Stago has listed articles and publications related to the current COVID-19 infection and focusing on thrombosis and haemostasis issues.
In this section, guidance and recommendations published by national and international societies are addressed.
This page is updated regularly once new information is published.
In a separate section, “Guidances & Recommendations”, all published scientific content of interest is collected.
Dec, 2020. Stefely JA, Christensen BB, Gogakos T, Cone Sullivan JK et al. Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am J Hematol. doi: 10.1002/ajh.25979.
In this series of 102 with COVID-19 infection, patients with factor V activity >150 IU/dL exhibited significantly higher rates of DVT/PE (16/49, 33%) compared to those with factor V activity≤150 IU/dL (7/53, 13%) (P = .03). Within this severe COVID-19 cohort, factor V activity associated with SARS-CoV-2 load in a sex-dependent manner. Subsequent decreases in factor V were linked to progression toward DIC and mortality.
Nov 12, 2020. Goudot G, Chocron R, Augy JL et al. Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload. Front Med (Lausanne). doi:10.3389/fmed.2020.586307
Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with right ventricular dilatation probably reflects a myocardial injury due to an increased right ventricular wall tension.
Sep 22, 2020. Gerotziafas GT, Sergentanis TN, Voiriot G et al. Derivation and Validation of a Predictive Score for Disease Worsening in Patients with COVID-19. Thromb Haemost. doi: 10.1055/s-0040-1716544
The COMPASS-COVID-19 score derived from a prospective study is composed of easily assessable clinical and hematological predictors. The score has high sensitivity (81%) for the identification of hospitalized patients at high risk of disease worsening.
Aug 19, 2020. Chatterjee S, Sengupta T, Majumder S et al. COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy. Aging (Albany NY). 12(16):15954-15961. doi: 10.18632/aging.103869
Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called "cytokine storm" and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. The authors highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and suggest a path to therapy.
Oct. 12 2020. Anti-Xa Monitoring improves Low-Molecular-Weight Heparin Effectiveness in patients with SARS-CoV-2 infection
Source: Trunfio M, Salvador E, Cabodi D, Marinaro L, Alcantarini C, Gaviraghi A, Trentalange A, Lipani F, Sciascia S, Roccatello D, Bonora S, Di Perri G, Calcagno A, for the e-COVID Study group - Thromb Res 2020,
This research paper suggests that close anti-Xa monitoring of COVID-19 patients administered LMWH treatment along with dose-adjustment based on the result of the anti-Xa activity assay could be beneficial in terms of outcome.
Oct. 12 2020. D-dimer cut-off points and risk of venous thromboembolism in adult hospitalized patients with COVID-19
Source: Choi JJ, Wehmeyer GT, Li HA, Alshak MN, Nahid M, Rajan M, Liu B, Schatoff EM, Elahjji R, Abdelghany Y, D'Angelo D, Crossman D, Evans AT, Steel P, Pinheiro LC, Goyal P, Safford MM, Mints G, DeSancho MT
Thromb Res 2020,
This paper confirms the importance of Dimer testing for prognosis evaluation in COVID-19 patients.
Oct. 12 2020. Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications
Source: Voicu S, Delrue M, Chousterman BG, Stépanian A, Bonnin P, Malissin I, Deye N, Neuwirth M, Ketfi C, Mebazaa A, Siguret V, Mégarbane B
Eur Rev Med Pharmacol Sci 2020; 24: 9161-8
This paper shows that mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway and that D-dimer may be a useful biomarker at the bedside for suspicion of VTE.
Sept. 15, 2020. Pulmonary Embolism, Pulmonary Microvascular Thrombosis, or Both in COVID-19?
Source: Páramo JA.
Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620933953. doi: 10.1177/1076029620933953.
Focusing on COVID-19 pathophysiology and the results of post-mortem examinations, the author differentiates pulmonary lesions between pulmonary embolism and intrapulmonary acute microvascular thrombosis and proposes to include the term primary pulmonary thrombi which develop directly in the lungs without traveling from DVT to refer to the most common thrombotic manifestations in patients with COVID-19 infection.
Sept. 15, 2020. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory.
