Chapter 27: Polyclonal Polycythemias (Primary and Secondary)

• Polycythemia, also referred to as erythrocytosis, is characterized by an increased red cell mass. There is no consensus on terminology (ie, primary familial polycythemia but postrenal transplantation erythrocytosis). Polycythemias can be primary or secondary and can be inherited or acquired.

• Classification of polycythemic disorders appears in Table 2–2 in Chap. 2.

• Primary polycythemias are caused by somatic or germline mutations within hematopoietic stem cells or erythroid progenitors that result in an augmented response to erythropoietin. This response is inappropriate; that is, it is not a compensation for hypoxia.

• Secondary polycythemias are caused by either an appropriate (compensatory) or inappropriate increase in the red cell mass as a result of augmented levels of erythropoietin.

• The most common primary polycythemia, polycythemia vera, is a clonal acquired multipotential hematopoietic progenitor cell disorder discussed in Chap. 41. It is a myeloproliferative neoplasms.

Primary Familial and Congenital Polycythemia

• This disorder is autosomal dominant, with normal leukocyte and platelet counts.

• Affected persons may be misdiagnosed as having polycythemia vera.

• Low plasma erythropoietin level is a constant feature (see Figure 27–1).

• Erythroid progenitors in in vitro cultures are hypersensitive to erythropoietin, but unlike the erythroid progenitors in polycythemia vera, they do not grow in the absence of erythropoietin.

• This condition is caused by a truncation of erythropoietin receptor and deletion of the negative regulatory cytoplasmic domain.

• Affected individuals may have an increased risk of cardiovascular complications, regardless of control of elevated hematocrit by phlebotomies.

• This group of disorders is marked by increased red cell mass (absolute polycythemia) because of stimulation of red cell production by increased erythropoietin production. The polycythemia is considered:

  — Appropriate if there is tissue hypoxia and the increased red cell mass (increased blood hemoglobin concentration) minimizes the hypoxia.

  — Inappropriate if tissue hypoxia is absent and the polycythemia serves no useful purpose.

Appropriate Secondary Polycythemias

High-Altitude Acclimatization

• There is a great variability in an individuals’ susceptibility to acute and chronic mountain sickness complications.

• Some populations such as Tibetans and Ethiopian dwellers of high mountains have a genetically determined resistance to these complications, whereas extreme polycythemia is often seen in Quechuas and Aymaras living at high-altitude (Andean natives).

• Acute mountain sickness involves:

  — Cerebral hypoxia is causal, and the condition may be life-threatening. Polycythemia does not occur.

  — Affected persons may have headaches, insomnia, palpitations, weakness, nausea, vomiting, and mental dullness, and they may develop pulmonary and cerebral edema.

  — Treatment is with oxygen, dexamethasone, and acetazolamide and if feasible rapid return to lower altitude.

• Chronic mountain sickness involves:

  — This condition occurs after prolonged exposure to high altitudes; there can be a genetic predisposition.

  — It is characterized by marked polycythemia, cyanosis, plethora, pulmonary hypertension, clubbing of the fingers, and signs of right heart failure.

  — Treatment with the angiotensin-converting enzyme inhibitor enalapril may be effective.

  — Iron deficiency (often induced by misguided phlebotomies) leads to deterioration of pulmonary hypertension.

  — A return to a normal state develops slowly after descent to lower altitude.

Pulmonary Disease

• This is associated with arterial oxygen desaturation cyanosis and clubbing.

• In chronic obstructive pulmonary disease, chronic inflammation and infection may blunt erythropoietin synthesis and secretion and compensatory red cell production.

• Venesection is controversial; many consider it ill-advised, but some recommend it to maintain the hematocrit at no more than 55%, presumably to optimize oxygen-carrying capacity as a result of lower blood viscosity and more optimal blood flow characteristics. The use of phlebotomy has not been shown to be useful in a clinical trial.

Alveolar Hypoventilation

• Central form may be a result of cerebral vascular accident, parkinsonism, encephalitis, or barbiturate intoxication.

