58 Primary and Secondary Erythrocytosis/Polycythemia Flashcards
Primary polycythemic disorders that have erythroid progenitors hypersensitive to erythropoietin (EPO)
- 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)
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
Secondary erythrocytosis
Secondary erythrocytosis: Appropriate erythrocytosis
- Pulmonary disease
- Eisenmenger complex
- High-altitude erythrocytosis
- Hemoglobins (Hbs) with increased affinity for oxygen
Secondary erythrocytosis: Inappropriate erythrocytosis
- 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)
Relative erythrocytosis
- Diuretic use
- Dehydration from excessive sweating
- Gaisbock syndrome
- Stress erythrocytosis
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
Relative erythrocytosis
Not a true erythrocytosis and is designated spurious, apparent, or relative erythrocytosis
Hypertensive patients had plethora and an elevated red cell count but no splenomegaly
Erythrocytosis hypertonica or Gaisbock syndrome
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
Cobalt-Induced Erythrocytosis
Cognitive deterioration, cardiomyopathy, hypothyroidism, and neuropathy; all are the clinical manifestations of prosthetic cobaltism
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
Gain of function of EPAS1 (hypoxia-inducible factor [HIF] 2α)
Syndrome of erythrocytosis, elevated erythropoietin and monoclonal gammopathy
TEMPI syndrome
(1) telangiectasias;
(2) elevated erythropoietin and erythrocytosis;
(3) monoclonal gammopathy;
(4) perinephric fluid collections; and
(5) intrapulmonary shunting
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
Post–Renal Transplant Erythrocytosis
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.
8–24 months
2 years
Factors that increase the likelihood of Post–Renal Transplant Erythrocytosis
- Lack of EPO therapy before transplantation
- History of smoking
- Diabetes mellitus
- Renal artery stenosis
- Low serum ferritin levels
- Normal or higher pretransplant EPO levels
The only known endemic congenital erythrocytosis in the world
Chuvash Erythrocytosis
Russia
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
Primary Familial and Congenital Polycythemia/Erythrocytosis
Gene mutation in Primary Familial and Congenital Polycythemia/Erythrocytosis
Eythropoietin receptor (EPOR)
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
JAK (Janus type tyrosine kinase) 2
Signal transducer and activator of transcription (STAT) 5
Enzyme used in dephosphorylation of EPOR
The “off ” signal
Hematopoietic phosphatase (HCP), also known as SHP1
Evidence of increased thrombotic risk in secondary erythrocytoses is lacking with the exception of secondary erythrocytoses resulting from ____________________
Augmented HIF signaling
Evidence for HIF-induced prothrombotic changes in leukocytes is emerging
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.
Monge’s disease or chronic mountain sickness
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 ________%.
50%
Arterial hypoxemia with erythrocytosis
Andean “classic” erythrocytosis
Arterial hypoxemia with normal venous Hb concentration
Tibetan erythrocytosis
Genes affected in Tibetan adaptation
EPAS1 gene
EGLN1 gene
EPAS1 gene
EGLN1 gene
EPAS1 gene: α subunit of HIF2
EGLN1 gene: prolyl hydroxylase 2 (PHD2)
The principal negative regulator of both HIF1 and HIF2
PHD2
Cause of Peruvian mining community of Cerro de Pasco (altitude, 4280 m) with excessive erythrocytosis
Toxic serum cobalt levels
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
Induced iron deficiency that inhibits PHD2 and increases HIF
Erythrocytosis is characterized by its association with extreme obesity and somnolence.
Pickwickian syndrome
TRUE OR FALSE
In smoking, either augmentation of red cell mass or shrinkage of plasma volume could easily explain the rise in the Hct.
TRUE
In smoking, either augmentation of red cell mass or shrinkage of plasma volume could easily explain the rise in the Hct.
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
Some ____________mutations interfere with deoxygenation
Most hemoglobins are unstable and are associated with hemolytic anemia and cyanosis
Heme pocket mutations
Occasionally, mild erythrocytosis occurs in patients with methemoglobinemia because of deficiency of this enzyme
Cytochrome b5 reductase (methemoglobin reductase) deficiency
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.
Erythrocytosis at birth is a normal physiologic response to
- Intrauterine hypoxia
- High oxygen affinity of red cells containing very high proportions of Hb F
The erythrocytosis in infants may become excessive and even symptomatic, especially
- In infants of mothers with diabetes
- If clamping of the cord is delayed
Mechanism of COPPER- Induced Augmented Hypoxia Sensing
Increases EPO production by increasing HIFs, likely by inhibition of proline hydroxylase, which increases HIF-1
Mechanism of MANGANESE- Induced Augmented Hypoxia Sensing
Blocking the negative HIFs regulator factor-inhibiting HIF (FIH)
The only known endemic congenital erythrocytosis
- Abnormality in the oxygen-sensing pathway
- Causes thrombotic and hemorrhagic vascular complications that lead to early mortality
Chuvash Erythrocytosis (Polycythemia)
Survival beyond age 65 years is uncommon
Features of Chuvash Erythrocytosis (Polycythemia)
- 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
Gene mutation involved in Chuvash Erythrocytosis (Polycythemia)
VHL gene (598C>T) (VHLR200W)
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
TRUE OR FALSE
Patients with Chuvash erythrocytosis display a predisposition to tumor formation.
