Aplastic anemia Dr. musa Q. Hussein Assistant professor Dep Aplastic anemia Dr.musa Q. Hussein Assistant professor Dep.of internal Medicine 9th Nov.2015

Aplastic anaemia A disorder of hematopoiesis characterized by marked reduction or absence of erythroid, granulocytic & megakaryocytic cells in the bone marrow with resultant pancytopenia. The basic problem is failure of the pluripotent stem cells, producing hypoplasia of the marrow elements.

1. primary idiopathic aplastic anemia: Causes: 1. primary idiopathic aplastic anemia: A rare disorder in developed countries with 3-6 new cases per million population per year. An autoimmune mechanism may be responsible in proportion of cases & may occur in association with pregnancy.The diagnosis rests on exclusion of other causes of secondary aplastic anaemia and rare congenital causes such as Fanconi's anaemia.

2. secondary aplasia: A/ drugs: drugs induced aplastic anemia may be dose related or idiosyncratic. They include: 1- cytotoxic drugs: (idiosyncratic) *anti metabolites: flurouracil, mercaptopurin *alkalyting agents: Busulfan, cyclophosphamid *cytotoxic anti biotics: daunorubicin, doxorubicin 2-anti microbial drugs: *anti bacterials: chloramphenicol, dapson, B-lactumantib *antifungals: amphotericin, flucytosine. *antiprotozoals: chlorquine, pyrimethamin 3-anti rheumatic agents: pencillamin, Gold,Indometacin 4-anti convulsants: carbamazepine, phenytoin 5-anti thyroid drugs: carbimazole, methimazol 6-immunosupprassives: azathioprine

*Benzen toluene misuse=glue-sniffing B/ chemicals: *Benzen toluene misuse=glue-sniffing *insecticides: chlorinated hydrocarbons(DDT), organophosphates, carbamates C/ radiation: Acute exposure causes a dose-related transient marrow suppression which is reversible at low doses, but permanent & life-threatening at high doses. D/ viruses: *viral hepatitis: most common. *Epstein-Barr virus *CMV, HIV E/ pregnancy: Women may develop aplastic anemia during pregnancy, in aproportion of cases, aplasia resolved with natural or premature termination of pregnancy the pathogensis & causal relationship is unknown

F/ paroxysmal nocturnal hemoglobinuria: The mechanisms where by PNH induced aplastic anemia are unknown G/associated with congenital disorders: *Fanconi's anemia: Autosomal recessive disorder characterized by progressive pancytopenia, divers congenital abnormalities & increase predisposition to malignancy

Pathophysiology Bone marrow failure results from severe damage to the hematopoietic cell compartment. In aplastic anemia, replacement of the bone marrow by fat is apparent in the morphology of the biopsy specimen and MRI of the spine.

Cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished, and in functional studies, committed and primitive progenitor cells are virtually absent; in vitro assays have suggested that the stem cell pool is reduced to   1% >of normal in severe disease at the time of presentation.

Clinical Features History Aplastic anemia can appear with seeming abruptness or have a more insidious onset. Bleeding is the most common early symptom; a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed.

With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage

Symptoms of anemia are also frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occur early).

A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia.

Physical Examination Petechiae and ecchymoses are typical, and retinal hemorrhages may be present. Pelvic and rectal examinations can often be deferred but, when performed, should be undertaken with great gentleness to avoid trauma; these will often show bleeding from the cervical os and blood in the stool

definitions ECYMOSIS: A macular red or purple hemorrhage more than 2mm diameter ,in skin or mucus membrane. PETECHIA :a hemorrhagic punctate spot 1-2 mm diameter. PURPURA: extravasations of blood resulting in red discoloration of skin or mucus membrane

(typical of platelet disorders) Petechiae (typical of platelet disorders) Do not blanch with pressure (cf. erythema) Not palpable (cf. vasculitis)

Ecchymosis

Pallor of the skin and mucous membranes is common except in the most acute cases or those already transfused. Infection on presentation is unusual but may occur if the patient has been symptomatic for a few weeks.

Lymphadenopathy and splenomegaly are highly atypical of aplastic anemia. Café au lait spots and short stature suggest Fanconi's anemia.

Investigations: 1.full blood count: pancytopenia, reticulocytopenia, normochromic normocytic or slightly macrocytic anemia 2.bone marrow aspirate: Numerous spiculs with empty fatty spaces & few hematopoietic cells 3.bone marrow biopsy : allows a better assessment of the cellularity & permits evaluation for the presence of tumour cells haivy cells & fibrosis.

Laboratory Studies Blood The smear shows large erythrocytes and a paucity of platelets and granulocytes . Reticulocytes are absent or few. lymphocyte numbers may be normal or reduced. The presence of immature myeloid forms suggests leukemia or MDS. nucleated RBCs suggest marrow fibrosis or tumor invasion. abnormal platelets suggest either peripheral destruction or MDS.

Bone Marrow The bone marrow is usually readily aspirated but dilute on smear, and the fatty biopsy specimen may be grossly pale on withdrawal. a "dry tap" suggests fibrosis or myelophthisis. In severe aplasia the smear of the aspirated specimen shows only red cells, residual lymphocytes, and stromal cells. the biopsy (which should be >1 cm in length) is superior for determination of cellularity and shows mainly fat under the microscope, with hematopoietic cells occupying <25% of the marrow space; in the most serious cases the biopsy is virtually 100% fat

treatment

All patients will require blood product support and aggressive management of infection. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die,usually in the first year. The curative treatment forpatients under 30 years of age with severe idiopathic aplastic anaemia is allogeneic HSCT if there is an available donor .

Those with a compatible sibling donor should proceed to transplantation as soon as possible; they have a 75–90% chance of long-term cure. In older patients, immunosuppressive therapy with ciclosporin and antithymocyte globulin gives5-year survival rates of 75%

Such patients may relapse or other clonal disorders of haematopoiesis may evolve, such as -paroxysmal nocturnal haemoglobinuria myelodysplastic syndrome - and acute myeloid leukaemia They must be followed up long-term.

=platelet transfusions Any rational regimen of prophylaxis requires transfusions once or twice weekly to maintain the platelet count >10,000/ L =Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing hormone (FSH/LH) antagonists. --=Aspirin and other nonsteroidal anti-inflammatory agents inhibit platelet function and must be avoided.

Red blood cells should be transfused to maintain a normal level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease); a regimen of 2 units every 2 weeks will replace normal losses in a patient without a functioning bone marrow. In chronic anemia, the iron chelators, deferoxamine and deferasirox, should be added at approximately the fiftieth transfusion to avoid secondary hemochromatosis

Antithymocyte globulin ATG therapy with doses of 15 -40 mg/kg daily for 4-10 days Fever and chills are common during first day of treatment. concomitant treatment with glucocorticoid ,such as methyl- Prednisolon 1 mg/kg/day lessens the reaction to ATG. ATG may accelerates platelets destruction, reduce absolute Neutrophil count and cause positive direct antiglobulin test This effect may increase transfusion requirements during 4-6 day Treatment interval . Serum sickness characterized by spiking fever ,skin rash and Arthralgias occurs commonly 7-10 days from the first dose Approximately one third of patients no longer require transfusion Support after treatment with ATG