-drug interactions between anti- platelet agents and anticoagulants with investigational COVID-19 therapies should be considered. ‘The available technology should be used optimally to care for patients without, COVID-19 who have thrombotic disease during the pandemic. zoonotic coronavirus infections such as SARS and Middle East respiratory syndrome, COVID-19 has the potential to result in severe illness including sys- temic inflammatory response syndrome (SIRS), acute respiratory disease syndrome (ARDS), multi organ involvement, and shock (18). Although older age and comorbidities such as cardiovascular dis ease confer a higher risk for severe disease, young and otherwise healthy patients are also at tisk for complications (19). Common laboratory abnormalities found in pa- tients with COVID-19 include lymphopenia (15) and elevation in lactate dehydrogenase and inflammatory ‘markers such as C-reactive protein, D-dimer, ferritin, and interleukin-6 (IL-6) (20). IL-6 levels may correlate with disease severity and a procoagulant profile (1). ‘COVID-19 AND HEMOSTASIS PARAMETERS ‘The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia (22) and increased D-dimer levels (23), which are associated with a higher risk of requiring mechanical ventilation; intensive care unit (ICU) admission; or death (Table) Data related to other tests are less certain and often contradictory (24,25). Disease severity is variably associated with prolongation of the prothrombin time (PT) and international normalized ratio (INR) (1,20,26), and thrombin time (TT) (27), and variably by a trend toward shortened activated partial thromboplastin time (@PTT) (1,16,19,28). Recently, Tang et al. (7) assessed 183 patients with COVID-19, 21 (115%) of ‘whom died, Among the notable differences between patients who died and those who survived were Biel2054 del eto COVD-19 ae Thrombotic Datos TABLE Select Summary of Thrombotic and Thromboembolc Events During Vira Outbreaks Proposed Mecham vent Tye EsidemitgicalDot aS Inflammatory evoke reease ve Retrospective ast of 45 rita patents with SARS showed 1] DVT an 7 PE vets ase seis of 8 SARS postive CU patients. Autopsy identified PE in 4 2nd Vn * inal 0) Crea hess ‘terial trombotcevents na prospective ste of 75 patents, 2 patents of acute myocardial frcton ‘ia Seek eid) (59) ‘ase eport of en NSTEM att who recived PCI but subsequently developed STEN several hur tr, concaring or mune eats plague reabUY (0) ‘oatonat esac (138) omer na case snes of 206 patents wth SARS, 5 develoned ge artery chemi ke ath UC present 2 of 5 (1) Ina retonpective aay of 57 patents wth SARS, toate, stil elevations In aPTT wee pated n 96 patents and OIC developed 4 patents (12, Noaspeciic mca pote into tne nasties of 57 ses of MERS (conta and probable) at last 2 were reported to SARS. Modes ses eevted rave sensumpeve coaguopaty (5). Intemmatorycytotn ea (3) "ransgnic murine modes show evidence of Imerovcular tvemboss (1) suena Possible de novo pulmonary emboli in certain ve Retopective sty of 19 patents showed VTE events in patents evn cases (35) rophylactcamtcoogulton 7). fae an eee contami 7a pt theres N67 hr ns Rasttinsmren ne ‘A mult, ebserationa, case-control study (N ~ 1.454) suggested that lower Possible trombosis owing to rupture of pre- ‘re fates ae assocatd wi voezavaconaton dato: 0.78, ‘ensting hihi plaques (23) 954s contdenceitanal 057-097) (19) Platelet aggrepation ovr infaned athero ‘Ths i representative but rot conorehensie Isto ssacate tues. sclerotic plagues noted i animal ‘Atel thombote events Ase cone sty of 64 patent hospital wih acute myocar faction modes (1), ound an nessa nen ao (5.05, 95% confsence mera: 386-950) or year facto daring pereds after inlurza compared with contol: (CO) Snr evidenes ext ror ten (15,5. ‘reuospectve cart study of 19 patents eps 3 ater Uvombotc evens, 2 wech had STEM (7. ‘Ths representative but rot conorehonsie Uist of scat ts. other DIC asbeon described withnfucrzinfecton in rumor of ase reports ard sma cae Snes (5213. coors hospalzed mth COMID-19 3), na sd fom 3 host othe Netheands,27% of 184 stay i pts ‘ath CO¥D-19 had tomo, with wat events bing VIE. Factors may nude intamtery tine rail theme events Data are cntining to emerge rego te kof rambo event exact ith teens Sn ert lesen ek ‘OVD fection and on iterate regi Fr AC planned. Please see factor test or more deta. SARS-CoV-2 binds ells expressng antes ter etopectve ans of 189 patents ound nonsovvors a sanfcanty ihr “anvertigenayne 2 (5), and ths may ‘dimer and PT values, compared with suis, Further, 15 of 21 7.950) Imei futher mechanisms of ry onsrivors met cite fr 1 of 162 (0.6%) suns. ‘tematic ew of rate pulsed pri to Febuary 22, 2020, suggests ‘devaons In PY and D-dimer levels wee stated with soo rogneth pent with COWO-19 3). cs = ste oa ane APT stated pl ontop tne OVD 9 = nin dees 201, - ened ane coxten DVT ~ dep ven ont (EU mera et MER Me Catton NSTEM~ op ST sone von mal io, Pps roy vein Pe pier em 7 potambe tn 5 are sae rapt rane SAS Ca 2 see ate espn apone coins 2 SWS seq eatin mr aro VI aout increased levels of D-dimer and fibrin degradation products (~3.5- and ~1.9-fold, respectively) and PT prolongation (by 14%) (p < 0.001). Further, 71% of COVID-19 patients who died fulfilled the International Society on Thrombosisand Haemostasis (ISTH) criteria (29) for DIC, compared with only 0.6% among survivors. Collectively, these hemostatic changes indicate some forms of coagulopathy that may pre- dispose to thrombotic events (Central illustration), although the cause is uncertain Nevertheless, it is yet unknown whether these hemostatic changes are a specific effect ofJace vou. 75, wo. 22,2020 Biel COWD-19 and Thrombotic Dasa [FIGURE Variability in Resources and Testing Strategies and in Contracting COVID-'S After Exposure to SARS-Co¥-2 oer) Pe Ce gee eet es oy See ey ene Pretty aye Su nid Maan oe) ‘Asymptomatic, tested, SARS-Cov-2+ Infection ‘SARS-CoV-2 - [uninfected population] ‘uc varity explains the sina popalton tes of theinetion andthe stint as aalty aes,ass vais eons and counts laranatryespanse, incented age, eed bein static re more frequently served sever coronviu ase-2019(COVIO-1)}-ray contrite to theron and adverse outcomes. DIC = dseminsted intravascular coagulation; SARS-CoV-2 = severe cue respiratory synctome-coronavius2; VIE = venus thomboembolsm SARS-CoV-2 or are a consequence of cytokine storm that precipitates the onset of SIRS, as observed in other viral diseases (30-3). Another consideration that has not yet been investigated is that the hemostatic changes seen with COVID-19 infection are related to liver dysfunction (34). A recent study reported 3 cases with severe COVID- 19 and cerebral infarction, with 1 associated with, bilateral limb ischemia, in the setting of elevated antiphospholipid antibodies. Whether anti- phospholipid antibodies play a major role in Pathophysiology