A new pedigree with thrombomodulin‐associated coagulopathy in which delayed fibrinolysis is partially attenuated by co‐inherited TAFI deficiency

Abstract

Background Thrombomodulin‐associated coagulopathy (TM‐AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis. Objectives To report the characteristics of pedigree with a novel THBD variant causing TM‐AC, and co‐inherited deficiency of thrombin‐activatable fibrinolysis inhibitor (TAFI). Patients/methods Identification of pathogenic variants in hemostasis genes by next‐generation sequencing and case recall for deep phenotyping. Results Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs*10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM_AC cases with THBD p.Cys537*. Coincidentally, some pedigree members also harbored a stop‐gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM‐AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation. Conclusions These data extend the reported genetic repertoire of TM‐AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra‐cellular domain. The data further confirm that the delay in fibrinolysis associated with TM‐AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin‐TM system and its regulation of TAFI.

Differences in coagulopathy indices in patients with severe versus non-severe COVID-19: a meta-analysis of 35 studies and 6427 patients

“…The obvious consideration is related to therapy with heparin to limit coagulopathy. However, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis and a nebulizer form of tissue‐type plasminogen activator (tPA) to treat COVID‐19 has been recently proposed 56 .…”

Fibrinolysis and bleeding of unknown cause

“…Consistent with mouse experiments that did not find an effect of TAFI deficiency on the hemostatic capacity, 26 subjects with only this genetic variation, but no thrombomodulin alterations, were asymptomatic. 25 To the best of our knowledge, no bleeding disorders related to a gain-of-function mutation in plasminogen have been described in humans.…”

“…Alterations in factors and regulators of the fibrinolytic system have been identified in both case series and families with a pattern of de- factors, as only few genetic confirmations for PAI-1 deficiency have been described. [22][23][24] Recently, Westbury et al 25 identified, in a family with a thrombomodulin-associated bleeding disorder, a stop-gain mutation in the CPB2 gene that encodes TAFI and resulted in 50% lower TAFI levels. Consistent with mouse experiments that did not find an effect of TAFI deficiency on the hemostatic capacity, 26 subjects with only this genetic variation, but no thrombomodulin alterations, were asymptomatic.…”

“…Recently, Westbury et al 25 identified, in a family with a thrombomodulin‐associated bleeding disorder, a stop‐gain mutation in the CPB2 gene that encodes TAFI and resulted in 50% lower TAFI levels. Consistent with mouse experiments that did not find an effect of TAFI deficiency on the hemostatic capacity, 26 subjects with only this genetic variation, but no thrombomodulin alterations, were asymptomatic 25 . To the best of our knowledge, no bleeding disorders related to a gain‐of‐function mutation in plasminogen have been described in humans.…”

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

“…Bleeding complications related to CPU inhibition have neither been reported in cpb2 knockout mice nor after administration of CPU inhibitors. Westbury et al recently showed that hemostasis was not significantly impacted in individuals with a partial proCPU deficiency, which underscores the potential of pharmacological inhibition of CPU for the treatment of thromboembolic diseases and encourages that this therapeutic strategy will unlikely result in bleeding complications [197,198]. However, data need to be interpreted with caution as only limited activation of proCPU (1-2%) can be enough to exert its antifibrinolytic effects.…”