Platelet Disorders

Published on 06/06/2015 by admin

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52 Platelet Disorders

Jennifer Mangino

Platelets are small anucleate cell particles (5-7 µL in volume) that play a critical role in primary hemostasis. At the time of vascular injury, platelets rush to the site of vascular damage and adhere to the exposed collagen, forming a temporary platelet plug to prevent continued bleeding. The platelets are then activated and undergo changes in their shape and structure. These changes allow the platelets to bind to fibrinogen and aggregate with one another, thus propagating the platelet plug. Activation of platelets also causes secretion of the chemicals contained in the platelet storage granules. These chemicals recruit new platelets and contain many compounds needed to continue primary hemostasis and activate secondary hemostasis (Figure 52-1).

Figure 52-1 Platelet adhesion, release, and aggregation.

Platelets are made in the bone marrow via fragmentation of megakaryocytes. Formation of platelets is controlled by thrombopoietin (TPO), which is a compound that controls megakaryocyte growth and maturation. Platelets typically circulate for 7 to 10 days and are then removed by the reticuloendothelial system. A normal platelet count is 150,000 to 400,000/µL. Platelet disorders can involve a qualitative or quantitative defect, and they are either inherited or acquired.

Etiology and Pathogenesis

Congenital Platelet Disorders

Congenital platelet disorders are individually very rare in the general population. They can have quantitative or qualitative abnormalities, and some disorders have both. Their mode of inheritance and their clinical significance vary. In general, children with congenital platelet disorders are more likely to have chronic bleeding symptoms that developed early in life. The following is a discussion of some of the important inherited platelet disorders.

Glanzmann’s Thrombasthenia

Glanzmann’s thrombasthenia is a rare autosomal recessive disorder of platelet function. It is the most common of the inherited platelet disorders. Patients with this disorder have an abnormality in the genes encoding either chain of the platelet αIIbβ3 integrin fibrinogen receptor. As a result, platelets cannot bind fibrinogen, resulting in clinically significant bleeding from infancy. Common types of bleeding include epistaxis, gastrointestinal hemorrhage, and menorrhagia. Carriers of this mutation have 50% normal fibrinogen receptors and generally do not have bleeding complications.

Bernard-Soulier Syndrome

Bernard-Soulier syndrome is an autosomal recessive syndrome that occurs with a genetic mutation in the glycoprotein (GP) 1b/IX complex. The GP Ib/IX complex binds platelets to von Willebrand factor, a key step in the initial attachment of platelets to an injured vessel wall. Patients with Bernard-Soulier syndrome also have a variable degree of thrombocytopenia, making it both a qualitative and quantitative platelet abnormality. Heterozygotes for this condition are clinically normal but may have mild thrombocytopenia. Of note, children with 22q deletion syndromes can be heterozygotes for the Bernard-Soulier mutation given the proximity of the gene encoding the GP 1b/IX complex. They may have associated mild thrombocytopenia and minor platelet function abnormalities.

Storage Pool Defects

Normal platelets contain granules that contain a number of biochemicals that are important for both primary and secondary hemostasis. Disorders related to abnormalities in granules are lumped together into a category of storage pool defects. These defects result in abnormalities of platelet function and have varying degrees of associated bleeding. There are a number of specific disorders in this category that are associated with other congenital anomalies. The most common disorders in this category are Hermansky-Pudlak syndrome (associated with albinism, vision problems, pulmonary fibrosis, and colitis) and Chediak-Higashi syndrome (associated with partial albinism and immune dysfunction).

Thrombocytopenia Absent Radii

Thrombocytopenia absent radii (TAR) is a disorder associated with thrombocytopenia and orthopedic abnormalities. Thirty percent of patients may also have cardiac abnormalities. The primary orthopedic problem is an abnormality or absence of both radii with maintenance of functional thumbs. This disorder is characterized by severe thrombocytopenia resulting from a decreased number of megakaryocytes in the bone marrow at birth. The thrombocytopenia improves as the children age and usually spontaneously resolves in the first year of life. Some patients with TAR may have an associated storage pool defect as well. The cause of this disorder is unknown.

Congenital Amegakaryocytic Thrombocytopenia

Congenital amegakaryocytic thrombocytopenia is an autosomal recessive disorder characterized by the absence of megakaryocytes in the bone marrow. This disorder results in severe thrombocytopenia at birth that persists throughout the lifetime of a child. This disorder often leads to aplastic anemia and can be fatal without bone marrow transplantation.

Wiskott-Aldrich

Wiskott-Aldrich is an X-linked disorder leading to a combination of thrombocytopenia, eczema, and immune deficiency. Often, the predominant feature of this disorder is a history of recurrent bacterial infections. The degree of thrombocytopenia varies with the extent of the genetic mutation. Of note, this disorder is associated with small platelets (microthrombocytes).

Macrothrombocytopenia Disorders

Several disorders characterized by macrothrombocytopenia are the result of various mutations in the cytoskeletal protein nonmuscle myosin heavy chain IIA (MYH9). These disorders are characterized by thrombocytopenia with large platelets (macrothrombocytes) and normal platelet function. May Hegglin anomaly is the most common, but other disorders in this spectrum include Sebastian, Epstein, and Fechtner syndromes. They may be associated with various other congenital anomalies, including sensorineural hearing loss, nephritis, or ocular abnormalities.

Essential Thrombocytosis

Essential thrombocytosis is a very rare disorder characterized by an increase in the number of platelets, with platelet counts often above 1,000,000 to 2,000,000/µL. This disorder may be associated with other myeloproliferative disorders, and it is associated with a significantly increased risk of thrombosis.

Acquired Platelet Disorders

Acquired platelet disorders are far more common than congenital platelet disorders. The most common reason for acquired thrombocytopenia or an acquired platelet abnormality is drug exposure. Dozens of medications can cause thrombocytopenia or abnormalities in platelet function. These medications can act by inhibiting bone marrow production of platelets or activating or creating antibodies to platelets, or they can have a direct toxic effect on platelets. Refer to Table 52-1

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