Purpura, thrombotic thrombocytopenic

Idiopathic thrombocytopenic purpura (ITP), also known as primary immune or autoimmune thrombocytopenic purpura, is a common cause of thrombocytopenia and bleeding complications in children and adults. ITP is defined as isolated thrombocytopenia (low platelet count with an otherwise normal complete blood count and peripheral blood smear) in a patient with no clinically apparent associated conditions that can cause thrombocytopenia.[1] However, the presence of isolated abnormalities on serologic tests (e.g., antinuclear or antiphospholipid antibodies) does not exclude the diagnosis, since these abnormalities are frequently encountered in patients with typical ITP.[2,3] Table 1[4] describes the differential diagnosis of ITP.

EDTA = ethylenediaminetetrnacetic acid; HIV = human immunodeficiency virus; ITP = idiopathic thrombocytopenic purpura.

Adapted from George JN, El-Harake MA, Raskob GE. Current concepts: chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994;331:1207. Copyright 1994, Massachusetts Medical Society. Used with permission.

ITP is primarily a disorder of increased platelet destruction, probably caused by the development of autoantibodies to platelet-membrane antigens.[4] The reported prevalence for adults and children is 1 to 13 cases per 100,000 persons,[5] but the clinical presentation and course differ in children and adults.

In children, ITP occurs most commonly at two to four years of age and with equal incidence in boys and girls. It is usually an acute, self-limited disorder that resolves spontaneously. Children typically present with a history of bruising and petechiae of less than one or two weeks' duration. Other bleeding symptoms characteristic of thrombocytopenia (e.g., epistaxis, gingival bleeding) occur in fewer than one-third of patients. Although anecdotal evidence indicates that infectious illnesses often precede the onset of ITP in children, a causal role for infection has not been established.

From 80 to 90 percent of untreated children have a complete remission within six to 12 months, usually within a few weeks.[1]

In adults, ITP typically occurs in young women and is insidious, chronic and, in about one-third of patients, relatively resistant to most treatments.[1] Most adults present with histories of prolonged purpura, in contrast to the more acute presentation typical in children. The routine reporting of platelet counts has expanded the clinical spectrum of ITP, and now many patients are diagnosed incidentally, in the absence of bleeding symptoms. Evidence suggests that only about 5 percent of adults with chronic ITP have spontaneous remission.[1]

The principal cause of death from ITP is intracranial hemorrhage. The reported incidence of fatal bleeding in children is about 1 percent and, in adults, about 5 percent.[1] However, these data were obtained before the availability of many current treatments and supportive-care techniques, and mortality rates may now be lower. Older adults have more frequent and severe hemorrhagic complications than younger patients.[6,7]

Among pregnant women with thrombocytopenia, relatively few have ITP. About 75 percent have gestational thrombocytopenia (also known as incidental thrombocytopenia of pregnancy and defined as mild thrombocytopenia developing late in pregnancy and resolving spontaneously after delivery), and most of the remainder have low platelet counts related to preeclampsia.[8] Newborns of women with ITP (in contrast to newborns of women with gestational thrombocytopenia) may be thrombocytopenic and face a slightly increased risk of intracranial hemorrhage at or following delivery. A recent review suggests that about 10 percent of newborns of women with ITP have a platelet count less than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L), and 4 percent have a platelet count less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L).[9] There may be a 1 percent risk of intracranial hemorrhage or death in the newborn infant.[1,9] Platelet counts may decrease further in the first week of life, but generally reach a nadir by day 1 or day 2.[10]

Guideline Development Process

The 15-member Practice Guideline panel included 13 hematologists, a clinical epidemiologist and a practice guidelines methodologist. A comprehensive literature search gathered all relevant English-language studies evaluating the natural history of ITP and the effectiveness of specific diagnostic and treatment options.[1] Studies evaluating treatment effectiveness were rated using the "levels of evidence" approach.[11] When it became clear that the ITP literature lacked reliable studies for developing evidence-based recommendations, the panel turned to expert opinion to generate interim guidelines. Special questionnaires and a scoring methodology, described in detail in the full report,[1] were used to quantify panel opinions about the necessity or appropriatness of each test and treatment. The testing and treatment recommendation that follow represent panel opinion scores that exceeded predetermined criteria for appropriateness or necessity. Tests or treatments that received a lack of consensus are not discussed in this article. Because of the inherent weakness of opinion-based recommendations, these guidelines should not form the basis for definitive decisions on health care policy or inflexible rules for patient care.

