A disorder known as polycythemia is characterized by an unnatural excess in the mass of red blood cells (RBCs), which is formed from the words poly (many) & cythemia (blood cells). RBC mass ranges from 23 – 29 mL/kg in females & 26 – 32 mL/kg in males for a typical healthy adult. Patients with increased RBC masses typically have hematocrit levels over 51% & 48% & hemoglobin values above 185 g/L & 165 g/L in males & females, respectively.
Erythrocytosis is not the same thing as polycythemia. An RBC mass larger than 125 percent of the projected value after adjusting for gender & body weight is referred to as absolute erythrocytosis. True or absolute erythrocytosis differs from relative polycythemia, which has an elevated hematocrit but a normal range for red cell mass. The reduced plasma volume may be the cause of the increased hematocrit.
Secondary polycythemia is caused by a high erythropoietin (EPO) level, which typically results from a secondary response to prolonged hypoxemia. Chronic hypoxemia may develop as a result of a number of disorders, such as muscle abnormalities, obese hypoventilation syndrome, obstructive sleep apnea, and lung pathology like COPD (chronic obstructive pulmonary disease).
Epidemiology
In a study by Galeus et al. (2015), it was discovered that severe pulmonary hypertension, congenital heart disease, and COPD were some of the most frequent causes of secondary polycythemia. Information on the epidemiology of secondary polycythemia is scarce.
Anatomy
Pathophysiology
The physiological activity that results in the creation & maintenance of RBC bulk is called erythropoiesis. Many receptors, hormones, and other elements control this process. Of all the RBC mass controllers, EPO is the most significant. The kidneys & erythroid progenitor cells both generate it. EPO is typically made in response to anemia and hypoxia.
The synthesis of hypoxia-inducible factors is boosted by hypoxia, which in turn causes EPO gene expression to increase. Red blood cells are necessary for the transportation of oxygen. The capability of the blood to carry oxygen will rise as the erythrocyte mass increases. For optimal tissue oxygen supply, individuals with secondary polycythemia caused to a physiologically suitable reaction need more erythrocyte mass than usual.
It has been noted that hyperviscosity in normovolemic patients is related to hematocrit levels of more than 45%. Reduced cerebral blood flow has also been linked to hematocrit levels higher than 45 percent; this is remedied by phlebotomy. In these patients, there is a delicate balance between normal tissue oxygenation & hyperviscosity; this is the therapeutic objective.
Etiology
Increased levels of EPO or other transcription factors, which in turn cause an increase in the creation of RBC mass, are the cause of secondary polycythemia. It should be highlighted that there is no inherent abnormality in the lineage of erythroid progenitor cells, unlike primary polycythemia. Many causes, including inherited and acquired ones that are detailed below, can contribute to the rise in EPO levels.
A system for classifying polycythemia
Polycythemia is further divided into primary and secondary forms based on how the erythroid progenitor cells react to the circulatory cytokines.
Primary Polycythemia:
The enhanced proliferation of erythroid progenitor cells as a result of an underlying cellular abnormality is the cause of primary erythrocytosis. Erythropoietin values are suppressed in these patients. There are mainly two forms.
Polycythemia vera: Due to a mutation known as the JAK mutant, this neoplastic condition is caused by an increase in erythroid progenitor cells and an increase in erythropoietin sensitivity. Pure erythrocytosis: A solitary increased RBC mass without any additional precipitating factors is present in the subset of patients with pure erythrocytosis.
Secondary Polycythemia:
A physiologically suitable response to tissue hypoxia, a physiologically incorrect release of erythropoietin, and other contributing variables can all cause this varied set of diseases, which are all defined by a high RBC mass. Depending on when the person developed the disease, secondary polycythemia can also be categorized as acquired or congenital. Studies have shown that there are about 100 alterations that lead to more than 50 variations of the alpha & beta globulin alleles, including mutations that change the affinities for 2,3-bisphosphoglycerate and oxygen (2,3-BPG).
These abnormalities are inherited in a dominant manner. The HIF (hypoxia-inducible factor) mutation causes familial erythrocytosis. A variation in the HIF cofactor causes aberrant oxygen sensing, which in turn causes an increase in erythropoietin production &, ultimately, an excess in red blood cell mass. According to reports, athletes’ usage of anabolic steroids is linked to an increase in erythrocytosis.
Secondary polycythemia with an appropriate physiological basis (tissue hypoxia)
Acquired
Renal disorder (renal artery stenosis, local renal hypoxia)
High-altitude habitat
Obstructive sleep apnea & obese hypoventilation syndrome are two examples of hypoventilation syndromes.
Smoker’s erythrocytosis
Poisoning by carbon monoxide
Cardiopulmonary vascular shunts from the right to the left and cyanotic cardiac disease
hepatocellular carcinomas, and renal cell carcinomas)
Erythropoietin therapy & androgen administration are drug related.
