Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis.

Genetic fibrinogen (FGN) variants that are associated with bleeding or thrombosis may be informative about fibrin polymerisation, structure and fibrinolysis. We report a four generation family with thrombosis and heritable dysfibrinogenaemia segregating with a c.[1541delC];[=] variation in FGA (FGN-Perth). This deletion predicts a truncated FGN αC-domain with an unpaired terminal Cys at residue 517 of FGN-Aα. In keeping with this, SDS-PAGE of purified FGN-Perth identified a truncated FGN-Aα chain with increased co-purification of albumin, consistent with disulphide bonding to the terminal Cys of the variant FGN-Aα. Clot visco-elastic strength in whole blood containing FGN-Perth was greater than controls and tPA-mediated fibrinolysis was delayed. In FGN-Perth plasma and in purified FGN-Perth, there was markedly reduced final turbidity after thrombin-mediated clot generation. Consistent with this, FGN-Perth formed tighter, thinner fibrin fibres than controls indicating defective lateral aggregation of protofibrils. Clots generated with thrombin in FGN-Perth plasma were resistant to tPA-mediated fibrinolysis. FGN-Perth clot also displayed impaired tPA-mediated plasmin generation but incorporated α2-antiplasmin at a similar rate to control. Impaired fibrinolysis because of defective plasmin generation potentially explains the FGN-Perth clinical phenotype. These findings highlight the importance of the FGN αC-domain in the regulation of clot formation and fibrinolysis.

Plasma thrombin-antithrombin complex, prothrombin fragments 1 and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is associated with hypercoagulability, evidenced by increased markers of coagulation activation, including thrombin-antithrombin complex (TAT), prothrombin fragments 1 and 2 (F1+2), and D-dimer. Our aim was to compare the effect of endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) on changes in coagulation activation markers after intervention. METHODS: Consecutive patients with AAAs reaching their intervention threshold in a tertiary vascular referral unit in the United Kingdom were invited to participate. The coagulation markers TAT, F1+2, and D-dimer were measured in venous blood collected at baseline and at 5 months after intervention. A forward stepwise multiple linear regression model was used to identify whether treatment by OAR or EVAR had an effect on changes in coagulation factors, independent of significant covariates. RESULTS: The study included 47 patients (14 EVAR, 33 OAR; 85% men) who were a median age of 76 years (range, 69.5-80 years). Aortic diameter at intervention was 5.9 cm (range, 5.5-6.8 cm). There were no significant differences in clinical, anthropometric, or hematologic parameters between groups. At baseline, TAT (P = .13), F1+2 (P = .08), and D-dimer (P = .11) were similar in EVAR and OAR patients. Postintervention, there was a significant increase in TAT (3.0 [2.1-6.0] vs 7.2 [6.3-8.4] ng/mL; P = .03), F1+2 (242 [189-323] vs 392 [312-494] ng/mL; P = .003), and D-dimer (457 [336-615] vs 1197 [840-1509] ng/mL; P = .002) in the EVAR group. No significant changes were observed after intervention in the OAR group. CONCLUSIONS: AAA-related hypercoagulability persists after intervention, with increased TAT, F1+2, and D-dimer levels after EVAR. These findings suggest a potential period of increased cardiovascular risk in the postoperative period after EVAR.

Clot architecture is altered in abdominal aortic aneurysms and correlates with aneurysm size.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized by widening of the aorta. Once the aneurysm exceeds 5.5 cm, there is a 10% risk of death due to rupture. AAA is also associated with mortality due to other cardiovascular disease. Our aim was to investigate clot structure in AAA and its relationship to aneurysm size. METHODS AND RESULTS: Plasma was obtained from 49 controls, 40 patients with small AAA, and 42 patients with large AAA. Clot formation was studied by turbidity, fibrin pore structure by permeation, and time to half lysis by turbidity with tissue plasminogen activator. Plasma clot pore size showed a stepwise reduction from controls to small to large AAA. Lag phase for plasma clot formation and time to half lysis were prolonged, with smaller AAA samples showing intermediate response. Clot structure was normal in clots made with fibrinogen purified from patients compared with controls, suggesting a role for other plasma factors. Endogenous thrombin potential and turbidity using tissue factor indicated that the effects were independent of changes in thrombin generation. CONCLUSIONS: Patients with AAA form denser, smaller pored plasma clots that are more resistant to fibrinolysis, and these characteristics correlate with aneurysm size. Clot structure may play a role in AAA development and concomitant cardiovascular disease.