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2.
Int J Mol Sci ; 23(6)2022 Mar 19.
Article in English | MEDLINE | ID: covidwho-1760654

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes.


Subject(s)
Blood Coagulation Disorders/etiology , COVID-19 Vaccines/adverse effects , COVID-19/complications , SARS-CoV-2 , Biomarkers , Blood Coagulation , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/prevention & control , Blood Coagulation Disorders/therapy , Blood Coagulation Tests , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Combined Modality Therapy , Disease Management , Disease Susceptibility , Fibrinolysis , Humans , Prognosis , Treatment Outcome
3.
Thromb Res ; 213: 97-104, 2022 May.
Article in English | MEDLINE | ID: covidwho-1747542

ABSTRACT

In this single-center cohort study, we applied a panel of laboratory markers to characterize hemostatic function in 217 consecutive patients that underwent testing for COVID-19 as they were admitted to Linköping University Hospital between April and June 2020. In the 96 patients that tested positive for SARS-CoV-2 (COVID-19+), the cumulative incidences of death and venous thromboembolism were 24.0% and 19.8% as compared to 12.4% (p = 0.031) and 11.6% (p = 0.13) in the 121 patients that tested negative (COVID-19-). In COVID-19+ patients, we found pronounced increases in plasma levels of von Willebrand factor (vWF) and fibrinogen. Excess mortality was observed in COVID-19+ patients with the following aberrations in hemostatic markers: high D-dimer, low antithrombin or low plasmin-antiplasmin complex (PAP) formation, with Odds Ratios (OR) for death of 4.7 (95% confidence interval (CI95) 1.7-12.9; p = 0.003) for D-dimer >0.5 mg/L, 5.9 (CI95 1.8-19.7; p = 0.004) for antithrombin (AT) ˂0.85 kIU/l and 4.9 (CI95 1.3-18.3; p = 0.019) for PAP < 1000 µg/L. Compounding increases in mortality was observed in COVID-19+ patients with combined defects in markers of fibrinolysis and coagulation, with ORs for death of 15.7 (CI95 4.3-57; p < 0.001) for patients with PAP <1000 µg/L and D-dimer >0.5 mg/L and 15.5 (CI95 2.8-87, p = 0.002) for patients with PAP <1000 µg/L and AT ˂0.85 kIU/L. We observed an elevated fraction of incompletely degraded D-dimer fragments in COVID-19+ patients with low PAP, indicating impaired fibrinolytic breakdown of cross-linked fibrin.


Subject(s)
COVID-19 , Hemostatics , Anticoagulants , Antithrombin III , Antithrombins , Biomarkers , COVID-19 Testing , Cohort Studies , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinolysin/metabolism , Fibrinolysis , Humans , SARS-CoV-2 , alpha-2-Antiplasmin
5.
Int J Mol Sci ; 23(3)2022 Jan 24.
Article in English | MEDLINE | ID: covidwho-1686810

ABSTRACT

Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.


Subject(s)
Aortic Aneurysm/complications , Disseminated Intravascular Coagulation/therapy , Fibrinolysis/drug effects , Anticoagulants/pharmacology , Antifibrinolytic Agents/blood , Fibrin Fibrinogen Degradation Products , Fibrinolysin , Fibrinolysis/physiology , Heparin/pharmacology , Humans , Partial Thromboplastin Time , Prothrombin Time , alpha-2-Antiplasmin
7.
J Thromb Haemost ; 20(4): 919-928, 2022 04.
Article in English | MEDLINE | ID: covidwho-1626880

