Altered Fibrin Clot Properties Research Articles

Altered fibrin clot properties are associated with the progression of chronic kidney disease in atrial fibrillation

IntroductionFormation of denser and resistant to lysis fibrin clot networks has been shown in chronic kidney disease (CKD) and atrial fibrillation (AF). We investigated whether such prothrombotic fibrin clot properties are associated with faster progression of CKD in AF patients. Material and methodsWe recruited 265 AF patients (men 49.1 %, median age of 64.0 years, median estimated glomerular filtration rate [eGFR] of 77.0 ml/min/1.73 m2), including 137 patients on non-vitamin K antagonist oral anticoagulants (NOACs) (51.7 %) and 109 patients (41.1 %) on vitamin K antagonists (VKAs). At baseline while off anticoagulation, we determined fibrin clot permeability (Ks), and clot lysis time (CLT), along with plasminogen activator inhibitor-1 (PAI-1), endogenous thrombin potential (ETP), and von Willebrand factor (vWF). The kidney function was assessed at baseline and after a median follow-up of 50.0 months. ResultsDuring follow-up, a median eGFR decreased by 8.0 (5.0–11.0) ml/min/1.73 m2, 1.8 ml/min/1.73 m2/year and this change correlated with age (R = 0.19, P = 0.002), Ks (R = 0.46, P < 0.0001), and CLT (R = -0.17, P = 0.005), but not ETP, fibrinogen, PAI-1 or vWF. A decrease in eGFR was lower in patients who used NOACs at baseline but not in those who started NOACs during follow-up (n = 101) as compared to the remaining patients. On multiple linear regression analysis, adjusted for age and fibrinogen, baseline Ks, eGFR, hypertension, and NOACs use independently predicted a decrease in eGFR. ConclusionsThis study is the first to show that more compact fibrin clot networks may contribute to faster progression of CKD in AF, indicating novel kidney-related harmful effects of prothrombotic clot properties in humans.

Changes in fibrin clot properties in patients after Roux-en-Y gastric bypass surgery

BackgroundObesity is a complex condition associated with prothrombotic fibrin networks that are resistant to fibrinolysis. Altered fibrin clot properties enhance cardiovascular risk and associate with a poorer prognosis following acute ischemic events. Bariatric surgery is commonly employed to improve cardiometabolic outcomes in individuals with obesity. However, the effects of this surgical intervention on fibrin clot properties have not been comprehensively studied. ObjectivesTo examine fibrin clot and lysis parameters in Roux-en-Y gastric bypass (RYGB) patients before and after surgery. MethodsThe fibrin clot properties of 32 individuals living with obesity before and 9 months after RYGB surgery were determined using turbidimetric analysis. Correlation and regression analyses were used to identify relationships between clot properties and anthropomorphic and clinical measures. ResultsRYGB surgery resulted in a significant reduction in adiposity-associated anthropometric measures as well as improvements in glycemia and lipid profile. Clot maximum absorbance was reduced from 0.43 ± 0.11 at baseline to 0.29 ± 0.10 at 9 months postsurgery (P < .0001), while fibrin clot lysis time failed to show a difference. The change in maximum absorbance was not caused by alterations in fibrinogen levels, while plasminogen activator inhibitor-1 concentration was significantly increased after surgery from 10,560 ± 6681 pg/mL to 15,290 ± 6559 pg/mL (P = .009). Correlation and regression analyses indicated that maximum absorbance was influenced by markers of adiposity as well as glycated hemoglobin and high-sensitivity C-reactive protein concentrations. ConclusionRYGB surgery led to a decrease in the maximum absorbance of the fibrin clot. Values of maximum absorbance were associated with measures of glycemic control and inflammation. In contrast to previous reports, fibrin clot lysis time was not affected after surgery.

Protein Carbonylation Contributes to Prothrombotic Fibrin Clot Phenotype in Acute Ischemic Stroke: Clinical Associations.