of thrombosis associated with COVID-19 requires further investigation (35) COVID-19, MARKERS OF MYOCARDIAL INJURY, AND THROMBOTIC DISEASE. Elevated troponin levels are associated with poor outcomes in several studies of COVID-19 (26) However, the differential diagnosis for elevated troponin in COVID-19 is broad (37) and includes nonspecific myocardial injury, impaired renal function (leading to troponin accumulation), ‘myocarditis, pulmonary embolism (PE), and type 1and 2 myocardial infarction (MI) (38,39). Similarly, eleva: tion of natriuretic peptides is nonspecific (38), and consideration for thrombotic events (e.g., PE) should “only be raised in the appropriate clinical context. COVID-19 INVESTIGATIONAL THERAPIES. AND CONSIDERATIONS FOR THROMBOTIC DISEASE Several investigational agents are being tested in the ‘management of COVID-19, especially for patients who develop severe disease. Some of these drugs have clinically important interactions with antiplatelet or anticoagulant agents (Tables 3 and 4). Further, a few of these investigational agents have been associated with excess risk (or, in other cases,al eo COVD-19 ae Thrombotic Datos TABLE 2 Assocation Between Coagulation Abnormalities or Markers of Thrombosis and Hemostasis and Clinical Outcomes in Patients With COVID-+3 Lipo Moneta. fang etal. Yangetal, owt ale Gavet al. Wangetal,wivetal, Tangetal, Upplet al. Farlor. Upp et at. yore) "“ze200) Res) BewE —aMBE “OIG?” ROK9}_"2OI)’ ONO. e202) 02000) 98) aS) A) THB) OH THS) ID) 38D) SAD Pate ine Setting of 1s. Dead v3 Dead vs. aie um nats Dead outcane 196 (65-265) 191,74) 5.166 107-229) 2 (10202) 162 (n1-230) ~acs7 per abe weiss eA we 220, 165s. 208 we rillereter (31-26) (065-27) (25185 (37-263) Desener Setting of Severe ve, KOs Desde sive Sevres. ICU ye esd vs, ead vs. severe vs comparton raneeere nomic ronrevere monic lve lve romevere Ortcone, 19.15.21 24106-1649 52052719 0500308) 040202) 4000: 2100853) 30 ah was W506 W502 v502 1O).05 OE 5357 (esos) (x1) = 249 rey 34H” HID Protrombin tine Sseting of Severe vs, Kus Oss Dendvs ve Severevs. ICU Osada ve femparson rencevere nomic ake fonesre nen-eU lke Owtcome,s 27452 201284) 9A) ve WIM Maids B20 — MEM 15504 W107 9G)” we BON) Mss sles eS. Geran torn eds 8 Bemo- Be MOR KO) Teponia eas) Setting of tu Dead ve alive teu Sewers cenparion omicu enc rower outcane, 33601550) 22668) n065- 26 (68 paint 3500754) 5 300155) 26a) ve aes sare “Me tere els reo a aby muh of sae. reduced risk) for thrombotic events, or for thrombo- cytopenta in prior studies of non-COVID-19 pop- ulations. For example, bevacizumab, 2 monoclonal antibody that binds to vascular endothelial growth factor, and is under investigational use for COVID-19,, is associated with increased risk for adverse cardio- vascular events, including MI, cerebrovascular acct- dents, and VTE (40,41). Alternatively, fingolimod, an immunomodulating agent being tried for COVID-19,, may reduce reperfusion injury and improve out- comes in patients suffering from acute ischemic stroke (42). Hydroxychloroquine, recently receiving Emergency Use Authorization from the U.S. Food and Drug Administration for treatment of COVID-19, may potentially exert antithrombotic properties, especially against antiphospholipid an bodies (#2). COVID-9 INVESTIGATIONAL THERAPIES AND. ANTIPLATELET AGENTS. Scientists are studying a number of agents for COVID-19 treatment that may hhave interactions with oral antiplatelet agents. ‘Table 3 presents potential drug interactions between investigational drugs for COVID-19 and commonly administered oral antiplatelet agents. Lopinavir/ri- tonavir is a protease inhibitor and inhibits CYP3A4 metabolism. Although the active metabolite for clopidogrel is mostly formed by CYP2C19, inhibition of CYP3A4 may also lead to reduction in effective dosage of clopidogrel. In contrast, inhibition of CYP3A4 may increase effects of ticagrelor. There- fore, the concomitant use of these agents along with lopinavir/ritonavir should be cautioned. Although limited clinical data exist, use of P2Yi2 platelet function testing to guide the use of clopi- dogiel or ticagrelor in this setting might be considered. An alternative, in the absence of con: tuaindications, Is to use prasugrel, which is not prone to these interactions (41-47). Remdesivir, a nuicleotide-analog inhibitor of RNA-dependent RNA polymerase, is reportedly an inducer of CYP3A4:, however, dose adjustments for oral antiplatelet agents are currently not recommended. Of note, there are no known major drug-drug interactions between investigational COVID-19 therapies and parenteral antiplatelet agents such as cangrelor and, slycoprotein Mb/itta inhibitors.Jace vou. 75, wo. 22,2020 kde eta 2057 ume 18, 2020:2080-72 COWD-19 and Thrombotic Dasa CENTRAL ILLUSTRATION Postulated Mechanisms of Coagulopathy and Pathogenesis of Thrombosis in COVID-19 SE CE + Acute illness Venous Thromboembolism + Bedridden, stasis + Genetics + Fever + Intravascular coagulopathy + Diarthea Poe + Myocardial injury + Liver injury + #Cardiac biomarkers +cKD. + COPD +HE ‘Malignancy + Pulmonary microthrombi i] ‘Myocardial infarction nna anced ie Tea ctca) + 4D-Dimer, FOPs, PT + #pPlatelets. Disseminated intravascular Coagulation Seay “BR Lymphopenia Intarmmatoryeytok fae Bikdei Beta. J Am Coll Cardiol. 2020,7523)2950-73. (09 Sever acute resaterysynome-2 times the upper limit of normal) who have low risk of bleeding (74,77,78). ‘The role of thromboprophylaxis for quarantined patients with mild COVID-19 but significant comor- bidities, or for patients without COVID-19 who are less active because of quarantine is uncertain, These patients should be advised to stay active at home. In the absence of high-quality data, pharmacological prophylaxis should be reserved for those patients at highest risk, including those with limited mobility and history of prior VTE or active malignancy. DIAGNOSIS OF VTEIN PATIENTS WITH COVID-19. AS described previously, elevated D-dimer levels repre- sent a common finding in patients with COVID-19 (23), and do not currently warrant routine investiga ton for acute VTE in absence of clinical manifesta- tions or other supporting information. However, the index of suspicion for VTE should be high in the case of typical deep vein thrombosis (DVT) symptoms, hypoxemia disproportionate to known respiratory pathologies, or acute unexplained right ventricu- lar dysfunction. ‘A diagnostic challenge arises among patients with COVID-19, as imaging studies used to diagnose DVT or PE may not be pursued given risk of transmitting infection to other patients ot health cate workers and. potentially due to patient instability. Moreover, im= aging studies may be challenging in the setting of patients with severe ARDS who require prone posi tioning. Investigation for PE is not feasible due to critical illness and prone position. Lower extremity ultrasound