ABNORMALITIES OF FIBRINOGEN AND FIBRINOLYSIS IN FAMILIAL THROMBOSIS
Authors: Samama M , Conard J , Horellou M H , Nguyen G , Dreden Van , Soria J H 
Published: August 2018

We have reviewed our own experience (400 patients with documented thromboembolic disease) as well as that recorded in the literature. Impaired fibrinolysis after venous occlusion (VO) was the most common finding in patients with history of thrombosis (35% in our series). In contrast, very few families with such an alteration and thrombosis have been reported, suggesting that this disorder is most frequently acquired. In a series of 59 patients with history of thromboembolism, 25 patients with an abnormal responseto an 10 min. V0 on 2 different occasions (group A) were compared with 34 patients who had a normal response toV0 (group B). A positive family history was present in 50% of cases of both groups. A congenital deficiency in AT III, protein C or plasminogen was ruled out in all patients. In group A, as compared to group B, t-PA antigen (Elisa method) and activity (fibrinplates) were significantly lower after V0, basal PAI activity (Verheijen method) was higher (increased in 84 and 11% of patients in groups A and B respectively) and PAI after V0 was also higher in group A (p < 0.01). In this group an associated abnormal t-PA release cannot be reliably ruled out. In patients with abnormal V0 but normal basal PAI (n = 4), a decreased plasminogen activator release may besuspected.According to animal and in vitro studies, bovine and, to a less degree,human activated protein C (APC) may stimulate fibrinoly-* sis. In a groupof 46 patients with congenital proteinC deficiency, we could not demonstrate a significant alteration of the fibri-lytic response to V0 by common lysis tests on diluted whole blood, euglobulins or plasma ; in addition basalPAI activity levels were not significantly different from normal values,even in one homozygous patient. However, an alteration of fibrinolysis localized at the vascular surface and/or irrelevance of the tests used in thesepatients cannot be excluded.In principle, a contact factor deficiency could predispose to thrombosis since intrinsic activation of fibrinolysis requires factor XII, prekallikrein (PK) and high molecular weight kininogen (HMWK). However,there is no strong evidence for this relationship. A small number of plasminogen deficiencies associated with thrombosis have been reported, with decreased activity and normal or concommitantly reduced antigen.We have observed onlyone case of familialplasminogen deficiency (both antigen and activity) out of the 400 patients studied. The relationship between the deficiencyandthe occurence of thrombosis has been questioned since,although thrombosis occuredin our propositus as well as in some of the patients reported in the literature, accidents were infre quent in other affected family members.Although predisposition to thrombosis in patients with hypo- or dysfibrinogenemia (D) seems paradoxical, several reasons can account for this apparent coincidence. Fibrin possesses antithrombin properties and enhances plasminogen activation induced by t-PA. Moreover, fibrinogen binding to platelets is an essential step in the mechanism of platelet aggregation. Alteration of these different functions could enhance thrombosis. In fact, thrombotic episodes were observed in about 10% of probands with D and in 4 patients with hypofibrinogenemia. The siblings with D are frequently asymptomatic. In few cases it has been shown that the abnormal fibrinogen could predispose tothrombosis such as in Dusard syndrome. Several family members suffered from a severe thrombotic disorder. A defective fibrinolysis due to an impaired fibrin enhanced plasminogen activation by t-PA was demonstrated. In Fibrinogen Oslo an increase of fibrinogen platelet aggregation cofactor activity was postulated to predispose to venous thrombosis.A defective thrombin bindingto fibrin was found in at least 3 cases ofD(fibrinogen New York I, Malmoe, Milano).Infibrinogen New York an associated defective binding of t-PA was shown. The findings concerning a defective thrombin, plasminogen, or t-PA binding to fibrin in some patients with fibrinogen alteration suggesttheimportant role of clot structure in the pathogenesis of some thrombotic disorders.In conclusion, the best tests to detecthypofibrinolysis have still to be determined : whole blood or plasma, lysis tests ormore specific assays such as t-PA or PAI, venous occlusion of 10 min. or more. In addition, a defective fibrinolysis can be associated with a well-defined congenital deficiency in coagulation inhibitors.