Acute ischemic stroke (AIS) is associated with enhanced oxidative stress and unfavorably altered fibrin clot properties. We investigated determinants of plasma protein carbonylation (PC) in AIS, its impact on the prothrombotic state, and prognostic value during follow-up. We included 98 consecutive AIS patients aged 74±12 years (male:female ratio, 50:48 [51%:49%]) at the Neurology Center in Warsaw, Poland, between January and December 2014. As many as 74 (75.5%) patients underwent thrombolysis, and 24 were unsuitable for thrombolysis. We determined plasma PC, along with thrombin generation, fibrin clot permeability, and clot lysis time on admission, at 24 hours, and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale and stroke outcome with the modified Rankin Scale. Hemorrhagic transformation was assessed on the computed tomography scan within 48 hours from the symptom onset, while stroke-related mortality was evaluated at 3 months. On admission, PC levels (median, 4.61 [3.81-5.70] nM/mg protein) were associated with the time since symptom onset (r=0.41; P<0.0001) and with the National Institutes of Health Stroke Scale score (P=0.36; P=0.0003). Higher PC levels on admission correlated with denser fibrin clot formation and prolonged clot lysis time but not with thrombin generation. In thrombolysed patients, lower PC levels were observed after 24 hours (-34%) and at 3 months (-23%; both P<0.001). PC levels at baseline and after 24 hours predicted the modified Rankin Scale score >2 at 3 months (OR, 1.90 [95% CI, 1.21-3.00]; OR, 2.19 [95% CI, 1.39-3.44], respectively). Higher PC at baseline predicted hemorrhagic transformation of stroke (OR, 1.95 [95% CI, 1.02-3.74]) and stroke-related mortality (OR, 2.02 [95% CI, 1.08-3.79]), while higher PC at 24 hours predicted solely stroke-related mortality (OR, 2.11 [95% CI, 1.28-3.46]). Elevated plasma PC levels in patients with AIS, related to prothrombotic fibrin clot properties, are associated with stroke severity. Thrombolysis reduces the extent of PC. The current study suggests a prognostic value of PC in AIS.

PB0765 Increased Complement C3a Anaphylatoxin is Associated with Elevated Factor VIII and Altered Fibrin Clot Properties in Normotensive Patients with Acute Pulmonary Embolism

PB0765 Increased Complement C3a Anaphylatoxin is Associated with Elevated Factor VIII and Altered Fibrin Clot Properties in Normotensive Patients with Acute Pulmonary Embolism

PB0016 Plasma Protein Carbonylation is Associated with Unfavorably Altered Fibrin Clot Properties in Patients with Atrial Fibrillation: A Novel Risk Factor of Ischemic Cerebrovascular Events

PB0016 Plasma Protein Carbonylation is Associated with Unfavorably Altered Fibrin Clot Properties in Patients with Atrial Fibrillation: A Novel Risk Factor of Ischemic Cerebrovascular Events

Unfavorably altered fibrin clot properties are associated with recurrent venous thromboembolism in patients following post‑discharge events.

Unfavorably altered fibrin clot properties are associated with recurrent venous thromboembolism in patients following post‑discharge events.

GnRH Antagonist Protocol Enhances Coagulation During Controlled Ovarian Stimulation for IVF.

