CHAPTER 61 POLYCYTHEMIA
CHAPTER 61 POLYCYTHEMIA
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Polycythemia is characterized by an increase of the total body red cell volume. It exists in the primary form, polycythemia rubra vera, a clonal neoplastic disorder, and in secondary forms due to appropriate or inappropriate increases in levels of EPO. Such increases may occur, for example, in persons residing at high altitudes, in heavy smokers, in patients with cardiopulmonary disease, and in patients who inherit abnormal, high-affinity hemoglobins. Although primary and secondary polycythemia are entirely different disorders, they are discussed together here because the patients’ presentations may be quite similar, and the correct diagnosis is of great importance. Primary polycythemia is characterized by increases not only of the numbers of red cells but also of granulocytes and platelets and by splenomegaly. These findings are not usually present in secondary polycythemia. Control of both types of polycythemia can be achieved by phlebotomy. Myelosuppression is usually used only in primary polycythemia, where drugs such as hydroxyurea, busulfan, chlorambucil, interferon, and anagralide may be useful in controlling not only the hemoglobin levels of blood but also the concentration of other formed elements.
Acronyms and abbreviations that appear in this chapter include: BFU-E, burst forming unit–erythroid; 2,3-BPG, 2,3-bisphosphoglycerate; CFU-E, colony forming unit–erythroid; COPD, chronic obstructive pulmonary disease; EPO, erythropoietin.
This chapter is based, in part, on Chapter 70 “Secondary polycythemia (erythrocytosis)” by Dr. Allan J. Erslev in the 5th edition of this text.
DEFINITION AND HISTORY
The term polycythemia, denoting an increased amount of blood, has traditionally been applied to those conditions in which the number of erythrocytes is increased. Primary polycythemia, polycythemia rubra vera (polycythemia vera), is an abnormality of the hematopoietic stem cell characterized by uncontrolled proliferation of erythroid, granulocytic, and megakaryocytic cells. Secondary polycythemia, more appropriately secondary erythrocytosis, refers to those conditions in which only the erythrocytes are increased in number and volume. Although the term secondary erythrocytosis is more descriptive of this group of disorders, secondary polycythemia is a time-honored name and will be used interchangeably with secondary erythrocytosis. A classification of these disorders is presented in Table 61-1.
TABLE 61-1 CLASSIFICATION OF POLYCYTHEMIA AND ERYTHROCYTOSES
Polycythemia vera was first described in 1892 by Vaquez.1 In 1903 Osler reviewed four cases of his own and an additional five from the literature. He wrote, “The condition is characterized by chronic cyanosis, polycythemia, and moderate enlargement of the spleen. The chief symptoms have been weakness, prostration, constipation, headache, and vertigo.”2 The increased proliferation of granulocyte precursors and megakaryocytes was first described by Türk in 1904.3
Secondary polycythemia is a term that describes a group of disorders characterized by an increased red cell mass brought about by enhanced stimulation of red cell production. Secondary polycythemia may be subdivided into appropriate polycythemia in which the erythron is responding normally to hypoxia and inappropriate polycythemia in which erythropoiesis is being stimulated by the aberrant production of or response to erythropoietin. In his famous monograph on barometric pressure published in 1878,4 Paul Bert showed that the physiologic impairment observed at high altitude was due to a reduction in the oxygen content of air. A few years earlier his friend and mentor Dennis Jourdanet had observed an increase in the number of red corpuscles in the blood of the highlanders of Mexico,5 and Bert recognized that such an increase would tend to ameliorate the effect of atmospheric hypoxia. However, neither he nor Jourdanet suspected a cause-effect relationship. It was actually not until Viault6 in 1890 observed a prompt increase in the number of his own red corpuscles after having traveled from Lima, Peru, at sea level to Morococha at 4570 m (15,000 ft) above sea level that altitude erythrocytosis was accepted as a compensatory adaptation to hypoxia.7 At about the same time, it was observed that many patients with cyanosis were also polycythemic. Both the cardiacos negros8 with severe pulmonary failure and arterial oxygen desaturation and the children with morbus caeruleus, or right-to-left shunt through a congenital cardiac malformation, were found to have increased red cell counts.9 Mechanical or neurogenic hypoventilation as a cause of cyanosis and polycythemia was first popularized in 1956 with the classic description of the Pickwickian syndrome by Burwell and colleagues.10,11 More recently, there has been an increasing interest in the polycythemia associated with arterial hypoxemia due to smoking and with tissue hypoxia due to inherited abnormal hemoglobins with high oxygen affinity. The erythrocytosis associated with abnormal hemoglobins with an increased affinity to oxygen also represents an appropriate response to hypoxia first noted by Charache and coworkers12 in 1966 when they described hemoglobin Chesapeake.
Inappropriate polycythemia may occur as a result of aberrant erythropoietin production by the kidney, by certain tumors, or by the ingestion of cobalt. Familial erythrocytosis is a rare autosomal dominant or a recessive form of inappropriate polycythemia.
In addition to appropriate and inappropriate secondary polycythemia there are some patients with mild erythrocytosis in which neither the cause or the clinical significance is clear. These patients do not have an increased red cell mass and their erythrocytosis is the result of a decreased plasma volume. The disorder is therefore not a true erythrocytosis and is designated apparent, spurious, or relative polycythemia. As long ago as 1905, Gaisbock reported that a number of hypertensive patients had plethora and an elevated red cell count but no splenomegaly, a condition he termed polycythemia hypertonica and that is now sometimes called Gaisbock syndrome.13,14 In 1952 direct measurement of the blood volume in patients with polycythemia led Lawrence and Berlin to identify a subgroup of patients with a normal red cell volume but a reduced plasma volume. Although some members of this group were hypertensive, the authors were more impressed by their tense and anxious behavior and coined the term stress polycythemia.14
ETIOLOGY AND PATHOGENESIS
Polycythemia vera arises from transformation of a single stem cell into a cell that has a selective growth advantage and that then gradually becomes the predominant source of marrow precursors. The clonal origin of polycythemia vera has been demonstrated in women heterozygous for a polymorphic X-chromosome marker, glucose-6-phosphate dehydrogenase.15 (see Chap. 9) In each case all hematopoietic cell lineages express either the enzyme encoded by the maternal or paternal X chromosome, whereas nonhematopoietic cells are a mosaic of both enzyme types.
