What Are Hereditary Intrinsic Platelet Disorders?
Hereditary intrinsic platelet disorders involve defects in platelet adhesion and aggregation. These disorders are usually found in patients with lifelong bleeding disorders. Rare mutations (changes in the genetic sequence) can cause complex reactions and disorders of platelet function. In cases of vascular injury, the inherited disorders of platelets' function may disrupt the normal functioning of platelets.
Blood platelets have important functions, including.
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Platelet Adhesion: It is an essential part of normal hemostasis (the mechanism that leads to the cessation of bleeding from a blood vessel). When a blood vessel is injured, the circulating platelets bind together at the site of damage to control bleeding. The adhered platelets get activated within seconds to secrete contents of storage organelles and recruit more platelets to the developing thrombus.
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Platelet Activation: This involves the release of adenosine diphosphate (ADP) from platelet storage granules and converting arachidonic acid to thromboxane A2. The activation of platelets is carried out in three steps. Firstly, the adhesion of platelets to adjacent platelets, collagen fibrils, or artificial surfaces. The spread and aggregation of platelets follow this through autocatalytic signaling. Thirdly, activation of platelets and formation of a thrombus clot. All three steps occur through interacting extracellular proteins and receptors on the platelet surface membrane.
Platelets play an important role in blood clotting, and failure to carry out the above biochemical reactions can lead to bleeding problems.
What Are the Major Hereditary Disorders of Platelet Function?
Disorders of Platelet Adhesion:
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Bernard-Soulier Syndrome - It is a rare autosomal recessive disorder in which there is a defect in the glycoprotein IB / X complex that binds the endothelial von Willebrand factor (involved in platelet adhesion). This impairs hemostasis and causes severe bleeding. The platelets are unusually large and do not cause aggregation with ristocetin (an antimicrobial substance) but normally aggregate with adenotriphosphate (ADP), collagen, and epinephrine. The giant platelets are due to a lack of interaction between the actin-binding protein in the platelet cytoskeleton and the cytoplasmic domain of the Gplba polypeptide. The Gplb / IX / V sites on the exch platelet are the major locus for platelet sialic acid residues, and the lack of it may shorten platelet survival, leading to thrombocytopenia.
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Von Willebrand Disease - People with von Willebrand disease present with a deficiency or defect in the clotting protein von Willebrand factor. The VWF binds to factor VIII (another clotting factor) and platelets in blood vessel walls. This process helps to form a platelet plug during the clotting process. Von Willebrand's disease causes failure of the formation of this platelet plug. The condition is named after a physician, Erik von Willebrand, who first described it. This bleeding disorder affects approximately one in every hundred. It occurs equally in men and women but may cause more symptoms in women. The condition is treated with VWF replacement with virally inactivated intermediate-purity factor VIII concentrate.
Disorders of Platelet Activation:
These conditions may result from decreased ADP in the platelet granules (storage pool deficiency), inability to generate thromboxane A2 from arachidonic acid or an inability of platelet to aggregate in response to thromboxane A2. It is caused mainly after exposure to collagen, epinephrine, and low levels of ADP. The use of nonsteroidal anti-inflammatory drugs or Aspirin can also impair platelet aggregation.
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Thrombasthenia - It is a rare autosomal recessive disorder caused due to defect in the platelet glycoprotein llb / IIIa receptor. It is also known as Glanzmann thrombasthenia (GT). The platelets fail to aggregate, causing symptoms like severe mucosal bleeding and heavy menstrual bleeding that stops only after nasal packing and platelet concentrate transfusion.
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Platelet Storage Pool Disease - This is a heterogeneous group of diseases in which there is an abnormality in the ability to store appropriate products within the platelet granules. It includes gray platelet syndrome (protein deficiency, like platelet factor 4, fibrinogen causing the appearance of gray-colored platelets), Quebec platelet disorder (associated with abnormal aggregation with epinephrine), Hermansky-Pudlak syndrome (autosomal recessive disorder associated with oculocutaneous albinism), Chediak-Higashi syndrome (autosomal recessive disorder with large abnormal granules in melanocytes, leukocytes, and fibroblast), and Wiskott-Aldrich syndrome (X-linked recessive disorder caused by a defect in a protein Wiskott-Aldrich).
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Release Defects - This occurs due to abnormalities in signal transduction from the membrane and abnormal metabolic pathways involved in the release functions. It is associated with a prolonged bleeding time and an abnormal platelet aggregation profile. Abnormalities of aggregation in association with ADP, epinephrine, and collagen characterize this condition. Patients can be treated with Desmopressin acetate (DDAVP).
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Afibrinogenemia - This rare autosomal recessive disorder is characterized by extremely low fibrinogen levels, causing prolonged bleeding. The patients have decreased platelet counts and an abnormal platelet aggregation profile due to impaired platelet-platelet interaction.
Defects in Platelet Procoagulant Activity:
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Scott Syndrome - The syndrome is described as a defect in platelet function in which the platelets have a defective binding of factor Ya-X and factor VIIIa-IX complexes. This results in impaired activity of factor X and prothrombin, platelet-dependent fibrin formation, and exhibits abnormal platelet factor 3 activity.
Other Congenital Disorders
Some disorders of platelet function are associated with connective tissue disorders, such as Ehlers-Danlos syndrome (inherited disorder affecting connective tissue in the skin), Marfan’s syndrome (affecting the connective tissue of the heart, eyes and blood vessels), osteogenesis imperfecta (characterized by fragile bones), and fragile X syndrome (causes intellectual disability). In addition, platelet function defects are also reported in thrombocytopenia and absent radii syndrome (characterized by thrombocytopenia and defects of the radial bone).
Conclusion
Platelets are essential for primary hemostasis. Defects in platelet functions are a group of bleeding disorders causing easy bruising and mucocutaneous bleeding. Therefore, early and accurate diagnosis of patients and close medical follow-ups are important. Unfortunately, the diagnosis of inherited platelet disorder is limited to clinical and laboratory. This often leads to many patients reaching adulthood undiagnosed or misdiagnosed and making unnecessary invasive treatment. Adjunctive therapies (such as antifibrinolytics, microfibrillar collagen, and fibrin glue), DDAVP, rFVIIa (recombinant activated factor VII), and platelet transfusions remain the mainstay of therapy. Defects in plasma coagulation factors, such as von Willebrand’s disease and afibrinogenemia, can be treated with the replacement of the deficient coagulation factor.