Changes in coagulation and fibrinolysis have been reported in women undergoing controlled ovarian hyperstimulation (COH) supporting a potential hypercoagulable condition related to this treatment. This study aimed at evaluating the changes in fibrin clot properties and thrombin generation induced by two different COH protocols: long with gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant). Primary outcomes included determination of plasma fibrin clot properties, including clot permeability (Ks) and efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1 + 2) and endogenous thrombin potential (ETP) and fibrinolysis inhibitor levels. One hundred twenty-nine infertile women were included in the final analysis. The GnRH-ant protocol resulted in increased ETP (+ 9.8%) and reduced Ks (- 2.4%). Conversely, COH with the GnRH-a protocol reduced thrombin generation by decreasing both ETP (- 6.6%) and F1 + 2 (- 30.8%) together with favorably altered fibrin clot properties represented by increased Ks (+ 21.7%) and reduced CLT (- 13.8%) as well as decreased PAI-1 levels (by 2.5 times). The GnRH-ant compared to the GnRH-a protocol increased PAI-1 levels (+ 77.3%), thrombin generation (9.3% higher ETP), and Ks (+ 13.7%). In the GnRH-a group, post-COH Ks was 14.3% higher (Ks ≥ 7.92 × 10-9 cm2) in women with positive vs. negative pregnancy outcomes. Our results show that the GnRH-ant protocol enhanced thrombin generation and slightly decreased fibrin clot density. COH with the GnRH-a reduced thrombin generation and improved fibrin clot features. This trial was registered (NCT04166825). Clinical Trial Registration Number: NCT04166825.

Fibrin clot properties in coronary artery disease: new determinants and prognostic markers.

Despite improved diagnosis and treatment options, coronary artery disease (CAD) is still the leading cause of mortality and morbidity worldwide. Established risk factors such as smoking, hypercholesterolemia, and hypertension only partly explain the pathophysiology of CAD. Besides the well-known role of platelets in atherosclerosis and arterial thrombus formation, reduced endogenous fibrinolytic activity may play a key role in CAD formation and progression. Thus, biomarkers of fibrinolysis may be future CAD risk markers. In this review, we provide an overview of regulators of fibrinolysis and the main factors of importance to fibrin clot formation including coagulation factor XIII, thrombin, and fibrinogen. We summarize markers of altered fibrinolysis and current laboratory methods applied in clinical practice and research. We present today’s evidence on fibrin clot properties in patients with stable CAD or acute coronary syndrome compared with healthy individuals and the significance of altered fibrinolysis as a risk for coronary thrombotic disease. In conclusion, we found evidence that altered fibrin clot properties and impaired fibrinolysis appear to contribute significantly to the thromboembolic risk in CAD patients. Therefore, more research is crucial in order to clarify whether modulation of the fibrinolytic system may pave the way for improved treatment of CAD.

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

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.

Fibrin clot properties among women with endometriosis and the impact of ovarian stimulation

Research questionIs there a difference in fibrin clot phenotype in women with endometriosis before and after ovarian stimulation? DesignProspective study including 73 infertile women in two age-matched groups: (i) with confirmed endometriosis (n = 29); (ii) without endometriosis (n = 44). Assessments of plasma fibrin clot permeability (Ks), efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1+2 [F1+2] and endogenous thrombin potential [ETP]) and fibrinolysis inhibitors were performed together with clinical pregnancy rate. ResultsEndometriosis was associated with increased thrombin generation, reflected by both higher F1+2 (+96.1%, P = 0.005) and ETP (+14.2%, P = 0.014) along with unfavourably altered fibrin clot properties represented by lower Ks (–31%, P < 0.001) and prolonged CLT (+13.5%, P = 0.02), compared with the non-endometriosis group. Moreover, women with endometriosis had higher plasminogen activator inhibitor-1 (PAI-1; +272%, P = 0.004) concentrations and alpha-2-antiplasmin activity (+39.9%, P < 0.001) in contrast to the other group. Ovarian stimulation led to reduction in F1+2 (–48.1%, P < 0.001), improvement of fibrin clot phenotype reflected by higher Ks (+25.9%, P < 0.001) and shortened CLT (–11.9%, P < 0.001), along with lower PAI-1 (–54%, P = 0.016) compared with the baseline in women with endometriosis. ConclusionsEndometriosis is associated with the prothrombotic fibrin clot phenotype and increased thrombin generation. Ovarian stimulation favourably alters fibrin clot properties and leads to comparable pregnancy outcomes to those in women without endometriosis.

Fibrinogen and Fibrin.

