A novel fibrinogen γ chain frameshift deletion (c.637delT) in a patient with hypodysfibrinogenemia associated with thrombosis

2015 ◽  
Vol 35 (S 01) ◽  
pp. S27-S31
Author(s):  
A. Biswas ◽  
H. Ensikat ◽  
U. Schmitt ◽  
S. Horneff ◽  
A. Pavlova ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Amino Acid Position ◽  
Fibrin Clot ◽  
Time Shift ◽  
Thrombin Time ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Sds Page ◽  
Chain Polymerization ◽  
Clot Structure

SummaryInherited fibrinogen (FG) disorders are rare and result in quantitative or/and qualitative FG deficiency. While the majority of patients with clinically relevant FG deficiencies demonstrate a bleeding phenotype, a subset of patients are at increased risk of thrombosis.We report a 54-years old man presenting with a thrombophilic phenotype characterized by two episodes of unprovoked venous thrombosis and a deep vein thrombosis several weeks after myocardial infarction. Recently, he developed A. carotis communis thrombosis and died. Coagulation tests were done using standard procedures. FG genes were screened using direct sequencing. Effect on fibrin clot structure was analyzed by scanning electron microscopy (SEM) and FG chain polymerization was analysed using SDS-PAGE.While thrombophilia testing was negative, we found a decreased concentration of clottable FG (126-148 mg/dl) compared to FG antigen (182-194 mg/dl of normal). The thrombin time was slightly prolonged, while aPTT and reptilase time were within the normal range. A novel deletion in FGG gene (c.637delT) resulting in a frameshift and the premature termination of the γ chain at amino acid position p.228 was identified. SDS-PAGE showed a time-shift in γ-γ and α-α cross linking. SEM showed no statistically significant differences between the patient´s and a healthy control´s fibrin clot structure.In addition to the reduction of FG concentration expected by the nature of the mutation also a functional defect (hypodysfibrinogenemia) was found. Moreover this mutation seems to increase the risk of thrombosis warranting long term anticoagulation possibly in a combination with antiplatelet drugs.

scholarly journals Effects of Diabetes Mellitus on Fibrin Clot Structure and Mechanics in a Model of Acute Neutrophil Extracellular Traps (NETs) Formation

2020 ◽  
Vol 21 (19) ◽  
pp. 7107 ◽  
Author(s):  
Judith J. de Vries ◽  
Tamara Hoppenbrouwers ◽  
Cristina Martinez-Torres ◽  
Rezin Majied ◽  
Behiye Özcan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Mechanical Properties ◽  
Acute Phase ◽  
Structural Parameters ◽  
Neutrophil Extracellular Traps ◽  
Fibrin Clot ◽  
Branch Points ◽  
Extracellular Traps ◽  
Increased Risk ◽  
Clot Structure

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.

scholarly journals Study of Optimum Condition for Rapid Preparation of Thrombin using Russell’s Viper Venom Factor X Activator

2018 ◽  
Vol 12 (1) ◽  
pp. 95-103
Author(s):  
Narin Kijkriengkraikul ◽  
Issarang Nuchprayoon
Keyword(s):  
Molecular Weight ◽  
Sodium Chloride ◽  
Optimum Condition ◽  
Incubation Time ◽  
Total Protein ◽  
Chloride Solution ◽  
Fibrin Clot ◽  
Thrombin Time ◽  
Sds Page ◽  
Prothrombin Activation

Background: The purpose of this study is to investigate a simple method with the optimum condition for rapid thrombin preparation from Cryoprecipitate-depleted Plasma (CDP) using RVV-X in the process. Methods: Thrombin preparation from human CDP was studied with the presence of different factors in batch condition including: 1) RVV-X; 2) volume of calcium chloride solution; 3) volume of sodium chloride solution for final extraction; and 4) incubation time. The properties of the prepared sample were analyzed for fibrin clot formation, total protein by Kjeldahl method, thrombin time, molecular weight and protein patterns by SDS-PAGE, and thrombin concentration by coagulation analyzer. The method and process of preparing thrombin and the study of optimum condition for rapidly preparing the highest yield of thrombin from starting CDP 100 ml were introduced. Results: The best four conditions were concluded: 1) RVV-X 50 mcg should be present in the process; 2) volume of 0.25 M calcium chloride should be 3 ml; 3) volume of 0.85% sodium chloride for the final protein precipitate extraction should be 10 ml and; 4) no incubation time needed for prothrombin activation process. A solution prepared from the optimum condition showed an obvious band on SDS-PAGE at a molecular weight about 36,000 Da which is our target protein thrombin. The prepared solution had a total protein content of 0.065 g/dl and gave satisfactory results of thrombin time (9 seconds) and fibrin clot formation. The test results of thrombin concentration between the method with and without incubation time were 269.4 and 295.2 IU/ml, respectively. Conclusion: This result showed that the method with RVV-X but without incubation time for prothrombin activation (optimum condition) gave the highest yield of thrombin.