is also limited due to patient positioning. However, it may be argued that the prognosis of pa- tients with ARDS requiring prone position is so grave that investigation for underlying VTE may not alter the course. A potential option may be to consider echocardiography to assess for signs of potentially worsening right ventricular dysfunction and, in rare circumstances, clot in transit (79). ROLE FOR EMPIRIC THERAPEUTIC ANTICOAGULATION. WITHOUT A DIAGNOSIS OF VTE. In view of the hemo- static derangements discussed previously and ob- servations from prior viral illnesses (80), some clinicians use intermediate- or full-dose (therapeu- tic) parenteral anticoagulation (rather than prophy- lactic dosing) for routine care of patients with COVID-19 (51), hypothesizing that it may confer benefit to prevent microvascular thrombosis. How- ever, the existing data are very limited, and are primarily based on a subgroup analysis (n ~ 97) from a single retrospective study with limited control for potential confounders (82). A single-center study from China suggested that D-dimer levels, >1,500 ng/ml has a sensitivity of 85.0% and speci- ficity of 88.5% for detecting VTE events. However, the study was limited by small sample size and lack of validation. At this moment, while practitioners use a variety of prophylactic, intermediate, or therapeutic doses of anticoagulants in patients, the optimal dosing in patients with severe COVID-19 remains unknown and warrants further prospective investigation. The majority of panel members consider prophylactic anticoagulation, although a minority consider an intermediate or therapeutic dose to be reasonable. INCIDENT VTE. Few published studies have com- mented on incident VTE in patients with COVID-19 (63,84). In a retrospective study from China, among 81 patients with severe COVID-19 admitted to ICU, 20 (25%) developed incident VTE. Of note, none of the patients had received VTE prophylaxis (85). In a study of 184 patients with severe COVID-19 from 3 academic medical centers in the Netherlands, the authors reported that 31% (95% confidence interval: 20% to 41%) of patients developed incident VTE. All patients received pharmacological prophylaxis, although underdosing was observed in 2 of the 3 participating centers (81). These findings require validation in additional studies. It is possible but unknown that VTE remains underdiagnosed in patients with severe COVID-19.. This is important, as ARDS in patients with COVID-19 is itself a potential etiology for hypoxic pulmonary vasoconstriction, pulmonary hyperten- sion, and right ventricular failure. Further insult from, PE may be unrecoverable. MEDICAL THERAPY FOR VTE. Therapeutic anti- coagulation is the mainstay of VTE treatment ((9,86,87). Selection of an agent requires consider- ation of comorbidities such as renal or hepatic dysfunction, thrombocytopenia, and gastrointestinal tract function, and the agent will ikely change across the hospital course to the time of discharge. In many ill inpatients with VTE, parenteral anticoagulation (e.g, UFH) is preferred as it may be temporarily withheld and has no known drug-drug interactions with investigational COVID-19 therapies. However, concerns with UFH include the time to achieve ther- apeutic aPTT and increased health care worker exposure for frequent blood draws. Therefore, LMWHs may be preferred in patients unlikely to need procedures. The benefit of oral anticoagulation with, DOACs includes the lack of need for monitoring,Bike eta 2961 COWD-19 and Thrombotic Dasa Poteet Na B e FH E Fi 4 a FA FB i 5 4 | ‘ik Stratification of ACS and Venous Thromboembolism With CVID-19 Tee ee Er) Cee eo eu For ACS: + GDMT per ACS algorithm + Urgent/emergent angiography and intervention + Consider need and safety of hemodynamic support and monitoring For VTE: + Anticoagulant therapy + Ifrecurrent symptoms or deterioration, consider systemic thrombolysis or potentially catheter-directed therapy as an alternative + Consider need and safety of hemodynamic support and monitoring For ACS: + GDMT per ACS algorithm + Angiography and intervention only if recurrent/ persistent symptoms or decompensation For VTE: + Anticoagulant therapy + Catheter-directed or surgical therapies only if recurrent/persistent symptoms ‘or decompensation For ACS: + GDMT per ACS algorithm + Consider emergent TTE + Urgent/emergent angiography and intervention vs. systemic fibrinolysis, + Consider need and safety of hemodynamic support and monitoring in select patients For VTE: + Anticoagulant therapy + Consider systemic fibrinolysis + Catheter-directed or surgical therapies in case not suitable for systemic fibrinolysis + Consider need and safety of hemodynamic support and monitoring For ACS: + GDMT per ACS algorithm + Other therapies reserved for select cases such as those with significant recurrent/persistent symptoms or decompensation For VTE: + Anticoagulant therapy + Other therapies reserved for select cases such as those with significant recurrent/persistent symptoms or decompensation Propsedalgorthn to sk stravty paves hase on sverty of acute covery syneomes (ACS), VIE, and COVID-S presentations “High ACS refers to patents wih bmodynanic ably, let venticular dystinction cecal wall mtn abnormality, oc wotsening or efacoy symptom, High-ik VTE refrs to pate with uimonary embolism who are hemedyramicaly unstable, evidence of right vena ysfinction or distaton oF worsaning of refactory symptoms Highs OWD-19 ees to patents wth igh suspicion fr or confimes COVIO-19, inducing dius with high ral lad, meat wth coughing oF seeing or othe respratory symptom an at for reuing ination an acoso val particles. Hered suppor ines ina-artchllaon pap, pera ‘etic ans device, ad extracorporeal memixane oxygenation. Hemayrmie monitor refers to Son-Gane catheter for evsve hemody atest For potent russ interactions pense ee Tables 3 and, GDMT~ gudeinecrcted medical therapy, TTE -teaathorace echocardiogram, other ab brevatons 2 ia Flgure facilitation of discharge planning, and outpatient ‘management. The potential risk (especially in the setting or organ dysfunction) may include clinical deterioration and lack of timely availability of effec- tive reversal agents at some centers. For patients who are ready for discharge, DOACs or LMWH would be preferred to limit contact of patients with health care services required for INR monitoring for vitamin K antagonists (VKAs). COVID-19 AND INTERVENTIONAL THERAPIES FOR VTE. PE response teams allow for multidisciplinary care for patients intermediate and high-risk with VTE (49,88-90). During the COVID-19 pandemic,2982 del eto COVD-19 ae Thrombotic Datos TABLE S Areas Requiring Further Investigation ‘Patios with rit COVIO (utpatert) To detomin the optimal method for riskasesmant for cutoatins with mit {COMD'19 wn area kof VTE Te determine the inience ACS im population-based studs