COVID‐19 coagulopathy: An in‐depth analysis of the coagulation system

Martín‐Rojas, Reyes María; Pérez‐Rus, Gloria; Delgado-Pinos, Valeria Estefanía; Domingo‐González, Amalia; Regalado‐Artamendi, Isabel; Alba-Urdiales, Natalia; Demelo‐Rodríguez, Pablo; Monsalvo, Silvia; Rodríguez‐Macías, Gabriela; Ballesteros, Mónica; Osorio-Prendes, Santiago; Díez-Martin, José L.; Izquierdo, Cristina Pascual

doi:10.1111/ejh.13501

Cited by 105 publications

(140 citation statements)

References 37 publications

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“…Of note, the interplay of acute-phase proteins with fibrinogen and D-dimer suggests that infection-induced inflammation (cytokines and chemokines) initiates a state of hyperfibrinolysis. This notion is supported by the disassociation of D-dimer with the entire coagulation panel (PT, APTT, factor VIII and XI, TAT) 52,53 . In general, hyperfibrinolytic homeostasis maintains vascular patency and normal organ function under physiological conditions ( Figure 3B).…”

Section: Discussionmentioning

confidence: 92%

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Zhao

et al. 2020

Preprint

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Background How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists. To investigate whether abnormal fibrinolysis is a culprit or protector or both, we associated elevated plasma D-dimer with clinical variables to identify a panoramic view of the derangements of fibrinolysis that contribute to the pathogenesis of COVID-19 based on studies available in the literature. Methods We performed this systematic review based on both meta-analysis and meta-regression to compute the correlation of D-dimer at admission with clinical features of COVID-19 patients in retrospective studies or case series. We searched the databases until Aug 18, 2020, with no limitations by language. The first hits were screened, data extracted, and analyzed in duplicate. We did the random-effects meta-analyses and meta-regressions (both univariate and multivariate). D-dimer associated clinical variables and potential mechanisms were schematically reasoned and graphed. Findings Our search identified 42 observational, or retrospective, or case series from six countries (n=14,862 patients) with all races and ages from 1 to 98-year-old. The weighted mean difference of D-dimer was 0.97 μg/mL (95% CI 0.65, 1.29) between relatively mild (or healthy control) and severely affected groups with significant publication bias. Univariate meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels, including 3 demographics, 5 comorbidies, 22 laboratory tests, 18 organ injury biomarkers, 8 severe complications, and 2 outcomes (discharge and death). Of these, 11 readouts were negatively associated with the level of plasma D-dimer. Further, age and gender were confounding factors for the identified D-dimer associated variables. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN, bilirubin, ALT, AST, systolic blood pressure, and CK. We thus propose that "insufficient hyperfibrinolysis (fibrinolysis is accelerated but unable to prevent adverse clinical impact for clinical deterioration COVID-19)" as a peculiar mechanism. Interpretation The findings of this meta-analysis- and meta-regression-based systematic review supports elevated D-dimer as an independent predictor for mortality and severe complications. D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and locally (i.e., in the lung) hyperactive derangements of fibrinolysis. D-dimer and associated clinical biomarkers and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.

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Section: Discussionmentioning

confidence: 92%

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Zhao

et al. 2020

Preprint

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“…potential in patients being treated in ICU, using highly sensitive laboratory techniques [64,65]. Increased levels or activities of proteins involved in blood coagulation, such as factor VIII, accompanied by decreased coagulation inhibitors, very strongly suggest a prothrombotic state during COVID-19 disease manifestation [28,[64][65][66].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…In addition, the pathophysiology of this fibrinolysis shutdown is also poorly understand. This pathology, which is typically accompanied by an increase in plasma D-dimer levels, is referred to by some authors as 'occult' hyperfibrinolysis and represents a local activation of fibrinolysis which does not reflect in the circulation and therefore cannot be detected by VEMs [66,71]. In a patient infected with SARS-CoV-2, the likely site of production of D-dimer is the lung tissue [72].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Hemostasis in Coronavirus Disease 2019—Lesson from Viscoelastic Methods: A Systematic Review

2021

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Haemostatic unbalance is often observed in patients with coronavirus disease 2019 (COVID-19), and patients with severe disease are at high risk of developing thromboembolic complications. Viscoelastic methods (VEMs), including thrombelastography (TEG) and thromboelastometry (TEM), provide data on the nature of haemostatic disturbance. In this systematic review, we assessed the performance of TEG and TEM in the assessment of blood coagulation and fibrinolysis in patients with COVID-19. PubMed, Scopus, Web of Science Core Collection, medRxiv and bioRxiv were systematically searched for clinical studies evaluating TEG and/or TEM variables in COVID-19 individuals. Ten studies, with a total of 389 COVID-19 patients, were included, and VEMs were performed in 292 of these patients. Most patients (90%) presented severe COVID-19 and required mechanical ventilation. TEG and TEM variables showed that these patients displayed hypercoagulability and fibrinolysis shutdown, despite the use of appropriate thromboprophylaxis. However, the mechanism underlying these phenomena and their clinical significance in COVID-19 patients who developed thrombosis, is still not clear. Further studies are warranted if VEMs might help to identify those at highest risk of thrombotic events and who therefore may derive the greatest benefit from antithrombotic therapy.

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“…7 However, this coagulopathy is not characterized by consumption of coagulation factors, as seen in disseminated intravascular coagulation (DIC). 8 The molecular mechanisms responsible for the hypercoagulable state observed in patients with COVID-19 are still incompletely elucidated; however, there appears to be a close link between inflammatory and hemostatic systems ( Figure 1). 9,10 Current data suggest that COVID-19 can infect endothelial cells with an ensuing associated immune response and attendant activation of inflammatory pathways resulting in dysregulation of the endothelium, leukocyte activation, neutrophil extracellular traps (NET) generation (a matrix of DNA decorated with neutrophil granule proteins, such as myeloperoxidase, cathepsin G, and neutrophil elastase), complement deposition, and platelet activation and consumption.…”

Section: Introductionmentioning

confidence: 99%

“…7 However, this coagulopathy is not characterized by consumption of coagulation factors, as seen in disseminated intravascular coagulation (DIC). 8…”

Section: Introductionmentioning

confidence: 99%

COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management

Manolis¹,

Manolis

et al. 2020

J Cardiovasc Pharmacol Ther

110

100

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Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.

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COVID‐19 coagulopathy: An in‐depth analysis of the coagulation system

Cited by 105 publications

References 37 publications

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Hemostasis in Coronavirus Disease 2019—Lesson from Viscoelastic Methods: A Systematic Review

COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management

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