scholarly journals Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19

2021 ◽  
Author(s):  
Malgorzata Wygrecka ◽  
Anna Birnhuber ◽  
Benjamin Seeliger ◽  
Laura Michalick ◽  
Oleg Pak ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Lag Phase ◽  
Factor Xii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Effect Analysis ◽  
High Incidence ◽  
Fibrinolysis Inhibitor

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in critically ill COVID-19 patients in comparison to patients with severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report 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 ARDS-influenza. Using confocal and electron microscopy, we showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers 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 ARDS-infleunza subjects. Dysregulatated 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 wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19 patients. Together, compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to high incidence of thrombotic events in COVID-19.

The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

1993 ◽  
Vol 70 (02) ◽  
pp. 301-306 ◽  
Author(s):  
Linda A Robbie ◽  
Nuala A Booth ◽  
Alison M Croll ◽  
Bruce Bennett
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Dependent Inhibition ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

Impaired Fibrinolysis in the Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Aleksandra Antovic ◽  
Maria Bruzelius
Keyword(s):  
Plasminogen Activator ◽  
Antiphospholipid Syndrome ◽  
Real Life ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Real Life Setting ◽  
Annexin 2 ◽  
Fibrinolysis Inhibitor

AbstractThe pathogenesis of the antiphospholipid syndrome (APS) is complex and involves the persistent presence of antiphospholipid antibodies (aPL) in the bloodstream causing a prothrombotic condition. aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. Increased levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, together with the presence of aPL against annexin-2, tissue-type plasminogen activator, and plasminogen contribute to the compromised fibrinolytic activity in these patients. Furthermore, unfavorably altered fibrin morphology, less amenable to fibrinolysis, has been proposed as a novel prothrombotic mechanism in APS. This review aims to summarize the present knowledge of the mechanisms involved in impaired fibrinolysis in APS patients. We also present a case from clinical practice as an illustration of fibrinolysis impairment in APS patients from a real-life setting.

scholarly journals Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zuo ◽  
Mark Warnock ◽  
Alyssa Harbaugh ◽  
Srilakshmi Yalavarthi ◽  
Kelsey Gockman ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Ex Vivo ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Bleeding Complications ◽  
Clot Lysis ◽  
Thrombosis Prophylaxis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

AbstractPatients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies. 118 hospitalized COVID-19 patients and 30 healthy controls were included in the study. We measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and performed spontaneous clot-lysis assays. We found markedly elevated tPA and PAI-1 levels in patients hospitalized with COVID-19. Both factors demonstrated strong correlations with neutrophil counts and markers of neutrophil activation. High levels of tPA and PAI-1 were associated with worse respiratory status. High levels of tPA, in particular, were strongly correlated with mortality and a significant enhancement in spontaneous ex vivo clot-lysis. While both tPA and PAI-1 are elevated among COVID-19 patients, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients. These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favor fibrinolysis. Further study of tPA as a biomarker is warranted.

scholarly journals The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 401-409 ◽  
Author(s):  
J Keijer ◽  
M Linders ◽  
AJ van Zonneveld ◽  
HJ Ehrlich ◽  
JP de Boer ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Regulatory Protein ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activators ◽  
Tissue Type ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Interaction Sites ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Plasminogen activator inhibitor 1 (PAI-1), an essential regulatory protein of the fibrinolytic system, harbors interaction sites for plasminogen activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin. In this study, anti-PAI-1 monoclonal antibodies (MoAbs) were used to identify interaction sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct “linear” areas of PAI-1. MoAbs, binding to two distinct areas of PAI-1, are able to prevent the inhibition of t-PA by PAI-1. In addition, two interaction sites for fibrin were identified on PAI-1. The area located between amino acids 110 and 145 of PAI-1 contains a binding site for both components and its significance is discussed in the context of the t-PA inhibition by fibrin-bound PAI-1. Subsequently, the MoAbs were used to assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis system was used to demonstrate that clot-lysis resistance is dependent on the presence of activated platelets and that PAI-1 is a major determinant for lysis-resistance. We propose that, upon activation of platelets, PAI-1 is fixed within the clot by binding to fibrin and retains its full capacity to inhibit t-PA and u-PA.

scholarly journals A monoclonal antibody specific for two-chain urokinase-type plasminogen activator. Application to the study of the mechanism of clot lysis with single-chain urokinase-type plasminogen activator in plasma

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1794-1800 ◽  
Author(s):  
PJ Declerck ◽  
HR Lijnen ◽  
M Verstreken ◽  
H Moreau ◽  
D Collen
Keyword(s):  
Monoclonal Antibody ◽  
Human Plasma ◽  
Plasminogen Activator ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Single Chain ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