Patients with moderate or severe COVIO-9 without DIC (osptaized) Te determine the nace and predicts of VTE amang patents ith COMD-19 ‘ho presert with respratr suficeny andor hemodynamic mab thas td lower entre VTS, canal Une assed BVT upper o& Te develop an saropistealgorth or he diagnos of nent VIE in patente ‘nt COTS eo dtamine the optimal ttl duration of propia anticaguation "eo determine te optimal dos of progtyactc amcooqation in spectic opus eg, those with ebesty or cancad kedney deas) eo detemine i LH constuts the prefered method of phamacsagal repos Te determine the optimal method fr is stratfcation and VIE propia ater determin if out use of higher doses of anconglnts (Le, higher tan propia doses a eribe inthe interstage) confer nt ent Toestermne the isgence and pressor of type 1 acute myocar nfrcton a tients with COV, and to conpare ther process meses and utmes “it nnintetes tents Te deterine te potenti role of agents nce dapat fondpaint, apd Soloed nsec patents ath odertelseereCOVIDTS Patents with moderate or severe COVD-19 ad suspected conte DIC "hospitals eo dtermin if routine use of pormsclana VIE propa o ow or ‘Standard dss antecogulaton with UFH or LMWH warated (Fro overt eeding Todetermineif ational nical characteris and arabes nthe sting of IC (eg. lymphopenia) Should be conscered to els say and aes progress {eo determin ity of ther interventions inci athrombin concentrates Patients without COVIO-19 bt with comorbtes and horibound rng the yncemie ‘eo detarmin the optimal method of seening an ik swaticton for ‘enadeatn a VE popians "conduct population-level stuces to cetemin the trends im cdece and ‘acoso rombti dns nthe prion of edie fe vs The options ince the Capi model the MPROVE model and the Padua mod, ‘nd others for ssesenan ofthe rn of VIE. These shold be weed 299s the ik of basing. Prospective muliconter chor observanal data ate nec 2 these rwacols Should no interfere, and cul unin parallel with, nerventorl tl tt re fared of aeady under. Deine lated n many pti with COO 79, although negate value my lb he In some ces of COV 19 eth worennghypoxema,CTPR may te coriered mead of roneantot CT (wich ony see the porary enchyma). Unresolved sues inte dapnoste tests for crea U patents Slain hone pone poo, with ted cpio fr CTPA tasanogeny Ltuasound screening nslect pts may need to be stud Weighted prophylactic dosing er patents with abs, of dosing sed on ‘Gea clsancr in patents th nay ase requ father mestoaon ‘The options ince the Capi model the MPROVE model an the Pata made “ae eter for ssc otek of VTE Thee shod be weed aga {he ik of bleeding. ‘important quston woud be wheter manitrng an-a act mod be referable over 2, ‘relevant qustion wether propyl, o thr, dose antcoagutin shad ‘be aor to patents wth DIC who do trav ceding, even without ‘mao. ‘The eptins incu the Capi model the MPROVE model and the Pada mod, ‘nd oter fo seseeaman ofthe eof VTE. The shoud be wed gant the nk of bleeding. ‘though telemacine reasonable to contra the COMID-19 pandemic, potent Invetse consequenes on ronconmuncble ene, lating tomate (Geece dere vestigeton, ‘TPR comatastomanogy ery wei: MFO tetas Ms Penrtin Rest co Yous Tomboebsizn LAN ow mle west ep UM —nacouted similar to other consultative services, PE response teams should transition from in-person inpatient evaluation to e-consults using phone calls or tele- ‘medicine systems whenever feasible. It is important to note that there are minimal available data demonstrating lower mortality from routine use of advanced VTE therapies (91,92). Therefore, the use of catheter-directed therapies during the current outbreak should be limited to the most critical sit- uations. Indiscriminate use of inferior vena cava filters should be avoided (93). Recurrent PE despite optimal anticoagulation, or clinically significant VTE in the setting of absolute contraindication to anti coagulation, would be among the few scenarios in which placement of an inferior vena cava filter may be considered (11). Even after inferior vena cavafilter placement, anticoagulation should be resumed as soon as feasible, and this is often done with ‘gradually increasing doses and close observation for bleeding. With regard to reperfusion strategies for acute PE, current guideline recommendations should be followed. Intermediate-risk hemodynam: ically stable patients (intermediate-low risk, or intermediate-high risk PE according to European Society of Cardiology [ESC] classification, sub- massive PE according to prior classifications) (49,87,91,94) should be managed initially with anticoagulation and close monitoring. In case of further deterioration, rescue systemic fibrinolysis should be considered, with catheter-directed op- tions as an alternative. For patients with overt he- ‘modynamic instability (high-risk PE according to the ESC classification, massive PE according to prior classifications) (49,87,91,94) systemic fibrinolysis is indicated, with catheter-based therapies reserved for scenarios that are not suitable for systemic fibrinolysis. If infection control settings are equal, bedside initiation of extracorporeal membrane ‘oxygenation (ECMO) is preferred in cases with known COVID-19 positivity or uncertain status, rather than support strategies requiring the use of a catheterization laboratory or an operating room (95). Figure 2 presents a potential algorithm for treatments based on risk due to VTE and COVID-19 severity ‘The vast majority of patients with symptomatic acute DVT, should be managed with anticoagulation, with home treatment whenever possible. The few that may require acute endovascular techniques (either local fibrinolysis or embolectomy) include those with phlegmasia, or truly refractory symptoms (a, COVID-19 AND Acs COVID-19 AND INCIDENT ACS. Myocardial injury in CovID-A9, as evidenced by elevated cardiac troponin levels or electrocardiographic and echo- cardiographie abnormalities, is associated with se- vere disease (5,36). Furthermore, higher troponin levels are associated with severe COVID-19 (5,36). However, not all such events are due to throm- otic ACS. Although anecdotal cases of patients with COVID-19 presenting with ACS due to plaque rupture have been described (type 1 MD, currently no such cases have been published. Such cases have been also previously described with influ- enza or other viral illnesses, and have een attributed to a combination of SIRS as COWD-19 and Thrombotic Dasa well as localized vascular or plague inflamma- tion (20,97,98). COVID-19 AND ANTITHROMBOTIC THERAPY FOR ACS. In presentations consistent with ACS due to plaque rupture (.e., type 1 MD) (39), dual anti- platelet therapy and full-dose anticoagulation per the American College of Cardiology (ACC)/American Heart Association (AHA) and ESC guidelines should be administered, unless there are contraindications (09-102). In patients with perceived elevated bleeding