PURE RED CELL APLASIA

By assistant lecture: Waleed fouad

Definition

• Erythropoietic hypoplasia occurring in the absence of abnormalities in the leukopoietic or thrombocytopoietic systems.

• The marrow is normally cellular but devoid of erythroblasts.

Classification

Congenital (Diamond-Blackfan syndrome)

Acquired:• Acute• Chronic

Acquired forms

Hemolytic Disorders (aplastic crisis)

Infection parvovirus B19 and others

Malnutrition

Drug therapy

Thymoma

Immunoglobulin inhibitors (cytotoxic for erythroid precursors, inhibitor of erythropoietin)

Idiopathic or unknown orgin

Congenital (diamond-Blackfan syndrome)

Acute Acquired Pure Red Cell Aplasia

Hemolytic Disorders• In chronic hemolytic anemias,

erythroblasts may suddenly disappear from the marrow for a short time.

• Transient aplastic crisis occurs when reticulocytes disappear from the peripheral blood and progressive anemia follows.

• These episodes often are accompanied by a prodromal illness and usually are followed by recovery, with return of reticulocytes in 7 to 10 days.

Transient erythroblastopenia of

childhood • Reported in children in the course of various

infections or in association with malnutrition.• It occurs most commonly in children between

1 and 4 years of age.• Often associated with prodromal symptoms,

and is almost always self–limited, with complete recovery in a few weeks.

• The presence of serum inhibitors of erythropoiesis has been demonstrated.

Infections • Acute arrest of erythropoiesis also has

been reported in adults during the course of: Respiratory infections. Gastroenteritis. Primary atypical pneumonia. Infectious mononucleosis. Mumps. Viral hepatitis. Parvovirus B19 infection.

DrugsAminosalicylic

acidPhenylbutazone Aspirin

co–trimoxazole Sulfonamide Isoniazid

Colchicines Azathioprine Heparin

Butabarbital Diphenylhydantoin Halothane

Tolbutamide Chlorpropamide Aminopyrine

Complete recovery follows withdrawal of the drug.

Chronic Acquired Pure Red Cell Aplasia

• It occurs in adults. • A rare disease and only a few

hundred cases have been reported. • It has been suggested that two

forms may exist:

Those associated with benign thymoma.Those unassociated with thymic abnormality.

Benign thymoma associated cases

• More than 50% of the patients are females.

• Myasthenia gravis was noted in 14% of the patients in one series.

• Thymectomy may provide immediate hematologic improvement in some patients.

Non Benign thymoma associated cases

• Noted more often in male patients than in females (2:1).

• Has been associated with immunologic, lymphoproliferative, and neoplastic disorders as well as drug and toxic exposures.

• An etiology cannot be established in many patients.

• Noted most often in the fifth to seventh decades of life.

• Antibody-mediated pure red-cell aplasia is a rare syndrome of anemia associated with a low reticulocyte count, an absence of erythroblasts in the bone marrow, resistance to recombinant human erythropoietin (epoetin) therapy, and neutralizing antibodies against erythropoietin.

• This syndrome was reported in patients who had been receiving epoetin administered subcutaneously.

Pathogenesis of acquired form

Two proposed theories:

• The first is called the "seed or stem cell-deficiency theory". It proposes that a common stem cell population is irreversibly altered, rendering it incapable of proliferation and differentiation.

• The second theory is the "microenvironmental deficiency theory", which proposes that the stem cell environment (the marrow) is altered so as to inhibit erythropoiesis.

Congenital Erythroid Hypoplasia of

Diamond–Blackfan

• In 1938, Diamond and Blackfan described a syndrome that they characterized as a slowly developing and progressive anemia, beginning early in infancy, in which the white blood cells and platelets were normal and only red cell precursors in bone marrow were deficient.

• 90% of cases are sporadic and are caused by in utero damage to erythroid stem cells while 10% of patients have a dominant, or more rarely recessive, familial pattern.

Manifestations

Anemia is the primary problem in PRCA.The degree of anemia can range fromsubclinical to severe according to type:

In acquired acute PRCA:

• Anemia is barely noticeable because the decrease in the hemoglobin level is gradual and self-limited.

• Evidence of a recent viral infection:

Rash, jaundice in viral hepatitis.Splenomegaly in infectious mononucleosis.Enlarged parotid glands in mumps.

In acquired chronic PRCA:

• Evidence of anemia.

