Thrombocytopen ia
Platelet counts below 100,000/u.l portend an increased bleeding risk, which correlates roughly with the depression of the platelet count. Counts above 50,000/u.l are rarely associated with spontaneous bleeding, whereas counts below 20,000/ H,l are frequently associated with spontaneous bleeding, especially if the patient is febrile or anemic. Bleeding is observed more often in a thrombocytopenic patient with a rapidly falling platelet count than in a patient with a low, stable count. The mechanisms for severe thrombocytopenia include (1) decreased or ineffective platelet production, (2) increased peripheral destruction, (3) splenic sequestration, and (4) intravascular dilution .
Decreased platelet production occurs with systemic infection, nutritional defects (folate or vitamin Bi2), radiation, chemotherapy, or marrow replacement by fibrosis or tumor. Transient decreases in platelet production are common in viral infections and are the rule after radiation therapy to bone or after most types of cancer chemotherapy. Bone marrow megakaryocytes may appear decreased or immature. Numerous drugs can inhibit megakaryocytopoiesis, including alcohol, anticonvulsants, and thiazides. Marrow hypoplasia as in aplastic anemia or Fanconi’s syndrome also results in thrombocytopenia.
Increased platelet destruction is a common cause of thrombocytopenia and may be induced by commonly used drugs, including digitalis, quinidine, thiazides, imipramine, phenothia-zines, sulfonamides, antibiotics (penicillins and cephalosporins), and gold salts. These agents usully produce thrombocytopenia by an immune mechanism in which a drug-antibody or drug-plasma protein complex adsorbs passively to the platelet surface (”innocent bystander”) via the platelet Fc receptor, coating the platelets and resulting in their rapid removal from the circulation by the spleen. Other drugs may directly adsorb to the platelet surface, resulting in neoantigens that provoke antiplatelet antibody formation. Stopping all drugs, if possible, and substituting drugs of different chemical structure if discontinuation is not possible is the first step in the evaluation and treatment of drug-induced immune thrombocytopenia. Unfortunately, direct tests of drug involvement are difficult to perform and often are insensitive, so that clinical assessment after drug discontinuation or switching is the main instrument for detecting drug-related thrombocytopenias.
Idiopathic (or autoimmune] thrombocytopenic purpura (ITP) represents immune thrombocytopenic purpura occurring without toxic or.-drug exposure. A polyclonal antiplatelet antibody has been demonstrated by transfer experiments. Platelet-associated IgG (and complement) may be elevated, large platelets circulate in the blood, and megakaryocytes are increased in the bone marrow. The spleen is not enlarged. The platelet survival is short. Acute ITP is mainly a disease of childhood, having a sudden onset following acute viral infection and resolving spontaneously in 80 per cent of affected children within a few weeks. In adults, chronic ITP is more common, has an insidious onset, and affects women more often than men. Fewer than 10 per cent of cases resolve spontaneously. In some cases an autoimmune hemolytic anemia is also present (Evan’s syndrome). Adult ITP occurs alone or in association with diseases of disturbed immunity such as systemic lupus erythematosus, lymphoproliferative disorders, or AIDS. ITP can herald such diseases, appearing even years in advance of the full blown disease. Pregnant women with ITP can deliver thrombocytopenic infants, as the antiplatelet antibody is usually an Igd or IgG3 and thus crosses the placenta. The infant’s platelet count does not correlate with the mother’s count, so that a mother with ITP by history and a normal platelet count can deliver a thrombocytopenic infant.
Diagnosis of FTP is by exclusion. It is made in a patient with thrombocytopenia, increased megakaryocytes in the bone marrow, and increased platelet-associated IgG in the absence of drug exposure or toxic exposure. Aside from thrombocytopenia marked by large platelets, the blood count is otherwise normal. Platelet function may be entirely normal or may show diminished aggregation responses. Platelet survival is shortened, sometimes to hours compared to the normal survival of 8 to 10 days. Direct measurement of, platelet survival can be made with 51Cr or ^In-labelled autologous platelets. This test, however,” is not routinely performed because of expense and technical difficulty.