Examination of marrow-derived colonies from patients with polycythemia vera indicates that BFU-Es with normal EPO sensitivity coexist in the marrows of patients along with cells that are EPO-independent or hyperresponsive.16,17,18 and 19 The latter cells are the hallmark of the neoplastic change that results in uncontrolled production of erythrocytes. Other abnormalities that have been described include impaired thrombopoietin-mediated platelet tyrosine phosphorylation20 expression of Bcl-x, an inhibitor of apoptosis in an increased proportion of erythroid precursors,21 and increased expression of protein tyrosine phosphatase activity by red cell precursors.22 The fibroblasts that accumulate in the marrow of patients with polycythemia vera as the disease progresses are not a part of the abnormal clone. Rather they seem to be a response to the proliferating marrow cells, perhaps to the platelet-derived fibroblast growth factor elaborated by megakaryocytes.23
About a quarter of the patients have karyotypic abnormalities at diagnosis,24,25 and the incidence rises as the disease progresses.25 It is very likely that a somatic mutation is responsible for the disorder, but its nature is currently unknown. Since most patients have a normal karyotype at the time of diagnosis, gross genetic rearrangements do not seem to be the cause of the disease. There do appear to be genetic factors in susceptibility to polycythemia vera. Although most patients with polycythemia vera do not have a family history of the disorder, there are a number of reports of familial incidence,26 but the mode of inheritance is unclear. The disease appears to be more common in Jews of European extraction27 than in most non-Jewish populations. Indeed, of Osler’s four original patients, two were Jewish.2 The incidence of polycythemia was reported to be 6.7/1,000,000 in Israel28 and 4.9/1,000,000 in Baltimore.29 However, a higher incidence, increasing from 10 in 1950 to 1959 to 26 per million in 1980 to 1984 has been reported from Malmo, Sweden.30
High-Altitude Polycythemia The adaptive adjustments of humans living at high altitude involve a series of steps that reduce the steepness of the oxygen gradient between the atmosphere and the mitochondria31 (Fig. 61-1). The initial oxygen gradient between atmospheric and alveolar air can be reduced by an increase in respiratory rate and volume. Since dead space and water vapor pressure are constant and acclimatized individuals do not ventilate excessively, the normal sea level gradient of about 60 torr is only reduced to about 40 torr at Morococha at 4540 m (14,900 ft) above sea level.31 Further reduction can be achieved, and at the top of Mount Everest extreme hyperventilation reduces the gradient to less than 10 torr. A shift in the oxygen dissociation curve to the right may be of benefit for short-term high-altitude acclimatization,32 but its usefulness for chronic acclimatization has probably been exaggerated.33 In the unacclimatized subject exposed acutely to high altitude, hyperventilation alkalosis leads initially to a shift of the oxygen dissociation curve to the left and to additional tissue hypoxia. The alkalosis and the hypoxia will in turn promote red cell synthesis of 2,3-bisphosphoglycerate (2,3-BPG) and ATP and cause the oxygen dissociation curve to shift back to a normal or even a right-shifted position (Chap. 26). In chronic acclimatization, the blood pH slightly increased, and when this is taken into account the dissociation curve is shifted approximately normal.34 It actually seems very questionable if a shift to the right would be to the advantage of high-altitude dwellers.35
FIGURE 61-1 The oxygen gradient from atmospheric air to the tissues in individuals living at sea level and in Morococha, Peru, at 4540 m (14,900 ft) above sea level.
Cardiac and Pulmonary Disease Degrees of arterial hypoxia comparable to those observed in individuals at high altitudes are observed in patients with right-to-left shunting due to cardiac or intrapulmonary shunts or to ventilation defects as in chronic obstructive pulmonary disease (COPD). Patients with right-to-left shunting develop a degree of erythrocytosis that is quite comparable to that observed with similar degrees of desaturation at high altitudes,36 but many patients with COPD with severe cyanosis are not polycythemic. This has been attributed to the infection that is often present in the lungs of these patients and to an increase in plasma volume. COPD is frequently associated with cyanosis, clubbing, and arterial oxygen desaturation.37,38 The sleep apnea syndrome39 can, if severe, cause arterial hypoxemia and hypercapnia, somnolence, and secondary polycythemia.40 Central alveolar hypoventilation due to an impaired respiratory center has been reported following cerebral thrombosis, parkinsonism, encephalitis, and barbiturate intoxication.41 Peripheral alveolar hypoventilation due to mechanical impairment of the chest may be seen in patients with myotonic dystrophy, poliomyelitis, or severe spondylitis.42,43 and 44 In the colorful Pickwickian syndrome,11 characterized by extreme obesity and somnolence, the associated erythrocytosis appears to be caused by a combination of central and peripheral hypoventilation. Eisenmenger syndrome, characterized by elevated pulmonary vascular resistance and right-to-left shunting of blood, is usually accompanied by erythrocytosis.45
Smoker’s Polycythemia Heavy smoking will result in the formation of carboxyhemoglobin, which does not transport oxygen and also causes an increase in oxygen affinity of the remaining normal hemoglobin. This leads to tissue hypoxia, erythropoietin production, and stimulation of red cell production.46 Smoking may also cause a reduction in plasma volume,47 and these two effects could easily explain the rise in the hematocrit without significant changes from normal in the red cell or plasma volumes. Chronic carbon monoxide poisoning is an important but generally unappreciated cause of mild polycythemia.48
Polycythemia Secondary to Abnormal (High-Affinity) Hemoglobins Hemoglobinopathies with certain amino acid substitutions may result in an increased affinity for oxygen, producing tissue hypoxia and a compensatory erythrocytosis. Mutations affecting the amino acids of the a1b2-globin chain contact affect normal rotation within the molecule and impair the rate of deoxygenation. Changes in the carboxy terminal and penultimate amino acids will also impair intramolecular motions and tend to keep the molecules in a high-affinity state. Alterations in the amino acids lining the central cavity will destabilize the binding of 2,3-BPG in this cavity and lead to increased oxygen affinity. Finally, heme pocket mutations may in some cases interfere with deoxygenation; however, most hemoglobins with mutations involving amino acids in the heme pocket are unstable and associated with hemolytic anemia and cyanosis. The inheritance of these hereditary disorders is autosomal dominant. An up-to-date listing that includes such hemoglobin variants may be found on the internet at the following addresses: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141900#VariantList; http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141800; and http://www.ncbi.nlm.nih.göv/htbin-post/Omim/dispmim?141850.
