Page 1247 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 68 The Polycythemias 1093

Leukocytosis is present in approximately two-thirds of cases also in patients with reactive thrombocytosis. An inverse correlation
and seems to be proportional to the burden of JAK2V617F. Throm- between the proportion of large vWF multimers and platelet numbers
bocytosis is observed in 50% of cases. Abnormalities of RBC, WBC, has been observed. In addition, normalization of the platelet count
and platelet morphology are frequently observed. The morphologic is accompanied by restoration of a normal vWF multimer pattern.
RBC changes observed during the erythrocytotic phases are charac- These findings suggest that thrombocytosis of any etiology may favor
teristic of iron deficiency and include microcytosis, hypochromia, and the adsorption of larger forms of vWF multimers onto platelet mem-
frequently polychromatophilia. Some anisocytosis and poikilocytosis branes, resulting in their removal from the circulation and subsequent
can be seen as well. Fetal hemoglobin levels and the number of RBCs degradation by platelet-associated proteases. Although patients with
containing fetal hemoglobin, known as F cells, may be increased. MPN frequently have bleeding tendencies, this is not the case in
The WBCs are characterized by normal morphology, although the secondary thrombocytosis, possibly because of the limited periods
numbers of basophils, eosinophils, and immature myeloid forms of extreme thrombocytosis observed in such patients. Patients with
can be increased. Platelet morphology is also quite striking in PV. PV with clinical courses punctuated by hemorrhagic events, extreme
Frequently, megathrombocytes (platelets the sizes of RBCs) are seen thrombocytosis, and acquired von Willebrand syndrome should not
on the peripheral blood smear. Patients frequently have platelet receive aspirin therapy if they are having a thrombotic episode but
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counts of less than 1 × 10 mm , but it is not unusual to observe should be phlebotomized, and platelet-reduction therapy should be
a patient with a platelet count higher than this value. PV-related initiated. Patients with PV and acquired von Willebrand syndrome
MF is characterized by a leukoerythroblastic blood picture, with the have recurrent bleeding from mucous membranes and the digestive
appearance in the peripheral blood of dacryocytes or teardrop RBCs, tract, and easy bruisability. These symptoms frequently resolve with
myelocytes, metamyelocytes, and (rarely) blasts and promyelocytes in normalization of the platelet count.
addition to nucleated RBCs in the peripheral blood. Deficiencies of one or more natural anticoagulants as well as
Platelet aggregation studies do not correlate frequently with the risk the antiphospholipid antibody syndrome have been observed in
of bleeding episodes. The most common abnormalities are decreased patients with PV and thrombosis. These studies indicate that either
primary and secondary aggregation to either or both epinephrine familial or acquired antithrombin III deficiency, protein C or S
and adenosine diphosphate, and decreased response to collagen deficiency, factor V Leiden mutation, or the prothrombin G gene
with generally a normal response to arachidonic acid. An abnormal mutation may contribute to the hypercoagulable state observed in
platelet storage pool disease is a characteristic feature and is caused PV. Of note, although hyperhomocysteinemia caused by deficiency
by abnormal platelet activation. Prothrombin times (PT) and partial of cobalamin or folate can be found in 32–56% of PV patients,
thromboplastin times (aPTT), as well as fibrinogen levels, are usually there is no agreement as to its role in the genesis of thrombotic
normal. Profound abnormalities of the PT and aPTT, however, are episodes. Such inherited disorders associated with the erythrocytosis
frequently reported. This is largely a laboratory artifact caused by the of PV provide a scenario that frequently favors thrombosis in affected
extreme erythrocytosis, which results in a relatively smaller volume of individuals. In attempting to determine if a patient with PV and an
plasma being present in the whole blood sample. Coagulation assays active thrombosis has such an inherited predisposition, it is important
are performed on blood anticoagulated with sodium citrate, and the to be aware that proteins C and S as well as antithrombin III levels
citrate concentration in the anticoagulant is calibrated to chelate the can be low in patients with an ongoing acute thrombosis or liver
plasma calcium and inhibit coagulation reactions. All coagulation cirrhosis. Normal prothrombin and factor VII levels in such patients
assays include the addition of calcium chloride to neutralize the eliminate liver cirrhosis as a cause of the reduction of these circulating
excess citrate and provide free calcium to mediate coagulation reac- anticoagulants. Individuals with inherited prethrombotic conditions
tions. In patients with extreme erythrocytosis, the ratio of citrate in frequently have levels of specific proteins below 10–20% of normal
the collection tube to the volume of plasma is too high; therefore, during periods of active thrombosis.