Diagnostic Tests

Little scientific evidence regarding the accuracy or reliability of tests for ITP exists. The diagnosis of ITP is best accomplished with a history, physical examination, complete blood count and examination of the peripheral blood smear. Clinicians sometimes perform additional tests, such as those for ruling out other causes of thrombocytopenia (e.g., human immunodeficiency virus [HIV] infection, systemic lupus erythematosus), bone marrow examination, imaging studies and so forth (e.g., platelet antibodies), but data regarding their predictive value or effectiveness in the routine patient are lacking.

In pregnant women with ITP, platelet counts do not accurately predict fetal or neonatal platelet counts,[1] and direct measurement of fetal platelet counts before delivery is problematic. Percutaneous umbilical blood sampling is performed only in specialized centers and can induce fetal complications.[12,13] Fetal scalp-vein sampling is performed after cervical dilation, but the platelet counts are frequently inaccurate.[1,10]

Treatment

The principal treatment options for ITP include glucocorticoid therapy, intravenous IgG, intravenous anti-[Rh.sub.o] immune globulin and splenectomy. Other regimens have been used in refractory cases, but no direct evidence proves that any of them reduce bleeding complications or mortality from ITP. Most outcome studies rely on evidence of increased platelet counts as a surrogate measure of the effectiveness of treatment. This strategy appears reasonable because studies demonstrate a correlation between severe thrombocytopenia and clinically important bleeding.[1,14] However, even if platelet counts are accepted as a surrogate measure for clinical outcomes, relatively little scientific evidence proves the effectiveness of treatments for ITP.

In children, randomized controlled clinical trials demonstrate that glucocorticoids and intravenous IgG increase platelet counts more quickly than observation alone.[15-18] These trials also suggest that this platelet increase is more rapid in children treated with intravenous IgG than in those treated with glucocorticoids.[18,19] However, these trials did not demonstrate any clinical benefit from treatment, such as decreased bleeding or mortality.

A study in adults reported no difference in outcomes between patients treated initially with glucocorticoids or intravenous IgG, but the study may have lacked the statistical power to detect an effect.[20]

Other ITP treatments are supported only by case series, the weakest form of clinical evidence. The absence of control groups in these reports makes it unclear whether similar outcomes would have occurred with other regimens or without treatment. A possible exception is splenectomy in adults, for which 36 case series consistently document a sustained normalization of platelet counts in more than one-half of patients who had previously been refractory to medical treatment for weeks or years.[1] All medical and surgical treatments for ITP carry the risk of potential adverse effects, but the probability and severity of complications vary.[1]

Special treatment issues arise in pregnant women with ITP, but relevant data to inform practice are limited. Certain medications used in ITP may harm the fetus, but few studies of these effects are available. Splenectomy may increase the risk of spontaneous abortion during the first trimester and can be technically difficult during the third trimester, but no data regarding the magnitude of risks exist. Pregnant women with low platelet counts are theoretically at higher risk of peripartum hemorrhage and bleeding complications from epidural anesthesia, but little direct evidence shows the magnitude of these risks or the need for or effectiveness of preventive measures.[21] Little evidence shows the threshold platelet count at which the fetus faces an increased risk of traumatic intracranial hemorrhage. It is believed that the risk is lowered by cesarean delivery, rather than vaginal delivery, but supporting data are lacking. In addition, little evidence shows that treating newborns of mothers with ITP improves morbidity or mortality, although some reports suggest that intravenous IgG treatment of newborns with ITP can increase platelet counts.[1]