Renal conditions, such as cysts, hydronephrosis, Bartter’s syndrome, ESRD, long-term hemodialysis, polycystic kidney
disorder, and Erythrocytosis following kidney transplant)
Hypersecretion from the adrenal cortex
Polycythemia idiopathic
Related Polycythemia (Stress Erythrocytosis, Gaisbock Syndrome, or Spurious)
A higher hematocrit is indicative of relative polycythemia, which is also characterized by normal to high normal RBC mass and low normal to decreased plasma volume. Individuals with relative polycythemia are at a greater risk for thromboembolic consequences even when they don’t have true erythrocytosis.
Chuvash Polycythemia
The Chuvash ethnic group in central Russia is the source of the term for this endemic & recessively inherited hereditary polycythemia. EPO values were discovered to be substantially above average. In addition to having increased EPO values, people with CP also have hypersensitive erythroid progenitor cells. Due to thrombotic & hemorrhagic incidents, it is linked to markedly higher mortality in the initial years. Because of the underlying pathogenesis, Chuvash polycythemia is linked to both secondary and primary erythrocytosis.
Genetics
Prognostic Factors
The median duration from diagnosis to death in research by Galeas et al. evaluating mortality outcomes in a multicity cohort was 21.1 months, which is roughly half the period for patients with polycythemia vera.
The study also revealed that patients with secondary erythrocytosis had a 5% incidence of thrombotic events. However, the fundamental cause and the emergence of complications have been tightly linked to the prognosis.
Clinical History
Clinical history
High red blood cell mass patients may have an abundance of red blood cells or a reddish complexion. Patients can also appear cyanotic if the polycythemia is linked to hypoxia, such as in venous-to-arterial shunts or reduced lung & oxygenation. Blood viscosity rises with red blood cell mass, which also lowers tissue perfusion.
Patients with decreased circulation to the central nervous system may exhibit less significant symptoms like headaches, drowsiness, and disorientation or more serious ones like stroke & obtundation. Additionally, polycythemia may put a patient at risk for thrombosis. Birth or early life is when congenital heart conditions first show symptoms. A family history of congenital cardiac disease may exist in specific situations.
However, a sizable portion of patients with congenital polycythemia has no family background of such illnesses, patients with familial hemoglobinopathies that cause increased oxygen affinity typically have a family background of similar problems in numerous family members. In contrast to secondary polycythemia, chronic pruritus without a rash is more suggestive of a primary myeloproliferative disease.
Physical Examination
Physical examination
Plethora shows itself as heightened skin & mucous membrane redness. On the palms or soles, where the skin is lighter in dark-skinned people, this discovery is easier to spot. Acrocyanosis may develop in some patients as a result of slow blood circulation through small vessels.
Splenomegaly favors a polycythemia vera diagnosis rather than a subsequent polycythemia diagnosis. Congenital heart disease may be indicated by cardiac murmurs and clubbing of the fingers.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential diagnosis
Tumors include craniopharyngioma, liver carcinoma, renal neoplasm, and adrenal carcinomas.
Adrenal cancers, including incidentalomas.
Arteriovenous malformation & kidney artery stenosis are two examples of kidney vascular pathogenesis.
Post-kidney transplant
Drug abuse
Obstructive sleep apnea
Cor pulmonale
Ventricular septal defect
Atrial septal defect
Chronic smoking
Polycythemia vera
Dehydration
COPD
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
The method of treatment for secondary polycythemia varies on the underlying cause. The overall strategy is to repair the triggering conditions, which will, in turn, cause the hematologic abnormalities to be corrected. Smokers should be counseled to stop and given the proper supporting, psychological, & pharmaceutical interventions. Diuretics should no longer be prescribed since they cause the plasma volume to constrict. If possible, the dose should be decreased, or they should be stopped & replaced with an adequate substitute. Androgen use is discouraged, and either the dosage should be lowered or the substance should be stopped altogether.
These patients require more iron than average in order to create normocytic, normochromic red blood cells that can provide oxygen as needed. In order to prevent any iron deficiency that results in the creation of microcytic hypochromic red blood cells that are connected to a hyperviscosity condition, iron should be replenished. Low-flow oxygen therapy, especially in individuals with COPD, can treat hypoxia and, subsequently, secondary polycythemia. In order to prevent oxygen toxicity & respiratory distress in COPD patients, oxygen use should be prudent and constantly monitored in accordance with pulse oximetry.