Fibrinogen is a large glycoprotein, synthesized primarily in the liver. With a normal plasma concentration of 1.5-3.5g/L, fibrinogen is the most abundant blood coagulation factor. The final stage of blood clot formation is the conversion of soluble fibrinogen to insoluble fibrin, the polymeric scaffold for blood clots that stop bleeding (a protective reaction called hemostasis) or obstruct blood vessels (pathological thrombosis). Fibrin is a viscoelastic polymer and the structural and mechanical properties of the fibrin scaffold determine its effectiveness in hemostasis and the development and outcome of thrombotic complications. Fibrin polymerization comprises a number of consecutive reactions, each affecting the ultimate 3D porous network structure. The physical properties of fibrin clots are determined by structural features at the individual fibrin molecule, fibrin fiber, network, and whole clot levels and are among the most important functional characteristics, enabling the blood clot to withstand arterial blood flow, platelet-driven clot contraction, and other dynamic forces. This chapter describes the molecular structure of fibrinogen, the conversion of fibrinogen to fibrin, the mechanical properties of fibrin as well as its structural origins and lastly provides evidence for the role of altered fibrin clot properties in both thrombosis and bleeding.

Altered fibrin clot properties and fibrinolysis in patients with atrial fibrillation: practical implications.

Compelling evidence indicates that a hypercoagulable state occurs in patients with atrial fibrillation (AF) including those in sinus rhythm following paroxysmal and persistent AF. Activation of blood coagulation in AF reflects heightened thrombin generation with the subsequent increased formation of fibrin as evidenced by elevated soluble fibrin monomers and D-dimer. Formation of denser fibrin meshworks, relatively resistant to plasmin-mediated lysis has been demonstrated in patients with AF. The presence of stroke risk factors in AF, such as diabetes, heart failure, hypertension, previous myocardial infarction, or stroke, advanced age have been shown to be linked to the prothrombotic clot characteristics, including reduced clot permeability and lysability. Importantly, biomarkers, including cardiac troponins and N-terminal pro-brain natriuretic peptide, are associated with thrombin generation and fibrin-related markers in AF patients. Recently, increased fibrin clot density (low clot permeability measured in plasma-based assays) and impaired fibrinolysis measured off anticoagulation have been demonstrated to predict ischaemic cerebrovascular events in patients with AF receiving vitamin K antagonists and those on rivaroxaban. The current review summarizes evidence for a role of altered fibrin clot properties and hypofibrinolysis in AF and their prognostic value in terms of adverse events.

Prothrombotic fibrin clot properties are associated with post-discharge venous thromboembolism in acutely ill medical patients

IntroductionReduced clot permeability and lysability have been reported in patients who experienced venous thromboembolism (VTE) following lower limb injury despite pharmacological thromboprophylaxis. We hypothesized that similarly altered fibrin clot properties characterize patients with post-discharge VTE despite thromboprophylaxis during prior hospitalization due to acute medical illnesses. MethodsIn a case-control study, we assessed 48 patients who developed VTE within 4 weeks post-discharge despite pharmacological thromboprophylaxis during hospitalization (the thromboprophylaxis group) and three age- and sex-matched control groups (n = 48 each): (1) patients who developed VTE following hospitalization without pharmacological thromboprophylaxis (the no-thromboprophylaxis group), (2) patients with unprovoked VTE and (3) individuals without history of VTE (the no-VTE group). Blood samples were obtained following ≥3 months of anticoagulation in VTE patients. Fibrin clot properties, thrombin generation and fibrinolysis activators and inhibitors were assessed. ResultsCompared with the no-VTE group, the thromboprophylaxis group formed denser fibrin networks reflected by lower clot permeability (Ks, −13%) and impaired fibrinolysis, as evidenced by prolonged clot lysis time (CLT, +14%) and lower rate of D-dimer release from clots (D-Drate, −9%) accompanied by elevated high-sensitivity C-reactive protein (hsCRP, +79%), peak thrombin generation (+55%) and α2-antiplasmin (+10%, all p < 0.05). Similar fibrin clot features were observed following unprovoked VTE. The thromboprophylaxis group had also lower Ks (−13%), elevated α2-antiplasmin (+18%) and higher peak thrombin generation (+25%, all p < 0.05) as compared with the no-thromboprophylaxis group. ConclusionsUnfavorably altered plasma clot properties and increased thrombin generation characterize medical patients with post-discharge VTE despite receiving pharmacological thromboprophylaxis during hospitalization for acute conditions.