Source: Hardy M, Lecompte T, Douxfils J, Lessire S, Dogné JM, Chatelain B, Testa S, Gouin-Thibault I, Gruel Y, Medcalf RL, Ten Cate H, Lippi G, Mullier F.
Thromb J. 2020 Sep 7;18:17. doi: 10.1186/s12959-020-00230-1. eCollection 2020.
This paper is a comprehensive review of the literature and provides a detailed focus on coagulation laboratory alterations observed in COVID-19 patients, including routine, specialized and global assays, as well as on anticoagulation in COVID-19 patients and its monitoring.
Sept. 15, 2020. Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.
Source: White D, MacDonald S, Edwards T, Bridgeman C, Hayman M, Sharp M, Cox-Morton S, Duff E, Mahajan S, Moore C, Kirk M, Williams R, Besser M, Thomas W.
Int J Lab Hematol. 2020 Sep 5. doi: 10.1111/ijlh.13329.
The authors looked at COVID-19-induced coagulation alterations using thrombin generation and esoteric lab testing. This helps better understand COVID-19 infection physiopathology.
Sept. 15, 2020. Rotational thromboelastometry to assess hypercoagulability in COVID-19 patients.
Source: van Veenendaal N, Scheeren TWL, Meijer K, van der Voort PHJ
Thrombosis Research (2020),
In this study, the authors looked at COVID-19-induced hypercoagulability using rotational thromboelastography. They confirmed the hypercoagulable state of COVID-19 patients admitted to the ICU. However, the study results do not support the use of ROTEM® in identifying COVID-19 patients at risk for developing thromboembolic complications.
Sept. 15, 2020. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation.
Source: Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, Ibañez C, Perdomo J, Reverter JC, Lisman T.
J Thromb Haemost. 2020 Aug 6:10.1111/jth.15043. doi: 10.1111/jth.15043.
In this paper, the authors confirm a hypercoagulable status of enhanced thrombin generating capacity, enhanced ex vivo clot formation likely related to hyperfibrinogenemia, and a decreased ex vivo fibrinolytic capacity in patients with COVID-19.
Sept. 15, 2020. COVID-19: A collision of complement, coagulation and inflammatory pathways.
Source: Chauhan AJ, Wiffen LJ, Brown TP.
J Thromb Haemost. 2020 Jun 30:10.1111/jth.14981. doi: 10.1111/jth.14981.
This paper focuses on interactions among the complement, coagulation, and inflammatory pathways following COVID-19 infection. More specifically, this review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19 infection.
July 31, 2020. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients?
Source: Siguret V, Voicu S, Neuwirth M, Delrue M, Gayat E, Stépanian A, Mégarbane B.
Thromb Res. 2020 Jul 8;195:74-76. doi: 10.1016/j.thromres.2020.07.016.
The presence of antiphospholipid antibodies in COVID-19 patients has been widely reported in the literature as well as the high prevalence of thrombotic manifestations. This paper raises the question of the contribution of antiphospholipid antibodies to thrombosis and points out some limitations of lupus anticoagulant testing in these patients.
July 31, 2020. Hematolological Manifestations of COVID-19: From Cytopenia to Coagulopathy.
Source : Agbuduwe C, Basu S.
Eur J Haematol. 2020 Jul 14. doi: 10.1111/ejh.13491
In this paper, authors provide a comprehensive overview of all haematological alterations observed in COVID-19 infection with a specific focus on the importance inflammation biomarkers, D-dimer and absolute lymphocyte count for patients’ stratification and for monitoring response to therapy.
July 31, 2020. D-dimer level is associated with the severity of COVID-19.
Source: Yu HH, Qin C, Chen M, Wang W, Tian DS.
Thromb Res 2020,
High levels of D-dimer have been reported in COVID-19 patients.
The study reported in this paper confirms the high level of D-dimer in patients with a poor outcome and a meta-analysis is on poor prognosis and elevated D-dimer is presented.
July 20, 2020. Thrombosis and coagulopathy in COVID-19: An illustrated review.
Source: Levi M, Hunt BJ.
Res Pract Thromb Haemost. 2020 Jul 11;4(5):744-751. doi: 10.1002/rth2.12400. eCollection 2020 Jul.