• Peripheral form may be a result of myotonic dystrophy, poliomyelitis, spondylitis, or severe obesity.

Sleep Apnea

• Only a minority (< 5%) of subjects develop erythrocytosis. This finding is as yet unexplained.

Cardiovascular (Eisenmenger Syndrome)

• In patients with congenital right-to-left intracardiac shunts, arterial PO₂ decreases significantly, erythropoietin secretion increases, and the hematocrit may reach 75% to 85%.

• Reduction of the hematocrit by phlebotomy to improve blood flow may not be beneficial, and such therapy is controversial.

• Treatment with phlebotomy is indicated for cerebral symptoms (headaches, difficulty to concentrate); however, if prompt improvement after phlebotomies does not ensue, phlebotomies are probably of no benefit.

• Dehydration should be avoided to prevent further increase in hematocrit.

• Other right-to-left shunts can result in secondary polycythemia in hepatic cirrhosis (pulmonary arteriovenous or portopulmonary venous shunts), hereditary hemorrhagic telangiectasia, and idiopathic pulmonary arteriovenous aneurysms.

Inappropriate Secondary Polycythemias

Acquired High-Affinity Hemoglobinopathy

• This may be a result of elevated blood carboxyhemoglobin (smoking).

Toxic Dysregulation of Hypoxia Sensing

• Cobalt chloride treatment inhibits principal negative regulator of hypoxia-inducible factors (HIFs) (ie, prolyl hydroxylase 2) and leads to an increased hematocrit. Particularly high hematocrits (as high as 90%) are recorded in cobalt miners in Peruvian mines in the high Andes.

Postrenal Transplantation Erythrocytosis

• Such erythrocytosis is defined as a persistent elevation of the hematocrit of more than 51%.

• It is found in approximately 5% to 10% of renal allograft recipients; incidence may be decreasing because of widespread use of angiotensin-converting enzyme inhibitors.

• It develops within 8 to 24 months after transplantation, despite good function of the allograft.

• Therapy with either angiotensin-converting enzyme inhibitor enalapril or with the angiotensin II receptor type 1 blocker losartan is generally effective.

Renal Cysts and Hydronephrosis

• Erythropoietin can be demonstrated in cyst fluid or is due to cyst-induced mechanical renal ischemia downstream of the cyst.

Renal Tumors

• One percent to 3% of patients with hypernephroma have erythrocytosis, probably as a consequence of excess erythropoietin formed by the tumor.

• Remission of erythrocytosis occurs after tumor removal.

• Reappearance of erythrocytosis heralds recurrence.

• These may be associated with von Hippel-Lindau (VHL) gene mutation.

Cerebellar Hemangiomas

• About 15% of patients have erythrocytosis, and erythropoietin can be demonstrated in cyst fluid and stromal cells.

• These may be associated with VHL gene mutations.

Other Tumors

• These are uterine myomas, usually huge. Treatment is removal of the myoma routinely followed by return to normal hemoglobin concentration.

• Hepatoma can cause erythrocytosis, probably because of erythropoietin production by the neoplastic cells.

Endocrine Disorders

• Pheochromocytoma, aldosterone-producing adenomas, Bartter syndrome, or dermoid cyst of ovary may be associated with increased erythropoietin levels and erythrocytosis, which respond to removal of the tumor.

• Pheochromocytoma may be associated with VHL or other gene mutations (see Chap. 6).

• In Cushing syndrome, cortisol and other corticosteroids may cause general marrow stimulation and mild erythrocytosis.

Androgen Usage

• Androgens of the 5α-H configuration stimulate erythropoietin production and result in erythrocytosis.

• Androgens of the 5α-H configuration also enhance differentiation of stem cells.

Neonatal Erythrocytosis

• This is a normal physiologic response to intrauterine hypoxia and high oxygen-affinity fetal hemoglobin.

• It may be excessive in infants of diabetic mothers.

• Late cord clamping may be contributory.

• Partial exchange transfusion is sometimes performed if the hematocrit is above 65% at birth.

