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Von Willebrand disease (VWD)

VWD is the most common hereditary bleeding disorder with, according to epidemiological studies, an estimated prevalence worldwide as high as 1 to 2% in the general population [5 - 7]. In contrast, estimates based on referral for symptoms of bleeding suggest a prevalence of 30 to 100 cases per million, similar to that of haemophilia A [8].

VWD results from a quantitative/qualitative deficiency of von Willebrand factor (VWF), a large, multimeric plasma glycoprotein that is required for normal platelet adhesion (primary haemostasis) and as the carrier protein for FVIII (secondary haemostasis).
Types 1 and 3 VWD are partial and virtually complete quantitative deficiencies, whereas type 2 represents qualitative VWF defects. Among them, type 3 is the deficiency characterized by severer clinical bleeding symptoms.
The large VWF gene (VWF) is located on chromosome 12 at 12p13.3. VWD displays both dominant and recessive inheritance [8].
Haemophilia is an X-linked recessive bleeding disorder arising from the deficiency of blood coagulation factor VIII (FVIII) or FIX, leading to haemophilia A and B, respectively. These diseases have an incidence of 1 in 5000 and 1 in 25 000 male births. No ethnic or geographic predisposition has been defined.
Both FVIII and FIX genes map to the long arm of X-chromosome at Xq28 and Xq27, separated by 35 cM [10,11].
Rare bleeding disorders (RBDs)
RBDs are autosomally inherited and are generally rare, with a prevalence in the general population ranging from ~1:2 million for factor II (FII) and factor XIII (FXIII) deficiency to 1:500,000 for FVII deficiency [12].
RBDs are generally inherited as recessive traits and are due, in most cases, to gene defects which encode the corresponding coagulation factors. Exceptions are the combined deficiencies of coagulation FV and FVIII and of vitamin-K-dependent proteins (FII, FVII, FIX, and FX), caused respectively by mutations in genes encoding proteins involved in the FV and FVIII intracellular transport and in genes encoding enzymes involved in post-translational modifications and in vitamin K metabolism.
Inherited platelet disorders
Inherited platelet disorders include abnormalities of platelet number (inherited thrombocytopenias) and function (inherited disorders of platelet function) [13-14].
Some disorders are characterized by both thrombocytopenia and abnormalities of platelet function.
The most rare and severe platelet disorders are Bernard-Soulier syndrome (BSS) and Glanzmann Thrombasthenia:

Bernard-Soulier syndrome - It is a severe inherited bleeding disorder, mainly inherited as an autosomal recessive trait. It is caused by a defect in glycoprotein GPIb-IX-V complex, the platelet membrane receptor for VWF, formed by the products of four separate genes (Iba, Ibß, IX and V) The GPIba and GPIbß genes map to chromosomes 17 and 22, while those encoding GPIX and GPV are both on chromosome 3 [16-17].
Glanzmann thrombastenia - It is an autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by a lack of platelet aggregation. It is caused by quantitative and/or qualitative abnormalities of aIIbß3 integrin, the receptor that mediates the incorporation of platelets into an aggregate or thrombus at sites of vessel injury [18]. The genes coding aIIb and b3 are located on the long arm of chromosome 17 [19].


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