This paper depicts as a cartoon the up-to-date knowledge on pathophysiology of COVID-19 infection coagulopathy and indicates the most relevant parameters for severe patients’ monitoring.
July 20, 2020.Antiphospholipid antibodies in patients with COVID-19: a relevant observation?
Source: Devreese KMJ, Linskens EA, Benoit D, Peperstraete H.
J Thromb Haemost. 2020 Jul 3:10.1111/jth.14994. doi: 10.1111/jth.14994. Online ahead of print.
In this paper the potential contribution of frequently observed antiphospholipd antibodies in patients with severe COVID-19 infection presentation to the pathophysiology of thrombotic manifestations is discussed based on a literature review and personal authors’ observation.
July 10, 2020. High prevalence of deep vein thrombosis in mechanically ventilated COVID-19 patients.
Source : Voicu S, Bonnin P, Stépanian A, Chousterman BG, Le Gall A, Malissin I, Deye N, Siguret V, Mebazaa A, Mégarbane B.
J Am Coll Cardiol. 2020 May 29:S0735-1097(20)35462-0. doi: 10.1016/j.jacc.2020.05.053. Online ahead of print.
This study shows the high prevalence of DVT in mechanically ventilated COVID-19 patients. Furthermore, the potential of D-dimer for DVT diagnosis in these patients is underlined.
July 10, 2020. Incidence of Deep Vein Thrombosis among non-ICU Patients Hospitalized for COVID-19 Despite Pharmacological Thromboprophylaxis.
Source : Santoliquido A, Porfidia A, Nesci A, De Matteis G, Marrone G, Porceddu E, Cammà G, Giarretta I, Fantoni M, Landi F, Gasbarrini A, Pola R; GEMELLI AGAINST COVID-19 Group.
J Thromb Haemost. 2020 Jul 6. doi: 10.1111/jth.14992
This paper shows the incidence of DVT in non-ICU COVID-19 patients despite prophylactic anticoagulation. Furthermore, the article highlights the potential role of D-dimer for DVT diagnosis.
June 22, 2020. Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy: Insights from a Prospective SingleCenter Cohort Study
This recent paper, published in Circulation, helps better understand the Covid-19 infection pathophysiology from a haemostasis perspective in patients with acute respiratory distress syndrome (ARDS), in comparison with non-Covid-19 ARDS patients. The test panel comprises core lab parameters along with data generated with the Quantra® point of care viscoelastic analyser. This study confirms the ability of Quantra® to show Covid-19-associated coagulopathy, as previously described by Ranucci et al. (please see article below), and to differentiate Covid-19 from non-Covid-19 ARDS coagulopathy.
May 29, 2020. Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID‑19
This short review uses easy-to-understand illustrations to summarize the complex mechanisms behind the haemostasis disorders observed in critically ill COVID-19 patients.
May 29, 2020. Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2
As thrombotic microangiopathy (TMA) is one of the consequences of sepsis, authors measured ADAMTS13 and vWF levels in 12 patients with SARSCoV-2 infection with a clinical suspicion of TMA. The combination of low ADAMTS13 activity and high vWF levels might contribute to the microangiopathic state observed in these patients.
Authors therefore suggest including ADAMTS13 and vWF in the diagnostic workup of patients infected with SARS-CoV-2 when a microangiopathic state is suspected.
May 29, 2020. COVID-19 and hypercoagulability in the outpatient setting
This article raises the issue of hypercoagulability in outpatients with COVID-19 infection. Caution should be taken not to omit exploring the development of VTE in COVID-19 outpatients.
Some of the issues raised in T. Akel’s article , which reported on outpatients who developed PE, are raised again here.
The authors suggest that risk stratification and anticoagulation could also be requested for outpatients.
May 29, 2020. Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection
In this paper, the authors highlight that the reduction of fibrinolysis, evidenced by an increased D-dimer level (proposed threshold 2600 ng/mL) and a complete failure in TEG® clot lysis after 30minutes, is correlated with thromboembolic events and renal failure requiring hemodialysis. These results would therefore suggest the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.