Recommendations for Children

DIAGNOSIS

Essential elements of the history and physical examination in children suspected of ITP are outlined in Table 2. The primary objective of the history is to assess the type of bleeding and to distinguish platelet-related mucocutaneous bleeding from delayed visceral hematomas, which are characteristic of coagulation disorders. Bleeding caused by thrombocytopenia is typically manifested by cutaneous petechiae and purpura (bruises) and, occasionally, epistaxis, and gingival and gastrointestinal bleeding. Bleeding related to coagulation disorders is typically marufested by the development of a large hematoma, occurring hours to days after trauma.

ITP = idiopathic thrombocytopenic purpura; HIV = human immunodeficiency virus.

Adapted from George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura; a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3-40. Used with permission

Although the physical examination of children and adults with ITP is generally the same, splenomegaly may be slightly more common in children, especially in infants. Data from six case series suggest that the spleen may be palpable in 12 percent of children with ITP,[1] but this rate may not differ from that of normal children.[22] Congenital anomalies in the patient or family members may suggest congenital thrombocytopenia, an important consideration in children with persistent thrombocytopenia.[23]

A complete blood cell count and examination of the peripheral blood smear (Table 3) should exclude other causes of thrombocytopenia. If these findings are compatible with the diagnosis of ITP and do not include atypical findings or suggest other etiologies, further diagnostic studies are not indicated in the routine work-up.

ITP = idiopathic thrombocytopenic purpura.

Adapted from George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura; a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:340. Used with permission.

Other etiologies are uncommon: a study of 127 consecutive pediatric patients with suspected ITP who had bone marrow aspirations identified other causes of thrombocytopenia in only 5 patients (4 percent), all of whom had atypical presenting features.[24]

Patients with risk factors for HIV infection should be tested for HIV antibody, and an abdominal imaging examination is appropriate in patients who are suspected of splenomegaly on initial physical examination. Bone marrow aspiration should be performed to establish the diagnosis in patients with persistent thrombocytopenia (lasting more than six to 12 months) and in those unresponsive to intravenous immunoglobulin, but it should not be performed to establish the diagnosis before initiating intravenous IgG therapy.

TREATMENT

Recommendations for the initial treatment of children presenting with ITP are categorized by platelet count and bleeding status in Table 4. Children with platelet counts greater than 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L) do not routinely require hospitalization or treatment if they are asymptomatic or have only minor purpura; they should not be given glucocorticoids, intravenous immunoglobulin, or intravenous anti-[Rh.sub.o] (D) as routine initial treatment.

[TABULAR DATA 4 NOT REPRODUCIBLE IN ASCII]

Children with platelet counts less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L) and significant mucous membrane bleeding and children with platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L) and minor purpura should be treated with intravenous IgG or glucocorticoids. Patients with severe or life-threatening bleeding should be hospitalized and receive conventional critical care measures, along with treatment for ITP: appropriate regimens include platelet transfusions, high-dose parenteral glucocorticoid therapy (e.g., 30 mg per kg per day of methylprednisolone) and/or intravenous IgG.

Splenectomy for ITP is performed less frequently in children than adults, often after thrombocytopenia has persisted for more than one year in the presence of clinically important bleeding. The panel did not reach consensus on the specific indications for this procedure. If an elective splenectomy is planned, appropriate preoperative therapy includes prophylactic intravenous IgG therapy for patients with platelet counts less than 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L), and intravenous IgG, parental glucocorticoids and/or intravenous anti-[Rh.sub.o] (D) immunoglobulin for patients with platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L). When platelet counts exceed 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L), preoperative prophylaxis is inappropriate. According to the Advisory Committee on Immunization Practices, children should be immunized with Haemophilus influenzae type b conjugate vaccine and, if over two years of age, polyvalent pneumococcal vaccine and quadrivalent meningococcal polysaccharide vaccine at least two weeks before elective splenectomy.[25]

If ITP symptoms persist following primary treatment (glucocorticoid, intravenous IgG) and splenectomy, further treatment is indicated in children with platelet counts less than 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L) who have active bleeding. Many treatments are considered reasonable options, but no treatment has been shown to be more effective than another.