• Physical findings of underlying thymomas, however, thymomas are rarely large enough to be detected during the physical examination.

• Lymphadenopathy and splenomegaly may indicate the presence of an underlying lymphoproliferative disorder.

In congenital PRCA:

• Some, but not all cases are associated with severe anemias.

• Anemia is often not observed during the early neonatal period, but pallor, weakness, and dyspnea develop during the first year of life.

• Physical abnormalities involving the head, upper limbs, thumbs, urogenital system or cardiovascular system may be detected.

Work up for a case of PRCA

Basic studies include:

• CBC counts. • Reticulocyte count.

Studies to rule out hemolysis include:• Lactate dehydrogenase.• Indirect bilirubin.• Serum haptoglobin.

• Parvovirus B19 infection.• Infectious mononucleosis.• Atypical mycoplasmic pneumonia.• Mumps.• Viral hepatitis.

In acute PRCA, rule out the following:

• HIV infection. • Thymoma. • Chronic active hepatitis. • Systemic lupus erythematosus. • Autoimmune disorders (direct Coombs test).• Collagenvascular disorders.

In acquired chronic PRCA, rule out the following:

• Fetal Hgb and erythrocyte adenine deaminase levels.

• Serum folate and vitamin B12 levels.• Genetic testing.• Peripheral smear results Can show

megaloblastic changes.

For congenital PRCA

• Bone marrow aspiration and biopsy are indicated to confirm the diagnosis.

• It usually reveals a selective depletion in RBC precursors.

• In acute PRCA, bone marrow aspiration and biopsy performed during the recovery phase may yield misleading findings that suggest active erythropoiesis.

Bone marrow

• In congenital PRCA, megaloblastosis of RBC precursors may be observed and occasionally, a depression in the level of megakaryocyte and WBC precursors occurs.

• Findings from biopsy of a thymoma usually reveal that the tumor is encapsulated and contains primarily spindle cells, with or without small lymphocytes.

TREATMENT

Acute self-limited PRCA:• Discontinue offending drugs and treatment

of associated infections or other illness. • Transfusion therapy is not usually indicated

because of the self-limited nature of acute PRCA.

• Transfusions may be indicated in patients with hemolytic anemias who develop PRCA.

Acquired chronic PRCA:

• The underlying disorder should be treated.

• Corticosteroids can be effective, but a high dosage is often required, and the adverse effects frequently preclude using these agents.

• However, some patients respond to low doses of corticosteroids.

• Prednisone can induce remission in approximately 45% of cases.

• If the underlying cause of PRCA is immunological and the response to corticosteroids has been inadequate, the next level of treatment is with cytotoxic or immunosuppressive drugs.

• Cyclophosphamide, 6-mercaptopurine, azathioprine, and cyclosporine have all been used.

• These drugs have been effective at dosages sufficient to induce leukopenia.

Congenital PRCA

• Treatment is complicated because this condition is a lifelong disorder, and the consequences of treatment can have devastating effects on growth and sexual maturity.

• Transfusion is an integral modality in treating congenital PRCA.

• With severe anemia, patients can have a lifelong dependency on transfusions.

• Two units of blood every 2 weeks is usually sufficient.

• Aggressive chelation using deferrioxamine infusions are critical to avoid hemosiderosis because transfusion therapy is usually started at a young age.

• Corticosteroids are also a principal therapeutic option, and this therapy is believed to allow the abnormal stem cells in patients with congenital PRCA to become more sensitive to growth factors.

• High doses of prednisone (1-2 mg/kg) are needed but should not be continued for more than 4-6 weeks.

• If prednisone therapy fails, a high-dose methylprednisolone can be tried.

• The major complications of corticosteroid therapy in these patients are growth retardation, muscle weakness, and osteopenia.

• Danazol and other androgens can be used in refractory cases, but these agents may be contraindicated in prepubertal children.

• Surgical Care: Surgical care may be indicated if a thymoma is suspected or if the patient has significant hypersplenism.

Prognosis• Prognosis varies widely, depending on:

Etiology.Underlying disorders.Clinical course.

• Acute self-limited PRCA usually has an excellent prognosis.

• Acquired chronic PRCA is associated with a number of complications.

• Congenital PRCA is usually a lifelong disorder and is associated with a high morbidity rate due to the disorder and the treatment adverse effects.

• Most patients survive through early adulthood.

THANK YOU