58 Primary and Secondary Erythrocytosis/Polycythemia

Question 1

Primary polycythemic disorders that have erythroid progenitors hypersensitive to erythropoietin (EPO)

Answer 1

• Polycythemia vera
• Primary familial and congenital erythrocytosis/polycythemia (PFCP)
• Chuvash erythrocytosis

Chuvash erythrocytosis, have erythroid progenitors that are hypersensitive to EPO, but also may have normal or even increased EPO levels despite the increased red cell volume.
(Parang both primary and secondary)

Question 2

Refers to those conditions in which only erythrocytes are increased in number and describes a group of disorders characterized by an increased red cell volume brought about by enhanced stimulation of red cell production by circulating physiologic mediators, most commonly EPO

Answer 2

Secondary erythrocytosis

Question 3

Secondary erythrocytosis: Appropriate erythrocytosis

Answer 3

• Pulmonary disease
• Eisenmenger complex
• High-altitude erythrocytosis
• Hemoglobins (Hbs) with increased affinity for oxygen

Question 4

Secondary erythrocytosis: Inappropriate erythrocytosis

Answer 4

• EPO-secreting tumors
• High levels of insulin growth factor 1
• Cobalt and manganese toxicities
• Self-administration of EPO
• High levels of androgens or adrenocorticotropic hormone
• Increased presence of other stimulators of erythropoiesis (as in post–renal transplant erythrocytosis)

Question 5

Relative erythrocytosis

Answer 5

• Diuretic use
• Dehydration from excessive sweating
• Gaisbock syndrome
• Stress erythrocytosis

Question 6

The term used to depict enhanced red cell count or blood Hb values that is caused by reduced plasma volume, not increased red cell mass

Answer 6

Relative erythrocytosis

Not a true erythrocytosis and is designated spurious, apparent, or relative erythrocytosis

Question 7

Hypertensive patients had plethora and an elevated red cell count but no splenomegaly

Answer 7

Erythrocytosis hypertonica or Gaisbock syndrome

Question 8

Publicized as Quebec beer-drinkers’ cardiomyopathy

Shown to increase erythropoiesis at least in part by increasing EPO

Also described in patients with hip replacement implanted with metal-on-polyethylene prostheses

Answer 8

Cobalt-Induced Erythrocytosis

Cognitive deterioration, cardiomyopathy, hypothyroidism, and neuropathy; all are the clinical manifestations of prosthetic cobaltism

Question 9

About 1% to 3% of all patients with pheochromocytoma or paraganglioma have erythrocytosis.

Rare patients with congenital erythrocytosis develop pheochromocytoma or paraganglioma; these are most likely caused by genomic mosaicism for

Answer 9

Gain of function of EPAS1 (hypoxia-inducible factor [HIF] 2α)

Question 10

Syndrome of erythrocytosis, elevated erythropoietin and monoclonal gammopathy

Answer 10

TEMPI syndrome

(1) telangiectasias;
(2) elevated erythropoietin and erythrocytosis;
(3) monoclonal gammopathy;
(4) perinephric fluid collections; and
(5) intrapulmonary shunting

Question 11

Syndrome defined as a persistent elevation of Hct at over 51%, is a relatively common condition found in approximately 5% to 10% of renal allograft recipients

Answer 11

Post–Renal Transplant Erythrocytosis

Question 12

Post–renal transplant erythrocytosis usually develops within_______months after transplantation, despite persistently good function of the allograft, and resolves spontaneously within_________ years in about 25% of patients.

