Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes. In secondary polycythemia, 6 to 8 million and occasionally 9 million erythrocytes may occur per cubic millimeter of blood. Secondary polycythemia resolves when the underlying cause is treated.
Primary polycythemia are due to factors intrinsic to red cell precursors. Polycythemia vera (PCV), polycythemia rubra vera (PRV), or erythremia, occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. PCV is classified as a myeloproliferative disease. Symptoms include headaches and vertigo, and signs on physical examination include an abnormally enlarged spleen and/or liver. In some cases, affected individuals may have associated conditions including high blood pressure or formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment. A hallmark of polycythemia is an elevated hematocrit, with Hct > 55% seen in 83% of cases.[rx] A somatic (non-hereditary) mutation (V617F) in the JAK2 gene is found in 95% of cases, though also present in other myeloproliferative disorders.[rx]
Primary Polycythemia (also known as polycythemia or polyglobulia) is a disease state in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are elevated in peripheral blood. It can be due to an increase in the number of red blood cells[rx] (“absolute polycythemia”) or to a decrease in the volume of plasma (“relative polycythemia”).[rx] Polycythemia is sometimes called erythrocytosis, but the terms are not synonymous, because polycythemia
The standard RBC mass does not usually exceed 36 ml/kg in males and 32 ml/kg in females. The reference ranges for normal hemoglobin levels, and hematocrits, vary depending on altitude, from ethnicity to ethnicity, and country to country.[rx] However, as a frame of reference, the hemoglobin, and hematocrit of a healthy adult male are 16% plus or minus 2 gm/dl and 47% plus or minus 6%, respectively. The hemoglobin and hematocrit of a menstruating adult female are usually 13% plus or minus 2 gm/dl and 40 plus or minus 6%, respectively.
Polycythemia vera is a sub-type of polycythemia. Often referred to colloquially as simply “ polycythemia,” it is an acquired, Philadelphia-chromosome negative,[rx], myeloproliferative disorder. This condition is associated with overproduction of all 3 cell lines, but with a notable prominence of red blood cells..
Types of Polycythemia
This occurs due to volume contraction rather than an increase in true RBC mass.
Severe dehydration due to isolated fluid loss: potentially seen in diarrhea and severe vomiting
Gaisbock syndrome: Usually seen amongst obese, hypertensive males. Consumption of cigarettes, excessive alcohol, and use of diuretics are contributory.[rx]
Further stratified based on serum erythropoietin (EPO) levels as follows:
Low serum EPO levels (Primary polycythemia)
Primary familial and congenital polycythemia
High serum EPO levels (Secondary polycythemia)
Respiratory disorders: Chronic obstructive pulmonary disease (COPD), Pickwickian syndrome
Cyanotic heart diseases with right-to-left shunts
Renal disorders: Renal cysts, cancer, renal artery stenosis, Bartter syndrome, focal sclerosing glomerulonephritis
Elevated carboxyhemoglobin: usually seen in smokers
Hemoglobinopathies: High-affinity hemoglobins such as Hb Yakima, methemoglobinemia
EPO-secreting tumors: sources include hepatomas, uterine leiomyomas, and cerebellar hemangiomas
Iatrogenic causes: Including erythropoietin administration, anabolic steroids, and testosterone replacement therapy
The pathophysiology would vary, depending on the cause in consideration.
High EPO Levels
- Cellular hypoxia can occur due to any cause that triggers the release of erythropoietin from the renal peritubular lining capillary cells. A small amount of EPO is produced by the liver as well. EPO, in turn, acts on erythroid progenitor cells and stimulates erythropoiesis.
Low EPO Levels
- The primary defect in nearly 95% of cases of polycythemia vera is an acquired mutation in exon 14 of the tyrosine kinase JAK2 (V617F). Mutations have also been described in exon 12 of JAK2. These mutations result in a loss of the auto-inhibitory pseudo-kinase domain of JAK2, resulting in its constitutive activation. This constitutive activation results in both hypersensitivity to EPO and EPO-independent erythroid colony formation.