Weight loss is a remedial action that can be accomplished through lifestyle changes, drug therapy, & bariatric surgery for people with obese hypoventilation disorder. In patients with this etiology, surgical excision of erythropoietin-producing tumors is therapeutic. Curative treatment also includes benign kidney lesions. Phlebotomy can be used to temporarily relieve symptoms in some people with secondary polycythemia. With the emergence of problems, secondary polycythemia care strategies also change. Aspirin taken in low doses may help to prevent thromboembolic events. This resulted from extrapolating research done on polycythemia vera.
Similarly, it has been discovered that venesection in polycythemia vera is linked to a lower risk of cardiovascular mortality & thrombosis. These results are typically extrapolated for secondary polycythemia while taking the treating clinician’s clinical judgment into consideration. Individuals with physiologically inappropriate erythrocytosis do not benefit from the elevated red cell mass, in contrast to patients with secondary polycythemia caused by physiologically adequate erythrocytosis.
Phlebotomy is therapeutic for these patients, aiming to keep hematocrit levels between 42% and 46%. Prior to any elective surgery, any individual with secondary polycythemia should have a phlebotomy. Phlebotomy should not be done in patients with physiologically acceptable erythrocytosis because the body uses the increased red cell mass as a defense mechanism, and it interferes with adequate tissue oxygenation. The therapeutic objective in these individuals is to strike a delicate balance between sufficient tissue oxygenation & hyperviscosity.
The therapeutic aim of hematocrit is determined by the underlying disorders and the unique reactions of each patient. In general, keeping hematocrit readings under 60% should be the objective.
Phlebotomy has been linked to improvements in right ventricular activity & hemodynamic reaction to exertion in individuals with COPD, as well as a decrease in pulmonary arterial resistance and the arteriovenous oxygen concentration imbalance. These gains are significant at hematocrit levels of 50% – 55%. Limited data support the use of medications such as ACE inhibitors or angiotensin receptor inhibitors in patients with hypoxic pulmonary illness who do not respond to venesection.
The target hematocrit should be carefully adapted to the underlying etiology of the patient and on an individual basis. The benefit of isovolumic phlebotomy is that it guards against acute hemodynamic consequences brought on by a drop in blood volume.
Isovolumetric venesections were advised to be beneficial in lowering viscosity in individuals with cyanotic cardiovascular diseases. However, it should be remembered that insufficiency is linked to excessive venesections.
If the hematocrit is beyond 54% in patients with idiopathic erythrocytosis, then lowering it to a baseline of 50 percent may be taken into consideration. If the objective is currently higher than 54% for individuals with comorbid illnesses that increase their risk of ischemia & thrombosis, a reduced baseline of 45% is also considered. Cytoreductive treatment is not recommended for this particular patient group.
In patients with erythrocytosis secondary to post-kidney transplant, it is advised to avoid a secondary component that predisposes to dehydration and uses ACE blockers. For this subset of patients, a hematocrit of less than 45% is the desired level.
Management Guidelines for Secondary Polycythemia
Eliminating all myelosuppressive treatments
Consider phlebotomy to maintain hematocrit.
Applying particular tactics in line with the pathogenesis & therapeutic objective
A significant iron deficit is avoided.
Identifying and removing all irritating elements
Identifying the fundamental cause, if at all possible
Considerations Before Phlebotomy
Physiologically proper or ineffective
Effects of increased red cell mass negatively
Symptoms such as faintness, dyspnea, and angina are present.
A disorder known as polycythemia is characterized by an unnatural excess in the mass of red blood cells (RBCs), which is formed from the words poly (many) & cythemia (blood cells). RBC mass ranges from 23 – 29 mL/kg in females & 26 – 32 mL/kg in males for a typical healthy adult. Patients with increased RBC masses typically have hematocrit levels over 51% & 48% & hemoglobin values above 185 g/L & 165 g/L in males & females, respectively.
Erythrocytosis is not the same thing as polycythemia. An RBC mass larger than 125 percent of the projected value after adjusting for gender & body weight is referred to as absolute erythrocytosis. True or absolute erythrocytosis differs from relative polycythemia, which has an elevated hematocrit but a normal range for red cell mass. The reduced plasma volume may be the cause of the increased hematocrit.
Secondary polycythemia is caused by a high erythropoietin (EPO) level, which typically results from a secondary response to prolonged hypoxemia. Chronic hypoxemia may develop as a result of a number of disorders, such as muscle abnormalities, obese hypoventilation syndrome, obstructive sleep apnea, and lung pathology like COPD (chronic obstructive pulmonary disease).
In a study by Galeus et al. (2015), it was discovered that severe pulmonary hypertension, congenital heart disease, and COPD were some of the most frequent causes of secondary polycythemia. Information on the epidemiology of secondary polycythemia is scarce.