Answer 12

8–24 months

2 years

Question 13

Factors that increase the likelihood of Post–Renal Transplant Erythrocytosis

Answer 13

• Lack of EPO therapy before transplantation
• History of smoking
• Diabetes mellitus
• Renal artery stenosis
• Low serum ferritin levels
• Normal or higher pretransplant EPO levels

Question 14

The only known endemic congenital erythrocytosis in the world

Answer 14

Chuvash Erythrocytosis

Russia

Question 15

Caused by germline rather than acquired somatic mutations

It is congenital and manifests autosomal dominant inheritance

The defect changes intrinsic responses of erythroid progenitors, and EPO levels are low

Answer 15

Primary Familial and Congenital Polycythemia/Erythrocytosis

Question 16

Gene mutation in Primary Familial and Congenital Polycythemia/Erythrocytosis

Answer 16

Eythropoietin receptor (EPOR)

Question 17

The first signal is initiated by conformation change-induced activation of ________________ and its phosphorylation and activation of a transcription factor, _____________________, which regulates erythroid-specific genes.

“on” signals

Answer 17

JAK (Janus type tyrosine kinase) 2

Signal transducer and activator of transcription (STAT) 5

Question 18

Enzyme used in dephosphorylation of EPOR

The “off ” signal

Answer 18

Hematopoietic phosphatase (HCP), also known as SHP1

Question 19

Evidence of increased thrombotic risk in secondary erythrocytoses is lacking with the exception of secondary erythrocytoses resulting from ____________________

Answer 19

Augmented HIF signaling

Evidence for HIF-induced prothrombotic changes in leukocytes is emerging

Question 20

In a subset of Andean high-altitude native dwellers, namely Quechuas and Aymaras, erythrocytosis becomes excessive and often results in _______________________ with its associated constitutional symptoms and pulmonary hypertension.

Answer 20

Monge’s disease or chronic mountain sickness

Question 21

In the normovolemic state, viscosity increases in a log-linear fashion as Hct increases, and the effect is particularly pronounced when the Hct rises above ________%.

Answer 21

50%

Question 22

Arterial hypoxemia with erythrocytosis

Answer 22

Andean “classic” erythrocytosis

Question 23

Arterial hypoxemia with normal venous Hb concentration

Answer 23

Tibetan erythrocytosis

Question 24

Genes affected in Tibetan adaptation

Answer 24

EPAS1 gene
EGLN1 gene

Question 25

EPAS1 gene EGLN1 gene

Answer 25

**EPAS1** gene: α subunit of **HIF2** **EGLN1** gene: prolyl hydroxylase 2 (**PHD2**)

Question 26

The principal negative regulator of both HIF1 and HIF2

Answer 26

PHD2

Question 27

Cause of Peruvian mining community of Cerro de Pasco (altitude, 4280 m) with excessive erythrocytosis

Answer 27

Toxic serum cobalt levels

Question 28

# Erythrocytosis of Eisenmenger Syndrome It may not be the microcytosis per se that is detrimental but the ____________________, which then directly causes pulmonary vasoconstriction and enhanced pulmonary vascular pressure

Answer 28

Induced **iron deficiency** that inhibits PHD2 and increases HIF

Question 29

Erythrocytosis is characterized by its association with **extreme obesity and somnolence**.

Answer 29

Pickwickian syndrome

Question 30

# TRUE OR FALSE In smoking, either augmentation of red cell mass or shrinkage of plasma volume could easily explain the rise in the Hct.

Answer 30

TRUE In **smoking**, either **augmentation of red cell mass or shrinkage of plasma volume** could easily explain the rise in the Hct. ## Footnote Heavy smoking results in the formation of **carboxyhemoglobin**, which does not transport oxygen and causes an **increase in oxygen affinity** of the remaining normal Hb

Question 31

Some ____________mutations interfere with deoxygenation Most hemoglobins are unstable and are associated with hemolytic anemia and cyanosis

Answer 31

Heme pocket mutations

Question 32

Occasionally, mild erythrocytosis occurs in patients with **methemoglobinemia** because of deficiency of this enzyme

Answer 32

Cytochrome b5 reductase (methemoglobin reductase) deficiency ## Footnote The same pathophysiology as that seen in high-affinity hemoglobins is also exhibited in mutations of the **2,3-BPG gene**, resulting in low 2,3 BPG.

