COVID-19 associated VTE is a new disease entity with high morbidity and mortality. The aim of this paper is to review contemporary emerging literature on the incidence, pathophysiology, predictive prognostic indicators, and management consensus for Covid-19 related thrombotic complications, in particular DVT and PE.
Methods
A literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All searches were done via PubMed. References of review articles were further screened according to the exclusion criteria.
Results
In total, 154 records were identified and 20 duplicates were removed. A final 68 articles were included in the qualitative analysis. COVID-19 related thrombosis can affect multiple organs of the body, presenting in the form of arterial or venous thrombosis such as ischemic stroke, myocardial infarction, mesenteric ischemia, limb ischemia, DVT, or PE. DVT and PE has an overall incidence of 6–26%, and severely ill COVID-19 patients have even higher incidence of thromboembolism. On the other hand, incidence of arterial thromboembolism is much lower with incidence of 0.7%–3.7%. D-dimer is found to be an independent risk factor, and IMPROVE score, Caprini score, and Padua score have all been used as predictors. International guidelines suggest the use of low molecular weight heparin (LMWH) or fondaparinux for prophylaxis of VTE, and therapeutic dosage of weight adjusted LMWH for treatment if confirmed diagnosis.
Conclusions
Contemporary rapidly evolving evidence shows that COVID-19 associated thrombosis was a novel clinical entity, especially in severely ill COVID-19 patients. There are multiple society-driven guidelines only, but without any level 1 evidence for management regimen. The ideal dose for prophylaxis is not established and may vary depending on balance of bleeding and thrombosis risk. The risk of bleeding may be increased in patients in intensive care unit.
HuangCWangYLiX, et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet Feb 15 2020; 395(10223): 497–506.
2.
SohrabiCAlsafiZO'NeillN, et al.World health organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19). Int Journal Surgery (London, England)2020; 76: 71–76.
3.
ChenNZhouMDongX, et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet Feb 15 2020; 395(10223): 507–513.
4.
KolliasAKyriakoulisKGLagouS, et al.Venous thromboembolism in COVID-19: a systematic review and meta-analysis. Vasc Med Apr 4 2021; 26(4): 415–425.
5.
Mestre-GomezBLorente-RamosRMRogadoJ, et al. Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis. J Thromb Thrombolysis Jan2021; 51(1): 40–46.
6.
PanigadaMBottinoNTagliabueP, et al.Hypercoagulability of COVID‐19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. Jul 2020; 18(7): 1738–1742.
7.
MoherDShamseerLClarkeM, et al.Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev Jan 1 2015; 4: 1.
8.
CuiSChenSLiX, et al.Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Jun 2020; 18(6): 1421–1424.
9.
PorfidiaAValerianiEPolaR, et al. Venous thromboembolism in patients with COVID-19: systematic review and meta-analysis. Thromb Res Aug 12 2020; 196: 67–74.
10.
HelmsJTacquardCSeveracF, et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. Jun 2020; 46(6): 1089–1098.
11.
KlokFAKruipMvan der MeerNJM, et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. Jul 2020;191:145–147.
12.
BellostaRLuzzaniLNataliniG, et al.Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc Surg. Dec 2020; 72(6): 1864–1872.
13.
MiddeldorpSCoppensMvan HaapsTF, et al.Incidence of venous thromboembolism in hospitalized patients with COVID‐19. J Thromb Haemost Aug 2020; 18(8): 1995–2002.
14.
LodigianiCIapichinoGCarenzoL, et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. Jul 2020; 191: 9–14.
15.
MeiZWvan WijkXMRPhamHP, et al. Role of von willebrand factor in COVID-19 associated coagulopathy. J Appl Lab Med Apr 30 2021; 6(5): 1305–1315.
16.
BilalogluSAphinyanaphongsYJonesS, et al.Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA Aug 25 2020; 324(8): 799–801.
17.
Demelo-RodriguezPCervilla-MunozEOrdieres-OrtegaL, et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. Thromb Res. Aug 2020; 192: 23–26.
18.
JimenezSMiroOLlorensP, et al.Incidence, risk factors, clinical characteristics and outcomes of deep venous thrombosis in patients with COVID-19 attending the emergency department: results of the UMC-19-S8. Eur J Emerg Med Jun 1 2021; 28(3): 218–226.
19.
TanBKMainbourgSFriggeriA, et al.Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax Feb 23 2021; 76(10): 970–979.
20.
NahumJMorichau-BeauchantTDaviaudF, et al.Venous thrombosis among critically Ill patients with coronavirus disease 2019 (COVID-19). JAMA Netw Open May 1 2020; 3(5): e2010478.
21.
BeunRKusadasiNSikmaM, et al.Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol. Jun 2020; 42: (Suppl 1): 19–20.