Recommendations for Adults

DIAGNOSIS

As in children, the diagnosis of ITP in adults requires a history, physical examination, complete blood cell count and examination of the peripheral blood smear. The most important elements of the history and physical examination are presented in Table 5. Drug-induced thrombocytopenia must always be considered and may be difficult to exclude. Alcohol also causes thrombocytopenia, as does chronic liver disease, as a result of increased platelet pooling from congestive splenomegaly. Finally, the history should consider the patient's lifestyle, which may influence the goals of treatment. A sedentary person, for example, may tolerate a lower platelet count than a patient whose profession or hobbies involve a high level of exertion or potential trauma.

ITP = idiopathic thrombocytopenic purpura; HIV = human immunodeficiency virus.

Adapted from George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura; a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:340. Used with permission.

Physical examination is principally directed at assessing the type and severity of bleeding and at excluding other causes of thrombocytopenia. Splenomegaly, for example, provides evidence against ITP. A large study[26] reported that less than 3 percent of patients with ITP had splenomegaly, about the same percentage as healthy young adults with palpable spleens.[27]

Signs of liver disease or lymphadenopathy may suggest lymphoproliferative, autoimmune or infectious diseases. Acute and severe thrombocytopenia may be a manifestation of bacteremia or viral infection; HIV infection is commonly associated with thrombocytopenia.[28] Neurologic function and funduscopic examination also provide a baseline in the event of subsequent central nervous system bleeding. In addition, hearing impairment and skeletal anomalies may suggest disorders associated with congenital thrombocytopenia.[23]

A complete blood cell count and examination of a peripheral blood smear are essential in diagnosing ITP. Thrombocytopenia incidentally detected on a routine blood count is often the first clue to the diagnosis. The evaluation of a low platelet count should distinguish between true thrombocytopenia and pseudothrombocytopenia, which occurs in about 0.1 percent of adults,[29] most commonly because of innocent platelet agglutinins that cause platelet clumping in the presence of the anticoagulant, ethylenediaminetetraacetic acid (EDTA). In each patient, thrombocytopenia must be confirmed by direct examination of the peripheral blood smear (Table 3).

Particularly in older patients, evidence of myelodysplasia should be carefully evaluated, including the presence of nucleated red cells, schistocytes and immature granulocytes.[30] Other peripheral blood smear abnormalities may suggest the presence of a viral infection, megaloblastic hematopoiesis or microangiopathic disorders. In the absence of findings that are atypical or suggest another diagnosis, further diagnostic studies are not indicated in the routine work-up. Bone marrow aspiration is appropriate to establish the diagnosis in patients over 60 years of age and in patients considered for splenectomy. Because thyroid disorders may be associated with ITP, preoperative thyroid function testing is appropriate to rule out occult hyperthyroidism or hypothyroidism before elective splenectomy.

TREATMENT

Recommendations for the initial treatment of adults presenting with ITP are summarized in Table 6. Again, treatment depends on platelet count and severity of bleeding.

ITP = idiopathic thrombocytopenic purpura; CDOG = conventional-dose oral glucocorticoids; IV IgG = intravenous IgG.

(*)--Options considered included observation (no specific initial treatment), CDOG (e.g., prednisone, 1 to 2 mg per kg per day), intravenous IgG (e.g., 1 to 2 g per kg for 1 to 5 days), splenectomy and hospitalization.