Question 33

Erythrocytosis at birth is a normal physiologic response to

Answer 33

* Intrauterine hypoxia * High oxygen affinity of red cells containing very high proportions of Hb F

Question 34

The erythrocytosis in infants may become excessive and even symptomatic, especially

Answer 34

* In infants of mothers with diabetes * If clamping of the cord is delayed

Question 35

Mechanism of COPPER- Induced Augmented Hypoxia Sensing

Answer 35

Increases EPO production by increasing HIFs, likely by **inhibition of proline hydroxylase**, which increases HIF-1

Question 36

Mechanism of MANGANESE- Induced Augmented Hypoxia Sensing

Answer 36

Blocking the negative HIFs regulator **factor-inhibiting HIF (FIH)**

Question 37

**The only known endemic congenital erythrocytosis** * Abnormality in the **oxygen-sensing pathway** * Causes **thrombotic and hemorrhagic vascular complications** that lead to **early mortality**

Answer 37

Chuvash Erythrocytosis (Polycythemia) ## Footnote Survival beyond age 65 years is uncommon

Question 38

Features of Chuvash Erythrocytosis (Polycythemia)

Answer 38

* Autosomal recessive inheritance * Have normal blood gases, normal calculated p50 * Normal to increased EPO levels * Absence of genetic linkage to EPO and EPOR loci, and no evidence of abnormal Hb

Question 39

Gene mutation involved in Chuvash Erythrocytosis (Polycythemia)

Answer 39

VHL gene (598C>T) (VHLR200W) ## Footnote Impairs the interaction of pVHL with both HIF-1α and HIF-2α, thus **reducing the rate of ubiquitin-mediated destruction of HIF-1α and HIF-2α** Increased expression of target genes, including the EPO, vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor genes (PAI-1), among others

Question 40

# TRUE OR FALSE Patients with Chuvash erythrocytosis display a predisposition to tumor formation.

Answer 40

FALSE Patients with Chuvash erythrocytosis **do not** display a predisposition to tumor formation.

Question 41

# TRUE OR FALSE Chuvash erythrocytosis homozygotes have decreased survival because of thrombotic and hemorrhagic complications, mostly in the venous circulation,and thus are under negative selection pressure.

Answer 41

TRUE Chuvash erythrocytosis homozygotes have decreased survival because of **thrombotic and hemorrhagic complications**, mostly in the **venous** circulation,and thus are under negative selection pressure.

Question 42

An **autosomal dominant** genetic abnormality affecting the posttranslational control of HIF-1α Characterized by a propensity for developing *renal cell carcinomas, retinal hemangioblastomas, cerebellar and spinal hemangioblastomas, pancreatic cysts, and pheochromocytomas.*

Answer 42

Classic von Hippel Lindau Syndrome | Erythrocytosis is not part of VHL syndrome!

Question 43

*Erythrocytosis is not part of VHL syndrom*e, but hemangioblastomas of the central nervous system and less commonly pheochromocytoma and renal cancer have been associated with erythrocytosis mediated by ____________________

Answer 43

Paraneoplastic EPO production

Question 44

# EPO levels EGLN1 Gene Mutations, Proline Hydroxylase Deficiency: EPAS1 (HIF-2α) Gain-of-Function Mutations :

Answer 44

EGLN1 Gene Mutations, Proline Hydroxylase Deficiency: **normal EPO levels** EPAS1 (HIF-2α) Gain-of-Function Mutations: **elevated EPO levels**

Question 45

Plays an important role in Post–Renal Transplantation Erythrocytosis pathogenesis

Answer 45

Angiotensin II ## Footnote Increased activity of the angiotensin II–angiotensin receptor 1 pathway makes the erythroid progenitors **hypersensitive to angiotensin II** --> **release of erythropoiesis stimulatory factors , including EPO and IGF-1**

Question 46

Pathogenetic mechanisms have been suggested in Aldosterone-Producing Lesions Aldosterone-producing adenomas, Bartter syndrome,and dermoid cyst of the ovary

