Chapter 29: Polyclonal Polycythemias (Primary and Secondary)

• Polycythemia (also known as erythrocytosis) is characterized by an increased red cell blood volume. Polycythemias can be primary or secondary and either inherited or acquired.

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

• Primary polycythemias are caused by somatic or germline mutations causing changes within hematopoietic stem cells or erythroid progenitors causing an augmented response to erythropoietin.

• Secondary polycythemias are caused by either an appropriate 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. 43.

Primary Familial and Congenital Polycythemia

• Autosomal dominant disorder, with normal leukocytes and platelets.

• Many affected persons are misdiagnosed as having polycythemia vera.

• Always low erythropoietin level (see Fig. 29–1).

• Erythroid progenitors in in vitro cultures are hypersensitive to erythropoietin but do not grow independent of erythropoietin.

• Caused by a truncation of erythropoietin receptor and deletion of negative regulatory cytoplasmic domain.

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

• A group of disorders with 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 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, Aymaras and Quechua natives of High Andes, and Ethiopian dwellers of high mountains have a genetically determined resistance to these complications.

• Acute mountain sickness:

  — Caused by cerebral hypoxia and may be life-threatening. Polycythemia does not occur.

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

  — Treatment is with oxygen, dexamethasone, and acetazolamide and/or rapid return to lower altitude.

• Chronic mountain sickness:

  — Occurs after prolonged exposure to high altitudes; there appears to be a genetic predisposition.

  — 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 has been reported to be effective.

  — A return to a normal state develops slowly.

Pulmonary Disease

• Associated with cyanosis, clubbing, and arterial oxygen desaturation.

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

• Venesection is controversial; many consider it ill-advised, but some recommend it to maintain the hematocrit at no more than 55 percent, presumably to optimize oxygen carrying capacity and blood flow characteristics.

Alveolar Hypoventilation

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

• Peripheral: May be a result of myotonic dystrophy, poliomyelitis, spondylitis, or extreme obesity.

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 percent.

• Reduction of the hematocrit by phlebotomy 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.

Acquired High-Affinity Hemoglobinopathy

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

Tissue Hypoxia (Histotoxic Anoxia)

• Cobalt chloride treatment inhibits oxidative metabolism and leads to an increased hematocrit. Particularly high hematocrits are recorded in cobalt miners in high Andes Peruvian mines (as high as 90).

Inappropriate Secondary Acquired Polycythemias

Post-Renal Transplantation Erythrocytosis

• Defined as a persistent elevation of the hematocrit over 51 percent.

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

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

• Therapy with either angiotensin-converting enzyme inhibitor enalapril or with angiotensin II receptor type 1 blocker, losartan.

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

• Remission of polycythemia occurs after tumor removal.

• Reappearance of polycythemia heralds recurrence.

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

Cerebellar Hemangiomas

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

• May be associated with VHL gene mutations.

Other Tumors

• Uterine myoma, usually huge. 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 gene mutations.

• Cushing syndrome: Hydrocortisone and other glucocorticoids may cause general marrow stimulation and mild polycythemia.

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

• Normal physiologic response to intrauterine hypoxia and high oxygen-affinity fetal hemoglobin.

• May be excessive in infants of diabetic mothers.

• Late cord clamping may be contributory.

• Partial exchange transfusion sometimes performed if the hematocrit is above 65 percent 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.

• 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.

Congenital Secondary Polycythemias

Hereditary High-Affinity Hemoglobins

• Autosomal dominant inheritance.

• Only about fifty percent of the abnormal hemoglobins are demonstrable by hemoglobin electrophoresis.

• The initial and sensitive test is determination of hemoglobin-oxygen affinity (estimated by measuring the p50).

• 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.

• For more details, see Chap. 19.

2,3-Biphosphoglycerate Deficiency

• Results in an increased oxygen affinity of hemoglobin (decreased p50).

• Caused by bisphosphoglyceromutase deficiency (see Chaps. 15 and 19).

Congenital Methemoglobinemias

• Mild polycythemia occurs in patients with methemoglobinemia caused by recessively inherited cytochrome b₅ reductase deficiency (see Chap. 15) or globin mutations causing dominantly inherited methemoglobinemia (see Chap. 19).

Congenital Disorders of Hypoxia Sensing

Chuvash Polycythemia

• Only known endemic congenital polycythemia, endemic in Chuvash autonomous region of Russia, Italian island of Ischia; sporadic worldwide.

• Autosomal recessive disorder.

• Caused by mutation in the von Hippel-Lindau (VHL) gene (VHL C598T) that upregulates HIF transcription factors that increase transcription of many genes including erythropoietin (see Williams Hematology, 8th ed, Chap. 56, p. 823.)

• Erythropoietin levels are normal or increased.

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

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

Congenital Polycythemia from Other VHL Gene Mutations

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

• Rare patients have only a single VHL mutation.

Proline Hydroxylase Deficiency

• Rare disorder causing mild or borderline polycythemia associated with upregulated HIF transcription factors.

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

HIF-2α Gain-of-Function Mutations

• Rare disorder due to increased activity of HIF-2 that increases transcription of many genes including erythropoietin.

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

Apparent Polycythemia (Relative or Spurious Polycythemia)

• Characterized by an increased hematocrit, normal red cell mass, and low plasma volume.

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

• 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).