Thrombocytopenia

Thrombocytopenia maybe defined as a subnormal number of platelets in the circulating blood. It is the most common cause of abnormal bleeding. In general, the severity and frequency of hemorrhagic manifestations correlate to the platelet count. Platelet counts below 20 0!"# usually are associated with spontaneous hemorrhage. Thrombocytopenia results from three processes$ % & deficient platelet production. Those that depopulate the stem cell or mega'aryocyte compartments are the most common, e.g., marrow in(ury by myelosuppressive drugs or irradiation and aplastic anemia.%2& accelerated platelet destrucion, utili)aton or loss, e.g., idiopathic thrombocytopenia purpura, diffuse intravascular coagulaton, thrombotic thrombocytopenia purpura. %*& abnormal distribution or pooling of the platelets within the body. This type of thrombocytopenia is seen in the various disorders associated with splenomegaly. Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura ia an acquired disease of children and adults characteri)ed by a low platelet count ,an normal or increased numbers of mega'aryocytes in the bone marrow, and absence of evidence for other disease. +lthough this disease is also referred to as immune thrombocytopenic purpura and autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura remains the most common designation. The clinical syndromes of ITP are divided into acute and chronic types. ,-tiology and pathogenesis. -vidence is mow convincing that the syndrome of ITP is caused by platelet destruction as the result of an immunologic process. . Platelet survival Platelet survival is greatly shortened in ITP. The survival time of isologous platelets labeled with / 0r1chromate ranges from 2 to *days to a matter of minutes. 2. Platelet antibodies Thrombocytopenia in ITP appears to result from the action of a platelet antibody. The infusion of plasma from patients with ITP predictably induces thrombocytopenia in normal recipients. The responsible factor is an immunoglobulin of the Ig2 class that is species specific. Increased quantities of Ig2 have been demonstrated on the platelet surface, and the

rate of platelet destruction in ITP is proportional to levels of such platelet1associated Ig2. *. Immune comple3es The frequency with which acute ITP is associated with antecedent viral infection have led to the suggestion that a viral antigen1antibody comple3, may be responsible for platelet sensiti)ation and destruction in this form of the disorder. 4. 5ole of the spleen 6hen / 0r1chromate1labeled isologous platelets are administered to patients with ITP, e3ternal scintillation counting reveals a rapid accumulation of radioactivity predominantly in the spleen. Platelet phagocytosis by splenic leu'ocytes has been demonstrated in vitro. 7epatic sequestration of platelets has been demonstrated in association with ITP, usually in patients with severe thrombocytopenia and mar'edly shortened platelet survival. The spleen also is important in ITP as a site of production of platelet antibodies. 8plenic tissue from patients with ITP produces more immunoglobulin than that of normal control sub(ects, and a significant percentage of that formed binds to homologous platelets. /. Impaired thrombopoiesis In chronic ITP, an immunoglobulin has been demonstrated on the surface of the mega'aryocytes by means of immunofluorescence and other techniques. 0onceivably, the attachment of antibody may impair platelet production. Thus, total mega'aryocyte mass and the platelet turnover rate were several times greater than normal. ,0linical features. . +cute ITP +cute ITP occurs most frequently in children 2 t0 9 years, it rarely affects adults and has no gender predilection. In patients with acute ITP, the onset of the disorder usually is sudden. + history of infection preceding the onset of bleeding has been documented repeatedly. +cute ITP usually is self1limited: spontaneous remissions occur in as many as !*; of patients. The duration of the disease ranges from a few days to a few months, with an average of 4 to 9 wee's. 2. 0hronic ITP 0hronic ITP affects persons of all ages, but it is relatively more common between puberty and /0 years of age. It occurs more frequently in women than in men, a ratio of
2

