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Wiskott-Aldrich syndrome is an X-linked disorder characterized by hypogammaglobinemia, eczema, and thrombocytopenia caused by a molecular defect in a cytoskeletal proteincommon to lymphocytes and platelets (see Chapter 74). Smallplatelets are seen on a peripheral blood smear. Nevertheless,thrombocytopenia often is improved by splenectomy. Hematopoietic stem cell transplantation cures the immunodeficiencyand thrombocytopenia. Familial X-linked thrombocytopeniacan be seen as a variant of Wiskott-Aldrich syndrome or amutation in the GATA1 gene. Autosomal macrothrombocytopenia is due to deletions in chromosomes 22q11 or mutationsin 22q12.
Thrombotic microangiopathy causes thrombocytopenia, anemia secondary to intravascular RBC destruction, and, in some cases, depletion of clotting factors. Children with thrombotic microangiopathy usually are quite ill. In a child with disseminated intravascular coagulation (DIC), the deposition of fibrin strands within the vasculature and activation of thrombin and plasmin result in a wide-ranging hemostatic disorder with activation and clearance of platelets. Hemolytic uremic syndrome occurs as a result of exposure to a toxin that induces endothelial injury, fibrin deposition, and platelet activation and clearance (see Chapter 164). In thrombotic thrombocytopenic purpura, platelet consumption, precipitated by a congenital or acquired deficiency of a metalloproteinase that cleaves von Willebrand factor, seems to be the primary process, with a modest deposition of fibrin and RBC destruction.
Disorders of Platelet Function
Etiology. Primary disorders of platelet function may involvereceptors on platelet membranes for adhesive proteins. Deficiency of glycoprotein Ib complex (vWF receptor) causesBernard-Soulier syndrome. A deficiency of glycoprotein IIb-IIIa (the fibrinogen receptor) causes Glanzmann thrombasthenia. Mild abnormalities of platelet aggregation and release,detectable by platelet aggregometry, are far more common.Secondary disorders caused by toxins and drugs (uremia, valproic acid, aspirin, nonsteroidal anti-inflammatory drugs, andinfections) may cause a broad spectrum of platelet dysfunction.
Clinical Manifestations. Disorders of platelet function present with mucocutaneous bleeding and a prolonged bleeding time or long PFA closure time and may be primary or secondary. The bleeding time is an insensitive screen for mild and moderate platelet function disorders but is usually prolonged in severe platelet function disorders, such as Bernard-Soulier syndrome or Glanzmann thrombasthenia.
Disorders of Clotting Factors
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Etiology. Hereditary deficiencies of most procoagulant proteins lead to bleeding. The genes for factor 8 and factor 9are on the X chromosome, whereas virtually all the otherclotting factors are coded on autosomal chromosomes. Factor 8 and factor 9 deficiencies are the most common severe inherited bleeding disorders. von Willebrand disease is the most common congenital bleeding disorder. Of the procoagulant proteins, low levels of the so-called contact factors(prekallikrein, high-molecular-weight kininogen, and Hageman factor [factor 12]) cause a prolonged activated partialthromboplastin time but are not associated with a predisposition to bleeding.