The physiological activity that results in the creation & maintenance of RBC bulk is called erythropoiesis. Many receptors, hormones, and other elements control this process. Of all the RBC mass controllers, EPO is the most significant. The kidneys & erythroid progenitor cells both generate it. EPO is typically made in response to anemia and hypoxia.
The synthesis of hypoxia-inducible factors is boosted by hypoxia, which in turn causes EPO gene expression to increase. Red blood cells are necessary for the transportation of oxygen. The capability of the blood to carry oxygen will rise as the erythrocyte mass increases. For optimal tissue oxygen supply, individuals with secondary polycythemia caused to a physiologically suitable reaction need more erythrocyte mass than usual.
It has been noted that hyperviscosity in normovolemic patients is related to hematocrit levels of more than 45%. Reduced cerebral blood flow has also been linked to hematocrit levels higher than 45 percent; this is remedied by phlebotomy. In these patients, there is a delicate balance between normal tissue oxygenation & hyperviscosity; this is the therapeutic objective.
Increased levels of EPO or other transcription factors, which in turn cause an increase in the creation of RBC mass, are the cause of secondary polycythemia. It should be highlighted that there is no inherent abnormality in the lineage of erythroid progenitor cells, unlike primary polycythemia. Many causes, including inherited and acquired ones that are detailed below, can contribute to the rise in EPO levels.
A system for classifying polycythemia
Polycythemia is further divided into primary and secondary forms based on how the erythroid progenitor cells react to the circulatory cytokines.
Primary Polycythemia:
The enhanced proliferation of erythroid progenitor cells as a result of an underlying cellular abnormality is the cause of primary erythrocytosis. Erythropoietin values are suppressed in these patients. There are mainly two forms.
Polycythemia vera: Due to a mutation known as the JAK mutant, this neoplastic condition is caused by an increase in erythroid progenitor cells and an increase in erythropoietin sensitivity. Pure erythrocytosis: A solitary increased RBC mass without any additional precipitating factors is present in the subset of patients with pure erythrocytosis.
Secondary Polycythemia:
A physiologically suitable response to tissue hypoxia, a physiologically incorrect release of erythropoietin, and other contributing variables can all cause this varied set of diseases, which are all defined by a high RBC mass. Depending on when the person developed the disease, secondary polycythemia can also be categorized as acquired or congenital. Studies have shown that there are about 100 alterations that lead to more than 50 variations of the alpha & beta globulin alleles, including mutations that change the affinities for 2,3-bisphosphoglycerate and oxygen (2,3-BPG).
These abnormalities are inherited in a dominant manner. The HIF (hypoxia-inducible factor) mutation causes familial erythrocytosis. A variation in the HIF cofactor causes aberrant oxygen sensing, which in turn causes an increase in erythropoietin production &, ultimately, an excess in red blood cell mass. According to reports, athletes’ usage of anabolic steroids is linked to an increase in erythrocytosis.
Secondary polycythemia with an appropriate physiological basis (tissue hypoxia)
Acquired
Renal disorder (renal artery stenosis, local renal hypoxia)
High-altitude habitat
Obstructive sleep apnea & obese hypoventilation syndrome are two examples of hypoventilation syndromes.
Smoker’s erythrocytosis
Poisoning by carbon monoxide
Cardiopulmonary vascular shunts from the right to the left and cyanotic cardiac disease
hepatocellular carcinomas, and renal cell carcinomas)
Erythropoietin therapy & androgen administration are drug related.
Renal conditions, such as cysts, hydronephrosis, Bartter’s syndrome, ESRD, long-term hemodialysis, polycystic kidney
disorder, and Erythrocytosis following kidney transplant)
Hypersecretion from the adrenal cortex
Polycythemia idiopathic
Related Polycythemia (Stress Erythrocytosis, Gaisbock Syndrome, or Spurious)
A higher hematocrit is indicative of relative polycythemia, which is also characterized by normal to high normal RBC mass and low normal to decreased plasma volume. Individuals with relative polycythemia are at a greater risk for thromboembolic consequences even when they don’t have true erythrocytosis.
Chuvash Polycythemia
The Chuvash ethnic group in central Russia is the source of the term for this endemic & recessively inherited hereditary polycythemia. EPO values were discovered to be substantially above average. In addition to having increased EPO values, people with CP also have hypersensitive erythroid progenitor cells. Due to thrombotic & hemorrhagic incidents, it is linked to markedly higher mortality in the initial years. Because of the underlying pathogenesis, Chuvash polycythemia is linked to both secondary and primary erythrocytosis.
The median duration from diagnosis to death in research by Galeas et al. evaluating mortality outcomes in a multicity cohort was 21.1 months, which is roughly half the period for patients with polycythemia vera.
The study also revealed that patients with secondary erythrocytosis had a 5% incidence of thrombotic events. However, the fundamental cause and the emergence of complications have been tightly linked to the prognosis.
