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

Abstract

Objective-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. Approach and Results-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 (K s ), 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 K s (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 K s , and reduced maximum rate of increase in D-dimer levels in the lysis assay (all P<0.05). Conclusions-Altered

Fibrinogen and Fibrin in Hemostasis and Thrombosis

“…37 Thus, the substantially thinner fibers observed at high thrombin concentrations in earlier studies may reflect fiber compaction or shrinkage that occurs during dehydration. Regardless, the association of fibrin clot structural parameters with clinical pathologies – dense networks of thinner/compact fibers with increased thrombotic risk 38–40 and coarse networks of thicker/less compact fibers with increased bleeding risk 36,41 – suggests fibrin structure is a critical determinant of hemostasis and thrombosis.…”

“…38–40 Following percutaneous coronary intervention, patients who develop in-stent thrombosis demonstrate abnormal plasma clot characteristics (e.g., permeability, turbidity, lysis time) compared to patients who did not develop in-stent thrombosis. 112 Similarly, compared to healthy controls, plasma clots from patients with abdominal aortic aneurysm have more densely-packed fibrin networks with smaller pores, and were more resistant to lysis.…”

Plasma fibrin clot structure and thromboembolism: clinical implications

“…In 2017, we observed that recurrent PE, diagnosed during follow -up in 23 patients (5% per year) following the first--ever provoked or unprovoked PE, is associated with formation of denser fibrin networks, as evidenced by reduced K s (HR, 1.82; 95% CI, 1.01-3.13; FIguRE 3). 65 Postthrombotic syndrome is a common complication of DVT that has been found to be associated with K s reduced by 11.7% when assessed 3 months after the index DVT. 66 Recurrent VTE occurred also more commonly in patients with postthrombotic syndrome, who were characterized by lower K s and prolonged clot lysis time (CLT).…”

Antiphosphatidylserine/prothrombin complex antibodies as a determinant of prothrombotic plasma fibrin clot properties in patients with antiphospholipid syndrome

“…Although APS patients compared to healthy controls have increased clot‐bound β2GPI, the mechanism by which aPL antibodies can modulate fibrin properties remains unclear. Since (pro)thrombin is a known modulator of fibrin clot characteristics, the current study was designed to evaluate aPS/PT antibodies as potential determinants of reduced clot permeability and susceptibility to lysis in patients with thrombotic APS.…”