Platelet Disorders

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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 for a list of some of the common medications resulting in thrombocytopenia and platelet function abnormalities. Heparin-induced thrombocytopenia (HIT) is a special case and is discussed again later this chapter.

Table 52-1 Common Medications Resulting in Thrombocytopenia or Platelet Function Abnormalities

Drugs Associated with Thrombocytopenia	Drugs Associated with Abnormal Platelet Function
Antibiotics • Linezolid • Penicillins • Quinidine • Rifampin • Sulfa-containing antibiotics (Bactrim) • Vancomycin Antiepileptics • Carbamazepine • Phenytoin • Valproate Chemotherapeutic agents GI medications • Cimetidine • Ranitidine

• NSAIDs (ibuprofen, ketorolac)

• Clopidogrel and ticlopidine

GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug.

In addition, there are many systemic disorders that are associated with thrombocytopenia by means of consumption, increased destruction or decreased production of platelets. Examples include disseminated intravascular coagulation, malaria, systemic lupus erythematosus, leukemia, lymphoma, thrombosis, viral infections, and HIV. Platelets can become sequestered in the spleen in syndromes associated with splenomegaly. Some systemic disorders, such as uremia, can cause abnormalities of platelet function as well. The following is a description of some acquired disorders of platelets.

Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an immune-mediated platelet disorder generated by immunoglobulin G (IgG) autoantibodies. It often presents acutely in childhood after a viral illness in an otherwise healthy child. IgG autoantibodies coat the surface of platelets and the platelets then undergo accelerated clearance through Fcγ receptors expressed on macrophages in the spleen and liver. In childhood, ITP is generally considered a benign self-limited disorder; 80% of patients spontaneously resolve within 6 months. However, a small percentage of patients (<20%) develop chronic ITP lasting longer than 12 months.

Neonatal Alloimmune Thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT) is associated with a mismatch between maternal and fetal platelets. The mother develops antibodies against an antigen on the surface of fetal platelets inherited from the father. The antibodies can cross the placenta and coat fetal platelets, forcing accelerated clearance in the spleen. This results in significant thrombocytopenia in the neonatal period. With the first pregnancy, the thrombocytopenia can be mild, but with subsequent pregnancies, it is severe and can lead to fetal intracranial hemorrhage. Human platelet antigen (HPA) 1a is the most common paternal–fetal antigen that results in the development of NAIT, causing 80% to 90% of the identified cases. The diagnosis of this disorder is confirmed by demonstration of maternal antibodies directed against a paternal platelet antigen.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by a clinical pentad of fever, neurologic dysfunction, microangiopathic hemolytic anemia, renal insufficiency, and thrombocytopenia. The thrombocytopenia seen in this disorder is secondary to platelet consumption in the development of thrombosis of the small vessels. TTP is associated with the presence of abnormally large von Willebrand multimers, which lead to increased activation of coagulation. It is now known that low levels of ADAMTS13, an enzyme responsible for cleaving large von Willebrand multimers, is at least partially responsible for this disorder. Low levels of ADAMTS13 can arise from an acquired IgG autoantibody or from a congenital deficiency.

Heparin-Induced Thrombocytopenia

HIT is a process in which exposure to heparin results in the development of moderate thrombocytopenia and arterial or venous thrombosis. This disorder is characterized by a mild to moderate thrombocytopenia (median, 50,000/µL) that typically develops within 5 to 10 days after heparin exposure but can occur within hours if the patient was previously exposed to heparin. The associated thrombocytopenia typically resolves within 1 to 2 weeks of stopping the drug. The mechanism of this disorder is related to the interaction of heparin and an antigen on the surface of platelets called platelet factor 4 (PF4). Heparin forms a complex with PF4, and in HIT, antibodies develop to the heparin–PF4 complex. These antibodies bind to the heparin–PF4 complex and cause platelet activation, resulting in undesired activation of platelets and resultant thrombosis.

Clinical Presentation And Differential Diagnosis

The clinical presentation of platelet disorders varies with the platelet count or the severity of the platelet function abnormality. The clinical picture of a patient with a platelet disorder is that of mucocutaneous bleeding. The patient may have epistaxis, easy bruising, petechiae, menorrhagia, or gingival bleeding. More significant mucocutaneous bleeding can be seen with a very low platelet count (<20,000/µL) or in disorders with severe platelet dysfunction. This may consist of gastrointestinal bleeding or hematuria. With extremely low platelet counts (<10,000/µL), there is a risk of spontaneous bleeding and an increased risk of intracranial hemorrhage. This is particularly of concern in NAIT (Figure 52-2). Some children may be asymptomatic but develop excessive bleeding with significant hemostatic challenges such as surgery, dental extractions, or trauma.

Figure 52-2 Clinical presentation of patients with bleeding disorders.

Diagnostic Approach

The diagnostic approach to a patient with a suspected platelet disorder starts with a thorough history and physical examination. In the history, one should pay special attention to any history of spontaneous bleeding, such as epistaxis, bleeding gums, or easy bruising. Pubertal girls should be questioned about their menses, specifically regarding the volume of bleeding and duration of menses. Parents should be questioned about prior hemostatic challenges such as circumcision, dental extractions, or surgical procedures. The past medical history may also provide clues about underlying medical diagnoses that can be associated with platelet abnormalities. A thorough medication history should be obtained, including herbal supplements, because many compounds have an effect on platelets. On physical examination, one should pay close attention to the skin examination, looking for bruises and petechiae. The mouth should be examined for the presence of wet purpura or gum bleeding. Congenital abnormalities such as albinism and radial defects should be noted because they can provide a clue to the diagnosis.

