Distinct Clinical Entities

AA/paroxysmal nocturnal hemoglobinuria syndrome

Recent studies using a sensitive flow cytometric method have demonstrated that a glycosyl phos-phatidyl inositol (GPI) deficient clone can be present in up to 1/3 of all patients with AA at presentation.7071 While in most of these patients PNH clones are tiny in size, in a significant minority of patients significantly expanded GPI-deficient PNH clones are present. These patients, unlike those with a primary hemolytic form of PNH, may have hypocellular bone marrow and low reticulocyte count. It has been hypothesized that the autoimmune attack responsible for the stem cell depletion in AA generates permissive conditions under which an otherwise dormant PNH clone can evolve.72 73 The finding of a large proportion of PNH cells may be a significant feature, as administration of antithymocyte globulin (ATG) may be associated with a precipitation of a major hemolytic episode.

AA/hepatitis syndrome

AA/hepatitis syndrome has been described as a rare but instructive variant of this disease clearly pointing to a viral etiology of some cases of AA.52'74 Despite extensive laboratory investigation, such a virus has not been

DEB Test found. It appears that the often fulminant hepatitis initiating the disease is caused by a non-A, non-B, non-C hepatitis virus. The hepatitis is associated with jaundice and an often pronounced rise in transaminases. It can result in fulminant liver failure. In patients who survive the hepatitic phase, transaminases, decrease and a latency period characterized by a period of a relative well-being follows. After a variable time period (often several months), pancytopenia develops with a clinical picture typical of severe AA. ATG therapy is effective and can often result in a complete remission. The time course of the syndrome is highly suggestive of virally induced hepatitis, which upon clearance of virus results in induction of cross-reactive T-cell response directed against hematopoietic stem cells.

Chronic moderate AA

In contrast to severe AA, AA with moderately depressed counts has a favorable prognosis and often does not require therapy. The definition of moderate AA is difficult, as it may represent a transition stage of severe AA. A sufficient observation period (>3 months) with chronically and not progressively depressed counts makes the diagnosis of moderate AA. Over time the blood counts may decline, with evolution to a severe AA. It remains unclear whether moderate AA represents a separate entity, a number of nosologic entities such as unrecognized congenital bone marrow failure syndromes or a stage/variant of typical AA.

AA in pregnancy

Pregnancy seems to predispose to AA, but this issue remains controversial. In fact, one of the first cases of AA documented in the early writings on this disease was a young pregnant woman.75 The mechanism that triggers AA in pregnancy remains unclear, but AA often resolves with the termination of pregnancy and can recur during subsequent pregnancies. Even if the initial presentation of AA was not associated with pregnancy, women with a recent history of successfully treated AA should be counseled to not get pregnant. Successful pregnancies have been described, and in the majority of case series most of the women had good outcomes.76 The therapy of pregnancy-associated AA depends on the gestational age of the fetus. The pregnancy of a women with severe AA may be terminated if it is close to term. Earlier in pregnancy, supportive measures are most commonly used. ATG has also been administered to women with severely depressed counts, especially low absolute neutrophil count (ANC). Overall, the prognosis for the mother and baby is good.

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