Polycythemia Secondary to Red Cell Enzyme Deficiencies Deficiencies of red cell enzymes in early steps of glycolysis sometimes cause marked decreases in the levels of 2,3-BPG. This results in an increased oxygen affinity of hemoglobin and, in some cases, polycythemia. Polycythemia is particularly likely to occur in bisphosphoglyceromutase deficiency49 and in phosphofructokinase deficiency.50 Polycythemia has also been observed in the “high ATP syndrome” associated with an abnormality of pyruvate kinase.51 Occasionally mild erythrocytosis occurs in patients with methemoglobinemia due to cytochrome b5 reductase (methemoglobin reductase) deficiency36 (see Chap. 49).
Chemically Induced Tissue Hypoxia A number of chemicals have been suspected of causing histotoxic anoxia and secondary polycythemia, but the only chemical with a predictable capacity to cause erythrocytosis is cobalt. Cobalt administration will increase the oxygen tension in subcutaneous air pockets in rats36 as well as increase erythropoietin production36; it seems likely that it acts by inhibiting oxidative metabolism. This erythropoietic effect has led to the therapeutic administration of 60 to 150 mg of cobalt chloride to patients with refractory anemias such as the anemias of chronic infection, cancer, or uremia.52 Consequently, in the treatment of anemias, an agent that causes histotoxic anoxia is not much better than a trip to the top of Pikes Peak.
Familial Erythrocytosis Most patients with familial erythrocytosis have been shown to have mutations of the EPO receptor. The mutations are usually ones that cause truncations of the carboxy terminal of the receptor,53,54,55,56 and 57 resulting in constitutive activity of the receptor or hypersensitivity to EPO. The disorder is inherited in an autosomal dominant manner.
An endemic form of erythrocytosis occurs in the population of the Chuvash Autonomous Republic, located on the west bank of the Volga River in the central part of European Russia.58 There is no abnormality in the EPO receptor in these patients, and there seems to be no linkage with the EPO gene. Unlike the patients who have lesions of their EPO receptors, genetic transmission seems to be autosomal recessive.
A child with hypersecretion of EPO without any evident cause has been studied.59 It was suggested that an abnormality in the pathway that regulates EPO levels may have been present in this patient.
Renal Polycythemia Absolute erythrocytosis has been observed in a considerable number of patients with solitary renal cysts, polycystic renal disease, or hydronephrosis.60 In most of these cases erythropoietin assays on cyst fluid, serum, or urine have disclosed the presence of erythropoietin.61 In general, it appears that patients with polycystic disease have a hematocrit value slightly higher than normal and definitely higher than would have been expected of patients with uremia. In some patients on prolonged dialysis treatment cystic transformation occurs in the native kidneys. This acquired cystic disease is occasionally associated with marked erythrocytosis.62 It has been estimated that about 1 to 3 percent of all patients with hypernephromas have erythrocytosis.63 In many of these, erythropoietin assays of serum and urine have disclosed higher-than-normal levels, and the erythrocytosis is most likely caused by excessive erythropoietin secretion. This assumption has been supported by the presence of erythropoietin mRNA in tumor cells.64 Wilms’ tumors65 and metanephric adenomas66 are also occasionally associated with an erythrocytosis.
Post–renal transplantation erythrocytosis occurs in about 10 percent of patients67 but is usually mild and time-limited and in many cases may have been caused by excessive use of diuretics. In some cases this erythrocytosis is associated with an increase in erythropoietin production and has been treated successfully in a few patients with theophylline or captopril, both believed to attenuate erythropoietin production.68,69 and 70 A role of insulin growth factor-1 has also been proposed in the erythrocytosis that occurs after transplantation,71 and the effect of angiotensin-activating enzyme in controlling the erythrocytosis72 may be due to suppression of this growth factor. Studies of venous effluents have determined that the native rather than the transplanted kidneys are the source of the inappropriate production of erythropoietin,73 and removal of the native kidneys has led to rapid restoration of normal hematocrit values.74
Successful extirpation of renal lesions in patients with erythrocytosis has in many cases been followed by hematologic remission.60 Subsequent relapses have been described in patients developing metastatic recurrence of the tumors in the contralateral kidney.75
A partial obstruction of the renal artery would be expected to cause renal tissue hypoxia and a physiologic stimulation of erythropoietin production. Nevertheless, it has proved quite difficult to induce an erythrocytosis in laboratory animals by inserting a Goldblatt clamp on the renal arteries.76 Only a few of the many patients who have arteriosclerotic narrowing of the renal arteries have been reported to have been polycythemic.77
Polycythemia with Connective Tissue Tumors Occasionally there is an association of erythrocytosis with large uterine myomas78 and rarely with cutaneous leiomyomas.79 Usually the tumor has been huge, and extirpation has routinely been followed by a hematologic “cure.” It has been suggested that the tumor may interfere with pulmonary ventilation, but arterial gas findings have been normal in the few patients so studied. Another possible mechanism is that the large abdominal mass causes mechanical interference with the blood supply to the kidneys, resulting in renal hypoxia and erythropoietin production. Inappropriate erythropoietin secretion by smooth muscle cells has been demonstrated both in uterine myomas and in one case of cutaneous leiomyoma.78,79 Isolated instances of polycythemia attributed to a myxoma of the atrium,80 hamartoma of the liver,81 and focal hyperplasia of the liver82 have been documented.
Brain Tumors Erythrocytosis and inappropriate secretions of erythropoietin may be found in about 15 percent of patients with cerebellar hemangiomas.83,84 In adequately studied patients the arterial gas tensions have been normal. That the tumors are directly responsible for the polycythemia can be surmised from the identification of erythropoietin in cyst fluid and stromal cells and from a case in which erythropoietin mRNA was present in the tumor.85
Hepatoma In 1958, McFadzean and coworkers reported that almost 10 percent of patients in Hong Kong with hepatocarcinoma developed erythrocytosis.86 Since then, this association has been recognized as an important clinical clue in the diagnostic consideration of patients with liver disease.87 The cause of erythrocytosis is probably inappropriate production of erythropoietin by the neoplastic cells.88 Normal hepatocytes and to a lesser degree nonparenchymal liver cells produce small amounts of erythropoietin both constitutively and in response to hypoxia.