May 20, 2020. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis
May 20, 2020. Incidence of venous thromboembolism in hospitalized patients wiath COVID‐19
These two articles confirm the elevated incidence of thromboembolic events in ICU COVID-19 patients: 49% (95% CI: 41–57) at 14 days in Klok’s study and 59% (95% CI: 42-72) at 21 days in Middeldorp’s study. Chronic anticoagulation therapy at admission is recommended in both articles to improve survival.
May 20, 2020. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19
Complete autopsy was performed on 12 patients with confirmed COVID-19 infection. Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients.
These findings underline the significant role of COVID-19–induced coagulopathy.
May 20, 2020. A Proposal for Staging COVID-19 Coagulopathy
COVID-19 is associated with thrombotic complications. This forum discusses the lungs as the epicenter for the haemostatic issues, puts forward a proposal for staging COVID-19 coagulopathy based on available diagnostic markers, and suggests current and future treatment options be considered based on these different stages.
High risk of thrombosis in patients with severe SARS‑CoV‑2 infection: a multicenter prospective cohort study
Source: Helms J, Tacquard C, Severac F et al. Intensive Care Med. 2020 May 4. doi: 10.1007/s00134-020-06062-x.
This study aims at evaluating the thrombotic risk in ARDS COVID-19 patients. Over 150 patients, 64 clinically relevant thrombotic complications were diagnosed (mainly pulmonary embolism, 17%). Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. 50/57 tested patients (87.7%) had positive lupus anticoagulant.
These results show that life-threatening thrombotic complications are frequent and that higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.
COVID-19 and its implications for thrombosis and anticoagulation
Source: Connors JM, Levy JH. Blood. 2020 Apr 27. doi: 10.1182/blood.2020006000.
This paper reviews the coagulation abnormalities that occur in association with COVID-19, and clinical management questions likely to arise. Authors thus suggest to perform coagulation test screening, including the measurement of D-dimer and fibrinogen levels, and to manage coagulopathy as it would be for any critically ill patient. However, they do not suggest the use of full intensity anticoagulation doses unless otherwise clinically indicated.
Lupus Anticoaulant and Abnormal Coagulation Tests in Patients with Covid-19
In this study, aPTT prolongation has been investigated in 35 patients and 31 of them were positive lupus anticoagulant (91%) and often had an associated factor XII deficiency.
In general cases, a prolonged aPTT could be seen as a reason to avoid the use of anticoagulation at both therapeutic and prophylactic doses. However no factor deficiency, nor bleeding tendency were reported. Authors suggest that a prolonged aPTT should not be a barrier to the use of anticoagulation therapies in the prevention and treatment of venous thrombosis in patients with Covid-19.
Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia
Source: Rovina N, Akinosoglou K, Eugen-Olsen J et al. Crit Care. 2020 Apr 30;24(1):187. doi: 10.1186/s13054-020-02897-4.
In this letter, authors suggest that the soluble urokinase plasminogen activator receptor (suPAR) may reflect the endothelial activation in patients with COVID-19 infection, and may thus be an early predictor of severe respiratory failure (SRF). Receiver operator characteristics curve analysis identified levels ≥ 6 ng/ml as the best predictor for SRF. At that cutoff point, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SRF was 85.7%, 91.7%, 85.7%, and 91.7%, respectively.
COVID-19 cytokine storm: the interplay between inflammation and coagulation
Source: Jose RJ, Manuel A. Lancet Respir Med. 2020 Apr 27. doi: 10.1016/S2213-2600(20)30216-2.
This letter reviews the interaction between coagulation and inflammatory systems in COVID-19 patients. The cytokine storm observed in patients enhances thrombin generation, and the thrombin generated may further augment inflammation via proteinase activated receptors (PARs). Authors thus suggest that targeting thrombin, coagulation factor Xa or PAR-1, might therefore be an attractive approach to reduce SARS-CoV-2 microthrombosis, lung injury, and associated poor outcomes.
Direct oral anticoagulant plasma levels striking increase in severe COVID-19 respiratory
Syndrome patients treated with antiviral agents. The Cremona experience
Source: Testa S, Prandoni P, Paoletti O et al. J Thromb Haemost. 2020 Apr 23. doi: 10.1111/jth.14871.
The authors showed in this paper that DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels, with C‐trough levels 6.14 times higher during hospitalization than in pre‐hospitalization period. They recommend to replace DOAC with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.