Clinical history
High red blood cell mass patients may have an abundance of red blood cells or a reddish complexion. Patients can also appear cyanotic if the polycythemia is linked to hypoxia, such as in venous-to-arterial shunts or reduced lung & oxygenation. Blood viscosity rises with red blood cell mass, which also lowers tissue perfusion.
Patients with decreased circulation to the central nervous system may exhibit less significant symptoms like headaches, drowsiness, and disorientation or more serious ones like stroke & obtundation. Additionally, polycythemia may put a patient at risk for thrombosis. Birth or early life is when congenital heart conditions first show symptoms. A family history of congenital cardiac disease may exist in specific situations.
However, a sizable portion of patients with congenital polycythemia has no family background of such illnesses, patients with familial hemoglobinopathies that cause increased oxygen affinity typically have a family background of similar problems in numerous family members. In contrast to secondary polycythemia, chronic pruritus without a rash is more suggestive of a primary myeloproliferative disease.
Physical examination
Plethora shows itself as heightened skin & mucous membrane redness. On the palms or soles, where the skin is lighter in dark-skinned people, this discovery is easier to spot. Acrocyanosis may develop in some patients as a result of slow blood circulation through small vessels.
Splenomegaly favors a polycythemia vera diagnosis rather than a subsequent polycythemia diagnosis. Congenital heart disease may be indicated by cardiac murmurs and clubbing of the fingers.
Differential diagnosis
Tumors include craniopharyngioma, liver carcinoma, renal neoplasm, and adrenal carcinomas.
Adrenal cancers, including incidentalomas.
Arteriovenous malformation & kidney artery stenosis are two examples of kidney vascular pathogenesis.
Post-kidney transplant
Drug abuse
Obstructive sleep apnea
Cor pulmonale
Ventricular septal defect
Atrial septal defect
Chronic smoking
Polycythemia vera
Dehydration
COPD
The method of treatment for secondary polycythemia varies on the underlying cause. The overall strategy is to repair the triggering conditions, which will, in turn, cause the hematologic abnormalities to be corrected. Smokers should be counseled to stop and given the proper supporting, psychological, & pharmaceutical interventions. Diuretics should no longer be prescribed since they cause the plasma volume to constrict. If possible, the dose should be decreased, or they should be stopped & replaced with an adequate substitute. Androgen use is discouraged, and either the dosage should be lowered or the substance should be stopped altogether.
These patients require more iron than average in order to create normocytic, normochromic red blood cells that can provide oxygen as needed. In order to prevent any iron deficiency that results in the creation of microcytic hypochromic red blood cells that are connected to a hyperviscosity condition, iron should be replenished. Low-flow oxygen therapy, especially in individuals with COPD, can treat hypoxia and, subsequently, secondary polycythemia. In order to prevent oxygen toxicity & respiratory distress in COPD patients, oxygen use should be prudent and constantly monitored in accordance with pulse oximetry.
Weight loss is a remedial action that can be accomplished through lifestyle changes, drug therapy, & bariatric surgery for people with obese hypoventilation disorder. In patients with this etiology, surgical excision of erythropoietin-producing tumors is therapeutic. Curative treatment also includes benign kidney lesions. Phlebotomy can be used to temporarily relieve symptoms in some people with secondary polycythemia. With the emergence of problems, secondary polycythemia care strategies also change. Aspirin taken in low doses may help to prevent thromboembolic events. This resulted from extrapolating research done on polycythemia vera.
Similarly, it has been discovered that venesection in polycythemia vera is linked to a lower risk of cardiovascular mortality & thrombosis. These results are typically extrapolated for secondary polycythemia while taking the treating clinician’s clinical judgment into consideration. Individuals with physiologically inappropriate erythrocytosis do not benefit from the elevated red cell mass, in contrast to patients with secondary polycythemia caused by physiologically adequate erythrocytosis.
Phlebotomy is therapeutic for these patients, aiming to keep hematocrit levels between 42% and 46%. Prior to any elective surgery, any individual with secondary polycythemia should have a phlebotomy. Phlebotomy should not be done in patients with physiologically acceptable erythrocytosis because the body uses the increased red cell mass as a defense mechanism, and it interferes with adequate tissue oxygenation. The therapeutic objective in these individuals is to strike a delicate balance between sufficient tissue oxygenation & hyperviscosity.
The therapeutic aim of hematocrit is determined by the underlying disorders and the unique reactions of each patient. In general, keeping hematocrit readings under 60% should be the objective.
Phlebotomy has been linked to improvements in right ventricular activity & hemodynamic reaction to exertion in individuals with COPD, as well as a decrease in pulmonary arterial resistance and the arteriovenous oxygen concentration imbalance. These gains are significant at hematocrit levels of 50% – 55%. Limited data support the use of medications such as ACE inhibitors or angiotensin receptor inhibitors in patients with hypoxic pulmonary illness who do not respond to venesection.