Endocrine Disorders Pheochromocytomas,89 aldosterone-producing adenomas,90 Bartter syndrome,91 and dermoid cyst of the ovary92 have been described in association with erythrocytosis. Erythropoietin levels were found elevated in the serum and returned to normal after extirpation of the tumors. A number of pathogenetic mechanisms have been suggested, including mechanical interference with renal blood supply; hypertensive damage to renal parenchyma; functional interaction between aldosterone, renin, and erythropoietin; and inappropriate secretion of erythropoietin by the tumors. The mild polycythemia frequently observed in patients with Cushing syndrome may be caused by an excessive release of glucocorticoids.
The erythropoietic effect of androgens is of considerable practical importance. For many years, it was assumed that the higher red cell count in males was caused by androgens, but it was not until pharmacologic doses of testosterone were administered to women with carcinoma of the breast that the erythropoietic potency of androgens was appreciated.93 Since then various androgen preparations have been used in the treatment of refractory anemias,94,95 occasionally causing dramatic overshoots into the polycythemic range (Fig. 61-2).
FIGURE 61-2 Erythropoietic response to testosterone derivatives in a patient with myelofibrosis.
The erythropoietic effect of androgens appears to be caused both by their capacity to stimulate erythropoietin production96 and by their capacity to induce differentiation of marrow stem cells directly. These two effects have specific structural requirements. Androgens with the 5a-H configuration stimulate renal and extrarenal erythropoietin production, while androgens with the 5b-H configuration enhance the differentiation of stem cells.96
Neonatal Erythrocytosis Erythrocytosis at birth is a normal physiologic response to intrauterine hypoxia and to the high oxygen affinity of fetal red cells (see Chap. 7 and Chap. 28). However, it may become excessive and even symptomatic, especially in infants of diabetic mothers or if the clamping of the cord is delayed, permitting placental blood to boost the blood volume of the infant.97 Since it is difficult to recognize symptoms of hyperviscosity in the neonate, many pediatricians perform a partial exchange transfusion if the venous hematocrit is above 65 percent at birth.98
Some believe that apparent polycythemia is merely a mild absolute polycythemia accentuated by a compensatory reduction in plasma volume. Others suggest that it is caused by a primary reduction in plasma volume and have associated it with hypertension, obesity, and stress. Its clinical significance has also been disputed. The high hematocrit with its associated high viscosity is believed by some to be a risk factor heralding cerebral and cardiac complications, while others believe it is merely a well-tolerated blemish. Because the designation apparent polycythemia99 is noncommittal, it is used here.
The main clinical associations with apparent polycythemia are obesity, hypertension, and smoking. In obese patients the finding of a normal red cell volume may be spurious, since if the volume is expressed in terms of lean body weight, some of these patients would have a significant increase in red cell mass. In hypertensive patients there is no adequate explanation for the apparent increase in red cell production or decrease in plasma volume. Sleep apnea (common in patients with congestive failure), excessive production of atrial natriuretic factor, increased adrenal activation, decreased aldosterone secretion, and hypoxic vasoconstriction are all factors that have been invoked,100,101 and 102 but with little enthusiasm. Chronic administration of diuretics to treat hypertension may be a more likely cause.102
Polycythemia vera usually has an insidious onset, most commonly during the sixth decade of life, although the onset may occur in childhood or in old age.103 Presenting symptoms include headache, plethora, pruritus, thrombosis, and gastrointestinal bleeding, but some patients are diagnosed simply because abnormal blood counts are found on routine screening. Symptoms reported by at least 30 percent of patients with polycythemia, in approximate decreasing order of frequency, are headache, weakness, pruritus, dizziness, and sweating.103
THROMBOSIS AND HEMORRHAGE
Thrombotic episodes are the most common complications of polycythemia vera, occurring in about one-third of the patients.104 These can be very serious, including episodes of hepatic vein thrombosis (Budd-Chiari syndrome), occurring in 10 percent of 140 patients in one series.105 Over a period of 10 years, 40 to 60 percent of patients develop at least one thrombotic event, the annual incidence being approximately equal throughout this period.106,107 The most common serious complication is a cerebrovascular accident, which accounts for about one-third of the thrombotic events, followed in frequency by myocardial infarction, deep-vein thrombosis, and pulmonary embolism.106
Bleeding and bruising, too, are common complications, being observed in about one-quarter of the patients.104 While such episodes are usually minor, such as gingival bleeding or easy bruising, serious thrombotic complications with a fatal outcome also occur.
Pruritus occurs in approximately 40 percent of patients.108 It is usually aggravated by bathing or showering and may be so severe as to markedly compromise the quality of life of the patient. Its cause is unclear, and it has been attributed to increased numbers of mast cells in the skin109 and to elevated histamine levels.110
The occurrence of Budd-Chiari syndrome has been noted above. Portal hypertension and varices are not uncommon.111 The incidence of peptic ulcer is four to five times as great as in the general population.112
Cardiovascular symptoms include angina, myocardial infarction, and congestive heart failure.