Abstract A murine monoclonal antibody (MA-12E6A8) was raised against human urokinase-type plasminogen activator (u-PA), which, in an enzyme-linked immunosorbent assay (ELISA), reacted 15,000-fold better with recombinant two-chain u-PA (rtcu-PA) than with recombinant single-chain u-PA (rscu-PA). The antibody had no effect on the activity of rtcu-PA or on its inhibition by a chloromethylketone, but reduced the inhibition of rtcu-PA by recombinant plasminogen activator inhibitor-1 (rPAI-1) at least 10-fold. The dissociation constant of the rtcu-PA/MA- 12E6A8 complex was 7 nmol/L. An ELISA was developed using MA-12E6A8 as capture antibody and a horseradish peroxidase conjugated u-PA specific antibody for tagging. It recognized free and active site blocked rtcu- PA but not rtcu-PA in complex with rPAI-1 or with alpha 2-antiplasmin. This ELISA was used to monitor the generation of rtcu-PA during fibrin clot lysis with rscu-PA in human plasma. Addition of 5 micrograms/mL rscu-PA to 3 mL plasma containing a 0.2 mL 125I-fibrin labeled plasma clot caused 50% clot lysis in 62 +/- 13 minutes (mean +/- SD, n = 6), at which time 99 +/- 28 ng/mL rtcu-PA was detected but no fibrinogen breakdown had occurred. Fifty percent fibrinogen breakdown did occur only when rtcu-PA had reached a level of 1,000 +/- 270 ng/mL (at 150 +/- 21 minutes). rscu-PA, 2 micrograms/mL, induced 50% clot lysis in 160 +/- 41 minutes (n = 6); no fibrinogen degradation occurred within 4 hours and rtcu-PA levels did not exceed 80 ng/mL. In the absence of a fibrin clot, 5 micrograms/mL rscu-PA added to human plasma did not result in significant generation of rtcu-PA (less than 50 ng/mL after 4 hours) and no fibrinogen degradation was observed. These results indicate that clot lysis with rscu-PA in a plasma milieu does not require extensive systemic conversion of rscu-PA to rtcu-PA, and that fibrinogen degradation occurs secondarily to systemic conversion of rscu-PA to rtcu-PA.

Herpesviruses enhance fibrin clot lysis

2012 ◽  
Vol 107 (04) ◽  
pp. 760-768 ◽  
Author(s):  
Edwin S. Gershom ◽  
Amanda L. Vanden Hoek ◽  
Scott C. Meixner ◽  
Michael R. Sutherland ◽  
Edward L.G. Pryzdial
Keyword(s):  
Vascular Disease ◽  
Plasminogen Activator ◽  
Disease Risk ◽  
Plasminogen Activator Inhibitor ◽  
Aminocaproic Acid ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Cell Infection ◽  
Proteolytic Activation

SummaryThe incorporation of virus- and host-derived procoagulant factors initiates clotting directly on the surface of herpesviruses, which is an explanation for their correlation to vascular disease. The virus exploits the resulting thrombin to enhance infection by modulating the host cell through protease activated receptor (PAR) 1 signalling. Prior reports demonstrated that at least one herpesvirus expresses surface annexin A2 (A2), a cofactor for tissue plasminogen activator (tPA)-dependent activation of plasminogen to plasmin. Since plasmin is both a fibrinolytic protease and PAR agonist, we investigated whether herpesviruses enhance fibrinolysis and the effect of plasmin on cell infection. Herpes simplex virus types 1 (HSV1) and 2, and cytomegalovirus (CMV) purified from various cell lines each accelerated the proteolytic activation of plasminogen to plasmin by tPA. Ligand blots identified A2 as one of several plasminogen binding partners associated with the virus when compared to an A2-deficient virus. This was confirmed with inhibitory A2-antibodies. However, A2 was not required for virus-enhanced plasmin generation. HSV1, HSV2 and CMV accelerated tPA-dependent fibrin clot lysis by up to 2.8-fold. Modest plasmin generation and fibrinolysis was detected independent of exogenous tPA, which was inhibited by plasminogen activator inhibitor type-1 and ε-aminocaproic acid; however, the molecular basis remains speculative. Up to a ∼6-fold enhancement of infection was provided by plasmin-mediated cell infection. Inhibitory antibodies revealed that plasmin increased HSV1 infection through a mechanism involving PAR2. Thus, virus-enhanced fibrinolysis may help explain the paradox of the highly procoagulant in vitro herpesvirus surface eliciting only relatively weak independent vascular disease risk.

Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator

2004 ◽  
Vol 91 (06) ◽  
pp. 1146-1151 ◽  
Author(s):  
Joan Montaner ◽  
Carlos Molina ◽  
Juan Arenillas ◽  
Esteban Santamarina ◽  
José Alvarez-Sabín ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Neurological Status ◽  
Artery Occlusion ◽  
Clot Lysis ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Fibrinolysis Inhibitor ◽  
The Impact ◽  
Pai 1

SummaryEndogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing stroke thrombolysis beneficts. We aim to determine the impact of pretreatment levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin-activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial recanalization and outcome. Forty-four consecutive patients with acute proximal middle cerebral artery occlusion were studied, including assessment of transcraneal Doppler artery patency. The neurological status was determined by NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS). Patients who recanalized after t-PA infusion had lower PAI-1 levels than those who remained occluded. Similarly, patients who achieved dramatic clinical recovery at 12 hours exhibited significantly lower PAI-1 levels as those independent (mRS≤2) at third month. We observed a trend towards lower lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no relation was found between TAFI or homocysteine levels and recanalization. After a regression model was applied the only independent predictor of thrombolysis resistance was baseline PAI-1≤34 ng/ml, such that high PAI-1 levels interfere with tPA-induced recanalization in stroke, predicting a higher susceptibility towards clot-lysis resistance and poor outcome.

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