Altered fibrin clot properties in advanced lung cancer: strong impact of cigarette smoking

BackgroundDense fibrin networks resistant to lysis have been reported in patients at high risk of thromboembolism. Little is known about fibrin clot properties in cancer. We investigated fibrin clot properties and their determinants in patients with inoperable lung cancer.MethodsWe enrolled 150 patients with advanced lung cancer prior to therapy and 90 control subjects matched by age, sex, cardiovascular disease, and diabetes. Plasma clot permeability (Ks), turbidimetric analysis of clot formation, clot lysis time (CLT), microparticle-associated tissue factor (MP-TF) activity, thrombin generation, and serum cotinine levels were determined.ResultsLung cancer patients, compared with controls, formed at a faster rate (− 8.1% lag phase) denser plasma fibrin networks (− 27.2% Ks) that displayed impaired lysis (+ 26.5% CLT), along with 19.5% higher MP-TF activity and 100% higher peak thrombin generated, also after adjustment for potential confounders. Cotinine levels were associated with fibrin maximum absorbance (r = 0.20, p = 0.016) and Ks (r = − 0.50, p < 0.0001) in cancer patients. On multivariate regression analysis, an increase in cotinine levels was a predictor of low Ks (the lower quartile, < 5.8 × 10−9 cm2; odds ratio = 1.21 per 10 ng/ml, 95% confidence interval 1.02–1.46), but not CLT.ConclusionAdvanced lung cancer is associated with the prothrombotic plasma clot phenotype largely driven by smoking.

Plasma phospholipid fatty acids are associated with altered fibrin clot properties in a population-based setting

Evidence regarding the relationship of plasma clot properties with fatty acids is contradictory, owing to different experimental protocols employed. The relationship of fibrinogen and plasma fibrin clot properties with plasma phospholipid fatty acids were cross-sectionally investigated in a population-based setting in 900 individuals. Composite saturated fatty acids (driven by stearic acid) and composite n-3 and n-6 polyunsaturated fatty acids (driven by docosahexaenoic and arachidonic acid respectively) were associated with prothrombotic clot properties. Composite monounsaturated fatty acids (driven by oleic acid) were associated with a profibrinolytic clot phenotype. Fibrinogen and BMI partly mediated these relationships. Individual plasma fatty acids from the same composite group had opposing associations with clot properties indicating that associations with composite fatty acid groups is dependent on the relative composition of the comprising fatty acids. The relationship of the plasma phospholipid fatty acid profile with disease should not be interpreted without considering the role of regulatory mechanisms.

Altered fibrin clot properties in advanced lung cancer: impact of chemotherapy.

Faster formation of dense and poorly lyzable fibrin networks have been reported in patients at risk of thromboembolism, including cancer patients. We sought to investigate whether chemotherapy affects plasma fibrin clot properties and their determinants in lung cancer patients. In this observational study we enrolled 83 consecutive patients with advanced inoperable lung cancer. Plasma fibrin clot permeability (Ks), turbidimetric analysis of clot formation, clot lysis time (CLT), microparticle-associated tissue factor (MP-TF) activity, and thrombin generation parameters were investigated at enrolment and 3-4 months after standard chemotherapy. Lung cancer patients after 4 (range, 4-5) cycles of chemotherapy had 35.6% higher D-dimer, 22.1% lower MP-TF activity, and unaltered fibrinogen compared with baseline. Chemotherapy resulted also in 7.5% increased Ks, 8.6% prolonged lag phase, and 5.4% shortened CLT, while thrombin generation was unchanged. Chemotherapy-related differences in clot structure were confirmed by scanning electron microscopy images. Fibrin clot properties after chemotherapy did not differ among histological types of lung cancer, cancer stages or chemotherapy regimens. Interestingly, never smoking (n=13, 16%) was associated with looser post-treatment fibrin structure as reflected by 12.3% higher Ks. Multiple linear regression showed that more advanced cancer stage, higher peak thrombin generation, and higher white blood cell count determined post-treatment change in Ks, while active smoking was associated with change in CLT. Three-month chemotherapy in lung cancer patients improves clot properties despite unaffected thrombin generation, suggesting that anticancer treatment might quickly produce antithrombotic actions.