risk, regimens with less potent antiplate- let agents, such as with clopidogrel, should be considered, given that hemorrhagic complications are not uncommon. Special attention should be also given to drug-drug interactions between anti platelet agents or anticoagulants and COVID-19 investigational therapies. Parenteral antithrombotic agents, in general, do not have known major in: teractions with the COVID-19 investigational thera pies (Tables 4 and 5). COVID-19 AND INTERVENTIONAL THERAPIES FOR ‘ACS. The ACC and Society for Cardiovascular Angi ‘ography and Interventions recently provided guid: ance regarding catheterization laboratory procedures in the current climate (64,103). The recommenda: tions note that it is reasonable to continue optimal ‘medical therapy and defer nonurgent cardiac pro- cedures, in order to preserve PPE, as well as hospital resources including inpatient and ICU beds, and minimize exposure for patients and health care workers alike, Prior to intervention, efforts should be made to distinguish nonspecific myocardial injury, myocar ditis, and true plaque rupture presentations (103). A low threshold to use transthoracic echocardiography to identify wall motion abnormalities should be considered prior to catheterization laboratory acti vation, Even in case of ST-segment elevation MI (STEMD, in which primary percutaneous coronary intervention (PCI) reduces mortality and reinfarc tion, risk of COVID-19 transmission from patients to health care workers, or vice versa (asymptomatic vectors) must be considered. In light of this, indi vvidual centers in China and elsewhere have devel- oped adjusted ACS protocols, which call for consideration of fibrinolytic therapy in selected pa tients with STEMI (104). Centers in which timely PCI is less feasible may be more likely to adopt such a strategy. However, given that presentations of COVID-19 can mimic ACS (e.g, in the setting of myocarditis), fibrinolytic therapy must be used with caution. Bielal eo COVD-19 ae Thrombotic Datos CRITICAL ILLNESS WITH SARS-CoV-2 AND. MANAGEMENT OF ANTITHROMBOTIC AGENTS ‘The risk of VTE, which is increased in critically ill patients, is likely even higher in those with SARS- CoV-2 and critical illness. Aside from hemostatic derangements, immobility (@ systemic inflamma: tory state), mechanical ventilation, and central venous catheters contribute to VTE risk within the ICU (105-107), nutritional deficiencies and liver dysfunction may also interfere with the produc tion of coagulation factors (108). Alterations. in pharmacokinetics in critically ill patients may necessitate anticoagulation dose adjustment (109), ‘owing to factors relating to absorption, meta- bolism, and renal (or hepatic) elimination of these drugs in the setting of potential organ dysfunction. Parenteral anticoagulation is recommended in ‘most cases in which anticoagulant therapy is needed: for known thrombotic disease. UFH can be used in the setting of anticipated procedures, or in patients with deteriorating renal function. If no urgent pracedures are anticipated, LMWHs are a reasonable alternative (69). In patients requiring ECMO, anticoagulation is frequently required to maintain circuit patency, especially at lower flow settings. Rates of complica tions are unknown in patients with SARS-CoV-2, but rates of thrombosis and hemorrhage may be as high as 53% and 16%, respectively, in other populations with, respiratory failure (110). The limited outcome data that are available for ECMO in patients with SARS- CoV-2 suggest poor outcomes, with 5 of 6 patients dying in one series and 3 of 3 in another (20,26). There are currently insufficient data to recommend anti- coagulation targets for COVID-19 patients requiring ECMO (111). ADDITIONAL CONSIDERATIONS. As previously ‘mentioned, severe COVID-19 may predispose to DIC, with such patients experiencing particularly poor outcomes (7). Supportive care and addressing the underlying hypoxia or coinfection are appropriate (9), There are insufficient data to recommend transfusion thresholds that differ from those recom= mended for other critically ill patients. If invasive procedures are planned, prophylactic transfusion of platelets, fresh frozen plasma, fibrinogen, and pro- thrombin complex concentrate may be considered (29). Last, patients requiring targeted temperature management may exhibit prolongations of both PT and aPTT without evidence of bleeding diathesis (112). Therefore, correction of coagulopathy in unselected patients without overt bleeding is not currently recommended. DIC AND CONSIDERATIONS FOR ANTITHROMBOTIC THERAPY DIAGNOSIS AND MANAGEMENT. DIC is common in many patients with critical illness (112), including those with COVID-19 (7,114). It is uncertain whether COVID-19 has unique characteristics to cause direct activation of coagulation. The diagnosis of DIC is best established using the ISTH DIC score calculator (09). Regular laboratory monitoring of platelet count, PT, D-dimer, and fibrinogen in patients with COVID-19 is important to diagnose worsening, coagulopathy. The first step in management of DIC is to identify and treat the underlying condition(s). Bacterial superinfections should be treated aggressively. In addition to preventing VTE, LMWH prophylaxis may decrease thrombin generation and modily the course of DIC. Preliminary results, albeit with small number of events and limited adjustment, may sug- gest a favorable response from LMWH prophylaxis (62,114). Long-acting antiplatelet agents should be generally discontinued in most patients with DIC, unless required (e.g., recent ACS or stent implanta- tion). For patients with moderate or severe COVID-19 and an indication for dual antiplatelet therapy (e.g. PCI within the past 3 months or recent MT) and with, suspected or confirmed DIC without overt bleeding, in the absence of evidence decisions for antiplatelet therapy need to be individualized. In general, itis reasonable to continue dual antiplatelet therapy if platelet count is =50,000, reduce to single anti- platelet therapy if platelet =25,000 and <50,000, and discontinue if platelets <25,000. However, these guidelines may be revised upward or downward depending on the individualized relative risk of stent-related thrombotic complications versus bleeding. Recovery from DIC is dependent on endogenous fibrinolysis breaking down the dissemi- nated thrombi count is MANAGEMENT OF BLEEDING. Clinically overt bleeding is uncommon in the setting of COVID-19., However, when bleeding occurs in COVID-19- associated DIC, blood products support should be considered as per septic coagulopathy (115). In sum- mary, the mainstay of blood products transfusion are as follows: platelet concentrate to maintain platelet count >50 x 10°/ in DIC patients with active bleeding, of >20 x 10°/L in those with a high risk of bleeding orFIGURE 3 Considerations for Switching