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Chapter 70 Primary Myelofibrosis 1131

a degradation product of VCAM-1, is elevated in the plasma of PMF Summary of Symptoms and Physical Findings of
patients, and these levels correlate with the absolute numbers of TABLE Patients With Primary Myelofibrosis Detected at
+
CD34 cells in the peripheral blood. In addition, these elevated levels 70.3 Diagnosis
of proteases have been shown to be responsible for degradation of the
+
chemokine CXCL12, which plays a role in retention of CD34 cells Symptom or Finding Incidence (%)
within the BM because the degradations products lack the ability to Asymptomatic 16–30
+
attract CD34 cells, thereby favoring their mobilization. By contrast,
the amount of intact CXCL12 present within the spleen is increased, Fatigue 47–71
likely favoring the homing and localization of HPC/HSC to extra- Fever 5–15
medullary sites such as the spleen. Furthermore, CXCR-4 expression Weight loss 7–39
+
by PMF CD34 cells is epigenetically downregulated, which may
account for altered CXCL12–CXCR-4 interactions, participating in Night sweats 6–21
+
CD34 cell mobilization. This downregulation of CXCR4 expression Symptoms due to enlarged spleen 11–48
can be reversed in vitro by treatment with chromatin-modifying agents. Bleeding 5–20
Furthermore, the expression levels of CXCR4 were significantly lower
in patients with a high burden of JAK2V617F (allele frequency: 75%) Gout or renal stones 6–13
compared with patients with low-burden JAK2V617F, suggesting the Pallor 60
dependence of gene expression on the frequency of the mutated allele. Petechiae or ecchymoses 15–20
+
Similar degrees of CD34 cell mobilization are observed in post-ET Splenomegaly 89–99
and post-PV MF, as occurs in PMF. In PV patients, Passamonti and
coworkers have demonstrated a relationship between JAK2V617F Hepatomegaly 39–70
+
allele burden and the degree of constitutive mobilization of CD34 Peripheral edema 13
cells, suggesting that such mobilization may be a consequence of the Evidence of portal hypertension 2–6
transition from JAK2V617F heterozygosity to homozygosity that is
accompanied by granulocyte activation. Drugs that target the prote- Lymphadenopathy 1–10
+
ases responsible for constitutive CD34 cell mobilization may present Jaundice 0–4
a possible strategy to prevent the establishment of extramedullary sites
of hematopoiesis in patients with PMF.
The kinetics of engraftment of normal stem cells after aSCT in
PMF patients and the slow regression of fibrosis after transplant
lead one to question if the distorted BM architecture associated Thrombotic episodes are rarely a presenting feature of the disease
with fibrosis in PMF actually disrupts the functions of the BM but may occur during its course, with a probability of 9.6% at 5 years,
microenvironment. In PMF patients, normal stem cells engraft a rate higher than in the control general population. Thromboses
after transplant and hematopoietic cell recovery occurs before the may be venous (cerebral venous sinus thrombosis, splanchnic vein
BM fibrosis has resolved. These observations raise some questions thrombosis, deep venous thrombosis, pulmonary thromboembolism)
concerning the prospects for success with strategies for the treatment or arterial (stroke, transient ischemic attacks, retinal artery occlusion,
of patients with PMF that are directed solely toward reversing the BM myocardial infarction, angina pectoris, and peripheral arterial disease).
fibrosis rather than eliminating the malignant clone and its progeny. The cellular phase of PMF with thrombocytosis and presence of
Furthermore, in mouse models of MF, inhibition of TGF-β1 was cardiovascular risk factors such as hypertension, smoking, hypercho-
7
capable of preventing the development of BM fibrosis but did not lesterolemia, and diabetes are independent predictors of thrombosis.
rescue animals from a fatal MPN. The prefibrotic phase of MF as defined by WHO criteria is associated
with a higher thrombotic risk than that observed in ET patients.
After splenectomy, the rate of thrombosis increases and is associated
CLINICAL MANIFESTATIONS with the development of thrombocytosis after the procedure. A sys-
tematic review of JAK2V617F-positive PMF patients failed to clearly
Table 70.3 lists the symptoms and physical findings of patients with define a statistically significant increased risk of thrombosis in this
PMF at presentation. population.
Approximately 25% of patients are entirely asymptomatic and Bleeding problems may complicate the clinical course of PMF
come to medical attention because of an enlarged spleen detected patients and range from petechiae and ecchymoses, to life-threatening
during routine physical examination or because of an abnormal blood issues such as uncontrollable esophageal variceal bleeding. Bleeding
cell count or peripheral blood smear. The most common symptom in can be a direct result of thrombocytopenia or impaired platelet func-
PMF is fatigue, which in the majority of patients affects the quality tion. Bleeding may be only initially encountered during a surgical
of daily life and social activities. Fatigue may be the result of anemia, procedure such as splenectomy; in this case, the bleeding diathesis
which leads to the associated complaints of weakness, dyspnea on may result from inapparent disseminated intravascular coagulopathy
exertion, and palpitations. But when patients were questioned with and has the potential for catastrophic consequences.
the aid of specific questionnaires, fatigue was found to be a significant Occurrence of isolated sites of ectopic sites of EMH occur
burden even in patients who were not anemic. The presence of anemia, particularly in the pulmonary, gastrointestinal, central nervous, and
splenomegaly, and other features associated with advanced disease genitourinary systems. EMH can rarely occur in the skin, manifesting
favors the development of higher levels of fatigue. Other nonspecific as nontender, occasionally pruritic red, pink, or violaceous plaques,
constitutional symptoms, including fever, night sweats, pruritus, bone papules, or hemangioma-like nodules. These dermal infiltrates, when
pain, and weight loss, are present at diagnosis in 20–50% of patients biopsied, are composed of combinations of myeloid, erythroid, and
with PMF and are more frequent in older patients. megakaryocytic cells. Patients with nonsplenic EMH, depending on
With enlargement of the spleen, various syndromes character- the location, can present with cough, headache, or paralysis resulting
ized by abdominal discomfort emerge. Pressure of the spleen on from “brain tumors or spinal cord tumors,” small-bowel obstruction,
the stomach may lead to delayed gastric emptying and early satiety. or intractable ascites from ectopic implants of hematopoietic tissue
Patients may merely complain of a dull, heavy sensation in the in the gut or peritoneum. Ascites occurring in a patient with PMF
left upper quadrant. Pain of extreme severity, simulating an acute may result from peritoneal or mesenteric implants of EMH or from
abdominal emergency, is produced by splenic infarction. Pressure of portal hypertension. If the ascites result from peritoneal implants, the
the spleen on the colon or small bowel may be responsible of severe, fluid is always exudative and sterile, and frequently contains myeloid,
disabling diarrhea. erythroid, and megakaryocytic elements. Such cytologic studies