([dagger])--Mucous membrane bleeding includes vaginal bleeding and other blood loss requiring clinical intervention. Severe bleeding includes life-threatening bleeding. "Severe" category not included for platelet counts of 50 to 100 x [10.sup.3] per [mm.sup.3] (50 to 100 x [10.sup.9] per L) because severe bleeding in such patients is unlikely to be caused by ITP

([double dagger])--Appropriateness was determined from a structured questionnaire as described in reference 1. Items not listed as "appropriate" or "uncertain" were considered inappropriate.

Adapted from George 1N, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura; a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:340. Used with permission.

Patients who have platelet counts less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L), and those who have counts less than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L) and significant mucous membrane bleeding (or risk factors for bleeding, such as hypertension, peptic ulcer disease or vigorous lifestyle) generally require treatment. Initial therapy with glucocorticoids (e.g., prednisone, 1 to 2 mg per kg per day) is appropriate in these patients.

Hospitalization is appropriate in patients with platelet counts less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L) who have significant mucous membrane bleeding. Patients with severe or life-threatening bleeding should also be hospitalized and receive conventional critical care measures, along with treatment for ITP: appropriate regimens include platelet transfusions, high-dose parenteral glucocorticoid therapy (e.g., methylprednisolone, 1 g per day for three days) and/or intravenous IgG.

Splenectomy should not be performed as initial therapy in patients who have no bleeding symptoms, minor purpura or even mucous membrane or vaginal bleeding. In a patient who has had bleeding symptoms (e.g., epistaxis, menorrhagia), splenectomy is often appropriate if the platelet count remains below 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L) after four to six weeks of medical treatment. If elective splenectomy is planned, appropriate preoperative therapy includes immunization two weeks preoperatively for all patients and prophylactic intravenous IgG or oral glucocorticoid therapy for patients with platelet counts less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L).

When ITP symptoms persist following primary treatment (glucocorticoid) and splenectomy, further therapy is recommended in patients with platelet counts less than 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L) who have active bleeding. As is the case with children, many treatments are considered reasonable options, but no treatment has been shown to be more effective than another. Women with ITP and platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L) after splenectomy and other treatments should be discouraged from becoming pregnant.

Recommendations for Pregnant Women

DIAGNOSIS

The differential diagnosis between ITP and gestational thrombocytopenia is generally of little clinical importance to the mother, since cases in which the diagnosis is unclear involve mild thrombocytopenia that does not threaten maternal health. The distinction is, however, clinically important with regard to the fetus, since ITP with even mild thrombocytopenia may harm the fetus, whereas gestational thrombocy-topenia does not.[8] However, special laboratory testing is not recommended. The patient's blood pressure should be measured to rule out preeclampsia, and liver-function testing is appropriate to rule out the HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count). Patients with risk factors for HIV infection should be tested for HIV antibody.

TREATMENT

Pregnant women with ITP and platelet counts greater than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L) do not routinely require treatment and should not receive glucocorticoids or intravenous IgG as routine initial therapy. Women with counts of 30 to 50 x [10.sup.3] per [mm.sup.3] (30 to 50 x [10.sup.9] per L) in the first two trimesters also should not receive routine initial treatment with glucocorticoids or intravenous IgG.

Treatment is required for patients with platelet counts of 10 to 30 x [10.sup.3] per [mm.sup.3] (10 to 30 x [10.sup.9] per L) who are in their second or third trimester or are bleeding, and for all pregnant women with platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L). Intravenous IgG is appropriate initial treatment for women with platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L) in the third trimester and for those with counts of 10 to 30 X (10.sup.3) per [mm.sup.3] (10 to 30 x [10.sup.9] per L) who are bleeding. If glucocorticoid and intravenous IgG therapy are unsuccessful, splenectomy is appropriate in the second trimester in women with platelet counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L) who are bleeding. Splenectomy should not be performed in asymptomatic pregnant women with platelet counts greater than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L).