Autotransfusion (Blood Doping)

• Autotransfusion of stored red cells prior to competition improves performance in cross-country skiers and long-distance runners but at the risk of life-threatening hyperviscosity when associated with fluid losses from strenuous activity.

• This should be suspected when an elevated hematocrit is associated with very low level of erythropoietin in an athlete.

• Injection of commercial erythropoietin preparations will achieve the same effect as autotransfusion. This approach, in addition to being unethical to improve athletic performance, bears the risk of overdose and life-threatening hyperviscosity under periods of athletic stress and dehydration, as well as from other nonerythroid cardiovascular effects of high erythropoietin levels.

Congenital Secondary Polycythemias

Hereditary High-Affinity Hemoglobins

• Inheritance is autosomal dominant.

• Only about 50% of the abnormal hemoglobins are demonstrable by hemoglobin electrophoresis. Thus, the initial and the only appropriate test is determination of hemoglobin-oxygen affinity (estimated by measuring the p50) determined by co-oximeter. If a co-oximeter is not available for measurement of full hemoglobin-oxygen dissociation kinetics, p50 can be calculated from venous blood (see Chap. 18).

• Increased hemoglobin-oxygen affinity (decreased p50) results in tissue hypoxia; erythropoietin may be high or normal.

• Phlebotomies are generally ill advised unless severe symptoms of hyperviscosity.

2,3-Biphosphoglycerate Deficiency

• This deficiency results in an increased oxygen affinity of hemoglobin (decreased p50).

• It is caused by bisphosphoglyceromutase deficiency (see Chaps. 14 and 18).

Congenital Methemoglobinemias

• Mild polycythemia occurs in patients with methemoglobinemia caused by recessively inherited cytochrome b₅ reductase deficiency (see Chap. 14) or globin mutations causing dominantly inherited methemoglobinemia (see Chap. 18).

Congenital Disorders of Hypoxia Sensing

Chuvash Polycythemia

• This disorder is endemic in the Chuvash autonomous region of Russia and the Italian island of Ischia; it is sporadic worldwide.

• Inheritance is autosomal recessive.

• The cause is mutation in the von Hippel-Lindau gene (VHL C598T) that upregulates HIF transcription factors that increase transcription of many genes, including erythropoietin.

• Erythropoietin levels are normal or increased.

• Erythroid progenitors in in vitro cultures are hypersensitive to erythropoietin, thus sharing features of both primary and secondary polycythemia.

• Strokes and other thrombotic vascular complications and pulmonary hypertension lead to early mortality and are not ameliorated by phlebotomies.

Congenital Polycythemia from Other VHL Gene Mutations

• Most patients are compound heterozygotes for Chuvash VHL C598T and other VHL gene mutation.

• Rare patients have only a single VHL mutation.

Prolyl Hydroxylase Deficiency

• Rare recessive loss-of-function mutation of EGLN1 gene (encoding prolyl hydroxylase 2) disorder causing mild or borderline polycythemia associated with upregulated HIFs.

• Because of its rarity, little is known about its clinical manifestations.

HIF-2α Gain-of-Function Mutations

• This rare disorder is due to gain-of-function mutations of EPAS1 gene (encoding HIF-2α), leading to increased activity of HIF-2 that increases transcription of erythropoietin.

• Its genetic mosaicism may be also associated with congenital polycythemia and at onset of pheochromocytoma and other tumors (see Chap. 6).

• Other clinical manifestations are being defined.

Apparent Polycythemia (Relative or Spurious Polycythemia)

• This condition is characterized by an increased hematocrit, normal red cell mass, and low plasma volume.

• In the past, it was referred to as Gaisbock syndrome; pseudo-polycythemia; or stress, spurious, and smokers’ polycythemia.

• It is associated with obesity, hypertension, use of diuretics, and smoking.

• Differential diagnosis includes severe dehydration.

• Treatment should be directed toward any underlying condition, if present, such as obesity (weight reduction) or cigarette smoking (cessation of smoking).