Answer 46

Decreased plasma volume; mechanical interference with renal blood supply; hypertensive damage to renal parenchyma; functional interaction between aldosterone, renin, and EPO; and inappropriate secretion of EPO by the tumors

Question 47

The mechanism of androgen action on erythropoiesis

Answer 47

* Stimulate EPO production * Capacity to induce differentiation of marrow stem cells directly ## Footnote **Testosterone** administration is associated with an **increase in EPO levels and a decrease in hepcidin levels**

Question 48

Configuration of androgens that **stimulate renal and extrarenal EPO production**

Answer 48

5α-H

Question 49

Configuration of androgens that **enhance the differentiation of stem cells**

Answer 49

5β-H

Question 50

The main clinical associations with apparent erythrocytosis are

Answer 50

Obesity, hypertension, and smoking

Question 51

Clinical features of Primary Familial and Congenital Erythrocytosis (vs PV)

Answer 51

* Lack splenomegaly, neutrophilia, basophilia, thrombocytosis and a JAK2 mutation. * Do not progress to acute leukemia or myelodysplastic syndrome. * Predisposes patients to **severe cardiovascular problems** perhaps caused by chronic augmented EPO signaling in all tissues bearing EPOR. * Erythrocytosis may be very severe, with Hb levels that typically exceed 20 g/dL in men and 18 g/dL in women. * **Headaches** are commonly present.

Question 52

# TRUE OR FALSE In Chuvash Erythrocytosis, the thrombotic risk may be independent of elevated Hct and viscosity but rather related to the upregulated hypoxic responses associated with this congenital disorder.

Answer 52

TRUE In Chuvash Erythrocytosis, the thrombotic risk may be **independent of elevated Hct and viscosity** but rather related to the upregulated hypoxic responses associated with this congenital disorder. ## Footnote Also with EPAS1 (HIF-2α) and HIF-2α gain-of-function mutation

Question 53

Symptoms constitute the syndrome of **acute mountain sickness**

Answer 53

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 that may lead to death. Cheyne-Stokes respiration commonly occurs, especially during sleep.

Question 54

# TRUE OR FALSE When erythrocytosis is present in patients with COPD, with or without smoking, elevated Hct is associated with higher survival rates than anemic and normocythemic subjects.

Answer 54

TRUE When erythrocytosis is present in patients with COPD, with or without smoking, **elevated Hct** is associated with **higher survival** rates than anemic and normocythemic subjects.

Question 55

# TRUE OR FALSE Moderate erythrocytosis in COPD has adverse effect on vascular function in COPD and is associated with venous thromboembolism.

Answer 55

FALSE Moderate **erythrocytosis** in COPD has no adverse effect on vascular function in COPD and is **not associated with venous thromboembolism**.

Question 56

Adults with **cyanotic congenital heart disease** are at risk of having **cerebrovascular events**. Risk is increased in the presence of

Answer 56

* Hypertension * Atrial fibrillation * History of phlebotomy * **Microcytosis**, strongest significance (P < .005) ## Footnote More conservative approach toward phlebotomy and more aggressive approach toward treating microcytosis with iron preparations in adults with cyanotic congenital heart disease.

Question 57

Characteristic laboratory findings of **PFCP** are

Answer 57

(a) increased red blood cell mass without increased leukocyte or platelet counts, (b) normal Hb-oxygen dissociation curve, (c) invariably low serum EPO levels, and (d) in vitro hypersensitivity of erythroid progenitors to EPO

Question 58

Laboratory findings of **Chuvash Erythrocytosis**

Answer 58

Increased Hb and Hct and lower white blood cell and platelet counts EPO ranges from normal (but never close to the lower limits of normal) to elevated Serum PAI-1 and VEGF levels are also increased Transferrin receptor levels are higher

Question 59

# TRUE OR FALSE Determination of red cell mass is invaluable for differentiation of apparent (spurious) erythrocytosis from true erythrocytoses states.

Answer 59

TRUE Determination of **red cell mass** is *invaluable* for differentiation of apparent (spurious) erythrocytosis from true erythrocytoses states.