Neurological symptoms, such as dizziness are very common.113 Neurological complications such as chorea114 or the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome (see Chap. 108)115 have been reported in single cases. Spinal cord compression secondary to extramedullary hematopoiesis has been documented.116
OTHER ORGAN SYSTEMS
The increased nucleic acid turnover that results from the excessive proliferation of marrow cells often leads to an increase in blood uric acid concentration, and gout is a frequent complication. Several patients have developed the dermatological disorder, acute febrile neutrophilic dermatosis (Sweet syndrome).117,118
Over 75 percent of patients with uncontrolled polycythemia vera develop complications during or after major surgery because both bleeding and thrombosis are common.119
ASSOCIATION WITH OTHER DISEASES
Patients with both polycythemia vera and chronic lymphocytic leukemia120,121 appear to have a relatively mild clinical course. An increased incidence of lymphocytic lymphomas has been documented.106
Tolerance to high altitudes varies greatly, but most normal individuals have no discomfort at altitudes of up to 2130 m (7000 ft). Above this level and especially if the ascent is rapid, some manifestations of cerebral hypoxia are common. Headaches, sleeplessness, and palpitations are frequently encountered, and weakness, nausea, vomiting, and mental dullness may be present. More severe manifestations include pulmonary and cerebral edema. Cheyne-Stokes respiration commonly occurs, especially during sleep. These symptoms constitute the syndrome of acute mountain sickness.122
Ruddy cyanosis and physiologic emphysema are the two characteristic features of humans living at high altitudes. Venous and capillary engorgement can be observed readily in the conjunctiva, mucous membranes, and skin and may contribute to the remarkable capacity of Sherpas to walk barefoot and sleep on ice and snow.123 Asymptomatic retinal hemorrhages are seen frequently at high altitudes but rarely at altitudes of 3000 m (9000 ft) or less.124 Splenomegaly and jaundice are unusual, although the sustained erythrocytosis is associated with an increased rate of red cell destruction and bilirubin generation.
The polycythemia associated with smoking is generally asymptomatic, but there may be an increase in thrombotic events.125
Familial Erythrocytosis Erythrocytosis may be very severe with hemoglobin levels of more than 20 g/dl. Headaches are commonly present. Hypertension, coronary artery disease, and strokes have been reported to occur55 but are not a constant feature of the disorder.57
Renal Polycythemia The erythrocytosis that occurs with renal polycythemia can be very severe with red counts as high as 8 × 1012/liter having been reported and associated with hypertension and congestive failure.126
Tumors The erythocytosis that occurs with tumors is generally mild,85 and the predominating clinical manifestations are those of the tumor itself. Even moderate elevations to a hematocrit of 64 percent have been encountered without symptoms referable to the polycythemia.82
Neonatal Of 55 infants with neonatal polycythemia, 85 percent had signs and symptoms attributed to this disorder. These included “feeding problems” (21.8%), plethora (20.0%), lethargy (14.5%), cyanosis (14.5%), respiratory distress (9.1%), jitteriness (7.3%), and hypotonia (7.3%). Other findings included hypoglycemia (40.0%) and hyperbilirubinemia (21.8%). In a larger group of nearly 1000 infants, 6 had an intracranial hemorrhage.97
The marrow is characteristically hypercellular, with involvement of all lineages. There are no characteristic cytogenetic findings, but occasional clonal abnormalities are observed (Chap. 10).
The erythrocyte count is usually increased, and in patients who have undergone phlebotomy or who have had gastrointestinal bleeding episodes it may be increased out of proportion to the increase in the hemoglobin and hematocrit, since there will be marked hypochromia and microcytosis. The plasma iron in such patients is decreased, the iron binding capacity increased, and plasma ferritin levels are low. The red cell mass is usually increased in proportion to the hematocrit value (Fig. 61-3).
FIGURE 61-3 The correlation of blood volume (ml/kg) and venous blood hematocrit (Hct) in 306 normal males, 140 normal females, and 157 patients with polycythemia vera, when measured by labeling of erythrocytes with 32P or 51Cr, as recommended by the International Committee on Standardization in Haematology. Panel A. Blood volume vs. Hct in normal males and females. Panel B. Blood volume vs. Hct in patients with polycythemia vera. Panel C. Comparison of the two populations shown in A and B. The leftward oval includes most of the normal subjects, and the overlapping rightward oval includes most of the polycythemia patients. The diagonal line is the regression line calculated for both groups when combined. (Data compiled from many sources by Fairbanks, et al.192,193,194 and 195)
In late stages of the disease the morphologic changes that are characteristic of myelofibrosis are present, with marked aniso- and poikilocytosis and abundant tear-drop cells (dacrocytes) (see Chap. 22). Alterations in red cell glycolytic metabolism have been documented127,128 but are not unique nor of any diagnostic value.
The PO2 of the arterial blood is often lower than normal, and levels as low as 63 torr were encountered in more than 10 percent of patients, and the percent saturation with oxygen was accordingly slightly reduced.129
An absolute neutrophilia occurs in about two-thirds of the patients.103 Occasional myelocytes and metamyelocytes are often present in the blood, and considerable degrees of immaturity are often present in patients with long-standing, advanced disease. Basophilia occurs in about two-thirds of patients with uncontrolled disease.130 Serum lysozyme levels are slightly increased in some patients,131 and because of the increased leukocyte turnover, levels of vitamin B12 are usually increased.132 The leukocyte alkaline phosphate level is elevated in about 70 percent of patients with polycythemia vera.103 Selective abnormalities in granulocyte chemoluminescent response to some agonists, e.g., leukotriene B2, but not to others, e.g., phorbol myristate acetate, have been reported,133 but there is no indication that patients with the disease have increased susceptibility to infection.
The platelet count is increased in about one-half of patients at the time of diagnosis, and in about 10 percent it is over 1,000,000/µl.103 In contrast to normal individuals, where phlebotomy results in an increase in the platelet count, platelet levels are not affected by phlebotomy of patients with polycythemia vera.134 There are no consistent abnormalities of thrombopoietin levels.135
Qualitative abnormalities of the platelets have been described. Patients with polycythemia vera, essential thrombocythemia, and other myeloproliferative disorders have a very unusual, nearly pathognomic defect in the primary wave of platelet aggregation induced by epinephrine.136 In contrast there is increased platelet thromboxane A2 generation137 and increased excretion of thromboxane metabolites,138 even though the response to thromboxane A2 may be subnormal.139 Platelet factor 4 levels are elevated,140 and platelet survival is normal141 or shortened.134,140 Fibrinogen binding after stimulation with platelet activating factor is diminished,142 and there is reduced expression of the thrombopoietin receptor.20
The prothrombin time, partial prothrombin time, and fibrinogen level are usually normal, but fibrinogen turnover may, at times, be increased.143
Characteristically only the numbers of erythrocytes in the blood are increased. Increase in the leukocyte count may be present as another feature of the underlying disease, e.g., the pulmonary infection in chronic obstructive lung disease. In patients with appropriate polycythemia the underlying defect is usually demonstrable. Arterial hypoxia can be demonstrated in most cases, However, some obese patients who, like Mr. Wardle’s proverbial boy, Joe, are always half asleep, will be very much awake when exposed to arterial punctures and ventilatory testing, and their apprehensive hyperventilation will cause the disappearance of all abnormalities in arterial gas composition. As soon as they return to bed, however, they will go to sleep again and display the characteristic somnolent cyanosis. In inappropriate polycythemia the laboratory findings will be those of the underlying defect.