ABSTRACT

BACKGROUND: Resistance to fibrinolysis, levels of procoagulant/antifibrinolytic neutrophil extracellular traps (NETs), and the severity of acute ischemic stroke (AIS) are increased by COVID-19. Whether NETs are components of AIS thrombi from COVID-19 patients and whether COVID-19 impacts the susceptibility of these thrombi to thrombolytic treatments remain unknown, however. OBJECTIVES: We aimed to characterize AIS thrombi from COVID-19 patients by immunohistology and to compare their response to thrombolysis to that of AIS thrombi from non-COVID-19 patients. PATIENTS/METHODS: For this monocentric cohort study, 14 thrombi from COVID-19 AIS patients and 16 thrombi from non-COVID-19 patients, all recovered by endovascular therapy, were analyzed by immunohistology or subjected to ex vivo thrombolysis by tissue-type plasminogen (tPA)/plasminogen. RESULTS: COVID-19 AIS thrombi were rich in neutrophils and contained NETs, but not spike protein. Thrombolysis assays revealed a mean resistance profile to tPA/plasminogen of COVID-19 AIS thrombi similar to that of non-COVID-19 AIS thrombi. The addition of DNase 1 successfully improved thrombolysis by potentiating fibrinolysis irrespective of COVID-19 status. Levels of neutrophil, NETs, and platelet markers in lysis supernatants were comparable between AIS thrombi from non-COVID-19 and COVID-19 patients. CONCLUSIONS: These results show that COVID-19 does not impact NETs content or worsen fibrinolysis resistance of AIS thrombi, a therapeutic hurdle that could be overcome by DNase 1 even in the context of SARS-CoV-2 infection.


Subject(s)
Brain Ischemia , COVID-19 , Ischemic Stroke , Stroke , Thrombosis , Brain Ischemia/drug therapy , COVID-19/drug therapy , Cohort Studies , Fibrinolysis , Humans , SARS-CoV-2 , Stroke/drug therapy , Stroke/metabolism , Thrombolytic Therapy , Thrombosis/metabolism , Tissue Plasminogen Activator/therapeutic use
8.
Acta Biomater ; 141: 114-122, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1611555

ABSTRACT

Fibrinolysis is the enzymatic digestion of fibrin, the primary structural component in blood clots. Mechanisms of fibrin fiber digestion during lysis have long been debated and obtaining detailed structural knowledge of these processes is important for developing effective clinical approaches to treat ischemic stroke and pulmonary embolism. Using dynamic fluorescence microscopy, we studied the time-resolved digestion of individual fibrin fibers by the fibrinolytic enzyme plasmin. We found that plasmin molecules digest fibers along their entire lengths, but that the rates of digestion are non-uniform, resulting in cleavage at a single location along the fiber. Using mathematical modeling we estimated the rate of plasmin arrival at the fiber surface and the number of digestion sites on a fiber. We also investigated correlations between local fiber digestion rates, cleavage sites, and fiber properties such as initial thickness. Finally, we uncovered a previously unknown tension-dependent mechanism that pulls fibers apart during digestion. Taken together these results promote a paradigm shift in understanding mechanisms of fibrinolysis and underscore the need to consider fibrin tension when assessing fibrinolytic approaches. STATEMENT OF SIGNIFICANCE: We developed a method for interrogating lysis of individual fibrin fibers, enabling the time-resolved observation of individual fiber digestion for the first time. Our results resolve longstanding disagreements about fibrinolytic processes and reveal previously unknown mechanisms that also play a role. Also, we developed the first microscale mathematical model of plasmin-fibrin interaction, which predicts the number of plasmin molecules on each fiber and can serve as a framework for investigating novel therapeutics.


Subject(s)
Fibrinolysis , Thrombosis , Fibrin/chemistry , Fibrinolysin , Humans
9.
J Neurosurg Anesthesiol ; 34(1): 136-140, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1555809

ABSTRACT

Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability that may cause thromobembolic complications. We describe our recent studies investigating the mechanisms of hypercoagulability in patients with severe COVID-19 requiring mechanical ventilation during the COVID-19 crisis in New York City in spring 2020. Using rotational thombelastometry we found that almost all patients with severe COVID-19 had signs of hypercoagulability compared with non-COVID-19 controls. Specifically, the maximal clot firmness in the fibrin-based extrinsically activated test was almost twice the upper limit of normal in COVID patients, indicating a fibrin-mediated cause for hypercoagulability. To better understand the mechanism of this hypercoagulability we measured the components of the fibrinolytic pathways. Fibrinogen, tissue plasminogen activator and plasminogen activator inhibitor-1, but not plasminogen levels were elevated in patients with severe COVID-19. Our studies indicate that hypercoagulability in COVID-19 may be because of decreased fibrinolysis resulting from inhibition of plasmin through high levels of plasminogen activator inhibitor-1. Clinicians creating treatment protocols for anticoagulation in critically ill COVID-19 patients should consider these potential mechanisms of hypercoaguability.


