Blood And Bone Marrow Changes

Anemia is present in 60-80% of patients at presentation.1-5 It is usually mild to moderate in severity and is normocytic, normochromic in morphology. The anemia has the characteristics of anemia of chronic inflammation (formerly anemia of chronic disease) with low serum iron, decreased transferrin saturation, and elevated ferritin. The reticulocyte count is low, reflecting a hypoproliferative state. A bone marrow examination commonly reveals erythroid hypoplasia and a varying degree of myeloma cell infiltration. The pathogenetic mechanisms of anemia in myeloma are beginning to be elucidated. Inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factors (TNFs), and IL-6, often elevated in myeloma patients, suppress hematopoiesis.12 Within the bone marrow microenvironment, myeloma cells, expressing high levels of cell surface Fas-L and TNF-related apoptosis-including lig-and (TRAIL), induce apoptosis of the surrounding immature erythroblasts by binding to the respective death receptors on erythroblasts.13 The increased level of IL-6 induces excessive hepatic production of hep-cidin, which inhibits the intestinal iron absorption and release of iron from reticuloendothelial cells, thus interfering with the iron use.14 In addition, inappropriate erythropoietin response, seen in 25% of patients (and more often as the disease progresses), contributes to the development of anemia, which frequently responds to erythropoietin treatment.1516 In addition to inflammatory cytokines, hyperviscosity may be a cause of the blunted erythropoietin response.1217 Finally, in some patients, the degree of anemia is accentuated because of an expanded plasma volume,18 which in turn is likely a consequence of an increased level of IL-6.19

Severe anemia can occur particularly in patients who have renal failure. Macrocytic anemia with an elevated mean corpuscular volume is seen in up to 20% of patients.20 A few patients may have concomitant folate or vitamin B12 deficiencies, but most have macrocytosis of unknown cause.20 On the other hand, microcytic, iron-deficiency anemia can develop from gastrointestinal (GI) bleeding in patients who have amyloid involvement of the GI tract. RBC rouleaux formation and high erythrocyte sedimentation rate are characteristically seen in patients with high monoclonal protein. Rarely, Howell-Jolly bodies may be present in patients with massive amyloid infiltration of the spleen.

Leukopenia and thrombocytopenia occur in 10-15% of patients at diagnosis. In some, thrombocytosis develops, presumably from the thrombopoietic effect of IL-6.1'2'21 This occurs more often in patients with osteosclerotic myeloma. Occasional plasma cells or plasmacytoid lymphocytes can be seen in the peripheral blood smear. A marked increase in plasma cells, 20% of leukocytes or >2000/^L, is seen in rare cases of primary plasma cell leukemia and more commonly in the terminal phase of myeloma.22

The bone marrow shows myeloma cell infiltration that varies from 10% to total replacement. Myeloma cells are morphologically monomorphic with large, round nuclei and an open chromatin pattern. This is in contrast to reactive plasmacytosis, in which a heterogeneous population of plasma/plasmacytoid cells with variously sized nuclei and condensed chromatin is seen. In some cases, plasmablastic morphology may predominate and predicts a poorer outcome.23 On the bone marrow section, the pattern of myeloma cell infiltration may be diffuse, interstitial, or focal. These patterns appear to be of prognostic significance.24 Some degree of fibrosis, unaccompanied by characteristic features of myeloid metaplasia, is found in up to 10% of patients but has no apparent effect on the clinical course of disease.2425 With special staining, increased microvascular density can be seen in patients with advanced disease and is a poor prognostic factor.26

with bleeding diathesis, manifested as epistaxis, ecchy-mosis, hematoma, or postsurgical bleeding, but more often it is asymptomatic. The underlying cause is the interference of fibrin monomer polymerization by paraproteins.3435 A heparin-like anticoagulant, unrelated to monoclonal protein, was also reported in some patients.36 Rarely, specific inhibitors to coagulation factors, such as factor VIII, and reduced plasma concentration of fibrinogen, factors II, V, VII, VIII, X, and XI were reported.3337 Acquired factor X deficiency, due to absorption and rapid clearance of factor X by the amyloid fibrils, was seen in a few patients with amyloid light chain (AL) amyloidosis.38 Bleeding time may be prolonged, and platelet aggregation, adhesion, and platelet factor III activity may be reduced, possibly from the coating of paraprotein on platelet surface. This abnormality is clinically significant in patients with paraprotein concentration in excess of 5 g/dL.39 Rarely, an acquired von Willebrand syndrome may develop. Monoclonal proteins either bind to von Willebrand factor itself, or interfere with its binding to platelet glycoprotein, or inhibit the binding of fibrinogen to platelets.4041

0 0

Post a comment