Polycythemia vera must be distinguished from secondary polycythemia and from apparent polycythemia. Some of the differences are summarized in Table 61-2.
TABLE 61-2 TYPICAL LABORATORY FINDINGS IN PATIENTS WITH POLYCYTHEMIA VERA, SECONDARY POLYCYTHEMIA, AND RELATIVE POLYCYTHEMIA
The most important diagnostic features of polycythemia vera are erythrocytosis, leukocytosis, thrombocytosis, and splenomegaly. Frequently only two or three of these features are found at presentation and if sufficiently pronounced suffice to establish the diagnosis. In some patients only one of these features is found initially, most commonly the erythrocytosis, but occasionally only thrombocytosis, leukocytosis, or splenomegaly. Such patients represent more difficult diagnostic challenges. A subset of patients with erythrocytosis as the only manifestation of unregulated proliferation of the erythron do not develop the other features of polycythemia vera, even after they have been followed for many years.144,145 Such patients have been designated as manifesting pure erythrocytosis or idiopathic erythrocytosis.146 Some patients who are classified in this way eventually develop typical polycythemia vera; this seems to be true in about one-half of the patients after several years. However, some patients have been observed for periods as long as 8 or 10 years without a change in their clinical state.145,146 and 147 Studies of red cell precursors suggest that patients who have been diagnosed as having pure erythrocytosis can be divided into two groups of about equal size, those with EPO-independent BFU-E and those without such precursors.145,147 It is possible that pure erythrocytosis is a distinct entity but that some of the patients who meet the criteria for this diagnosis actually have polycythemia vera.
Other clinical features that may be helpful in arriving at a diagnosis include the presence of elevated vitamin B12 levels, elevated serum uric acid levels, normal or near-normal arterial oxygen saturations, and pruritus.
Since polycythemia is distinguished by the fact that erythroid cells proliferate even in the absence of substantial levels of EPO, one would expect that at high hematocrit levels the production of EPO would be inhibited and the serum levels consequently reduced. Overlapping values are frequently observed.148,149 With more sensitive assay methods it has been reported that quite reliable differentiation of polycythemia vera from secondary and relative polycythemia can be achieved.150,151,152 Another potential approach to diagnosis is to demonstrate the presence of a population of erythroid progenitors that proliferates in the absence of EPO.18,147,153,154,155 There are occasional cases in which such colonies do not form, particularly when blood rather than marrow is examined156 and when cytotoxic treatment has been administered.147
The Polycythemia Vera Study Group has employed the direct determination of the red cell mass as the sine qua non of the diagnosis of polycythemia vera in patients entered into their studies.106 It has been suggested that even in the routine clinical setting, this procedure should be performed on all patients to establish this diagnosis.106 Unfortunately, the determination of the red cell mass is expensive and, when performed by the inexperienced, often inaccurate.157 It is not useful in distinguishing polycythemia vera from secondary polycythemia, the differentiation that is usually needed, because red cell mass is increased in both disorders. The principal value of a red cell mass determination might then be to distinguish apparent or spurious polycythemia from polycythemia vera and secondary polycythemia. Fortunately, in most cases the diagnosis of polycythemia vera can be established with confidence without measuring the red cell volume.
Patients with secondary polycythemia, like those with polycythemia vera, have a genuine increase in the number of circulating erythrocytes and of the red cell mass. However, in secondary polycythemia the increase in the red cell mass is a response to the stimulation of the marrow by EPO or the abnormal functioning of a mutant EPO receptor. Such patients do not have the increase in the platelet count and leukocyte count or the splenomegaly that is characteristic of polycythemia vera, and it is the lack of involvement of other formed elements in hematopoietic proliferation that should arouse suspicion that the patient may have secondary polycythemia. In patients in whom the cause of the secondary polycythemia is lung or cardiac disease, clubbing is often present. In some cases determining the arterial oxygen saturation will often clarify the diagnosis, but modest arterial oxygen saturation may also be present in polycythemia vera.36,129 Imaging of the kidneys may reveal a neoplasm or cyst in some patients. Determining the oxygen dissociation curve will detect abnormalities related to increased oxygen affinity, either because of 2,3-BPG depletion, as in phospho-glyceromutase deficiency (see Chap. 45) or because of inheritance of a high-affinity hemoglobin. The nature of the polycythemia in such patients is also sometimes apparent because of the familial nature of the disorder; polycythemia due to a high-affinity hemoglobin is inherited as an autosomal dominant disorder. It may also be useful to determine the carboxyhemoglobin level of the blood if smoker’s polycythemia is suspected. Sequence analysis of the EPO receptor will define the defect in most patients with hereditary erythrocytosis.
The erythrocytosis observed in patients with spurious polycythemia (apparent polycythemia, stress polycythemia) is a consequence of a decrease in the plasma volume.99 The erythrocytosis that is observed does not represent a true increase in the red cell mass. Usually the increase in the hematocrit is very modest. Such patients do not have an increased white blood count, thrombocytosis, or splenomegaly. The arterial oxygen saturation is normal. The estimation of the red cell mass is required to establishing a diagnosis of spurious polycythemia, but it must be recognized that during the natural history of patients who develop primary or secondary polycythemia their red cell mass is, at some point, within the normal range while it is rising to abnormal values.
THERAPY, COURSE, AND PROGNOSIS
Polycythemia vera usually remains in a plethoric phase for many years, after which a “spent” phase characterized by falling red cell counts and progressive splenomegaly supervenes.
THE PLETHORIC PHASE
The treatment of patients in the plethoric phase of the disease is aimed at ameliorating symptoms and decreasing the risk of thrombosis or bleeding by reducing the blood counts. The red count and hematocrit can be controlled in some patients by periodic phlebotomy, while the administration of drugs that suppress marrow activity is required also to control the platelet count and white count. In most patients both treatment modalities are used. The advantages and disadvantages of various forms of therapy are summarized in Table 61-3.