As labor and delivery approach, women with ITP do not require testing for maternal platelet antibodies, and percutaneous umbilical blood sampling (PUBS) and fetal scalp vein sampling are unnecessary in pregnant women without known ITP even with platelet counts of 40 to 75 x [10.sup.3] per [mm.sup.3] (40 to 75 x [10.sup.9] per L) at term. Women with ITP should be delivered by cesarean section in selected circumstances.[1] Assuming the fetal platelet count and the platelet count of previous babies is unknown, cesarean section is not indicated when the maternal platelet count is greater than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L). A maternal platelet count of greater than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L) is considered sufficient to prevent complications from excessive maternal bleeding at vaginal delivery or cesarean section. If the fetal platelet count is known, cesarean section is appropriate if the fetal count is less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L). Prophylactic platelet transfusions before delivery are appropriate in women with counts less than 10 x [10.sup.3] per [mm.sup.3] (10 x [10.sup.9] per L) who (1) have a planned cesarean section or (2) have epistaxis or other mucous membrane bleeding and are expected to deliver vaginally; they are unnecessary in women with platelet counts greater than 30 x [10.sup.3] per [mm.sup.3] (30 x [10.sup.9] per L) and no bleeding symptoms.

Recommendations for Newborns of Mothers with ITP

DIAGNOSIS

The neonatal platelet count should generally be measured for three to four days after birth. Brain imaging (e.g., ultrasound) is appropriate if the neonatal platelet count at birth is less than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L), even in the absence of neurologic abnormalities.

TREATMENT

In newborns without evidence of intracranial hemorrhage, treatment with intravenous IgG is appropriate if the infant's platelet count is less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L). Newborns with platelet counts of 20 to 50 x [10.sup.3] per [mm.sup.3] (20 to 50 x [10.sup.9] per L) do not necessarily require intravenous IgG, and those who have counts greater than 50 x [10.sup.3] per [mm.sup.3] (50 x [10.sup.9] per L) should not be treated with intravenous IgG or glucocorticoids. Newborns with imaging evidence of intracranial hemorrhage should be treated with combined glucocorticoid and intravenous IgG therapy if their platelet count is less than 20 x [10.sup.3] per [mm.sup.3] (20 x [10.sup.9] per L); they should not be treated with glucocorticoids alone. Women with ITP should not be discouraged from breast feeding.

The authors constituted the American Society of Hematology ITP Practice Guideline Panel: James N. George, M.D., University of Oklahoma Health Sciences Center, Oklahoma City; Steven H. Woolf, M.D., M.PH., Medical College of Virginia, Richmond, Va.; Gary E. Raskob, M.Sc., University of Oklahoma Health Sciences Center, Oklahoma City; Jeffrey S. Wasser, M.D., University of Connecticut School of Medicine, Manchester, Conn.; Louis M. Aledort, M.D., Mount Sinai School of Medicine, New York, N.Y.; Penny J. Ballem, M.D., University of British Columbia Faculty of Medicine, Vancouver, British Columbia; Victor S. Blanchette, M.D., University of Toronto Faculty of Medicine, Toronto, Ontario; Ames B. Bussel, M.D., Cornell University Medical College, New York, N.Y.; Douglas B. Cines, M.D., University of Pennsylvania School of Medicine, Philadelphia, Pa.; John G. Kelton, M.D., Chedoke-McMaster Hospitals, Hamilton, Ontario; Alan E. Lichtin, M.D., Cleveland Clinic, Cleveland, Ohio; Robert McMillan, M.D., Scripps Clinic, La Jolla, Calif.; Iohn A. Okerbloom, M.D., Heartland Hematology-Oncology, Council Bluffs, Iowa; David H. Regan, M.D., Hematology Clinic, Portland, Ore., and Indira Warrier, M.D., Wayne State University School of Medicine, Detroit, Mich.

Address correspondence to James N. George, M.D., University of Oklahoma Health Sciences Center, Hematology-Oncology Section, P.O. Box 26901, Oklahoma City, OK 73190.

REFERENCES

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This article is based on a clinical practice guideline developed by the American Society of Hematology.

COPYRIGHT 1996 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group