von Willebrand disease (VWD)
VWD is the most common inherited bleeding disorder in the world, affecting approximately 1% of the general population [5]. von Willebrand disease, due to deficiencies or dysfunction of von Willebrand factor, 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. VWF is a large multimeric glycoprotein that functions as the carrier protein for FVIII. It is also required for normal platelet adhesion. As such, it functions both in primary (involving platelet adhesion) and secondary (involving FVIII) haemostasis. In primary haemostasis, VWF attaches to platelets by its specific receptor glycoprotein Ib on the platelet surface and acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. In secondary haemostasis, VWF protects FVIII from degradation and delivers it to the site of injury. 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 [9].
Haemophilia
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]. There is a 50% chance that a carrier mother will transmit the defective X-linked gene to a male or female child and 100% of daughter of a haemophilic patient are obligate carriers of haemophilia.
Rare bleeding disorders (RBDs)
RBDs are autosomally inherited and are generally rare, with prevalences of the presumably homozygous forms in the general population ranging from approximately 1 in 2 million for factor II (FII) and factor XIII (FXIII) deficiency to 1 in 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. www.rbdd.org
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. Inherited platelet disorders are typically manifested by symptoms of excessive mucocutaneous bleeding (such as bruising) and fairly rapid onset, excessive bleeding following invasive surgical and dental procedures or exposures to trauma [14,15]. Bleeding syndromes in inherited platelet defects are of varying severity. The most rare and severe platelet disorders are Bernard-Soulier syndrome (BSS) and Glanzmann Thrombasthenia: Bernard-Soulier syndrome. Bernard-Soulier syndrome is a severe inherited bleeding disorder that is inherited mainly as an autosomal recessive trait. It is caused by a defect in glycoprotein GPIb-IX-V complex, the platelet membrane receptor for VWF. The products of four separate genes (Iba, Ibß, IX and V) assemble within the maturing megakaryocyte in the bone marrow to form the GPIb-IX-V complex, as present in the platelet membrane. The genes for GPIba and GPIbß map to chromosomes 17 and 22, while those encoding GPIX and GPV are both on chromosome 3 [16,17]. Glanzmann thrombastenia. Glanzmann thrombastenia is an autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by a lack of platelet aggregation. It is a moderate to severe hemorrhagic disorder with mainly mucocutaneous bleeding. The molecular basis is linked to 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 at a physical distance of about 3.2 Mb [19].