Treatment of both drug-induced thrombocytopenia and ITP is similar. Any suspected drug is stopped, and essential drugs are switched to substitutes of different chemical composition. All aspirin-like drugs are avoided. If the thrombocytopenia is severe, with purpura on the mucous membranes or retina, corticosteroids (1 to 2 mg/ kg/day prednisolone) are given. Platelet transfusion should be avoided except for treatment of intracerebral bleeding because of the extremely short survival of transfused platelets. Plasmapheresis is generally not effective because of the IgG nature of the antiplatelet antibodies, which are inefficiently removed by this technique. In acute ITP of childhood or drug-induced thrombocytopenia, steroids can be tapered within a few weeks as platelet counts rise. In chronic ITP steroids should be administered for two to three months before tapering the dose or moving to alternative therapy, in order to achieve the maximum number of remissions and responses. In 70 per cent of patients the platelet count will rise toward normal within that period. Once a normal platelet count has been reached, the steroid dosage should be slowly tapered to avoid precipitating a relapse. The probable actions of steroids include inhibition of splenic reticuloendothelial phagocytic activity, decreased immune complex binding to platelets, decreased capillary fragility, and decreased immunoglobulin synthesis. When steroids are tapered following an initial increase in platelet count to the normal range, thrombocytopenia recurs in as many as 80 per cent of initially responding adult patients. Reinstitution of steroids may restore the platelet count, but many patients may require splenectomy for permanent remission. After splenectomy, 60 to 80 per cent of patients with ITP will maintain an adequate platelet count, while the remainder will require further therapy with steroids (at a lower dose) or with immunosuppressive drugs such as vincristine, cyclophosphamide, or azathioprine. For short-term therapy intravenous high-dose gamma globulin can transiently raise the platelet count in patients with refractory ITP (e.g., in preparation for emergency surgery), but adults do not respond well to repeated high-dose IgG therapy. Children with chronic ITP who are refractory to other therapy have been successfully managed with repeated infusion of high-dose intravenous IgG. Anabolic steroids such as danazol have also been reported to raise platelet counts in refractory ITP. Other Causes of Immune Thrombocytopenia. Post-transfusion purpura is a rare syndrome that follows the administration of PL^-positive blood to patients who lack this common platelet antigen and who have developed anti-PL^ antibodies after previous transftfsion or pregnancy. An explosive thrombocytopenia develops five to eight days after transfusion (anamnestic response) which may require plasmapheresis and exchange transfusion with PL^-negative blood. The thrombocytopenia may persist a’few weeks but is self-limited. Other platelet antigen systems are occasionally involved. Neonatal purpura may be seen in infants of PL^-negative mothers or mothers with ITP. In systemic anaphylactic reactions thrombocytopenia may result from sequestration of platelets coated with circulating antigen-antibody complexes. Thrombocytopenia may also result from platelet coating with “i”-cold antibodies that arise following viral infections such as rubella or infectious mononucleosis.
Platelet consumption syndromes include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and the hemolytic uremic syndrome or can result from platelet damage during extracorporeal circulation. Intravascular activation of the coagulation mechanism is associated with sepsis, shock, exposure to toxins, or malignancies and may present with hemorrhage or thrombosis (see below). Thrombin-induced platelet aggregation or vascular damage that initiates platelet activation can cause thrombocytopenia. Vascular malformations such as cavernous hemangiomas (Kasabach-Mer-ritt syndrome) sometimes produce localized DIC and platelet trapping, resulting in chronic thrombocytopenia.
Thrombotic thrombocytopenic purpura (Moschkowitz’s syndrome) is an acute, relapsing disease affecting the microcirculation. There is a pentad of signs and symptoms including thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal dysfunction, and fever. Two-thirds of affected persons are young women. There is often a history of preceding viral infection. The characteristic lesions are hyaline thrombi, consisting of platelet aggregates and fibrin, plugging small arterioles and capillaries. Endothelial proliferation may be seen, but vasculitis is not present. The blood smear shows schistocytes, increased reticulocytes, and normoblasts, reflecting the microangiopathic and hemolytic nature of the characteristic anemia; thrombocytopenia is usually severe, the serum bilirubin is elevated, and the Coombs’ test is negative. Early in the disease DIC is absent, but it appears as renal failure ensues. Abnormal forms of von Willebrand factor have been observed (released by injured endothelium), and some patients possess a plasma factor that promotes platelet activation. TTP is frequently fatal. Treatment by splenectomy, steroids, or platelet-inhibitory drugs such as aspirin and dipyridamole has had variable results. Exchange transfusion, plasmapheresis, and plasma infusion have more recently been used with greater success and represent the current approach of choice.
Hemolytic-uremic syndrome, usually seen in children, involves a Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia, diarrhea, and acute renal failure. Unlike TTP, this disorder does not affect the brain to produce neurologic signs. DIC may be present. The major pathologic lesion consists of hyaline thrombi in the renal microcirculation, probably representing a form of immune complex disease. Renal dialysis is the mainstay of therapy. The role of plasmapheresis has not been defined.
The use of therapeutic extracorporeal circulation frequently produces thrombocytopenia as the result of platelet activation, with subsequent adherence of platelets to the surface of the membrane oxygenator, dialyzer membrane, or other extracorporeal device. Platelet dysfunction induced by such contact may contribute to postoperative hemorrhage, over and above the contribution of thrombocytopenia.
Thrombocytopenia Produced by Platelet Sequestration. Normally the spleen contains about one third of the circulating pool of platelets. Increased splenic sequestration occurs with splenomegaly; very large spleens may sequester up to 90 per cent of the circulating platelets, resulting in a moderate thrombocytopenia of 50,000 to 100,000/cu mm. Platelet lifespan, however, is not shortened in hypersplenism, and severe hemorrhage is unusual.
Dilutional thrombocytopenia can follow massive transfusion of whole blood or plasma and lasts for several days. Platelet transfusions may be needed if the patient’s residual platelets are dysfunctional or if bone marrow function is depressed and there is threatened or actual hemorrhage; the condition is transient in patients with normal marrow function.