Altered Fibrin Clot Properties Predict Stroke and Bleedings in Patients With Atrial Fibrillation on Rivaroxaban.

Background and Purpose- We investigated whether clot permeability can predict clinically relevant outcomes in patients with atrial fibrillation (AF) treated with rivaroxaban. Methods- In the cohort study, we enrolled 232 consecutive patients with AF on rivaroxaban 20 mg/d (76.3%) or 15 mg/d (23.7%) for at least 3 months. Plasma clot permeability (Ks), a measure of fibrin network density, was determined 24 to 30 hours since the intake of rivaroxaban at undetectable drug's levels. Ischemic cerebrovascular events and bleedings were recorded. Results- During a median follow-up of 48 months, patients with Ks below median (6.8 cm2·10-9) had higher prevalence of stroke (5.84 versus 0.88% per year; P<0.0001) and relevant bleeding (7.06 versus 0.88% per year; P<0.0001) compared with those above median. The mortality rate was 1.53% per year and was not associated with Ks. Lower Ks predicted cerebrovascular ischemic events (hazard ratio, 6.64; 95% CI, 2.2-20.1) and relevant bleedings (hazard ratio, 7.38; 95% CI, 2.58-21.10). Minor bleeds (32.8% of patients) were observed more often in patients with Ks above median (50.9 versus 14.7%; P<0.0001). Multivariate Cox regression analysis showed that in AF patients on rivaroxaban lower Ks increased the risk of stroke (hazard ratio, 6.51; 95% CI, 2.14-19.75) and relevant bleedings (hazard ratio, 9.68; 95% CI, 3.21-29.18). Conclusions- Decreased clot permeability in AF patients can predict thromboembolic and clinically relevant bleeding events during therapy with rivaroxaban, while looser clot networks predispose to minor bleeds.

Unfavorably altered plasma clot properties in women with a HERDOO2 score equal to or greater than 2 and prediction of recurrent venous thromboembolism.

Introduction The HERDOO2 rule can help identify patients in whom anticoagulation can be safely discontinued. Unfavorably altered fibrin clot properties predict recurrent venous thromboembolism (VTE). Objectives We aimed to assess a possible association between fibrin clot properties and the HERDOO2 score in women after unprovoked VTE. Patients and methods Eighty women younger than 70 years after a first unprovoked VTE separately and combined with 32 women after hormone‑related VTE were followed for a median of 48.5 months (interquartile range, 37.5-67 years). Plasma fibrin clot permeability (Ks), lysability, turbidity measurements, and thrombin generation were assessed 3 months after the index event in relation to the HERDOO2 score. Results Nineteen women (23.8%) with a HERDOO2 score equal to or higher than 2 were characterized by lower Ks (-6.8%), indicating formation of more compact clots, impaired fibrinolysis as evidenced by a reduced maximum rate of D‑dimer release from clots (D‑D rate, by 6.8%), and prolonged clot lysis time (CLT, by 23.8%). No increased thrombin generation or differences in the remaining fibrin clot properties were observed. When combined with estrogen‑related VTE, the same trends were observed. D‑D rate and CLT correlated with the HERDOO2 score (r = -0.28, P = 0.01 and r = 0.35, P = 0.002, respectively) in 80 women with unprovoked VTE. Unfavorable clot phenotype, defined as Ks ≤6.55×10-9 cm2 and CLT >99.5 minutes, was associated with high risk of recurrence in the HERDOO2 rule (P = 0.02). Conclusions We showed that middle‑aged women after unprovoked VTE with high risk of recurrence based on the HERDOO2 rule are characterized by formation of denser fibrin clots and impaired fibrinolysis.

Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy.

Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism with a high recurrence rate after anticoagulation cessation. Recently, we have reported that prothrombotic clot phenotype in venous thromboembolism patients is associated with an increased risk of recurrent deep-vein thrombosis. We tested whether abnormal clot properties are predictive of recurrent PE. We investigated 156 consecutive white patients aged 18 to 65 years after the first-ever provoked or unprovoked PE (n=89), with or without deep-vein thrombosis. Plasma fibrin clot permeability (Ks), turbidity measurements, calibrated automated thrombography, and efficiency of fibrinolysis using clot lysis time, maximum D-dimer levels, and rate of increase in D-dimer levels were evaluated at ≥3 months of anticoagulant therapy, at least 4 weeks since the anticoagulation withdrawal. The primary end point was recurrent PE during a median follow-up of 50 months. Recurrent PE was diagnosed in 23 (14.7%; 5%/yr) patients. Recurrent PE was associated with formation of denser fibrin networks reflected by lower Ks (P=0.007) and impaired fibrinolysis, as evidenced by prolonged clot lysis time (P=0.012) and reduced maximum rate of increase in D-dimer levels in the lysis assay (P=0.004). Patients with recurrent PE had higher plasma D-dimer (P<0.001) and thrombin peak (P=0.007) compared with the remainder, whereas turbidity measurements and maximum D-dimer levels did not differ in the recurrence. Multivariate model showed that independent predictors of recurrent PE were female sex, unprovoked venous thromboembolism, higher plasma D-dimer, reduced Ks, and reduced maximum rate of increase in D-dimer levels in the lysis assay (all P<0.05). Altered fibrin clot properties including formation of more compact clots displaying impaired susceptibility to lysis may predispose to recurrent PE.

Prothrombotic State in Patients With a Left Atrial Appendage Thrombus of Unknown Origin and Cerebrovascular Events.

We hypothesized that formation of left atrial appendage (LAA) thrombi of unknown origin is associated with altered fibrin clot properties and blood hypercoagulability. In a case-control study, we investigated 32 patients with a history of LAA thrombus after successful anticoagulant treatment versus 32 control subjects matched for age, sex, and diabetes mellitus. All subjects had previous ischemic stroke, transient ischemic attack, or migraine associated with patent foramen ovale. Patients with documented atrial fibrillation were excluded. We determined plasma fibrin clot permeability, fibrinolytic efficiency, thrombin generation, platelet and endothelial markers. Stroke or transient ischemic attack were assessed during a median follow-up of 74 (range 19-98) months. Compared with controls, patients with LAA thrombus more frequently were smokers (43.8% versus 18.8%) and had 20% prolonged clot lysis time, lower plasminogen (-14%), and higher plasminogen activator inhibitor-1 (+17%), thrombin-antithrombin complexes (+17%), CD40 ligand (+30%), P-selectin (+29%), and von Willebrand factor (+30%, all P<0.05). Occurrence of LAA thrombus was predicted by von Willebrand factor (β=0.038, P=0.004), plasminogen (β=-0.048, P=0.01), plasminogen activator inhibitor-1 (β=-0.161, P=0.03), and clot permeability (β=-1.076, P=0.03). During follow-up, cerebrovascular events occurred in 10 (33.33%) of the 30 available patients in the LAA thrombus group, including 7 (23.3%) with recurrent LAA thrombus and 4 (13.33%) with documented atrial fibrillation. Recurrent LAA thrombus was associated with lower baseline Ks and higher thrombin generation, fibrinogen, plasminogen activator inhibitor-1, and soluble CD40 ligand (all P<0.05). Prothrombotic blood alterations could be involved in the LAA thrombus formation in patients without documented atrial fibrillation and are associated with increased risk of stroke or transient ischemic attack during follow-up.