Rare Inherited Coagulation Disorders PDF

Rare inherited coagulation disorders Supervised by: Dr.Ihsan Mardan Presented by: Kawthar Aqeel (2nd year hematopathology student) Introduction The rare bleeding disorders (RBDs), including the inherited deficiencies of coagul...

Rare inherited coagulation disorders Supervised by: Dr.Ihsan Mardan Presented by: Kawthar Aqeel (2nd year hematopathology student) Introduction The rare bleeding disorders (RBDs), including the inherited deficiencies of coagulation factors; fibrinogen, prothrombin, factor V, combined FV and FVIII, FVII, FX, FXI, FXIII and of multiple deficiency of vitamin-K-dependent factors, are usually transmitted in an autosomal recessive manner. Epidemiology The incidence of RBDs in the general population is low, and homozygous or double heterozygous deficiencies vary from 1 in 500,000 for FVII deficiency to 1 in 2 million for prothrombin (FII) and FXIII deficiencies. This incidence is also strongly influenced by ethnicity and is significantly increased by a high rate of consanguinity in the population. FVII and FXI deficiencies are the most prevalent RBDs (representing about 38% and 27% of the total number of affected patients, respectively), followed by deficiencies of fibrinogen, FV and FX (8–9%), FXIII (∼6%) and combined FV and FVIII (∼3%), while the rarest disorder was FII deficiency with a prevalence of 1%. Classification Clinical bleeding episodes were classified into four categories of severity, based on the location and the potential clinical impact, as well as the trigger of bleeding (spontaneous, after trauma or drug induced). A strong association between coagulant activity level and clinical bleeding severity for fibrinogen, combined FV + VIII, FX and FXIII deficiencies. A weak association with clinical bleeding severity was present for FV and FVII deficiencies. While coagulation-factor activity level of FXI did not predict clinical bleeding severity. Fibrinogen deficiency The heterogeneous collection of inherited disorders affecting fibrinogen function and quantity. Fibrinogen (also known as Factor I) is a plasma protein that plays an integral role in coagulation and is therefore required for normal haemostasis and wound healing. Fibrinogen plays a pivotal role in acutely containing tissue damage, preventing excessive bleeding through clot formation and longer term wound healing. Types: Type I disorders (afibrinogenemia and hypofibrinogenemia) affect the quantity of fibrinogen in circulation. Type II disorders (dysfibrinogenemia and hypodysfibrinogenemia) affect the quality of circulating fibrinogen. Clinical presentation: Dysfibrinogenemic and hypofibrinogenemic patients are usually asymptomatic, while those with afibrinogenemia have a bleeding tendency that usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding. Bleeding may also occur in the skin, gastrointestinal tract (GI), genitourinary tract or the CNS, First-trimester abortion, epistaxis and menometrorrhagia. Diagnosis: Diagnosis is suspected in the setting of both abnormal bleeding and a prolonged PT and aPTT. Thrombin time and reptilase time, both of which will typically be prolonged. Immunoassays to measure fibrinogen antigen concentration and genotyping of fibrinogen-associated genes are also available to confirm the diagnosis. Treatment: Depending on the country of residence, patients receive fresh-frozen plasma (FFP), cryoprecipitate or fibrinogen concentrate, the last being the treatment of choice because it is virally inactivated and thus safer than cryoprecipitate or FFP. Prothrombin deficiency Prothrombin deficiency is perhaps the rarest inherited coagulation disorder, with a prevalence of about 1 in 2 million. FII, a vitamin-K- dependent glycoprotein synthesized by the liver. Prothrombin is activated into the active enzyme thrombin when cleaved by the activated factor X (FXa)-activated factor V (FVa) prothrombinase complex on the phospholipid-rich surface of platelets. Thrombin is a critical factor in multiple pathways of clot formation through activation of platelet aggregation and clot potentiation by activation of FV, FVIII, and FIX that forms a positive feedback loop resulting in further thrombin generation.  Furthermore, thrombin helps to stabilize fibrin clot formation through the activation of FXIII and thrombin activatable fibrinolysis inhibitor (TAFI). Thrombin also plays a role in mechanisms of anticoagulation. Thrombin interacts with endothelial protein thrombomodulin to activate protein C, which in turn inactivates FVa and activated FVIII (FVIIIa) to reduce clot formation. Thrombin regulation is important for preventing excessive clot formation. Types: It presents in two forms: Type I, true deficiency (hypoprothrombinemia). Type II, in which a dysfunctional prothrombin is produced (dysprothrombinemia). XIIIa Crosslinked fibrin clot Clinical presentation: Severe deficiency of FII, a condition in which plasma levels are