VKAs Because of Limitations With Access to Care or Heath Care Resources During the Were the last 2 INRs therapeutic in previous 30-60 days? Cy eet cesar Seen Resume VKA. Extend testing eae eee eee eres) een ore ey eee) Seer nee) ae eee) Pree ts ete ed eae Dee) contraindication to use DOACs? ee ae ate valves, APLS, pregnancy/ oe ees Cre monitoring at clinics during off eds oy gad Pec tnd Pera DOAC if feasible and start ¥wching the ntcaguan agent planned, cae shouldbe taken to bee tht the ptt abet afford nd receive theatre ‘heray.Contsindations to dst ra antcoagulat (ODAC incuce chan hear vals, vail atria ition AR, regnaney or bressfeeng, antishoshalip yncome (APL), and coadmststrtion of mecicaton indy strongCYP3A and P.gycopctein hhibtors (Cole medion, MV protease brs (dependent on DOAC, may st Fequre dose ecucton,CYPSAA induces (nlp, St ots wart, amyl et. Patient econ about stable tary habs whe ecg VKAS sso impart. DOACS te not avaiable ar spproved by isuance, low molecular-weight heparin (LMWH) cold be wsedn select cases, COMID-19 = coronavirus 3558-2019; INR = international normalize ato; VKA-= arin K antagonist. requiring invasive procedures, fresh frozen plasma 5 to 25 ml/kg) in patients with active bleeding with either prolonged PT or aPIT ratios (>15 times normal) or decreased fibrinogen (<1.5 g/), fibrinogen concentrate, or cryoprecipitate to patients with persisting severe hypofibrinogenemia (<1.5 g/l), and prothrombin complex concentrate if fresh frozen plasma transfusion is not possible, With the existing data, tranexamic acid should not be used routinely in COVID-19-associated DIC. Biel COWD-19 and Thrombotic Dasa2965 del eto Ace VOL. 75, NO. 2, 2020 COVD-19 ae Thrombotic Datos BUNE 16, 2020:2950-75 TABLE 6 Summary of Consensus Recommendation on Antithrombetic Therapy During the COVID-19 Pandemic Patients wth mid COVID-19 (outpatient) Fer outetants wth mld COVIO-9, eas moby soul be encouraged. though ndcmnate us of pharmacological VTE popylans shoud nt be pursue, _Ssesuent f the ih VTE atid ied resonable, Pharmac pops cul be Conse er testa on anda case bss opts to hae elevated ik VIE, without high een ik" ‘Thee no known kof developing severe COVD-19 de to taking antitvombotie agents (Le, apltelet agents a antcaagulans) Mf patents hve been thing ‘titiomo0e agent fe rr known trombote sae they shad eons ther aRvombote agents as econmended Fer outpatients on tama K antagonists wha do rat have recent table INS, nd af urale to undego homeo dine tvough NR esting, tis easonble to warstion the trestent DOA if there reno conansations and no problems with ug avatabity and arbi. H DOACs ae not approved or avate, LMWH can be ‘nedera altestive| Patents with moderate or severe COV-19 without DIC (hospital) espa paves wth COVIO-19 shld undergo rk station fr VTE raphy Fo hospaized patents with COMD-18 an rat in 1, proptyactc doses of antcanguaon should be administered to pevent VTE pamaclogicl prota i cotramacate, es reasonabe to consider trent prema compression Fee hozptalied patents with COVID-T and notin DI thre are nein ta to conser tine teapeuti or ntrmecate cae patentee antcnogstion wh UH or ws Rowtinescreenna for VIE (et, iatral lower estrerity ultrasound fr hospi patents mth COVIO-1 wiheevate D-dimer (1500 ng canot be recommended at this point Patients with mera or severe COID-9 and suspect or confirmed DIC Cositalized) Fr patient with moderate a severe COVID-19 an in IC bt without overt eding. prophylactic ntiongultion sou be aise“ Fr hospitalized patients with COVD-19 with suspected or confred DC, bt no ovr Bening, ther are afin data to cane oie teapeticornteradte- ose prentea tcanguaton wth UFH or LMWH” Fr patents with madera of svere COVO-1910 chon therapaut artsagto, who develop suspected er confimed OC without vert Heading reasonable to Eade the indestion for andeoaguaton and weg wh sk of Being when raking lial Sesons regain dov austen of dcotuation. The many oF ‘tors of ths pager econmended ecg the nenty of aneaguation ths cine scumstancs, ules the ak of trombone considered to Be acest on Fer patents with madera severe COVIO-19 and an cat for al antipatlt theepy (eg. percutaneous corner intervention within the pst 2 months recent ‘nycaratinfrction end with suspected or confirmed DC without overt teed, nthe aseeeofevdnce, decors or arta therapy need to De Individual In geal ear to contin al atlas therapy platelet cont 50,000, reduce to ata apy pate count is 25,00 are 50,000, od dscrtnve if platelet courts 25,000. However, hese ques nay be reise upward oF coward depend on the nda ‘eatnerskoftrombetccomplestions bleeding, Fr pation who were sited and ae now aig escharges fr COVID1, rune srering fr VTE ks resonable fo consideration of phrmocalagcal rohan for {nto 4 cays port dacarge, Pharmacological prpnyani shold be conadeved tee elevated ek for tombe event, witout high Desig ek" ‘Ambul and physica ety shuld be encouraged Patents wih COVID-19 presenting wth ACS Fer presentations concerning fr STEMI and COVO-9,clnns shuld weigh the ss and Sevety of STEM! presentation with tat of potenti COMID-19 Severity inthe Dott an wel ink of COVIO-19 to the nevi cist an othe et cae ste tage Dens fr parry pecstanee cranny nerve or lary thro seb red by as sure Paints without COVID-19 who have previously Known tombote dase ‘There tno known ek of developing severe COVD-19 det taking attrombotc ago, Patents teu continue ther antithrombotic gents 3 ecormende Tomine res azote with health are wore nd patient in person interactions, flow wth ews nd telemedicine i preferable most ces Patonts without COVD-9 who develop new thrombotic seace Tominimize risks associated wit ealth are wore nd patient in-person interactions, home wetment or erty schrge soul be prize Temininize risks associated wit health are woke nd pai in-person interactions, flow with evs and telemedicine i preferable in mest cases Patients withowt COVID-19 bt ith comorbid conditions (eg ror VTE, active cancer, major carhpulmenary dees), who are homebound during the pandemic Reconmendtons lide crested ably and ek asesrent forthe kf VTE a kof leding is reazonable. rinsttn of pharmscolagc rohan coube “dered ae asessment ln an wd case bas or patents who ave elevated i or voi events, without high ean “cs canny td by cre ft eet 6% lute tied 8 te Sd AD uy te ig ert ment SR coed ‘enti ne ert ara mes bets wh severe COMD' ten to rao ross pce sf anh ed ed ata eine oe (ooo = pts hh aca t Pons myn OWT HVT eps =cut nap Og yer UPN ne a tars 3000 cn be anne Sibomc hp (000 tema cn bu ae parr thn ket hcetin nese og he at wg ‘tite is ecmedsn 36% he grup ween noe meditate. emp may, emma ie aly FH ae ST 50709 ‘Stone ach esting Se mrt oe nein inset pep anqasan 4 Ainoy omen 9 ate wees ve ee congas a {hsm sno Pecamcnes termes angen tah ne mrt a mes td to reas meray acnouatn seman wert ae) re) (Quer set met be pote to he mary ewe guy eerie apa win