excess citrate is present, and the standard amount of calcium chloride The leukocyte alkaline phosphatase activity level is elevated
added during the performance of the PT and aPTT is insufficient in 70% of patients. Moreover, recent data indicate an increase of
to neutralize the excessive citrate, and the coagulation assays are neutrophil elastase levels in granulocytes and in plasma that cor-
frequently and factually prolonged. To avoid this problem, the clini- relates with JAK2 mutational status. Whereas serum vitamin B 12
cian should calculate the relative amount of plasma compared with concentrations have been found to be elevated in 40% of patients,
the normal amount and remove the corresponding volume of sodium serum vitamin B 12 -binding proteins are elevated in 70% of patients.
citrate from the blood collection tube. Normal values can then be Hyperuricemia occurs in an overwhelming number of patients, and
confidently anticipated in patients with erythrocytosis. A shortened elevated histamine levels are also frequently observed. BM aspirates
fibrinogen half-life has been detected in some patients with PV and a and biopsies obtained at the time of diagnosis of patients with PV
significantly increased fractional catabolic rate of the plasma fibrino- are hypercellular and display characteristic erythroid, granulocytic,
gen pool per day. In addition, elevated platelet β-thromboglobulin and megakaryocytic hyperplasia. The cellular elements (Fig. 68.6) are
and plasma β-thromboglobulin levels are observed. The constellation frequently morphologically normal. Iron stores are almost uniformly
of findings is indicative of increased platelet turnover. Prothrom- absent in pretreatment biopsy specimens. Significant increases in
bin fragments F1 and 2, thrombin–antithrombin complex, and BM reticulin may be present in biopsies obtained early in the course
D-dimer levels are frequently elevated in PV patients. These are but also may develop during the erythrocytotic phase and may be
enzyme–inhibitor complexes or byproducts of active thrombosis that present for long periods before the onset of the post-PV MF. It is
serve as a biochemical signature of the hypercoagulable state that important to emphasize that individuals may have considerable BM
characterizes PV. fibrosis, which occurs as a consequence of the underlying MPN.
Acquired von Willebrand syndrome occurs frequently in patients The presence of minimal BM fibrosis should not be considered
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with PV and ET with over 1 × 10 /L platelet numbers. This syndrome a harbinger of the development of post-PV MF. In patients with
is characterized by a normal or prolonged bleeding time, normal post-PV MF, a moderate-to-marked increase in reticulin fiber is
factor VIII level, and normal von Willebrand factor (vWF) antigen observed, either simultaneously with or within 1 year of this clinical
level, but abnormal vWF ristocetin cofactor actively associated with transformation.
a decrease or absence of large vWF multimers. This acquired defect Several investigators have attempted to use BM biopsy morphol-
resembles type II vWF disease. Because the molecular size of vWF is ogy as a differential diagnostic tool to differentiate between PV and
a major determinant of its adhesive function and the larger multimers secondary forms of erythrocytosis. The marked hypercellularity,
are most active in achieving hemostasis, the deficiency of large vWF erythroid and megakaryocytic hyperplasia with pleiomorphic enlarged
multimers is associated with a bleeding tendency. The decrease in the megakaryocytes that are the hallmarks of MPNs are useful parameters
frequency of large vWF multimers occurs in patients with platelet for identifying such individuals (see Fig. 68.6). It is imperative to use
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counts over 1000 × 10 L . This abnormality has been reported not the BM biopsy rather than the aspirate specimens for this purpose.
only with patients with severe thrombocytosis caused by MPN, but It has been suggested that those PV patients with minor BM fibrosis