appro3imately *$ having been found repeatedly. The onset of the chronic form of the disorder usually is insidious. Patients usually have a fluctuating clinical course. -pisodes of bleeding may last a few days of a few wee's, and may be intermittent or even cyclic. 8pontaneous remissions are uncommon and are li'ely to be incomplete. *. <leeding manifestation <leeding into the s'in in the form of petechiae is characteristec. Petechiae are asymptomatic, not palpable, and occur most in dependent region. 8ymptoms and signs are predictable from the 'nown pattern of bleeding associated with platelet disorders$ purpura, menorrhagia, epista3is, and gingival bleeding are common: gastrointestinal bleeding and hematuria are less common. Intracerebral hemorrhage is uncommon, but it is the most common cause of death and may occur acutely or at any time during a prolonged course. 4. =thers 5epeated bleeding may lead to anemia of iron deficiency type. The spleen is occasionally palpable on deep inspiration but never greater. ,laboratory >inding. . The blood Isolated thrombocytopenia is the essential abnormality. +bnormalities in platelet si)e and morphologic appearance are common. The platelets often are abnormally large, e.g., * to 4m in diameter, and reveal more than normal variation in si)e and shape. =ther morphologic changes may be seen in some patients, e.g., ?giant@forms % 0 m or more in diameter&, bi)arre shapes, and deeply stained forms. The white blood cell count and hemoglobin concentration are usually normal unless significant hemorrhage due to the thrombocytopenia has occurred. -osinophilia of blood and marrow may be noted, but this is more common in the acute ITP of childhood. Tests of hemostasis and blood coagulation reveal only changes attributable to thrombocytopenia, such as a prolonged bleeding time, absent or deficient clot retraction, a positive reaction to the tourniquet test, and deficient prothrombin consumption. The results of tests of blood coagulation, e.g., prothrombin time, partial thromboplastin time, and coagulation time, are normal in patients with uncomplicated thrombocytopenia. 2. The marrow
*

+lterations in the bone marrow are limited to the mega'aryocytes, with the e3ception of the normoblastic hyperplasia that may develop as the results of blood loss. Increased marrow mega'aryocytes with a shift to younger, less polyploid mega'aryocytes and fewer mature, platelet1producing mega'aryocytes has been commonly reported. *. Tests for platelet antibodies +ssays of P+Ig2 represent the first sensitive and reproducible method for demonstrating antibodies in ITP. P+Ig2 is increased in patients with ITP, and the magnitude of increase is greater in patients with more severe thrombocytopenia. ,Aifferential diagnosis. The diagnosis of ITP is made by e3cluding other causes of thrombocytopenia, e.g., acute infectious illness, myelodysplastic syndrome, hypersplenism, disseminated

intravascular coagulation, aplastic anemia, acute leu'emia, systemic lupus erythematous. 8everal differences e3ist between acute ITP and chronic ITP that are of particular significance in the interpretation of data concerning the incidence of the disorder, its prognosis, and the results of therapy %see Table&. Table. >eatures of acute and chronic ITP >eatures Pea' age incidence 8e3 predilection +ntecedent infection =nset of bleeding 7emorrhagic bullae mouth Platelet count Auration 8pontaneous remissions ,Treatment. Physical activity should be restricted to minimi)e the ha)ards of trauma, particularly head in(ury. Arugs that impair platelet functions should be avoided. <lood loss should be treated as otherwise indicated. =bservation$ Fost patients who are incidentally discovered to have asymptomatic mild
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+cute ITP 0hildren 219 years of age Bone 0ommon 1* wee's before onset +brupt in Present in severe cases D20 0!"# 219 wee's: rarely longer =ccur in E0; of cases

0hronic ITP +dults, 20140 years of age *$ , female to male patients Cnusual Insidious Csually absent *01E0 0!"# Fonths or years Cncommon: fluctuating course common