ONSEN) sas mrty GON) encod IW aed MANAGEMENT OF PATIENTS WITH COVID-19 is to provide sufficient antithrombotic THROMBOEMBOLIC DISEASE protection, while minimizing physical contact be- WITHOUT CovID-19, tween patients, health care workers, and health sys- tems. outpatient management or early discharge for ‘The main goal of management for patients with acute VTE should be instituted when possible known or new onset thrombotic disease but without (116-118), and early discharge after medicationJace vou. 75, wo. 22,2020 kde etal 2987 ume 18, 2020:2080-72 COWD-19 and Thrombotic Dasa FIGURE 4 Considerations for Thrombotic Disease fr Patents Health Care Providers. nd Melt Systems and Professional Societies During the ook Piatra i Se ee a le acai = Pharmacological VTE prophylaxis, ~ Continue therapy, unless otherwise unless contraindicated specified by practitioners = Careful assessment for incident - Extend VTE prophylaxis in appropriately thrombotic events selected cases - Follow PT/INR, APTT, D-dimer, fibrinogen = Home INR checks or drive-through INR ~ Continuation of precedent antithrombotic check for patients on VKAs who need therapy based on clinical condition and testing assessment for drug-drug interaction Encourage home exercise [see Tables 3 and 4] - Home treatment for low-risk acute VTE - Early, safe discharge after VTE or ACS UG Cee aid = Proper use and conservation of PPE = Outpatient tele-visits Minimal team structure to reduce contact with COVID-19 - Deferring elective procedures, or those of less certain benefit = Age/comorbidity restriction for patient visits PROFESSIONAL SOCIETIES, FUNDING AGENCIES - Research priority setting and knowledge ~ Provide tele-health infrastructure generation = Drive-through INR checks - Advocacy and improved public knowledge = In appropriate cases, consider switching ~ Expedited funding for research in \VKAs to DOACs thrombotic disease - Frequent disinfection of patient room - Updated evidence-based guidelines - Negative pressure procedure rooms when possible = Cancel or postpone elective procedures and visits - Improve knowledge generation and dissemination ‘he approach to sf evaluation and management of twomBot dseasein patents with COMID-9 has several ees finvlvenant Hospalzd patents wth easing \VTE sould cntnue on antcesqulaton with caneérason of dug-dug interactions, expecially wth atvrl medeatone (Table 4), Hespaled tents wth reduced mobilty sould be started on VTE prophylas. Pains who ae dscharged or not hospitalized shoul continue recommended antceaglaton tery Telemeccine ad dive trcugh or hae INR checks can edu the rk of exposure of beth pats and hel care provides to COMIO-19 whe ssl proper ‘management of anscoaulation. a appoprate cases, consid stching VKAS 1 DOACS to mash the ned for fequent INR checks. Heath cre workers sho contin exiting precaution including ue of persona protective equipent (PE) and minimizing ini contac with COVIDT9 patie erergentpocedies for trombotc cease ecard catheterization, pulmonary trombectomy) ae needed, procedure coms should be dined, and the use of negative presire ‘opesting rooms shoul be irpemented as avalabl, Expected funding for obseratonal nd ancarizeaconrl tals in management of theo dese encouraged. APT ~ acbata prt wonbopastn time; PT peativanbin time; other abcevatons asin Figures 1 and 3al eo COVD-19 ae Thrombotic Datos stabilization for low-risk ACS or PCI for high-risk ACS should be considered (99-101). Telemedicine should be the preferred method of follow-up, and in-person visits should be reserved only for scenarios that cannot be addressed by telemedicine, or that may potentially warrant hospitalization. In general, pharmacotherapy in patients with known thrombotic disease and without COVID-19 should be followed similar to the period prior to the pandemic. Although @ recent document from the CDC indicated an increased risk of severe COVID-19 in patients receiving “blood thinners” (19), there is no evidence that antiplatelet agents or anticoagulants, increase the risk of contracting COVID-19, or of developing severe COVID-19. Sufficient education should be provided to patients for self-monitoring of symptoms, and to avoid unnecessary emergency department visits for nuisance bleeding. For patients receiving VKAs, frequent INR moni- toring may pose logistical challenges because of lockdowns and may unnecessarily increase the risk of being exposed to SARS-CoV-2. Therefore, thoughtful considerations should be given to potential alterna- tives, including using extended INR testing intervals if ptior INRs have been stable (120). Other alternatives include home-based INR checks, if this can be set up promptly, drive-through INR testing, or switching toa DOAG or LMWHs when clinically appropriate (Figure 3). A summary of key recommendations is presented in Table . IMPACT OF COVID-19 ON HEALTH CARE WORKERS AND HEALTH SYSTEMS CONSIDERATIONS FOR HEALTH CARE WORKERS. The enters for Disease Control and Prevention recom- ‘mends contact and droplet personal PPE for health care workers in their routine care of patients with COVID-19, If an aerosol-generating procedure is be- ing performed (eg., intubation, extubation, cardio pulmonary resuscitation), additional airborne PPE with an No§ respirator Is recommended. Use of telemedicine in place of in-person office visits is a strategy to minimize physical exposure. Further details have been discussed else where (5,103) ‘The following considerations specific ta the care of patients with thrombotic disease may be useful. Over- the-phone and telemedicine approaches should be considered for all nonurgent appointments. For necessary in-person visits, visitor restrictions and staggering of appointments are important con- siderations (20). For patients with COVID-19 who require urgent procedures, such as interventions for ACS, high-risk PE, or critical limb ischemia, the fewest number of staff necessary should be involved. For patients without Known infection, health care workers should screen patients for COVID-19 expo- sures or infectivity, consider appropriate PPE during the procedure, and apply disinfection techniques, post-procedure, as outlined previously (105). In pa- tients who require emergent cardiac catheterization with unknown COVID-19 status, airborne PPE with an 'Na5 respirator or powered air-purifying respirator is recommended (121,122). CONSIDERATIONS FOR HEALTH SYSTEMS. Active involvement of health systems with respect to the care of patients with thrombotic disease are critical to achieving optimal outcomes for both COVID-19- infected and uninfected patients. If feasible, re- sources should be allocated to enable at-home or drive-through INR checks. Further, system-based considerations should be made to monitor and make necessary adjustments to algorithms for management of suspected STEMI or severe PE requiring PERT teams. If procedures are