COVID‐19 Coagulopathy in Caucasian patients
This paper shows haemostasis parameters depicting the coagulopathy in Caucasian patients (until now, most of reports reports were from Chinese patients).
Authors conclude that the marked increase in D-dimer levels is consistent with progressive coagulation activation, along with concurrent activation of fibrinolysis within the lungs. They also suggest that the pulmonary inflammation observed in COVID-19 is associated with a novel pulmonary-specific vasculopathy which they termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC.
Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19
It appears that in addition to high-dose anticoagulation, fibrinolytic therapy may be necessary to degrade microthrombi present in the pulmonary alveoli of COVID-19 patients with ARDS. This review presents the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated with ARDS. Nebulizer plasminogen activators, currently in Phase II clinical trial, may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.
Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2
The high risk for arterial or venous thrombosis lead clinician to set up anticoagulant therapy in COVID-19 patients. As they observed heparin resistance in some patients, the authors suggest to monitor the heparin activity of UFH treatment based on anti-Xa levels with a target value of 0.3 - 0.7 U/L in all patients with SARS-CoV-2 instead of treatment based on aPTT levels.
Changes in Blood Coagulation in Patients with Severe Coronavirus Disease 2019 (COVID-19): a Meta-Analysis
In this article, authors pooled data from 9 studies performed in China evaluating coagulation abnormalities in COVID-19 patients, between severe and mild patients.
Pooled results revealed that prothrombin time and D-dimer levels were significantly higher in patients with severe COVID-19. However, no significant difference in PLT and APTT values between severe and mild patients were observed
The procoagulant pattern of patients with COVID‐19 acute respiratory distress syndrome
Source: Ranucci M, Ballotta A, Di Dedda U, et al. J THromb Haemost, 17 April 2020. Doi: 10.1111/jth.14854
Sixteen patients with COVID-19 ARDS were followed with haemostasis assays (aPTT, PT, platelet count, fibrinogen,D-dimer and antithrombin activity) and the Quantra® analyzer (Haemosonics, Charlottesville), a viscoelastic POC testing. The authors confirmed the pro‐coagulant pattern of these patients that may justify the thromboembolic complications (pulmonary embolism) during the course of the disease. Further studies are needed to assess the best prophylaxis and treatment of this condition.
Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series
Source: Wang J, Hajizadeh N, Moore EE et al. J Thromb Haemost. 2020 Apr 8. doi: 10.1111/jth.14828.
As thrombosis and DIC are frequently observed in patients who die from COVID-19, an American team has reported the off-label use of tPA (Alteplase®) in 3 critically-ill patients. They report clinical improvement in these patients with a decrease in hypoxemia as long as the tPA infusion lasted. These preliminary data, subject to confirmation in independent study, provide insights for improving the anticoagulant and fibrinolytic strategy in critically ill COVID-19 patients. The risk of catastrophic bleeding from use of tPA must be considered in the context of patient treatment.
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
Source: Tang N, Li D, Wang X, Sun Z. J Thromb Haemost. 2020 Apr;18(4):844–7.
In this paper, the coagulation features of patients with COVID-19 infection is described, by use of datacomparing survivors (n=162) and non-survivors (n=21). The non-survivors revealed significantly higher D-dimer and FDP levels, longer PT results (expressed in seconds) and significantly lower antithrombin levels compared with survivors on admission. A decrease in fibrinogen levels in non-survivors was found on days 10 and 14. DIC, mostly due to virus sepsis, appeared in most of the non-survivors.
Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
A paper retrospectively investigating the effect of anticoagulation on COVID-19 outcomes included 449 patients, 22% received treatment with UFH or LMWH. Use of anticoagulant treatment was associated with better prognosis in severe COVID‐19 patients meeting sepsis-induced coagulopathy criteria (SIC score) >4 or with markedly elevated D‐dimer (> 3 μg/L).
The above information is presented as scientific literature from the above publications, which, through their editorial boards consisting of independent reviewers with expertise in the subject of the article, have been made available electronically. Please see the original journal article for further information on how to access the content, as well as to review any relevant conflicts or biases for all authors, contributors, or editors associated with the journal or organization.
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