Page 1286 - Hematology_ Basic Principles and Practice ( PDFDrive )

1132 Part VII Hematologic Malignancies

should routinely be performed on ascitic or pleural fluid obtained LABORATORY MANIFESTATIONS
from patients with PMF. Table 70.3 lists the prominent physical
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findings in patients with PMF. Splenomegaly serves as the hallmark Careful examination of the peripheral blood smear and BM (Fig.
of the disease. Its extent may vary, but massive splenomegaly, with 70.2) permits ready diagnosis of PMF. Leukoerythroblastosis with
the organ occupying the entire left side of the abdomen and extend- teardrop RBCs strongly suggests this diagnosis. The leukoerythro-
ing into the pelvis, may occur in 35% of patients. Hepatomegaly blastic condition is characterized by the presence of nucleated RBCs
occurs in almost 70% of cases, and lymphadenopathy is observed and immature myeloid elements in 96% of cases. Megathrombocytes
in 10–20%, but the degree of nodal enlargement is frequently only and megakaryocytic fragments are frequent findings. The number of
moderate. Other important physical findings include pallor, signs teardrop erythrocytes (i.e., dacryocytes) decreases after splenectomy
of cachexia peripheral edema, jaundice, and bony tenderness. Acute or institution of chemotherapy, which has led some to suggest that
monoarticular inflammation caused by secondary gout is seen in 6% splenic fibrosis causes the development of these RBC changes. In
of patients. approximately 60% of patients, hemoglobin levels drop to less
Portal hypertension may occur and is a result of massive increases than 10 g/dL. The degree of anemia is not infrequently difficult
in hepatic blood flow and intrahepatic obstruction. Clinical features to estimate by hemoglobin or hematocrit determinations because
of portal hypertension, such as ascites or esophageal varices, occur individuals with large spleens often have expanded plasma volumes
in 9–18% of patients with PMF. Occasionally, cirrhosis or evidence and apparent anemia, which is largely dilutional in nature. Most
of thrombosis of the portal or hepatic veins has been reported. In patients have normochromic normocytic RBC indices. The anemia
patients with portal hypertension, thrombotic lesions in small- or may be caused by decreased production due to erythroid hypoplasia
medium-sized portal veins and in extrahepatic portal veins were or ineffective erythropoiesis and shortened RBC survival. The cause
observed. Nodular regenerative liver hyperplasia occurred in 14.6% of the hemolytic anemia is usually multifactorial, with contribu-
of cases and correlated closely with the presence of portal vein tions from hypersplenism, a defect in RBCs resembling paroxysmal
lesions. nocturnal hemoglobinuria, and antierythrocyte autoantibodies.
Rarely, the development of PMF can be preceded by the appearance Hypochromic microcytic anemia resulting from iron deficiency
of multiple cutaneous edematous plaques and nodules characteristic secondary to blood loss may develop in 5% of PMF patients. Blood
of Sweet syndrome, a cutaneous process occurring in response to a loss may be caused by leaking esophageal varices, duodenal ulceration,
number of hematologic malignancies. Pyoderma gangrenosum has or intravascular hemolysis. Occasionally, a patient with PMF may
been reported to be associated with PMF, and atypical pyoderma develop an occult malignancy or a site of EMH within the gastro-
gangrenosum is reported to be a complication at splenectomy intestinal tract, which may serve as a bleeding source. Unexplained
incision. microcytosis (mean corpuscular volume <80 fL) has been reported as
PMF may be associated with the development of pulmonary a laboratory feature in PMF and in general has not been shown to
hypertension. These patients present with progressive dyspnea, have prognostic relevance. Macrocytic anemia may complicate PMF.
signs of biventricular heart failure, and rapidly increasing hepato- Folic acid absorption is normal in these patients, and folic acid
splenomegaly. An elevation in pulmonary artery pressure can be deficiency probably results from increased use.