deemed necessary for COVID-19- infected patients, specific protocols should be put into place regarding PPE use and room disinfection. ROLE OF PROFESSIONAL SOCIETIES Professional societies, along with other partners, have an important role in knowledge generation and, dissemination for various aspects of COVID-19 ,84,102), as well as leading by example. Mustra- tive examples include the responsible and wise de- cisions by the ACC to cancel the 2020 Annual Scientific Sessions, the Society for Cardiovascular Angiography and Interventions to cancel the 2020 Annual Scientific Sessions, and the ISTH to cancel the XXVIII Congress of the ISTH to promote social distancing and to avoid further spread of the dis- ease. Enabling meetings to continue virtually, as with the recent ACC scientific sessions (in this case at no charge) further promotes knowledge dissemi- nation and sense of community, allowing a semblance or normality in challenging times. Many professional societies, including the ACC, AHA, ‘American Society of Hematology, ESC, ISTH, and. others, are compiling COVID-related resources in dedicated websites. Professional societies can further foster collaborative knowledge generation by supporting multicenter multinational original research studies to address the pressing clinical or laboratory questions (Figure 4)PUBLIC HEALTH CONSIDERATIONS RELATED TO CARE FOR THROMBOTIC DISEASE ‘The World Health Organization and government agencies have recognized the critical importance of Public health interventions at the societal level (including social distancing and self-isolation) to decrease transmission rates and alleviate the burden on health systems (123). In the most affected areas, governments have enacted manda- tory home quarantine for all nonessential personnel (124-126), There ate several important issues to consider as these interventions relate to thrombotic disease. First, given the recommendations to stay at home, with decreased daily activity and sedentary lifestyles, patients may be at increased risk for VPE (127-131) Clinicians should be aware of this (especially in older adults and higher-tisk patients) and provide educa tion on the importance of home activities to mitigate this risk (132). Second, as daily routines are disrupted, ietary changes (especially in daily intake of green vegetables, which are the major source of vitamin K in the Western diet) may affect patients who receive VKAs, As quarantine measures become more severe, ‘changes in diet and vitamin K intake may impact INR values. Practitioners and patients should be aware of these risks, and patients should be advised to main- tain a stable diet to the best of their ability. Third, the COVID-19 pandemic has produced damaging eco: nomic effects (133), with the United Nations esti- mating that COVID9 is likely to cost the world economy more than $2 trillion in 2020. These losses ‘may adversely affect patients’ treatment for throm- botic diseases. Socioeconomic disadvantage has been linked to higher rates of VTE and adverse outcomes (154,135). AS the economic effects of COVID-19 continue to evolve, these communities may come under new and significant stress. CONCLUSIONS AND FUTURE DIRECTIONS ‘More data and higher-quality data are requited to learn how COVID-19 and thrombotic disease interact. Such data, ideally derived from prospective, multi- center, multinational studies, could help to elucidate the similarities and distinctions in disease presenta- tion and outcomes of patients with COVID-19 and pre- existing and incident thromboembolic disease, and help to identify management strategies to optimize ‘outcomes in these patients. Currently, one large in- ternational registry of patients with venous throm- boembolism (the RIETE [Registro Informatizado Enfermedad TromboEmbélical registry) (136) is COWD-19 and Thrombotic Dasa incorporating data elements for COVID-19, and a dedicated adjudicated prospective registry to study COVID-19 and other cardiovascular outcomes is being initiated (CORONA-VTE registry; BWA Thrombosis Research Group; principal investigator: G.P.). A multicenter, multinational ACS registry has been initiated, as well as a new AHA registry for cardio: vascular care and outcomes of these patients. Special attention should also be given to patients with pre- existing thromboembolic disease who have limited access to care in the face of the COVID-19 pandemic, ‘which has hindered transportation and limited the resources of the health care system. Funding agencies, professional societies, and orga- nizations with active patient participation wall all play an important role when it comes to future research in this area. Funding agencies, including the National Institutes of Health (which has already responded swiftly) 137), should continue to pay specificattention to this pandemic, Coordination and cooperation are necessary to quickly address research priorities including those related to thrombotic disease (Table5). Organizations such as the Patient-Centered Outcomes Research Institute and the North American Throm: bosis Forum can ensure the voices and concerns of patients are at the forefront of research questions Professional societies, including the AHA, ESC, ISTH, International Union of Angiology, and others, should promote knowledge generation and dissemination and advocacy in this challenging climate. ‘The current paper has provided an interim sum- mary and guidance for considerations related to thrombotic disease and antithrombotic therapy dur ing the COVID-19 pandemic. Such guidance should supplement, rather than supplant, clinical decision ‘making. Nuances of conversations between patients and practitioners should be considered for appro: priate patient-centered decisions. Inconclusion, thrombotic disease may be precedent factors or incident complications in patients with COVID-19. Important considerations for the preven- tive and therapeutic use of antithrombotic agents should be kept in mind to mitigate the thrombotic and hhemorthagic events in these high-risk patients Funding agencies, professional societies, patients, clinicians, and investigators should work collabora tively to effectively and efficiently address numerous critical areas of knowledge gap. ACKNOWLEDGMENTS The authors thank Kathryn Mikkelsen, MBA, from the North American Throm- bosis Forum, and Adriana Visona, MD, from the Eu ropean Society of Vascular Medicine for thelr comments related to this initiative. The authors Biel2070 del cto COVD-19 ae Thrombotic Datos credit Julle Der Nigoghossian for assistance with graphic design, ADDRESS FOR CORRESPONDENCE: Dr. Behnood Bikdeli, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, 622 West 168th Street, PH 3-347, New York, New York 10032. E-mail: bb2813@cumc-columbia.edu, Behnood bikdeli@ yaleedu. Twitter: @bbikdell. 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