After the history and physical examination, a complete blood count should be obtained looking for thrombocytopenia. A blood smear should be examined, revealing differences in platelet size and the presence or absence of other hematologic abnormalities (Figure 52-3). If there is no thrombocytopenia present, formal platelet aggregation assays can help determine abnormalities in platelet function. A bleeding time is no longer recommended as a screening test for platelet disorders secondary to difficulty with standardization and unreliable results.

Figure 52-3 Peripheral blood smears.

Platelet aggregation studies are laboratory tests in which compounds known to stimulate platelet aggregation are added to patient platelets, and the ability of platelets to aggregate in the presence of each compound is ascertained. These studies are particularly helpful if the diagnosis of a platelet function defect is under consideration. In Glanzmann’s thrombasthenia, there are abnormalities in aggregation in the presence of all tested compounds, with the exception of ristocetin. Conversely, in Bernard-Soulier syndrome, platelets demonstrate poor aggregation in the presence of ristocetin, but they have normal aggregation when stimulated with epinephrine, collagen, or adenosine diphosphate.

ITP is a diagnosis of exclusion. Diagnostic tests, including antiplatelet antibodies, can be confirmatory, but these are only detected in approximately half of patients with ITP. In patients who have a classic presentation of ITP, a bone marrow evaluation is generally not necessary. Some providers perform bone marrow aspirates on patients with suspected ITP to exclude leukemia before treatment with steroids.

Management and Therapy

The primary goal in the management of patients with platelet disorders is to prevent bleeding complications. Avoidance of significant trauma is integral in the management of these patients. In addition, preventive measures should be implemented before surgery and significant dental procedures.

In many of the congenital platelet disorders, judicious use of platelet transfusion may be required. However, transfusions should be used with caution in both Glanzmann’s thrombasthenia and Bernard-Soulier syndrome because these patients can develop antibodies to normal transfused platelets and become refractory to platelet transfusions. DDAVP (desmopressin) has been effective in treating patients with bleeding associated with platelet function abnormalities and can be an alternative to platelet transfusions. In addition, antifibrinolytics such as aminocaproic acid can be used. There are small published case reports on the successful use of recombinant factor VIIa in patients with qualitative or quantitative platelet defects and severe bleeding. Recombinant factor VIIa works by increasing the thrombin generation on the surface of activated platelets. Patients with severe disorders of the bone marrow such as congenital amegakaryocytic thrombocytopenia require frequent platelet transfusions and bone marrow transplantation for definitive management.

In acquired platelet abnormalities secondary to an underlying disorder or medications, therapy is aimed at treating the underlying disorder or withdrawal of the offending agent. This is particularly true with HIT. If HIT is suspected, heparin should be discontinued immediately, and therapy with a direct thrombin inhibitor should be initiated.

In NAIT, infants are at risk for intracranial hemorrhage and spontaneous bleeding. In that instance, washed maternal platelets can be given to the infant. If maternal platelets are unavailable, either HPA-1a negative platelets or intravenous immunoglobulin (IVIG) can be used. In addition, if NAIT is suspected prenatally, the mother can be treated with immunosuppression before delivery to improve the infant’s platelet count or fetal platelet transfusions can be performed. For acquired TTP, the treatment of choice is emergent plasmapheresis. For congenital TTP, infusions with fresh-frozen plasma are effective.

Controversy exists regarding the treatment of acute ITP. There is no evidence at this time that treatment alters the course of the disease. The sole purpose of treatment is to prevent significant bleeding complications and most importantly to prevent intracranial hemorrhage, Treatment is recommended if the patient has significant bleeding or if the platelet count is below 10,000/µL. In general, spontaneous bleeding is unlikely to occur in patients with platelet counts above 20,000/µL. Several therapies are available for the treatment of patients with acute ITP, including IVIG (1 g/kg), WinRho (50-75 µg/kg), or glucocorticoids (1 mg/kg twice a day). Treatment of patients with refractory or chronic ITP can include several other modalities from splenectomy to a variety of immune modulators, including rituximab, cyclosporine, vincristine, or cyclophosphamide.

Future Directions

Hematologists are continuing to research platelet disorders and possible therapies. The genetic components of many disorders are now known, and researchers are actively working on targeted genetic-based therapies for these disorders. A new class of medications was recently approved for the treatment of ITP that mimics the action of TPO. These medications are approved for use in adults, and clinical trials are opening in pediatrics for their use in a variety of the platelet disorders seen in childhood. In addition, advances in bone marrow transplantation continue to make them attractive options for children with severe platelet disorders such as congenital amegakaryocytic thrombocytopenia.

Suggested Readings

Aster RH, Bougie DW. Drug induced immune thrombocytopenia. N Engl J Med. 2007;357(6):580-587.

Cines DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathologic and clinical diversity. Blood. 2009;113(26):6511-6521.

Drachman JG. Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood. 2004;103(2):390-398.

Handin RI. Blood platelets and the vessel wall. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, editors. Nathan and Oski’s Hematology of Infancy and Childhood. ed 6. Philadelphia: Saunders; 2003:1457-1474.

Poncz M. Inherited platelet disorders. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, editors. Nathan and Oski’s Hematology of Infancy and Childhood. ed 6. Philadelphia: Saunders; 2003:1527-1546.

Warkentin T. Heparin induced thrombocytopenia. Hematol Oncol Clin North Am. 2007;21(4):589-607.

Wilson DB. Acquired platelet defects. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, editors. Nathan and Oski’s Hematology of Infancy and Childhood. ed 6. Philadelphia: Saunders; 2003:1597-1630.

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