Subject(s)
COVID-19 , Tissue Plasminogen Activator , Critical Illness , Fibrinogen , Fibrinolysis , Humans , SARS-CoV-2
10.
Blood Adv ; 6(3): 1074-1087, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1551193

ABSTRACT

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.


Subject(s)
COVID-19 , Thrombosis , Fibrin , Fibrinolysis , Humans , SARS-CoV-2 , Thrombosis/etiology
11.
Nutrients ; 13(12)2021 Nov 29.
Article in English | MEDLINE | ID: covidwho-1542693

ABSTRACT

Bromelain is a major sulfhydryl proteolytic enzyme found in pineapple plants, having multiple activities in many areas of medicine. Due to its low toxicity, high efficiency, high availability, and relative simplicity of acquisition, it is the object of inexhaustible interest of scientists. This review summarizes scientific reports concerning the possible application of bromelain in treating cardiovascular diseases, blood coagulation and fibrinolysis disorders, infectious diseases, inflammation-associated diseases, and many types of cancer. However, for the proper application of such multi-action activities of bromelain, further exploration of the mechanism of its action is needed. It is supposed that the anti-viral, anti-inflammatory, cardioprotective and anti-coagulatory activity of bromelain may become a complementary therapy for COVID-19 and post-COVID-19 patients. During the irrepressible spread of novel variants of the SARS-CoV-2 virus, such beneficial properties of this biomolecule might help prevent escalation and the progression of the COVID-19 disease.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Bromelains/therapeutic use , COVID-19/drug therapy , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Neoplasms/drug therapy , Plant Proteins/therapeutic use , SARS-CoV-2 , Ananas/enzymology , Anti-Inflammatory Agents/chemistry , Anticoagulants/chemistry , Bromelains/chemistry , Cardiotonic Agents/chemistry , Fibrinolysis/drug effects , Humans , Plant Proteins/chemistry
12.
Cell Immunol ; 371: 104451, 2022 01.
Article in English | MEDLINE | ID: covidwho-1499702

ABSTRACT

The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.


Subject(s)
Blood Coagulation/immunology , COVID-19/immunology , Fibrinolysis/immunology , Immunity/immunology , SARS-CoV-2/immunology , Tissue Plasminogen Activator/immunology , Antigen-Presenting Cells/immunology , COVID-19/epidemiology , COVID-19/virology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Models, Immunological , Pandemics , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Tissue Plasminogen Activator/metabolism
13.
Semin Thromb Hemost ; 48(1): 31-54, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1493298

ABSTRACT

Patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19), the infectious pathology caused by severe acute respiratory syndrome coronavirus 2, have a high risk of thrombosis, though the precise mechanisms behind this remain unclarified. A systematic literature search in PubMed and EMBASE identified 18 prospective studies applying dynamic coagulation assays in ICU COVID-19 patients. Overall, these studies revealed normal or slightly reduced primary hemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome. We also prospectively included 51 COVID-19 patients admitted to the ICU. Blood samples were examined on day 1, 3-4, and 7-8 with platelet function tests, rotational thromboelastometry (ROTEM), in vivo and ex vivo thrombin generation, and clot lysis assay. Data on thrombosis, bleeding, and mortality were recorded during 30 days. Primary hemostasis was comparable to healthy controls, but COVID-19 patients had longer ROTEM-clotting times and higher maximum clot firmness than healthy controls. Ex vivo thrombin generation was similar to that of healthy controls while in vivo thrombin generation markers, thrombin-antithrombin (TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2) were higher in ICU COVID-19 patients than in healthy controls. Impaired fibrinolysis was present at all time points. TAT complex and F1 + 2 levels were significantly higher in patients developing thrombosis (n = 16) than in those without. In conclusion, only few previous studies employed dynamic hemostasis assays in COVID-19 ICU-patients and failed to reveal a clear association with development of thrombosis. In ICU COVID-19 patients, we confirmed normal platelet aggregation, while in vivo thrombin generation was increased and fibrinolysis decreased. Thrombosis may be driven by increased thrombin formation in vivo.


