Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia

Abstract

To elucidate potential causes for differing bleeding phenotypes of haemophilic patients of identical degree of coagulation factor deficiency, we investigated 21 male patients with severe haemophilia. Median annual coagulation factor demand and the extent of haemophilic arthropathy were used to discriminate between intensely and less intensely haemorrhagic phenotypes. Haemophiliacs with a median annual coagulation factor demand of 800 IU per kg bodyweight or more and with three or more joints affected by haemophilic arthropathy represented the intensely haemorrhagic phenotype group; all other patients comprised the less intense group. The discriminator values represent the respective medians of the overall group. The results of activated partial thromboplastin time, endogenous thrombin potential, pro- and anticoagulant factor analysis did not differ between the two groups. Median tissue-type plasminogen activator concentration (TPA) was elevated significantly in haemophiliacs with an intensely haemorrhagic phenotype, as was the activity of the thrombin-activatable fibrinolysis inhibitor. Median activity of the plasminogen activator inhibitor 1 (PAI 1) and the concentration of TPA-PAI 1 complexes were increased to approximately double those in nonsevere haemophiliacs. Coexistent congenital thrombophilia was found significantly more often in the less intensely haemorrhagic group. Thus, increased stimulation of the fibrinolytic system was associated with a more intensely haemorrhagic phenotype in our patients. We hypothesize that ineffective haemophilic haemostasis in response to trauma evokes a protracted stimulation of the entire haemostatic system, including costimulation of fibrinolysis. The absence of coexistent congenital thrombophilia predisposes to excess stimulation of fibrinolysis, which cannot be downregulated effectively due to the dysfunctional intrinsic pathway. The association of a more intensely haemorrhagic phenotype with a paradoxical hyperstimulation of the fibrinolytic system resembles a vicious circle, where bleeding seems to cause predisposition to more bleeding.

Development and validation of a high throughput whole blood thrombolysis plate assay

“…The precise analysis of thrombolysis rate provided by the method presented in this paper could effectively upgrade this guidance therapy approach. It could potentially help to estimate altered fibrinolysis in several other pertinent clinical situations such as liver or bone marrow transplantation, liver cirrhosis, and haemophilia, or to assess the haemorrhagic risk after thrombolytic therapy 47–50 . The assay has an intra-assay coefficient of variation of 5.15% which is similar to that reported for the thromboelastrography methods 41, 51 (3 to 6%), but higher than that for the optimised ECLT assay 13, 44 (0.7 to 2.6%).…”

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

“…Increased levels of tissue plasminogen activator and thrombin-activatable fibrinolysis inhibitors are also found to associate with severe clinical outcomes in hemophilia. 41 Owing to rarity of the disease and the exorbitant treatment costs, prophylactic management of moderate and severe HB with plasma-derived or recombinant FIX concentrates is a major challenge in the developing countries. Identification of factors modulating phenotypic heterogeneity may prove beneficial in management of such cases and will open new avenues in the treatment of HB.…”

Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

“…Several retrospective studies have looked at the effect of coinheritance of prothrombotic mutations, with contradictory results. 6,9,[14][15][16][17][18][19][20][21][22][23][24][25] Some studies have found that severe hemophiliacs carrying a prothrombotic mutation have a milder phenotype characterized by older age at diagnosis, 25 older age at first bleed, 15,17,26 lower annual bleeding frequency, and less arthropathy. 21,22 In contrast, other studies failed to find significant differences in severity of disease attributable to the presence of a prothrombotic mutation.…”