Page 2340 - Hematology_ Basic Principles and Practice ( PDFDrive )

2082 Part XII Hemostasis and Thrombosis

compression of major veins by tumor. Surgical procedures, indwelling mass in PV, enhanced platelet activation, and a prothrombotic
central venous catheters, and chemotherapy can produce vessel wall endothelial phenotype.
injury. In addition, tamoxifen, selective estrogen receptor modulators An acquired point mutation in the Janus kinase 2 gene (JAK2
(SERM), L-asparaginase, and other drugs may induce an acquired V617F) is found in up to 95% of patients with Ph-neg PV and
hypercoagulable state by reducing the levels of natural anticoagulant in 50% to 60% of those with ET. The JAK2 gene encodes a cyto-
proteins. plasmic tyrosine kinase that is critical for signaling between type
L-Asparaginase and combination chemotherapeutic regimens, 1 cytokine receptors and intracellular proliferation mechanisms.
such as breast cancer regimens of cyclophosphamide, methotrexate, Clinical observations, supported by laboratory studies, suggest an
and 5-fluorouracil increase the risk for thrombosis. The incidence of association between the JAK2 mutation and increased leukocyte and
thromboembolic events in children receiving L-asparaginase for treat- platelet activation, particularly in reticulated platelets, and there is a
ment of acute lymphocytic leukemia ranges from 1.1% to 36.7%, correlation between the burden of the mutant allele and thrombin
depending on whether or not catheter-related events are included. generation. Acquired activated protein C resistance secondary to a
The mechanism likely involves decreased synthesis of antithrombin, reduction in free protein S levels has also been demonstrated in
protein C, and protein S, in addition to the retention of antithrombin patients with ET and PV. Overall, there is little to support routine
within the endoplasmic reticulum. Concomitant administration of JAK2 screening unless splenomegaly or an elevated hemoglobin,
steroids increases the risk for thrombosis, and age seems to be an white blood cell, and/or platelet count raises the possibility of an
important risk factor; older children demonstrate a more marked underlying myeloproliferative disorder. However, it may be justifi-
decrease in anticoagulant and fibrinolytic proteins than younger able to check for the JAK2 mutation in patients with unexplained
children, as well as a slower recovery to normal. splanchnic or mesenteric vein thrombosis, even in the absence of
Patients with multiple myeloma and other plasma cell dyscrasias evidence of these findings.
are at increased risk for arterial and venous thrombosis. The reason Current management of PV and ET is aimed at prevention of
for this is unclear, but may include acquired activated protein C major cardiovascular events and is based on the patient’s risk category.
resistance, elevated levels of factor VIII and/or von Willebrand factor, Low-risk patients with PV are managed with phlebotomy, whereas
and the influence of the paraprotein on blood viscosity and fibrino- high-risk patients are given cytoreductive therapy. Low-dose aspirin
lysis. Patients treated with thalidomide or lenalidomide are at high (70–100 mg daily) is recommended for all PV patients regardless of
risk for venous thromboembolism, particularly when these drugs are risk category, and such therapy is highly effective for treatment of the
given in combination with dexamethasone. Current guidelines rec- microcirculatory disturbances in patients with ET.
ommend low-dose aspirin or LMWH thromboprophylaxis for
patients receiving these agents. 20,21
A proportion of patients who present with unprovoked venous Paroxysmal Nocturnal Hemoglobinuria
thromboembolism have occult cancer. This observation has prompted
some experts to recommend extensive screening for cancer in such A rare but serious disorder, paroxysmal nocturnal hemoglobinuria
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patients. Benefits of this approach, however, are likely to be offset by (PNH) is associated with intravascular hemolysis and cytopenia.
potential harms. These include procedure-related morbidity, the PNH is caused by the clonal expansion of a hematopoietic stem
psychological impact of false-positive tests and the cost of screening. cell that has a somatic mutation in the X-linked PIG-A gene,
Furthermore, early detection of cancer is only of benefit if there is which encodes cell surface proteins that serve as phosphatidylino-
potentially curative therapy. To date, only screening for breast, cervi- sitol anchors (see Chapter 31). Patients with PNH may have life-
cal, and possibly colon cancer has been shown to reduce mortality. threatening thrombosis that can be difficult to recognize when it
A careful history should be taken to identify any symptoms sug- affects the splanchnic or cerebral veins. Severe persistent abdominal
gestive of underlying cancer. If such symptoms are present, further pain or headache in patients with PNH should prompt appropriate
investigation is warranted. If there are no symptoms suggestive of radiologic investigations to exclude thrombosis. Although patients
underlying cancer, patients should be encouraged to undergo age- with PNH who have documented thrombosis should be treated
appropriate screening tests for breast, cervical, colon, or prostate with anticoagulants, phlebotomy, cytoreductive therapy, and ecu-
cancer. lizumab are important adjunctive measures to reduce the risk for
recurrence.

Myeloproliferative Disorders
Pregnancy
The most common Philadelphia chromosome-negative (Ph-neg)
myeloproliferative disorders, essential thrombocythemia (ET) and Pregnancy is an independent risk factor for venous thromboembo-
polycythemia vera (PV), are associated with an increased risk for lism: the risk for venous thromboembolism in pregnant women is up
thrombosis, especially arterial thrombosis, and venous thrombosis to sixfold higher than that in age-matched nonpregnant women.
affecting the splanchnic vessels, including the hepatic and portal About 1 in 1000 pregnancies are complicated by venous thrombo-
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veins, which can lead to the Budd-Chiari syndrome, or the mesenteric embolism, and the risk is highest in the postpartum period. Thus
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veins. Thrombosis involving the microcirculation is common in venous thromboembolic disease is the leading cause of maternal
patients with ET, and patients may complain of erythromelalgia, morbidity and mortality and is estimated to account for 12% of
characterized by burning pain, redness and swelling of the fingers and fatalities in pregnancy.
toes, transient visual defects, or recurrent headache. Although ET and The individual risk for venous thromboembolism in pregnancy
PV may evolve to myelofibrosis or transform into acute myeloid and the puerperium, defined as the 6-week period after delivery, is
leukemia, fatal cardiovascular events are a leading cause of mortality. influenced by patient-related factors. These factors include age over
The reported cumulative risk for thrombosis ranges from 2.5% to 35 years, body mass index over 29, cesarean delivery, prolonged
5.0% per patient-year in PV and from 1.9% to 3% per patient-year immobilization, obesity, and thrombophilia or family history of
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in ET, depending on the patient risk category. Age over 60 years venous thromboembolism. Multiparity, ovarian hyperstimulation,
and a previous history of thrombosis are risk factors for serious and a past history or family history of venous thromboembolism are
thrombosis, whereas usual cardiovascular risk factors, such as hyper- other risk factors.
tension, diabetes, dyslipidemia and smoking, may place patients at Over 90% of deep vein thrombosis in pregnancy occurs in the left
intermediate risk. leg because the enlarged uterus further compresses the left iliac vein
The pathogenesis of thrombosis in patients with myeloprolifera- by placing pressure on the overlying right iliac and ovarian arteries.
tive disorders is multifactorial in origin and includes leukocytosis, A similar mechanism likely explains the isolated left iliofemoral
leukocyte activation, rheologic abnormalities due to raised red cell thrombosis that can occur in pregnancy.