Causes of Secondary polycythemia
Mutations in the JAK2 and TET2 genes are associated with polycythemia vera. Although it remains unclear exactly what initiates polycythemia vera, researchers believe that it begins when mutations occur in the DNA of a hematopoietic stem cell. These stem cells are located in the bone marrow and have the potential to develop into red blood cells, white blood cells, and platelets. JAK2 gene mutations seem to be particularly important for the development of polycythemia vera, as nearly all affected individuals have a mutation in this gene. The JAK2 gene provides instructions for making a protein that promotes the growth and division (proliferation) of cells. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells.
JAK2 gene mutations result in the production of a JAK2 protein that is constantly turned on (constitutively activated), which increases production of blood cells and prolongs their survival. With so many extra cells in the bloodstream, abnormal blood clots are more likely to form. Thicker blood also flows more slowly throughout the body, which prevents organs from receiving enough oxygen. Many of the signs and symptoms of polycythemia vera are related to a shortage of oxygen in body tissues.
The function of the TET2 gene is unknown. Although mutations in the TET2 gene have been found in approximately 16 percent of people with polycythemia vera, it is unclear what role these mutations play in the development of the condition.
Symptoms of Secondary polycythemia
The symptoms of polycythemia may become more apparent over time. More common symptoms include:
- Headaches, dizziness, and weakness
- Shortness of breath and problems breathing while lying down
- Feelings of pressure or fullness on the left side of the abdomen due to an enlarged spleen (an organ in the abdomen)
- Double or blurred vision and blind spots
- Itching all over (especially after a warm bath), reddened face, and a burning feeling on your skin (especially your hands and feet)
- Bleeding from your gums and heavy bleeding from small cuts
- Unexplained weight loss
- Fatigue (tiredness)
- Excessive sweating
- Very painful swelling in a single joint, usually the big toe (called gouty arthritis)
- Excessive sweating
- Itchy skin
- Ringing in the ears
- Blurred vision
- reddish or purplish skin on the palms, earlobes, and nose
- Bleeding or bruising
- A burning sensation in the feet
- Abdominal fullness
- Frequent nosebleeds
- Bleeding gums
Without treatment, people with PV may also be more likely to experience complications, such as:
- enlarged spleen
- blood clots
- peptic ulcers
- heart disease
- other blood disorders, such as myelofibrosis or leukemia
Diagnosis of Secondary polycythemia
Bone marrow examination is not routinely employed. Its utility largely remains restricted to cases where the clinical suspicion of polycythemia vera is high, despite the absence of a JAK2 (V617F) mutation, or if facilities to test for the mutation are unavailable. Classical findings, when coexistent with other suggestive hematologic parameters, help support a diagnosis of polycythemia vera.[rx]
Strongly suggestive findings include a hypercellular marrow with erythroid hyperplasia and subtle megakaryocytic atypia.[rx] Tri-lineage hyperproliferation is also an expected feature.
Common presenting symptoms, usually non-specific, include fatigue, headache, dizziness, transient blurring of vision, amaurosis fugax and other symptoms suggestive of transient ischemic attacks (TIAs).
Infrequently, patients may complain of pruritus after a warm water shower, particularly over the back.
A history of epistaxis, gastrointestinal (GI) bleed or easy bruising may be forthcoming.
Peptic ulcer disease commonly co-exists, and patients may present with non-specific abdominal pain. Left, hypochondrial pain and early satiety should arouse the suspicion of splenomegaly.
Rarely, patients may present with a history of unexplained thrombotic complications, such as Budd-Chiari syndrome or digital infarcts.
It is vital to try and elicit etiology-specific history such as a history of smoking, an extended stay at high altitudes, congenital cardiac disease, among others. A significant family history may be elicited in patients with hemoglobinopathies.
Abnormal facial ruddiness may be prominent.
Cyanosis and clubbing, along with the presence of a murmur on auscultation, provide strong evidence favoring a congenital cyanotic heart disease. Nicotine staining of the nails and teeth provide presumptive evidence of smoking, even in a non-forthcoming patient.
The presence of morbid obesity could raise the possibility of Pickwickian syndrome; whereas, a barrel chest could suggest an obstructive lung disease.Examination of the abdomen may lead to finding a palpable spleen or eliciting the bruit of renal arterial stenosis.