TABLE 61-3 TREATMENT OF POLYCYTHEMIA VERA
Phlebotomy The initial treatment for most patients is phlebotomy. The hematocrit may be reduced to normal or near-normal values by the removal of 450 to 500 ml of blood at intervals of 2 to 4 days for the average-size patients, with smaller amounts being removed from patients who weigh less than 50 kg. The shorter interval is appropriate for patients with hematocrits that are over 64 percent, while less energetic bleeding suffices for those who have only a modest increase in their hematocrit. Patients with impaired cardiovascular functions are better treated with smaller phlebotomies at more frequent intervals.
The immediate effect of phlebotomies is to reduce the hematocrit, which results in improvement of symptoms such as headaches. It neither reduces the leukocyte or platelet count nor affects symptoms such as pruritus or gout. Iron deficiency is the usual consequence of repeated phlebotomy. The deficient state helps to control the hematocrit; when iron is administered to polycythemia vera patients who have been rendered iron deficient by phlebotomy, a dramatic rise of the hemoglobin level and hematocrit usually occurs. The iron deficiency that results from repeated phlebotomies causes striking microcytosis, but the viscosity of the blood is a function of the hematocrit and appears to be independent of the number of red cells,158 and the deformability of iron-deficient erythrocytes appears to be normal159; phlebotomy clearly is an effective way in which to normalize the viscosity of the blood of patients with polycythemia vera.
A randomized study106,160 comparing phlebotomy alone with treatment with 32P and with chlorambucil indicated that the life span of patients treated only with phlebotomy is better than that of patients treated with chlorambucil and no worse than the life span of those given 32P. Early in their course patients undergoing phlebotomy suffered more thrombotic episodes, but this was balanced by a lower incidence of leukemia late in their course. Surprisingly, there was no correlation between the level of the platelet count and the development of thrombotic complications. Apparently many patients can be well controlled by phlebotomy alone during much or all of their course, and the role of myelosuppressive therapy in the treatment of polycythemia vera has sometimes been questioned.161 It has been suggested that patients under the age of 50 who have no prior history of thrombosis might be treated with phlebotomy alone.162
Myelosuppression Although treatment with myelosuppressive agents appears to increase the incidence of leukemic transformation of patients with polycythemia vera, patients are usually treated with such drugs when the platelet count rises to levels of higher than 800,000 to 1,000,000/µl. Platelet counts at these levels usually cause concern about the risk of bleeding and thrombosis. Myelosuppressive therapy is also considered when thrombotic or bleeding complications occur, when the patient requires phlebotomy at intervals exceeding one every month or two, and in patients with severe pruritus.
Hydroxyurea (Hydrea) Hydroxyurea is probably the most commonly used myelosuppressive agent used in the treatment of polycythemia vera. Its suppressive effect is of short duration. Thus, continuous rather than intermittent therapy is required. Because hydroxyurea is short-acting, it is relatively safe to use; when excessive marrow suppression occurs, the blood counts rise within a few days or weeks of discontinuing the drug. Moreover, because it is not an alkylating agent, it is believed to have much less potential for causing leukemic transformation than other myelosuppressive agents. When used in conjunction with phlebotomy, the incidence of thrombotic complications appeared to be decreased, and after about 7 years’ maximum follow-up the incidence of leukemia was slightly higher than that in patients treated with phlebotomy alone, but not significantly so.163 Experience in the use of hydroxyurea in the treatment of essential thrombocythemia has suggested a leukemogenic risk of about 3.5 percent.164,165
Busulfan (Myleran) The administration of busulfan is a convenient and effective means for the treatment of polycythemia vera. Marrow suppression produced by this drug is long-lasting, and as a consequence it can be given intermittently. The administration of 2 or 4 mg daily over a period of several weeks is usually sufficient to normalize the blood counts; the counts continue to fall for several weeks after drug administration is discontinued. The counts may then remain normal for many months or even years. In one large study the median first remission duration of busulfan-treated patients was 4 years.166
The prolonged depression of marrow activity that is brought about by busulfan is its major advantage in the treatment of polycythemia vera, but it also poses a hazard. If therapy is continued too long or given at too high a dose, the marrow suppression that results may persist for many months or even a year. For this reason it is safer not to exceed a daily dose of 4 mg but to extend the period of treatment rather than to increase the daily dose. The incidence of transformation to acute leukemia in patients treated intermittently with busulfan is relatively low. Of 145 patients followed from 2 to 11 years, only 3 developed acute leukemia.166
Radioactive Phosphorus 32P therapy was one of the first effective modes of treatment used. Extensive investigations of the long-term outcome of treatment with 32P have been documented.106,167 Good control of the disease usually can be achieved with initial doses of 2 to 4 mC of 32P given intravenously, followed in 6 to 8 weeks by doses that are based upon the response to the first dose. 32P treatment is associated with a moderate increase in the incidence of leukemic transformation, similar in magnitude to that observed with busulfan.166 Since the treatment is administered directly by a physician, it is more suitable than busulfan for patients who cannot be relied upon to take their medication as prescribed. However, the logistics of 32P administration have made it an inconvenient and expensive mode of therapy. Consultation with a radiotherapist is usually required, and each dose must be ordered especially for the patient. It is largely for this reason and because it is generally supposed that the leukemogenic potential of hydroxyurea is lower than that of radioactive phosphorus, that the latter has been used less frequently. Some investigators, however, consider radioactive phosphorus the treatment of choice, especially among older patients.168,169
Interferon Administration of recombinant interferon a (rIFN-a) at a starting dose of 3 million units given 3 times weekly, produces a therapeutic response in 50 percent170 or more171,172 of patients with polycythemia vera. A decrease in the red cell mass, the leukocyte count, and the platelet count has been documented, and it seems effective in ameliorating the pruritus that is common in polycythemia vera. Indeed, the amelioration of the pruritus does not seem directly related to the hematologic response.172 It is not clear whether this treatment, which requires frequent injections of a drug that causes toxicity that is troublesome to the patients, has any advantage over less costly, more convenient therapies. However, the possibility exists that the incidence both of leukemia and myelofibrosis may be lower in interferon-treated patients.172
Pipobroman (Vercyte) Although it was described in the early 1960s and appears to be effective in controlling polycythemia vera, pipobroman has not been used as frequently as has 32P, busulfan, or hydroxyurea. However, it remains in active use in some countries.173,174 Hematologic remission is achieved in over 90 percent of previously untreated patients175,176 and is maintained for long periods of time. Gastrointestinal intolerance can be a problem.137,174 The risk of leukemia is relatively high, being observed in 6 percent and 9 percent of patients at 5 and 7 years of treatment and in 27 percent at 14 years in one study.174
Anagrelide (Agrelin) Among 113 patients with polycythemia vera who had thrombocytosis, administration of anagrelide produced a platelet response in 85 (75%).177 It was suggested that the higher rates of response might be expected when the drug was administered by those more skilled in its use. The starting dose was 0.5 or 1.0 mg given four times daily, and a response was noted in most patients within a week. The average dose required to control the platelet count was 2.4 mg per day. Adverse events included headache, palpitations, diarrhea, and fluid retention and were occasionally sufficiently severe to require discontinuation of the treatment.