The target hematocrit should be carefully adapted to the underlying etiology of the patient and on an individual basis. The benefit of isovolumic phlebotomy is that it guards against acute hemodynamic consequences brought on by a drop in blood volume.
Isovolumetric venesections were advised to be beneficial in lowering viscosity in individuals with cyanotic cardiovascular diseases. However, it should be remembered that insufficiency is linked to excessive venesections.
If the hematocrit is beyond 54% in patients with idiopathic erythrocytosis, then lowering it to a baseline of 50 percent may be taken into consideration. If the objective is currently higher than 54% for individuals with comorbid illnesses that increase their risk of ischemia & thrombosis, a reduced baseline of 45% is also considered. Cytoreductive treatment is not recommended for this particular patient group.
In patients with erythrocytosis secondary to post-kidney transplant, it is advised to avoid a secondary component that predisposes to dehydration and uses ACE blockers. For this subset of patients, a hematocrit of less than 45% is the desired level.
Management Guidelines for Secondary Polycythemia
Eliminating all myelosuppressive treatments
Consider phlebotomy to maintain hematocrit.
Applying particular tactics in line with the pathogenesis & therapeutic objective
A significant iron deficit is avoided.
Identifying and removing all irritating elements
Identifying the fundamental cause, if at all possible
Considerations Before Phlebotomy
Physiologically proper or ineffective
Effects of increased red cell mass negatively
Symptoms such as faintness, dyspnea, and angina are present.
A disorder known as polycythemia is characterized by an unnatural excess in the mass of red blood cells (RBCs), which is formed from the words poly (many) & cythemia (blood cells). RBC mass ranges from 23 – 29 mL/kg in females & 26 – 32 mL/kg in males for a typical healthy adult. Patients with increased RBC masses typically have hematocrit levels over 51% & 48% & hemoglobin values above 185 g/L & 165 g/L in males & females, respectively.
Erythrocytosis is not the same thing as polycythemia. An RBC mass larger than 125 percent of the projected value after adjusting for gender & body weight is referred to as absolute erythrocytosis. True or absolute erythrocytosis differs from relative polycythemia, which has an elevated hematocrit but a normal range for red cell mass. The reduced plasma volume may be the cause of the increased hematocrit.
Secondary polycythemia is caused by a high erythropoietin (EPO) level, which typically results from a secondary response to prolonged hypoxemia. Chronic hypoxemia may develop as a result of a number of disorders, such as muscle abnormalities, obese hypoventilation syndrome, obstructive sleep apnea, and lung pathology like COPD (chronic obstructive pulmonary disease).
In a study by Galeus et al. (2015), it was discovered that severe pulmonary hypertension, congenital heart disease, and COPD were some of the most frequent causes of secondary polycythemia. Information on the epidemiology of secondary polycythemia is scarce.
The physiological activity that results in the creation & maintenance of RBC bulk is called erythropoiesis. Many receptors, hormones, and other elements control this process. Of all the RBC mass controllers, EPO is the most significant. The kidneys & erythroid progenitor cells both generate it. EPO is typically made in response to anemia and hypoxia.
The synthesis of hypoxia-inducible factors is boosted by hypoxia, which in turn causes EPO gene expression to increase. Red blood cells are necessary for the transportation of oxygen. The capability of the blood to carry oxygen will rise as the erythrocyte mass increases. For optimal tissue oxygen supply, individuals with secondary polycythemia caused to a physiologically suitable reaction need more erythrocyte mass than usual.
It has been noted that hyperviscosity in normovolemic patients is related to hematocrit levels of more than 45%. Reduced cerebral blood flow has also been linked to hematocrit levels higher than 45 percent; this is remedied by phlebotomy. In these patients, there is a delicate balance between normal tissue oxygenation & hyperviscosity; this is the therapeutic objective.
Increased levels of EPO or other transcription factors, which in turn cause an increase in the creation of RBC mass, are the cause of secondary polycythemia. It should be highlighted that there is no inherent abnormality in the lineage of erythroid progenitor cells, unlike primary polycythemia. Many causes, including inherited and acquired ones that are detailed below, can contribute to the rise in EPO levels.
A system for classifying polycythemia
Polycythemia is further divided into primary and secondary forms based on how the erythroid progenitor cells react to the circulatory cytokines.
Primary Polycythemia:
The enhanced proliferation of erythroid progenitor cells as a result of an underlying cellular abnormality is the cause of primary erythrocytosis. Erythropoietin values are suppressed in these patients. There are mainly two forms.