Question 60

Permit the study of erythroid progenitor cells responsiveness to EPO

Answer 60

Erythroid Colony Cultures ## Footnote * Used to be the most specific test for polycythemia vera. * EPO hypersensitive erythroid colonies : PFCP, Chuvash erythrocytosis *** Abrogated by pretreatment with EPO and EPOR blocking antibodies: Polycythemia vera**

Question 61

# ERYTHROPOIETIN LEVELS PFCP : PV: Budd-Chiari syndrome in PV : Secondary erythrocytosis

Answer 61

PFCP : below normal levels PV: below normal levels **Budd-Chiari syndrome in PV : normal or even increased** Secondary erythrocytosis: normal to elevated EPO levels

Question 62

Used to differentiate polycythemia vera with an incomplete phenotype or atypical presentation from idiopathic or as-yet undiagnosed erythrocytosis

Answer 62

Clonality assay ## Footnote Clonality studies based on the phenomenon of X-chromosome inactivation have shown that red cells, granulocytes, platelets, monocytes, and B lymphocytes are all part of the clone.

Question 63

An **autosomal dominant** disorder is likely due to erythrocytosis from

Answer 63

* Gain-of-function EPOR * EPAS1 (HIF2a) or EGLN1 (PHD2) mutations * High-affinity Hb

Question 64

A **recessively** inherited disorder is likely due to erythrocytosis from

Answer 64

VHL gene mutations

Question 65

Used to detect abnormalities related to increased oxygen affinity either because of inheritance of a high affinity Hb or because of very rare 2,3-BPG depletion caused by phosphoglyceromutase deficiency

Answer 65

Hb oxygen dissociation curve or estimation of p50 from venous blood

Question 66

The mild erythrocytosis associated with_________________ is often diagnosed because of frequent **coexistent cyanosis**.

Answer 66

Hereditary methemoglobinemia

Question 67

# TRUE OR FALSE No treatment is required for individuals with chronic stress erythrocytosis, and fluids are all that is necessary for dehydrated individuals who present with acute increases in Hgb or Hct.

Answer 67

TRUE **No treatment** is required for individuals with **chronic stress erythrocytosis**, and **fluids** are all that is necessary for dehydrated individuals who present with acute increases in Hgb or Hct.

Question 68

Treatment of patients with post–renal transplant erythrocytosis

Answer 68

Drugs that suppress the renal–angiotensin system Angiotensin-converting enzyme inhibitor enalapril or the angiotensin II receptor type 1 blocker losartan

Question 69

The maximal reduction of Hb and Hct levels in patients with post–renal transplant erythrocytosis usually manifests by_________ after starting therapy

Answer 69

6 months

Question 70

Treatment when erythrocytosis is secondary to a renal tumor or cyst, pheochromocytoma, myoma, or brain tumor

Answer 70

Removal of the neoplasm

Question 71

# TRUE OR FALSE In the syndrome of congenital erythrocytosis with pheochromocytoma caused by EPAS1 mutations, erythrocytosis persist after tumor resection.

Answer 71

TRUE In the syndrome of congenital erythrocytosis with **pheochromocytoma caused by EPAS1 mutations**, **erythrocytosis persist after tumor resection**.

Question 72

# TRUE OR FALSE Lowering the Hct to a normal or near-normal level by phlebotomy is the common but empiric treatment of secondary erythrocytosis, although it has not been proven to be beneficial.

Answer 72

TRUE Lowering the Hct to a normal or near-normal level by **phlebotomy** is the common but empiric treatment of secondary erythrocytosis, although it has **not been proven to be beneficial.** ## Footnote One should phlebotomize only those patients who are symptomatic from the elevated red cell mass and continue to do so cautiously only if symptoms respond promptly to phlebotomy.

Question 73

# TRUE OR FALSE Polycythemia vera is always an acquired condition.

Answer 73

TRUE Polycythemia vera is always an acquired condition.