22.
PoissyJGoutayJCaplanM, et al.Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation Jul 14 2020; 142(2): 184–186.
23.
CantadorENunezASobrinoP, et al.Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients. J Thromb Thrombolysis Oct 2020; 50(3): 543–547.
24.
CollingMEKanthiY. COVID-19-associated coagulopathy: an exploration of mechanisms. Vasc Med Jun 19 2020; 25(5): 471–478.
Al-SamkariHKarp LeafRSDzikWH, et al.COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood Jul 23 2020; 136(4): 489–500.
27.
SalamannaFMaglioMLandiniMP, et al.Platelet functions and activities as potential hematologic parameters related to coronavirus disease 2019 (Covid-19). Platelets Jul 3 2020; 31(5): 627–632.
28.
Martin-RojasRMPerez-RusGDelgado-PinosVE, et al.COVID-19 coagulopathy: an in-depth analysis of the coagulation system. Eur J Haematol. Dec 2020; 105(6): 741–750.
29.
SmadjaDMMentzerSJFontenayM, et al.COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Angiogenesis, Jun 28 2021.
30.
BikdeliBMadhavanMVJimenezD, et al.COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. Jun 16 2020; 75(23): 2950–2973.
31.
Abou-IsmailMYDiamondAKapoorS, et al.The hypercoagulable state in COVID-19: incidence, pathophysiology, and management. Thromb Res. Oct 2020; 194: 101–115.
32.
ChenXZhaoBQuY, et al.Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically Ill patients with coronavirus disease 2019. Clin Infect Dis. Nov 5 2020; 71(8): 1937–1942.
33.
McGonagleDSharifKO'ReganA, et al.The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. Jun 2020; 19(6): 102537.
34.
SchettGSticherlingMNeurathMF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases?Nat Rev Immunol. May 2020; 20(5): 271–272.
35.
Gonzalez CanasEGimenez GaibarARodriguez LorenzoL, et al.Acute peripheral arterial thrombosis in COVID-19. Role of endothelial inflammation. Br J Surg Sep 2020; 107(10): e444–e445.
36.
CiceriFBerettaLScandroglioAM, et al.Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc Apr 15 2020; 22(2): 95–97.
37.
PeriniPNabulsiBMassoniCB, et al.Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19. Lancet May 16 2020; 395(10236): 1546.
38.
GriffinDOJensenAKhanM, et al.Pulmonary embolism and increased levels of d-dimer in patients with coronavirus disease. Emerg Infect Dis. Aug 2020; 26(8): 1941–1943.
39.
YuBLiXChenJ, et al.Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis. J Thromb Thrombolysis. Oct 2020;50(3):548–557.
40.
ChoESMcClellandPHChengO, et al.Utility of d-dimer for diagnosis of deep vein thrombosis in coronavirus disease-19 infection. J Vasc Surg Venous Lymphat Disord Jul 30 2020; 9(1): 47–53.
41.
ZhangLYanXFanQ, et al.D‐dimer levels on admission to predict in‐hospital mortality in patients with Covid‐19. J Thromb Haemost Jun 2020; 18(6): 1324–1329.
42.
Leonard-LorantIDelabrancheXSeveracF, et al.Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels. Radiol. Sep 2020; 296(3): E189–E191.
43.
ZhouFYuTDuR, et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Mar 28 2020; 395(10229): 1054–1062.
44.
YaoYCaoJWangQ, et al.D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care2020; 8: 49.
45.
GuanWJNiZYHuY, et al.Clinical characteristics of coronavirus disease 2019 in China. New Engl Journal Medicine Apr 30 2020; 382(18): 1708–1720.
46.
WuCChenXCaiY, et al.Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med Jul 1 2020; 180(7): 934–943.
47.
Gabbai-ArmelinPRde OliveiraABFerrisseTM, et al.COVID-19 (SARS-CoV-2) infection and thrombotic conditions: a systematic review and meta-analysis. Eur J Clin Invest. Jun 2021; 51(6): e13559.
48.
TanLWangQZhangD, et al.Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. Mar 27 2020; 5(1): 33.
49.
GibsonCMSpyropoulosACCohenAT, et al.The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open. Jun 2017; 1(1): e56–e65.
50.
RosenbergDEichornAAlarconM, et al.External validation of the risk assessment model of the international medical prevention registry on venous thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc. Nov 17 2014; 3(6): e001152.
51.
CapriniJAArcelusJIHastyJH, et al.Clinical assessment of venous thromboembolic risk in surgical patients. Semin Thromb Hemost1991; 17(Suppl 3): 304–312.
52.
SoomroQYousufNBhuttoAA, et al.Venous thromboembolism (VTE): risk assessment in hospitalized patients. J Coll Physicians Surg Pak. Jul 2014; 24(7): 455–458.