or moderate thrombocytopenia can safely be followed with no treatment. . 0orticosteroids 0orticosteroids are widely used as the initial means of therapy. Fechanism of action$ % & significantly diminish immunoglobulin synthesis. %2& inhibit the binding of antibodies to platelets. %*& impair reticuloendothelial function and thereby to diminish platelet destruction. =ne commonly used in initiation therapy consists of administering 40 to 90mg of prednisone daily to adults, and mg"'g body weight to children. The initial course of steroids should be maintained for * to 4 wee's, followed by a gradual tapering of the dosage. 8teroid therapy should not be maintained for long periods, a reasonable rule of thumb being 9 months at most. 8ome increase in platelet numbers and a favorable clinical response can be e3pected in G0 to !0; of patients with ITP who receive adrenal corticosteroid therapy. 7owever, most patients will relapse when prednisone is tapered or discontinued. 2. 8plenectomy The ma(or effects of splenectomy are twofold$ % & removal of the ma(or site of destruction of antibody1sensiti)ed platelets. %2& removal of a ma(or site of antibody synthesis. The indications for splenectomy in patients with ITP may be stated as follows$ % & failure of spontaneous remission to occur after 9 months of observation in patients with moderate or severe bleeding. %2& failure to respond to steroid therapy, relapse after discontinuance of steroid therapy or reduction in the dosage, or the necessity of high doses for maintenance of a clinical status free of serious hemorrhage. %*& difficulty in assuring adequate follow1up care. %4& overriding contraindications due to the use of steroids. 8plenectomy is contraindicated in the following situations$ % & early in the first episode of bleeding, especially in children, because of the frequency of spontaneous remissions. %2& in patients with cardiac or other complications who are at ris' of serious sequelae from any ma(or surgical procedure. %*& in children under 2 years of age, in whom the ha)ard of fulminating infection after splenectomy is greater than at a later age. %4& in many cases of ITP in pregnant women. %/& in patients with acute ITP and ma(or uncontrolled bleeding in whom the mortality rate after splenectomy is high. Fost patients who will respond to splenectomy do so within several days. 0omplete and sustained remissions have occurred after splenectomy in from /0 to over !0; of
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patients. <y measuring the pattern of splenic versus hepatic sequestration with radiolabeled platelets may predict the response to splenectomy. *. Immunosuppressive drugs 0yclophosphamide %/0 to 200mg"day orally or *00 to 900 mg"m2 intravenously every 2 wee's& has induced remissions in from 44 to //; of patients. Hincristine %0.02/mg"'g not to e3ceed a total dose of 2mg& and vinblastine %0.0 2/mg"'g&, administered intravenously at wee'ly intervals, appear to be as effective as cyclophosphamide, but act more rapidly. +)athioprine, actinomycin, and other immunosuppressive agents, either alone or in combination with corticosteroids, have been administered to patients with ITP, with variable success. +ll of these immunosuppressive agents may be leu'emogenic and"or carcinogenic. 4. -mergency treatment of acute bleeding In patients with severe bleeding, in addition to conventional critical care measures, appropriate treatment includes platelet transfusions, high1dose parenteral glucocorticoids, and IHIg. Platelet transfusions$ Platelet transfusions may produce some increase in platelet numbers in many patients, often diminish bleeding for a time, and can be effective in the management of serious complications, e.g., subarachnoid hemorrhage. They should be reserved for such life1threatening emergencies or for the immediate preoperative treatment of patients with serious hemorrhage before splenectomy. In patients with platelet counts above /0 0!"#, preoperative platelet transfusions are not indicated. Platelet replacement should be avoided in patients with chronic ITP because of the possible development of alloantibodies. 7igh1dose immunoglobulin. The mechanism of this therapeutic effect is not entirely clear, but most evidence points to bloc'ade of the >c receptors of the reticuloendothelial cells, and perhaps neutrali)ation of antiplatelet autoantibodies by antiidiotypic antibodies in the preparations. + regimen of 400mg"'g"day for / days usually is recommended. Treatment with immunoglobulin appears to be effective in patients who failed to respond to splenectomy, in pregnant women, and in some patients who are refractory to all other modes of treatment.
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7igh doses of glucocorticoids, such as

g of methylprednisolone given by intravenous

infusion daily for * days, may also cause a rapid increase of the platelet count and may ameliorate bleeding even if platelet counts remain low due to an effect on the vasculature. /. =thers Aana)ol, an androgen with minimal virili)ing side effects, has proved effective in the treatment of ITP. In doses of 400 to E00mg"day, presumably acts by inducing reticuloendothelial dysfunction, possibly by diminishing >c %Ig2& receptors. -3change plasmapheresis. It may be valuable in critically ill patients, and may be particularly effective in children. +nti1A. Intravenous 5h %A& immune globulin has been studied in children with acute ITP and refractory chronic ITP as an alternative to intravenous Ig. The mechanism of action is un'nown: however, it is believed that the antibody coats the red blood cells of 5h1positive patients and either bloc's the reticuloendothelial clearance of the patients platelets or modulates the immune system, resulting in an increase in the platelet count. 0hildren respond better than adults, and nonsplenectomi)ed patients respond better than splenectomi)ed patients. The only clinically important side effect of anti15h%A& is the predictable alloimmune hemolysis.