Polycythemia vera: Due to a mutation known as the JAK mutant, this neoplastic condition is caused by an increase in erythroid progenitor cells and an increase in erythropoietin sensitivity. Pure erythrocytosis: A solitary increased RBC mass without any additional precipitating factors is present in the subset of patients with pure erythrocytosis.
Secondary Polycythemia:
A physiologically suitable response to tissue hypoxia, a physiologically incorrect release of erythropoietin, and other contributing variables can all cause this varied set of diseases, which are all defined by a high RBC mass. Depending on when the person developed the disease, secondary polycythemia can also be categorized as acquired or congenital. Studies have shown that there are about 100 alterations that lead to more than 50 variations of the alpha & beta globulin alleles, including mutations that change the affinities for 2,3-bisphosphoglycerate and oxygen (2,3-BPG).
These abnormalities are inherited in a dominant manner. The HIF (hypoxia-inducible factor) mutation causes familial erythrocytosis. A variation in the HIF cofactor causes aberrant oxygen sensing, which in turn causes an increase in erythropoietin production &, ultimately, an excess in red blood cell mass. According to reports, athletes’ usage of anabolic steroids is linked to an increase in erythrocytosis.
Secondary polycythemia with an appropriate physiological basis (tissue hypoxia)
Acquired
Renal disorder (renal artery stenosis, local renal hypoxia)
High-altitude habitat
Obstructive sleep apnea & obese hypoventilation syndrome are two examples of hypoventilation syndromes.
Smoker’s erythrocytosis
Poisoning by carbon monoxide
Cardiopulmonary vascular shunts from the right to the left and cyanotic cardiac disease
hepatocellular carcinomas, and renal cell carcinomas)
Erythropoietin therapy & androgen administration are drug related.
Renal conditions, such as cysts, hydronephrosis, Bartter’s syndrome, ESRD, long-term hemodialysis, polycystic kidney
disorder, and Erythrocytosis following kidney transplant)
Hypersecretion from the adrenal cortex
Polycythemia idiopathic
Related Polycythemia (Stress Erythrocytosis, Gaisbock Syndrome, or Spurious)
A higher hematocrit is indicative of relative polycythemia, which is also characterized by normal to high normal RBC mass and low normal to decreased plasma volume. Individuals with relative polycythemia are at a greater risk for thromboembolic consequences even when they don’t have true erythrocytosis.
Chuvash Polycythemia
The Chuvash ethnic group in central Russia is the source of the term for this endemic & recessively inherited hereditary polycythemia. EPO values were discovered to be substantially above average. In addition to having increased EPO values, people with CP also have hypersensitive erythroid progenitor cells. Due to thrombotic & hemorrhagic incidents, it is linked to markedly higher mortality in the initial years. Because of the underlying pathogenesis, Chuvash polycythemia is linked to both secondary and primary erythrocytosis.
The median duration from diagnosis to death in research by Galeas et al. evaluating mortality outcomes in a multicity cohort was 21.1 months, which is roughly half the period for patients with polycythemia vera.
The study also revealed that patients with secondary erythrocytosis had a 5% incidence of thrombotic events. However, the fundamental cause and the emergence of complications have been tightly linked to the prognosis.
Clinical history
High red blood cell mass patients may have an abundance of red blood cells or a reddish complexion. Patients can also appear cyanotic if the polycythemia is linked to hypoxia, such as in venous-to-arterial shunts or reduced lung & oxygenation. Blood viscosity rises with red blood cell mass, which also lowers tissue perfusion.
Patients with decreased circulation to the central nervous system may exhibit less significant symptoms like headaches, drowsiness, and disorientation or more serious ones like stroke & obtundation. Additionally, polycythemia may put a patient at risk for thrombosis. Birth or early life is when congenital heart conditions first show symptoms. A family history of congenital cardiac disease may exist in specific situations.
However, a sizable portion of patients with congenital polycythemia has no family background of such illnesses, patients with familial hemoglobinopathies that cause increased oxygen affinity typically have a family background of similar problems in numerous family members. In contrast to secondary polycythemia, chronic pruritus without a rash is more suggestive of a primary myeloproliferative disease.
Physical examination
Plethora shows itself as heightened skin & mucous membrane redness. On the palms or soles, where the skin is lighter in dark-skinned people, this discovery is easier to spot. Acrocyanosis may develop in some patients as a result of slow blood circulation through small vessels.
Splenomegaly favors a polycythemia vera diagnosis rather than a subsequent polycythemia diagnosis. Congenital heart disease may be indicated by cardiac murmurs and clubbing of the fingers.
Differential diagnosis
Tumors include craniopharyngioma, liver carcinoma, renal neoplasm, and adrenal carcinomas.
Adrenal cancers, including incidentalomas.