53.
BarbarSNoventaFRossettoV, et al.A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua prediction score. J Thromb Haemost. Nov 2010; 8(11): 2450–2457.
54.
KucherNKooSQuirozR, et al.Electronic alerts to prevent venous thromboembolism among hospitalized patients. New Engl Journal Medicine. Mar 10 2005; 352(10): 969–977.
55.
ZengDXXuJLMaoQX, et al.Association of Padua prediction score with in-hospital prognosis in COVID-19 patients. QJM. Nov 1 2020; 113(11): 789–793.
56.
GerotziafasGTSergentanisTNVoiriotG, et al.Derivation and validation of a predictive score for disease worsening in patients with COVID-19. Thromb Haemost Dec 2020; 120(12): 1680–1690.
57.
Du ClosTWMoldC. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res2004; 30(3): 261–278.
58.
KermaliMKhalsaRKPillaiK, et al.The role of biomarkers in diagnosis of COVID-19 - A systematic review. Life Sci Aug 1 2020; 254: 117788.
59.
LiuFLiLXuM, et al.Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. Jun 2020; 127: 104370.
60.
QinCZhouLHuZ, et al.Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. Jul 28 2020; 71(15): 762–768.
61.
TanCHuangYShiF, et al.C‐reactive protein correlates with computed tomographic findings and predicts severe COVID‐19 early. J Med Virol. Jul 2020; 92(7): 856–862.
62.
XueGGanXWuZ, et al.Novel serological biomarkers for inflammation in predicting disease severity in patients with COVID-19. Int Immunopharmacol Dec 2020; 89(Pt A): 107065.
63.
KloucheKCristolJPDevinJ, et al.Diagnostic and prognostic value of soluble CD14 subtype (Presepsin) for sepsis and community-acquired pneumonia in ICU patients. Ann Intensive Care Dec 2016; 6(1): 59.
64.
UgajinMMatsuuraYMatsuuraK, et al.Impact of initial plasma presepsin level for clinical outcome in hospitalized patients with pneumonia. J Thorac Dis. Apr 2019; 11(4): 1387–1396.
65.
ZaninottoMMionMMCosmaC, et al.Presepsin in risk stratification of SARS-CoV-2 patients. Clin Chim Acta. Aug 2020; 507: 161–163.
66.
TosatoFGiraudoCPellosoM, et al.One disease, different features: COVID-19 laboratory and radiological findings in three Italian patients. Clin Chem Lab Med. Jun 25 2020; 58(7): 1149–1151.
67.
LippiGPlebaniM. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chim Acta. Jun 2020; 505: 190–191.
MooresLKTritschlerTBrosnahanS, et al.Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019. Chest2020; 158(3): 1143–1163.
70.
ZhaiZLiCChenY, et al.Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost. Jun 2020; 120(6): 937–948.
71.
SongJCWangGZhangW, et al.Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19. Mil Med Res Apr 20 2020; 7(1): 19.
72.
TangNBaiHChenX, et al.Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost May 2020; 18(5): 1094–1099.
73.
ParksALAuerbachADSchnipperJL, et al.COVID-19 coagulopathy and thrombosis: analysis of hospital protocols in response to the rapidly evolving pandemic. Thromb Res. Dec 2020; 196: 355–358.
74.
FraisseMLogreEPajotO, et al.Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study. Crit Care Jun 2 2020; 24(1): 275.
75.
ParanjpeIFusterVLalaA, et al.Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol Jul 7 2020; 76(1): 122–124.
76.
PanelCTG. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. 2020.
77.
ParsiKvan RijAMMeissnerMH, et al.Triage of patients with venous and lymphatic diseases during the COVID-19 pandemic - the venous and lymphatic triage and acuity scale (VELTAS). J Vasc Surg Venous Lymphat Disord2020; 35: 550–555. DOI: 10.1177/026835552093088410.1016/j.jvsv.2020.05.002. https://creativecommons.org/licenses/by-nc-nd/4.0/).Phlebology
78.
GerotziafasGTCatalanoMColganMP, et al.Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European independent foundation in angiology/vascular medicine. Thromb Haemost Dec 2020; 120(12): 1597–1628.
79.
LiaoSWoulfeTHyderS, et al.Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb Haemost. Feb 2014; 12(2): 214–219.
80.
WhiteRHKeenanCR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res2009; 123(Suppl 4): S11–S17.
81.
PrandoniP. Acquired risk factors of venous thromboembolism in medical patients. Pathophysiol Haemost Thromb2006; 35(1–2): 128–132.
82.
PulivarthiSGurramMK. Effectiveness of d-dimer as a screening test for venous thromboembolism: an update. N Am J Med Sci. Oct 2014; 6(10): 491–499.