Symptomatic Therapy Many of the symptoms of polycythemia are controlled either by phlebotomy or by controlling the number of circulating blood cells with myelosuppressive therapy. Pruritus is a frequent exception. It tends to be more severe when the disease is active and becomes milder or disappears when control is achieved by myelosuppression. Nonetheless, in some patients it becomes a nearly intolerable annoyance. Since the itching is usually intensified by bathing or showering, often the best advice that can be offered is to bathe less frequently.
Photochemotherapy with psoralens and ultraviolet light has been found to be helpful.178 Antihistamines are usually not very effective. Aspirin179 and cyproheptadine130 have each been recommended. Interferon alpha has been helpful in some patients.170,171,180
Since thromboembolic episodes represent a major source of morbidity and mortality in patients with polycythemia, attempts using aspirin and dipyridamole to prevent such episodes have been made. The results of early trials using 300 mg of aspirin daily have been an increase in the incidence of bleeding without a favorable impact on the incidence of thrombotic episodes.181 The administration of low-dose aspirin has been suggested in patients who have a vascular occlusion.182 A pilot controlled trial showed that low-dose aspirin was well tolerated by polycythemia vera patients,183 but the efficacy of this approach has not been shown in any controlled studies.
Since dehydration may be a precipitating factor for thrombosis, patients should be kept well hydrated when they develop intercurrent gastrointestinal disorders.
THE SPENT PHASE
Ultimately, sometimes after only a few years and sometimes after 20 or more, the erythrocytosis of patients with polycythemia who have not succumbed to other complications gradually abates, and anemia develops. During this “spent” phase of the disease, marrow fibrosis becomes more marked, and the spleen often becomes greatly enlarged. Instead of phlebotomies, transfusions now may be required. The platelet count may remain high or may decline, even to thrombocytopenic levels. Marked leukocytosis may occur with the appearance of immature granulocytes in the blood. Treatment of this phase of the disease is almost entirely symptomatic. Irradiation of the spleen is usually not helpful, and the use of chemotherapy with busulfan or hydroxyurea is precluded by the advancing thrombocytopenia. Occasionally splenectomy may be warranted, particularly if there is severe thrombocytopenia, if the transfusion requirement becomes very high, or if a greatly enlarged spleen produces severe physical discomfort.184 Usually periodic transfusions are the only possible treatment, although a few younger patients have undergone marrow transplantation.185
Polycythemia vera is a disease that is compatible with normal or near-normal life for many years. However, ultimately leukemia may develop or the disease enters the spent phase. Leukemia occurs even in patients who have been treated only by phlebotomy, although its incidence is increased somewhat by the various forms of cytotoxic therapy that have been employed (Table 61-3). While acute myeloid leukemia is most common, acute lymphoid leukemia186 and neutrophilic leukemia187 have been documented as well.
The Polycythemia Vera Study Group106 found that the median survival from the beginning of treatment was 13.9 years for those treated by phlebotomy alone, 11.8 years for 32P-treated patients, and 8.9 years for chlorambucil-treated patients. Thrombosis was the most common cause of death, accounting for 31 percent of the fatalities. Nineteen percent of the patients died of acute leukemia, 15 percent from other neoplasms, and about 5 percent each from hemorrhage or the development of the spent phase. Similarly a large French study revealed a median survival of 13.5 years of polycythemia vera patients initially treated with 32P, only slightly less than the 15.2 years of age-matched controls.172
The clinical course of secondary polycythemia is largely a function of the severity of the erythrocytosis. This can be quite marked with hemoglobin levels in excess of 20 g/(dl) in patients with dominant familial erthrocytosis secondary to mutations of the HFE gene, and in such patients hypertension, coronary artery disease, and strokes have been reported,55 although not in all series.57 The apparently recessive erythrocytosis that is endemic in Chuvashia is characterized by elevations of the hemoglobin level to a mean of 22.6 with a standard deviation of 1.4 g/dl.58 Most of the patients are symptomatic with headache and fatigue and with signs including clubbing, thrombosis, and peptic ulcer. Eleven of the 103 patients died at ages ranging from 16 to 58 years of age during a 10-year period. The milder erythrocytosis that is associated with abnormal hemoglobins and with tumors is often asymptomatic or associated with only mild symptoms.
The morbidity that attends marked erythrocytosis is presumably related to the increase in blood viscosity.188 The blood viscosity increases very rapidly as levels rise beyond 50 percent (see Fig. 30-2). Therefore, lowering the hematocrit to a normal or near-normal level by phlebotomy is the usual treatment.59,189 The appropriate level is that at which the patient becomes asymptomatic.45,190 Although cytotoxic agents are sometimes used for this purpose, phlebotomy is preferred because of the leukemogenic risk of the agents that are used in polycythemia vera. Theophylline and enalapril have been used to lower the hematocrit of patients with polycythemia following renal transplantation,68,69,70 and theophylline has been given to patients with chronic obstructive lung disease.191 These drugs apparently exert their beneficial effect by lowering erythropoietin levels.
When erythrocytosis is secondary to a renal tumor or cyst, to a myoma, or to a brain tumor, removal of the neoplasm has usually resulted in disappearance of the erythrocytosis.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn