Hemorrhagic disorders of fibrinolysis: a clinical review

Abstract

Hyperfibrinolytic bleeding can be caused by a deficiency of one of the inhibitors of fibrinolysis (plasminogen activator inhibitor type 1 [PAI-1] or α2-antiplasmin [α2-AP]), or an excess of one of the activators of fibrinolysis: tissue-type plasminogen activator or urokinase-type plasminogen activator. This review focuses on the clinical implications of these disorders. The bleeding phenotype of fibrinolytic disorders is characterized by delayed bleeding after trauma, surgery and dental procedures. Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. Patients with α2-AP deficiency present with the most severe bleeding episodes. Recently, it was discovered that hyperfibrinolytic disorders are associated with a high rate of obstetric complications such as miscarriage and preterm birth, especially in PAI-1 deficient patients. Hyperfibrinolytic disorders are probably underdiagnosed because of lack of knowledge and lack of accurate diagnostic tests. A substantial part of the large group of patients diagnosed as 'bleeding of unknown origin' could actually have a hyperfibrinolytic disorder. In the case of a high index of suspicion (i.e. because of a positive family history, recurrent bleeding or uncommon type of bleeding such as an intramedullary hematoma), further testing should not be withheld because of normal results of standard hemostatic screening assays. Timely diagnosis is important because these disorders can generally be treated well with antifibrinolytic agents.

Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study

“…To avoid overdiagnosis and false-positive results, laboratory tests for diagnosing a PAI-1 deficiency or hyperfibrinolysis are performed only in case of an ISTH BAT score $10, a positive family history of a fibrinolysis disorder, or in patients with a typical fibrinolytic bleeding pattern (ie, delayed bleeding after interventions and/or co-occurrence with obstetric failure). 5,18 Patients with a PAI-1 deficiency were eligible for inclusion if the PAI-1 activity level was below the detection limit and the PAI-1 antigen level was below the lower limit of normal (reference range, 3.4-39 ng/mL). Patients with hyperfibrinolysis were eligible if the euglobulin clot lysis time ratio before and after application of a tourniquet was $5.8 (reference range, 1.2-5.7, locally validated assay).…”

“…The bleeding phenotype of patients with fibrinolytic disorders is characterized by delayed bleeding after trauma, surgery, and dental procedures. 5 Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. 5 Another category of RBDs is FV Amsterdam.…”

“…5 Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. 5 Another category of RBDs is FV Amsterdam. This bleeding disorder is caused by a pathogenic gain-of-function variant in the FV gene leading to an aberrant FV that binds tissue factor pathway inhibitor (TFPI), prolonging the half-life and concentration of TFPI, which results in severely reduced thrombin generation and a bleeding tendency.…”

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency

“…1 Plasminogen is a zymogen activated by tissue-type plasminogen activator enzymes to produce plasmin, the central enzyme in fibrinolytic pathway that dissolves fibrin networks. 1 Plasminogen is a zymogen activated by tissue-type plasminogen activator enzymes to produce plasmin, the central enzyme in fibrinolytic pathway that dissolves fibrin networks.…”

A novel variant causing α2 antiplasmin deficiency: case report and experience in a UK centre

“…Congenital deficiency of α 2 ‐AP is extremely rare, with fewer than 18 cases reported worldwide (Pozzi et al , ) and causes a significant bleeding disorder due to uninhibited hyperfibrinolysis. A recent review highlighted that only three women have been described with homozygous α 2 ‐AP deficiency, with limited published experience of management (Saes et al , ). We report a family with a novel germline variant in SERPINF2 causing α 2 ‐AP deficiency and discuss some of the challenges faced in the management of this rare bleeding disorder.…”