Polycythemia is an increase in the total blood RBCs over the upper limit of the reference range. This usually entails a concurrent increase in hemoglobin and hematocrit values. Since various studies disagree somewhat on the values that should be considered the upper limits of normal, partially arbitrary criteria are used to define polycythemia. A hemoglobin level more than 18 gm/100 ml (180 g/L) for men and 16 gm/100 ml (160 g/L) for women, with a hematocrit of more than 55% for men and 50% for women are generally considered consistent with polycythemia.
Polycythemia may be divided into three groups: primary (polycythemia vera), secondary, and relative.
Polycythemia vera has sometimes been included with CML and AMM as a myeloproliferative disease. Polycythemia vera is most frequent in persons between ages 40 and 70 years. Splenomegaly occurs in 60%-90% of patients and is more common in those with leukocytosis. Hepatomegaly is less frequent but still common (40%-50%). Polycythemia vera is reported to progress to myelofibrosis with myeloid metaplasia in about 20%-25% (range, 15%-30%) of cases, usually in 5-15 years. Five percent to 6% of polycythemia vera cases terminate in acute leukemia; this is more frequent after therapy with radioactive phosphorus (average, 10%-20% of cases) or after chlorambucil chemotherapy. The incidence of acute leukemia after phlebotomy therapy is not known with certainty but is believed to be considerably less than that associated with radioactive phosphorus. Clinically, there is an increased incidence of peptic ulcer and gout and a definite tendency toward the development of venous thrombosis.
Laboratory picture.— In classic cases, peripheral blood WBC counts and platelets are also increased with the RBC counts; however, this is not always found. The peripheral blood WBC count is more than 10,000/mm3 (10 x 109/L) in 50%-70% of the cases. About 20%-30% of patients have leukocytosis of more than 15,000/mm3 with relatively mature forms; about 10% have leukocytosis of more than 15,000/mm3 with a moderate degree of neutrophil immaturity (myelocytes and metamyelocytes present). Platelets are elevated in about 25% of cases. There may be small numbers of polychromatophilic RBCs in the peripheral blood, but these are not usually prominent. Bone marrow aspirates usually show marrow hyperplasia with an increase in all three blood element precursors—WBCs, RBCs, and megakaryocytes and with absent marrow iron. A marrow section is much more valuable than marrow smears to demonstrate this. The serum uric acid level is elevated in up to 40% of cases due to the increased RBC turnover.
The classic triad of greatly increased RBC mass (hemoglobin and hematocrit levels), leukocytosis with thrombocytosis, and splenomegaly makes the diagnosis obvious. However, the hemoglobin and hematocrit values are often only moderately elevated, and one or both of the other features may be lacking. The problem then is to differentiate between polycythemia vera and the other causes of polycythemia.
True polycythemia refers to an increase in the total RBC mass (quantity). Relative polycythemia is a term used to describe a normal total RBC mass that falsely appears increased due to a decrease in plasma volume. Dehydration is the most common cause of relative polycythemia; in most cases, the hematocrit value is high-normal or only mildly increased, but occasionally it may be substantially elevated. In simple dehydration, the values of other blood constituents, such as the WBCs, electrolytes, and blood urea nitrogen, also tend to be (falsely) elevated. The most definitive test is a blood volume study (Chapter 10), which will demonstrate that the RBC mass is normal. Stress polycythemia (Gaisbьck’s syndrome) also is a relative polycythemia due to diminished plasma volume. Most persons affected are middle-aged men; there is a strong tendency toward mild degrees of hypertension, arteriosclerosis, and obesity.
Secondary polycythemia is a true polycythemia, but, as the name implies, there is a specific underlying cause for the increase in RBC mass. The most common cause is either hypoxia (due to chronic lung disease but sometimes to congenital heart disease or life at high altitudes) or heavy cigarette smoking (“smoker’s polycythemia,” due to carboxyhemoglobin formation). In some cases associated with heavy smoking the RBC mass is within reference limits but the plasma volume is reduced, placing this group into the category of relative polycythemia. Cushing’s syndrome is frequently associated with mild, sometimes moderate, polycythemia. A much less common cause is tumor, most frequently renal carcinoma (hypernephroma) and hepatic carcinoma (hepatoma). The incidence of polycythemia is 1%-5% in renal carcinoma and 3%-12% in hepatoma. The rare tumor cerebellar hemangioblastoma is associated with polycythemia in 15%-20% of cases. There are several other causes, such as marked obesity (Pickwickian syndrome), but these are rare.
Laboratory tests useful to differentiate secondary and relative polycythemia from polycythemia vera
1. Blood volume measurements (RBC mass plus total blood volume) can rule out relative polycythemia. In relative polycythemia there is a decreased total blood volume (or plasma volume) and a normal RBC mass.
2. Arterial blood oxygen saturation studies frequently help to rule out hypoxic (secondary) polycythemia. Arterial oxygen saturation should be normal in polycythemia vera and decreased in hypoxic (secondary) polycythemia. Caution is indicated, however, since patients with polycythemia vera may have some degree of lowered PO2 or oxygen saturation from a variety of conditions superimposed on the hematologic disease. In smoker’s polycythemia, arterial blood oxygen saturation measured directly by a special instrument is reduced, but oxygen saturation estimated in the usual way from blood gas data obtained by ordinary blood gas analysis equipment is normal. In heavy smokers with polycythemia, a blood carboxyhemoglobin assay may be useful if arterial oxygen saturation values are within reference limits. A carboxyhemoglobin level more than 4% is compatible with smoker’s polycythemia (although not absolute proof of the diagnosis).
3. Leukocyte alkaline phosphatase is elevated in approximately 90% of patients with polycythemia vera; the elevation occurs regardless of the WBC count. Elevated LAP is unlikely in other causes of polycythemia unless infection or inflammation is also present.
4. Bone marrow aspiration or biopsy is often useful, as stated earlier. If aspiration is performed, a marrow section (from clotted marrow left in the syringe and fixed in formalin or Bouin-type fixatives, then processed like tissue biopsy material) is much better than marrow smears for this purpose. However, even bone marrow sections are not always diagnostic. In one study, about 5% of patients had normal or slightly increased overall marrow cellularity in conjunction with normal or only slightly increased numbers of megakaryocytes.
5. Erythropoietin hormone assay may be needed in a few equivocal cases (in most instances this would not be necessary). In polycythemia vera, erythropoietin levels are decreased, whereas in relative or secondary polycythemia, erythropoietin levels are normal or increased.
6. An elevated serum uric acid level without other cause favors the diagnosis of polycythemia vera, since secondary polycythemia is associated with normal uric acid values. However, since uric acid is normal in many cases of polycythemia vera, a normal value is not helpful.