documented by transthoracic Doppler echocardiography and right- Leukopenia can occur in 13–25% of patients, and leukocytosis is
heart catheterization. Many of these patients succumb to cardio- seen in one third. Occasional blast cells and granulocytes with the
pulmonary complications within 18 months of the documentation pseudo–Pelger-Huët anomaly are frequent findings. The leukocyte
of pulmonary artery hypertension. The development of pulmonary alkaline phosphatase score is high in more than half of patients but
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artery hypertension can be attributed to thromboembolic disease, low in about one third. Platelet counts of less than 100,000/mm are
EMH diffusely involving the lung, or pulmonary fibrosis due to the observed in 31% of patients, and platelet counts of more than
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elaboration of fibrogenic cytokines from dysfunctional circulating 800,000/mm have been observed in 12%. In the prefibrotic phase
megakaryocytes and platelets. BM fibrosis also occurs in patients of the disease, almost 90% of patients had platelet counts greater than
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with primary pulmonary hypertension and can be associated with 500,000/mm . Defective platelet function is common, and platelets
anemia and thrombocytopenia. These patients can be distinguished frequently do not respond to collagen or epinephrine. A variety of
from patients with PMF by their lack of high levels of circulat- qualitative platelet anomalies have been documented as abnormal
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ing CD34 cells, teardrop RBCs, hematopoietic cell clonality, and using automated platelet function analyzers such as the platelet func-
absence of molecular markers such as JAK2V617F, CALR, or MPL tion analyzer PF100 or light transmission platelet aggregometry. In
mutations. 15% of patients, abnormalities suggestive of ongoing DIC are found,
The nephrotic syndrome can occasionally be associated with PMF. including decreased platelet numbers, decreased levels of factor V and
Renal EMH is a constant finding in these cases, but renal biopsy VIII, and increased fibrin-split products. Usually, when DIC occurs
may also reveal a picture of mesangioproliferative glomerulopathy or in PMF, it produces no symptoms and unfortunately may only
membranous glomerulonephritis. Immunocomplex deposition with become clinically apparent after surgical intervention. Associated liver
subepithelial electron-dense deposits caused by immunodysfunction dysfunction may also be a contributory factor to prolongation of the
of PMF has been proposed as the pathogenetic explanation for this prothrombin time. In addition, patients with a prefibrotic form of
association. MF with extreme thrombocytosis can develop acquired form of Von
PMF may be associated with preexisting or simultaneously Willebrand disease, which is not infrequently associated with
appearing autoimmune diseases, such as systemic lupus erythe- bleeding.
matosus (SLE), scleroderma, primary biliary cirrhosis, ulcerative Additional laboratory abnormalities are quite common. In one
colitis, polyarteritis nodosa, or juvenile rheumatoid arthritis. These series, lactic acid levels were elevated in 95% of patients, bilirubin
nonmalignant autoimmune forms of MF are most commonly associ- levels in 40%, uric acid in 60%, and alkaline phosphate and serum
ated with SLE. These patients characteristically are young females glutamic oxaloacetic transaminase levels in 50%. Patients with PMF
who have cytopenias and BM fibrosis, but have a limited degree of have decreased levels of total cholesterol. The ratio of high-density
splenomegaly and only mild numbers of teardrop RBC and immature lipoprotein cholesterol to low-density lipoprotein cholesterol is
myeloid cells in the peripheral blood. Circulating immune complexes diminished.
and autoantibodies in SLE are thought to act on the megakaryocyte A variety of immunologic abnormalities have been reported in
Fc-receptors and release growth factors, which are known to induce PMF, including the presence of ANAs, elevated rheumatoid factor
collagen production. titers, direct Coombs test positivity, lupus-type circulating anticoagu-
Patients with autoimmune MF frequently have a positive direct lants, hypocomplementemia, BM lymphoid nodules, and increased
antiglobulin test result and antinuclear antibodies (ANAs) but are circulating immune complexes. In one series of 50 patients with PMF,
negative for MPN-associated genetic markers. They also lack marker increased quantities of circulating immune complexes were detected
cytogenetic abnormalities in 39% and found to be associated with increased disease activity, as