Subject(s)
COVID-19 , Thrombosis , Blood Coagulation Tests , Cohort Studies , Critical Care , Fibrinolysis , Hemostasis , Humans , Prospective Studies , SARS-CoV-2 , Thrombelastography , Thrombin
14.
Sci Transl Med ; 13(620): eabj7790, 2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1467665

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.


Subject(s)
COVID-19 , Cellular Senescence , Fibrinolysis , Humans , Lung , SARS-CoV-2
16.
Clin Immunol ; 232: 108852, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401324

ABSTRACT

BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ±â€¯2 and 23 ±â€¯2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 µg/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.


Subject(s)
Blood Coagulation/physiology , COVID-19/complications , Fibrinolysis/physiology , Inflammation/etiology , Inflammation/virology , Adult , Anticoagulants/pharmacology , Blood Coagulation/drug effects , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/pathology , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19/pathology , China , Disease Progression , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/metabolism , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Hemorrhage/etiology , Hemorrhage/pathology , Hemorrhage/virology , Humans , Inflammation/pathology , Male , Middle Aged , Prothrombin Time , SARS-CoV-2/pathogenicity
17.
Biosci Rep ; 41(8)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1334001

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Subject(s)
COVID-19/pathology , Fibrin/metabolism , Fibrinolysis/physiology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Adult , Aged , Amyloid/metabolism , Blood Platelets/metabolism , Complement C3/metabolism , Female , Fibrinogen/metabolism , Humans , Lung/pathology , Male , Microfluidic Analytical Techniques , Middle Aged , Prothrombin/metabolism , SARS-CoV-2/metabolism , Thrombosis/virology , Trypsin/metabolism
19.
Thromb Haemost ; 121(8): 1031-1042, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1324458

ABSTRACT

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35-56) years, with a median body mass index of 30 (27-35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8-16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin-antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p < 0.01) and fibrin formation markers (fibrin monomers, p < 0.001) significantly increased, further resulting in significant decreases in platelet count (p < 0.0001) and fibrinogen level (p < 0.001). PAI-1 levels significantly decreased from baseline to day 7 (p < 0.0001) in all ARDS patients. These changes were more marked in COVID-19 patients, resulting in 14 nonfatal and 3 fatal bleeding. Additional studies are warranted to determine whether monitoring of thrombin generation and fibrinolysis markers might help to early predict bleeding complications in COVID-19 patients supported by ECMO.


Subject(s)
Blood Coagulation , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Fibrinolysis , Respiratory Distress Syndrome/therapy , Adult , COVID-19/blood , COVID-19/complications , Female , Hemorrhage/etiology , Humans , Male , Middle Aged , Prospective Studies , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/complications , von Willebrand Factor/analysis
20.
Int J Lab Hematol ; 43 Suppl 1: 36-42, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1319316

ABSTRACT

The alterations in the hemostatic balance in COVID-19 patients are strongly disturbed and contribute to a high prothrombotic status. The high rate of venous thromboembolism in COVID-19 patients goes along with derangements in coagulation laboratory parameters. Hemostasis testing has an important role in diagnosed COVID-19 patients. Elevated D-dimer levels were found to be a crucial laboratory marker in the risk assessment of thrombosis in COVID-19 patients. The diagnostic approach also includes prothrombin time and platelet count. Fibrinogen might give an indication for worsening coagulopathy. Other markers (activated partial thromboplastin time (aPTT), fibrinolysis parameters, coagulation factors, natural anticoagulants, antiphospholipid antibodies and parameters obtained by thromboelastography or thrombin generation assays) have been described as being deranged. These may help to understand the pathophysiology of thrombosis in COVID-19 patients but have currently no place in diagnosis or management in COVID-19 patients. For monitoring the heparin anticoagulant therapy, the anti-Xa assay is suggested, because the severe acute-phase reaction (high fibrinogen and high factor VIII) shortens the aPTT.


Subject(s)
Blood Coagulation Tests , COVID-19/blood , SARS-CoV-2 , Thrombophilia/etiology , Antibodies, Antiphospholipid/blood , Biomarkers/blood , Blood Coagulation Factors/analysis , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/etiology , Factor Xa/analysis , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Fibrinolysis , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Partial Thromboplastin Time , Platelet Count , Prothrombin Time , Thrombelastography , Thrombin/biosynthesis , Thrombophilia/blood , Thrombophilia/drug therapy
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