Arteriovenous malformation & kidney artery stenosis are two examples of kidney vascular pathogenesis.
Post-kidney transplant
Drug abuse
Obstructive sleep apnea
Cor pulmonale
Ventricular septal defect
Atrial septal defect
Chronic smoking
Polycythemia vera
Dehydration
COPD
The method of treatment for secondary polycythemia varies on the underlying cause. The overall strategy is to repair the triggering conditions, which will, in turn, cause the hematologic abnormalities to be corrected. Smokers should be counseled to stop and given the proper supporting, psychological, & pharmaceutical interventions. Diuretics should no longer be prescribed since they cause the plasma volume to constrict. If possible, the dose should be decreased, or they should be stopped & replaced with an adequate substitute. Androgen use is discouraged, and either the dosage should be lowered or the substance should be stopped altogether.
These patients require more iron than average in order to create normocytic, normochromic red blood cells that can provide oxygen as needed. In order to prevent any iron deficiency that results in the creation of microcytic hypochromic red blood cells that are connected to a hyperviscosity condition, iron should be replenished. Low-flow oxygen therapy, especially in individuals with COPD, can treat hypoxia and, subsequently, secondary polycythemia. In order to prevent oxygen toxicity & respiratory distress in COPD patients, oxygen use should be prudent and constantly monitored in accordance with pulse oximetry.
Weight loss is a remedial action that can be accomplished through lifestyle changes, drug therapy, & bariatric surgery for people with obese hypoventilation disorder. In patients with this etiology, surgical excision of erythropoietin-producing tumors is therapeutic. Curative treatment also includes benign kidney lesions. Phlebotomy can be used to temporarily relieve symptoms in some people with secondary polycythemia. With the emergence of problems, secondary polycythemia care strategies also change. Aspirin taken in low doses may help to prevent thromboembolic events. This resulted from extrapolating research done on polycythemia vera.
Similarly, it has been discovered that venesection in polycythemia vera is linked to a lower risk of cardiovascular mortality & thrombosis. These results are typically extrapolated for secondary polycythemia while taking the treating clinician’s clinical judgment into consideration. Individuals with physiologically inappropriate erythrocytosis do not benefit from the elevated red cell mass, in contrast to patients with secondary polycythemia caused by physiologically adequate erythrocytosis.
Phlebotomy is therapeutic for these patients, aiming to keep hematocrit levels between 42% and 46%. Prior to any elective surgery, any individual with secondary polycythemia should have a phlebotomy. Phlebotomy should not be done in patients with physiologically acceptable erythrocytosis because the body uses the increased red cell mass as a defense mechanism, and it interferes with adequate tissue oxygenation. The therapeutic objective in these individuals is to strike a delicate balance between sufficient tissue oxygenation & hyperviscosity.
The therapeutic aim of hematocrit is determined by the underlying disorders and the unique reactions of each patient. In general, keeping hematocrit readings under 60% should be the objective.
Phlebotomy has been linked to improvements in right ventricular activity & hemodynamic reaction to exertion in individuals with COPD, as well as a decrease in pulmonary arterial resistance and the arteriovenous oxygen concentration imbalance. These gains are significant at hematocrit levels of 50% – 55%. Limited data support the use of medications such as ACE inhibitors or angiotensin receptor inhibitors in patients with hypoxic pulmonary illness who do not respond to venesection.
The target hematocrit should be carefully adapted to the underlying etiology of the patient and on an individual basis. The benefit of isovolumic phlebotomy is that it guards against acute hemodynamic consequences brought on by a drop in blood volume.
Isovolumetric venesections were advised to be beneficial in lowering viscosity in individuals with cyanotic cardiovascular diseases. However, it should be remembered that insufficiency is linked to excessive venesections.
If the hematocrit is beyond 54% in patients with idiopathic erythrocytosis, then lowering it to a baseline of 50 percent may be taken into consideration. If the objective is currently higher than 54% for individuals with comorbid illnesses that increase their risk of ischemia & thrombosis, a reduced baseline of 45% is also considered. Cytoreductive treatment is not recommended for this particular patient group.
In patients with erythrocytosis secondary to post-kidney transplant, it is advised to avoid a secondary component that predisposes to dehydration and uses ACE blockers. For this subset of patients, a hematocrit of less than 45% is the desired level.
Management Guidelines for Secondary Polycythemia
Eliminating all myelosuppressive treatments
Consider phlebotomy to maintain hematocrit.
Applying particular tactics in line with the pathogenesis & therapeutic objective
A significant iron deficit is avoided.
Identifying and removing all irritating elements
Identifying the fundamental cause, if at all possible
Considerations Before Phlebotomy
Physiologically proper or ineffective
Effects of increased red cell mass negatively
Symptoms such as faintness, dyspnea, and angina are present.
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