Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation

Abstract

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding

“…There is scant data on a role for PKK in human thromboembolism. Only ϳ 75 cases for congenital PKK deficiency have been published, 7,8,29 precluding meaningful epidemiologic analysis, and an association between elevated PKK levels and thrombosis has not been established. 49 Small molecule inhibitors, antibodies and ASOs targeting fXI or fXIa are currently under development for therapeutic use.…”

“…Humans and other animals deficient in a contact activation protein are largely asymptomatic. 4,[6][7][8] However, the contact system may play an important role in thrombotic disease, as pharmacologic inhibition of fXIIa or ablation of the fXII or HK genes can protect mice from experimentally induced thrombosis in a variety of models. [9][10][11][12][13] Interestingly, fXII deficiency confers somewhat greater protection from thrombosis than fXI deficiency in some models, 11 implying that fXII may contribute to thrombus formation through additional pathways distinct from fXI-dependent intrinsic pathway activation.…”

Epidemiologic and clinical data linking factors XI and XII to thrombosis

“…10 Although fXII deficiency per se was considered to be a risk factor for VTE, 11 in retrospect, this conclusion was likely explained by reporting bias. Reevaluation of the reported cases 16 and extended fXII-deficient pedigrees 17 suggested that the majority of affected patients had other inherited or acquired risk factors that were more likely to explain the thrombotic events. In addition, it has been reported that a subset of antiphospholipid antibodies bind to fXII and may lead to an acquired "pseudo fXII deficiency" 18 ; these antibodies, rather than the measured fXII deficiency, may therefore account for the observed thrombotic events.…”

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

“…32 Therefore, the available data on factor XII is much more limited compared with factor XI. In recent years, however, there is renewed interest in factor XII and its role in thrombosis.…”