Coagulation cascade:

Hereditary coagulation disorders Haemophilia A: Is most common hereditary disorder of blood coagulation. The inheritance is: sex linked, but 33% of patients have no family history & result from spontaneous mutation. The incidence: 30-100/106 The defect is: absence or low level of plasma factor VIII . The gene for factor VIII is located near the tip of the long arm of the X chromosome (Xq2.8), the genetic defects include many deletions & different point mutations.

Clinical features: * Recurrent painful haemarthroses & muscle haematomas dominate the clinical course of severely affected patients with progressive deformity &crippling. *prolonged bleeding occurs after dental extractions. *Haematuria is more common than GIT bleeding. *The clinical severity of the disease is correlate with the extent of coagulation factor deficiency. *Spontaneous intracerebral haemorrhage is an important cause of death in severe disease.

Clinical features: *Haemophilic pseudotumours: may occur in the long bones, pelvis, fingers &toes .These result from repeated subperiosteal haemorrhages with bone destruction, new bone formation, expansion of bone pathological fractures. *many patients have subclinical liver disease & few have clinical features of chronic hepatitis This is largely due to many infusions of blood products & consequence transmission of hepatitis B or C & other non A non B hepatitis & HIV transmission

Factor IX deficiency (Christmas disease, Haemophilia B) The inheritance & clinical features of Factor IX deficiency are identical to those of haemophilia A . The two disorders are distinguished by specific coagulation factor assays. The incidence is 1/5 that of haemophilia A . The factor IX is coded by gene near to that of factor VIII (Xq2.6 region). The factor IX is 1/5 the size of haemophilia A, As in haemophilia A number of mutations & deletions have been found.

Von willenbrand's disease: The incidence: 30-100/106 The inheritance: autosomal dominant with varying expression.

Pathogenesis: The primary defect appears to be reduced synthesis of VWF ,this protein promotes platelet adhesion & is also the carrier molecule for factor VIII ,protecting it from premature destruction & this explain the reduction of factor VIII level in Von willenbrand's disease. The molecular defects that have been identified include: point mutation & major deletions.

Clinical feature: *post operative & post traumatic hemorrhage, mucosal membrane bleeding & excessive blood loss from superficial cuts & abrasions. *haemarthrosis & muscle haematomas are rare except in homozygous cases.

Hereditary disorders of other coagulation factors All these disorders (deficiency of fibrinogen, prothrombin, factors V, VII, combined V and VIII, factors X, XI, XIII) are rare. In most the inheritance is autosomal recessive.

Factor XI deficiency is seen mainly in Ashkenazi Jews and occurs in either sex. The bleeding risk is not related to severity of the deficiency, and is absent from muscles and joints. The severity is poorly related to the factor XI level in plasma. It usually causes excess bleeding only after trauma such as surgery, and is treated by factor XI concentrate or fresh frozen plasma.

Factor XIII deficiency produces a severe bleeding tendency, characteristically with umbilical stump bleeding.