FALSE
Patients with Chuvash erythrocytosis do not display a predisposition to tumor formation.
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.
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.
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.
Classic von Hippel Lindau Syndrome
Erythrocytosis is not part of VHL syndrome!
Erythrocytosis is not part of VHL syndrome, but hemangioblastomas of the central nervous system and less commonly pheochromocytoma and renal cancer have been associated with erythrocytosis mediated by ____________________
Paraneoplastic EPO production
EPO levels
EGLN1 Gene Mutations, Proline Hydroxylase Deficiency:
EPAS1 (HIF-2α) Gain-of-Function Mutations :
EGLN1 Gene Mutations, Proline Hydroxylase Deficiency: normal EPO levels
EPAS1 (HIF-2α) Gain-of-Function Mutations: elevated EPO levels
Plays an important role in Post–Renal Transplantation Erythrocytosis pathogenesis
Angiotensin II
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
Pathogenetic mechanisms have been suggested in Aldosterone-Producing Lesions
Aldosterone-producing adenomas, Bartter syndrome,and dermoid cyst of the ovary
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
The mechanism of androgen action on erythropoiesis
- Stimulate EPO production
- Capacity to induce differentiation of marrow stem cells directly
Testosterone administration is associated with an increase in EPO levels and a decrease in hepcidin levels
Configuration of androgens that stimulate renal and extrarenal EPO production
5α-H
Configuration of androgens that enhance the differentiation of stem cells
5β-H
The main clinical associations with apparent erythrocytosis are
Obesity, hypertension, and smoking
Clinical features of Primary Familial and Congenital Erythrocytosis (vs PV)
- 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.
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.
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.
Also with EPAS1 (HIF-2α) and HIF-2α gain-of-function mutation
Symptoms constitute the syndrome of acute mountain sickness
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.
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.
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.
TRUE OR FALSE
Moderate erythrocytosis in COPD has adverse effect on vascular function in COPD and is associated with venous thromboembolism.
FALSE
Moderate erythrocytosis in COPD has no adverse effect on vascular function in COPD and is not associated with venous thromboembolism.
Adults with cyanotic congenital heart disease are at risk of having cerebrovascular events.
Risk is increased in the presence of
- Hypertension
- Atrial fibrillation
- History of phlebotomy
- Microcytosis, strongest significance (P < .005)
More conservative approach toward phlebotomy and more aggressive approach toward treating microcytosis with iron preparations in adults with cyanotic congenital heart disease.
Characteristic laboratory findings of PFCP are
(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
Laboratory findings of Chuvash Erythrocytosis
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
TRUE OR FALSE
Determination of red cell mass is invaluable for differentiation of apparent (spurious) erythrocytosis from true erythrocytoses states.
TRUE
Determination of red cell mass is invaluable for differentiation of apparent (spurious) erythrocytosis from true erythrocytoses states.
Permit the study of erythroid progenitor cells responsiveness to EPO
Erythroid Colony Cultures
- 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
ERYTHROPOIETIN LEVELS
PFCP :
PV:
Budd-Chiari syndrome in PV :
Secondary erythrocytosis
PFCP : below normal levels
PV: below normal levels
Budd-Chiari syndrome in PV : normal or even increased
Secondary erythrocytosis: normal to elevated EPO levels
Used to differentiate polycythemia vera with an incomplete phenotype or atypical presentation from idiopathic or as-yet undiagnosed erythrocytosis
Clonality assay
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.
An autosomal dominant disorder is likely due to erythrocytosis from
- Gain-of-function EPOR
- EPAS1 (HIF2a) or EGLN1 (PHD2) mutations
- High-affinity Hb
A recessively inherited disorder is likely due to erythrocytosis from
VHL gene mutations
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
Hb oxygen dissociation curve or estimation of p50 from venous blood
The mild erythrocytosis associated with_________________ is often diagnosed because of frequent coexistent cyanosis.
Hereditary methemoglobinemia
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.
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.
Treatment of patients with post–renal transplant erythrocytosis
Drugs that suppress the renal–angiotensin system
Angiotensin-converting enzyme inhibitor enalapril or the angiotensin II receptor type 1 blocker losartan
The maximal reduction of Hb and Hct levels in patients with post–renal transplant erythrocytosis usually manifests by_________ after starting therapy
6 months
Treatment when erythrocytosis is secondary to a renal tumor or cyst, pheochromocytoma, myoma, or brain tumor
Removal of the neoplasm
TRUE OR FALSE
In the syndrome of congenital erythrocytosis with pheochromocytoma caused by EPAS1 mutations, erythrocytosis persist after tumor resection.
TRUE
In the syndrome of congenital erythrocytosis with pheochromocytoma caused by EPAS1 mutations, erythrocytosis persist after tumor resection.
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.
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.
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.
TRUE OR FALSE
Polycythemia vera is always an acquired condition.
TRUE
Polycythemia vera is always an acquired condition.