The vulnerable blood

2015 ◽  
Vol 35 (01) ◽  
pp. 25-33 ◽  
Author(s):  
K. Hess
Keyword(s):  
Platelet Function ◽  
Plaque Rupture ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Complement Components ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Clot Structure

SummaryPatients with diabetes are at increased risk of cardiovascular morbidity and mortality. While arteriosclerotic lesions have long been recognized as the underlying cause more recent studies suggest that alterations of the blood are also critically involved. Following plaque rupture, adherence of platelets is followed by the formation of a cross-linked fibrin clot. Patients with diabetes exhibit a prothrombotic milieu consisting of hyper reactive platelets, a tight and rigid clot structure which is due to up-regulation of coagulation factors and prolongation of clot lysis. Metabolic alterations as well as inflammatory processes, which are up–regulated in diabetes, are thought to be the main underlying causes. More recently, the complement cascade has emerged as a potential new player in this context with several complement components directly influencing both platelet function and coagulation.This review provides an overview concerning the changes that lead to alterations of platelet function and clot structure in diabetes.

Laboratory Diagnosis of Dysfibrinogenemia

2002 ◽  
Vol 126 (4) ◽  
pp. 499-505 ◽  
Author(s):  
Mark T. Cunningham ◽  
John T. Brandt ◽  
Michael Laposata ◽  
John D. Olson
Keyword(s):  
Family Members ◽  
Liver Function Tests ◽  
Laboratory Diagnosis ◽  
Fibrin Clot ◽  
Screening Tests ◽  
Confirmatory Test ◽  
Coagulation Disorder ◽  
Thrombin Time ◽  
Increased Risk ◽  
Structural Abnormalities

Abstract Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in abnormal fibrinogen function. It can be inherited or acquired. The inherited form is associated with increased risk of bleeding, thrombosis, or both in the same patient or family. Traditionally, dysfibrinogenemia is diagnosed by abnormal tests of fibrin clot formation; the thrombin time and reptilase time are the screening tests, and the fibrinogen clotting activity–antigen ratio is the confirmatory test. The inherited form is diagnosed by demonstrating similar laboratory test abnormalities in family members, and if necessary by analysis of the fibrinogen protein or fibrinogen genes in the patient. The acquired form is diagnosed by demonstrating abnormal liver function tests and by ruling out dysfibrinogenemia in family members. This article reviews the laboratory testing of dysfibrinogenemia and presents an algorithm for sequential test selection that can be used for diagnosis.

Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4272-4278 ◽  
Author(s):  
Anetta Undas ◽  
Krystyna Zawilska ◽  
Mariola Ciesla-Dul ◽  
Agata Lehmann-Kopydłowska ◽  
Agnieszka Skubiszak ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Structure Function ◽  
Ex Vivo ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Vein Thrombosis ◽  
Reactive Protein ◽  
History Of ◽  
Deep Vein ◽  
Clot Structure

Abstract We tested the hypothesis that fibrin structure/function is unfavorably altered in patients after idiopathic venous thromboembolism (VTE) and their relatives. Ex vivo plasma fibrin clot permeability, turbidimetry, and efficiency of fibrinolysis were investigated in 100 patients with first-ever VTE, including 34 with pulmonary embolism (PE), 100 first-degree relatives, and 100 asymptomatic controls with no history of thrombotic events. Known thrombophilia, cancer, trauma, and surgery were exclusion criteria. VTE patients and their relatives were characterized by lower clot permeability (P < .001), lower compaction (P < .001), higher maximum clot absorbancy (P < .001), and prolonged clot lysis time (P < .001) than controls, with more pronounced abnormalities, except maximum clot absorbance, in the patients versus relatives (all P < .01). Fibrin clots obtained for PE patients were more permeable, less compact, and were lysed more efficiently compared with deep-vein thrombosis patients (all P < .05) with no differences in their relatives. Being VTE relative, fibrinogen, and C-reactive protein were independent predictors of clot permeability and fibrinolysis time in combined analysis of controls and relatives. We conclude that altered fibrin clot features are associated with idiopathic VTE with a different profile of fibrin variables in PE. Similar features can be detected in VTE relatives. Fibrin properties might represent novel risk factors for thrombosis.

Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3008-3013 ◽  
Author(s):  
Alisa S. Wolberg ◽  
Dougald M. Monroe ◽  
Harold R. Roberts ◽  
Maureane Hoffman
Keyword(s):  
Plasma Levels ◽  
Thrombin Generation ◽  
Fibrin Clot ◽  
Length Ratio ◽  
Dependent Manner ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Clot Structure ◽  
Dose Dependent ◽  
Fibrin Clots

AbstractIndividuals with elevated prothrombin levels are at increased risk of venous thrombosis. To understand the mechanism behind this observation, we studied the effect of prothrombin concentration on thrombin generation and fibrin clot structure. The pattern of thrombin generation was directly related to the prothrombin level at all concentrations tested. From 0% to 300% of normal plasma levels of prothrombin, increasing the prothrombin concentration increased the initial rate, peak, and total amount of thrombin generated. Importantly, fibrin clot structure was also affected by the prothrombin concentration. Fibrin clots made from prothrombin concentrations less than 10% of plasma levels were weak and poorly formed. Fibrin clots made at 10% to 100% of plasma levels of prothrombin had similar fiber structures (mass-to-length ratio; μ). However, the fiber mass-to-length ratio decreased with increasing prothrombin levels more than 100% of plasma levels, in a dose-dependent manner. These results suggest that increased levels of prothrombin alter thrombin generation and clot structure. Specifically, elevated prothrombin levels produce clots with reduced fibrin mass-to-length ratios compared with normal clots. We hypothesize that this alteration in fibrin clot structure is an important determinant of the risk of thrombosis.

scholarly journals Fibrin Clot Properties in Atherosclerotic Vascular Disease: From Pathophysiology to Clinical Outcomes

2021 ◽  
Vol 10 (13) ◽  
pp. 2999
Author(s):  
Michał Ząbczyk ◽  
Joanna Natorska ◽  
Anetta Undas
Keyword(s):  
Vascular Disease ◽  
Limb Ischemia ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Acute Limb Ischemia ◽  
Atherosclerotic Vascular Disease ◽  
Increased Risk ◽  
Arterial Thromboembolic Events ◽  
And Function ◽  
Clot Structure

Fibrin is a major component of thrombi formed on the surface of atherosclerotic plaques. Fibrin accumulation as a consequence of local blood coagulation activation takes place inside atherosclerotic lesions and contributes to their growth. The imbalance between thrombin-mediated fibrin formation and fibrin degradation might enhance atherosclerosis in relation to inflammatory states reflected by increased fibrinogen concentrations, the key determinant of fibrin characteristics. There are large interindividual differences in fibrin clot structure and function measured in plasma-based assays and in purified fibrinogen-based systems. Several observational studies have demonstrated that subjects who tend to generate denser fibrin networks displaying impaired clot lysis are at an increased risk of developing advanced atherosclerosis and arterial thromboembolic events. Moreover, the majority of cardiovascular risk factors are also associated with unfavorably altered fibrin clot properties, with their improvement following effective therapy, in particular with aspirin, statins, and anticoagulant agents. The prothrombotic fibrin clot phenotype has been reported to have a predictive value in terms of myocardial infarction, ischemic stroke, and acute limb ischemia. This review article summarizes available data on the association of fibrin clot characteristics with atherosclerotic vascular disease and its potential practical implications.

scholarly journals Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism

2021 ◽  
Vol 22 (4) ◽  
pp. 1607
Author(s):  
Michał Ząbczyk ◽  
Joanna Natorska ◽  
Anetta Undas
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xiii ◽  
Active Form ◽  
Coagulation Factor ◽  
Proteome Analysis ◽  
Fibrin Clot ◽  
Subsequent Increase ◽  
Vein Thrombosis ◽  
Acute Pe ◽  
Fxiii Activity

Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. Better understanding of FXIII’s involvement in the pathophysiology of acute VTE might help to improve current therapeutic strategies in patients with acute VTE.

Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

2014 ◽  
Vol 112 (08) ◽  
pp. 287-296 ◽  
Author(s):  
Magdalena Celińska-Löwenhoff ◽  
Teresa Iwaniec ◽  
Agnieszka Padjas ◽  
Jacek Musiał ◽  
Anetta Undas
Keyword(s):  
Structure Function ◽  
Antiphospholipid Syndrome ◽  
Thrombotic Event ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Lag Phase ◽  
Lysis Time ◽  
Clot Structure ◽  
Clot Lysis Time ◽  
D Dimer

SummaryWe tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with “triple-antibody positivity” were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and “triple-positivity” were the independent predictors of clot permeability, while “triple-positivity” predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

scholarly journals The Role of Portal Vein Thrombosis in the Clinical Course of Inflammatory Bowel Diseases: Report on Three Cases and Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Emanuele Sinagra ◽  
Emma Aragona ◽  
Claudia Romano ◽  
Simonetta Maisano ◽  
Ambrogio Orlando ◽  
...  
Keyword(s):  
Portal Vein ◽  
Portal Vein Thrombosis ◽  
Inflammatory Bowel Diseases ◽  
Vascular Complications ◽  
Hepatic Abscess ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Thromboembolism Events

Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic.

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