An evaluation must proceed sequentially. Due to the broad array of potential causes, it is vital to consider the appropriate investigation in that specific clinical context. However, the following may provide a frame of reference:
Based on the WHO 2017 criteria, hematocrit levels above 49% in males and 48% in females, at sea level, are to be considered suggestive of polycythemia vera. In cases of polycythemia vera, there could be a concurrent increase in platelet and leucocyte counts as well. The leucocyte count is usually between 10,000 to 20,000/microliter and may show eosinophilia and basophilia. Platelet counts may rarely exceed 100,000/microliter.
Radioisotope studies using Cr-labeled autologous RBC transfusions accurately determine the true RBC mass and conclusively exclude spurious polycythemia.
Serum EPO Levels
The presence of either high or low EPO levels directs the further plan of evaluation.
Low EPO Levels – Low EPO levels indicate primary polycythemia. Subsequent evaluation should be targeted toward the detection of polycythemia vera. JAK2 mutation studies are virtually diagnostic for polycythemia vera (95% cases). Mutations may occur either in exon 14 (more commonly) or in exon 12.
High EPO Levels – High EPO levels indicate secondary polycythemia. Subsequent evaluation should be aimed at determining the cause. This should include, but not be limited to, the following:
- Measurement of arterial oxygen saturation levels using a pulse-oximeter: low levels would likely indicate a pulmonary or cardiac cause.
Normal saturation levels could require further evaluation such as:
- The use of a co-oximeter to rule out methemoglobinemia
Measurement of carboxyhemoglobin levels (for smokers)
Measurement the P50 of Hb to detect high-affinity hemoglobinopathies
Relevant investigations to detect a possible EPO-secreting tumor
- Complete blood count (CBC) – Your doctor takes a sample of your blood and sends it to a lab, where a machine counts the number of red blood cells, white blood cells, and platelets. An unusually high number of any of these could be a sign of polycythemia vera.
- EPO level – This test measures how much of the hormone EPO is in your blood. EPO tells your bone marrow to make blood cells. People who have polycythemia vera have very low amounts of it.
- Blood smear – Your doctor looks at a sample of your blood through a microscope. It’s a way to check for other diseases that are sometimes linked to PV.
If you have polycythemia vera, blood tests might reveal
- More red blood cells than normal – and, sometimes, an increase in platelets or white blood cells
- A greater percentage of red blood cells – that make up total blood volume (hematocrit measurement)
- Elevated levels of the iron-rich protein – in red blood cells that carries oxygen (hemoglobin)
- Very low levels of a hormone – that stimulates bone marrow to produce new red blood cells (erythropoietin)
Serum Ferritin, Vitamin B12, and Folate Levels
- Low serum ferritin and low folate levels have been associated more with primary polycythemia.[rx] Raised vitamin B12 levels, often striking, may be observed. This occurs due to increased transcobalamin III secretion by leucocytes.
Assessment of Renal Function
- Renal function abnormalities indicate a higher likelihood of secondary polycythemia. Uric acid levels are often raised, due to increased cell proliferation and subsequent turnover.
Assessment of Hepatic Status
- Liver cirrhosis and inflammatory liver disease have been associated with secondary polycythemia and increased RBC proliferation.[rx]
Bone marrow aspiration or biopsy
- If your doctor suspects that you have polycythemia vera, he or she might recommend collecting a sample of your bone marrow through a bone marrow aspiration or biopsy. A bone marrow biopsy involves taking a sample of solid bone marrow material. A bone marrow aspiration is usually done at the same time. During an aspiration, your doctor withdraws a sample of the liquid portion of your marrow.
Specific gene testing
- If you have polycythemia vera, analysis of your bone marrow or blood might show the gene mutation that’s associated with the disease.
- An ultrasound and Doppler study of the abdomen would help identify a secondary cause. In cases of suspected secondary polycythemia, the utility of additional investigations such as a chest radiograph, lung function tests, sleep studies, and an echocardiograph are to be considered as appropriate.
Treatment of Secondary polycythemia
The treatment of secondary polycythemia is directed at correcting the cause.
For polycythemia vera, available treatment modalities include:
Phlebotomy was established as the backbone of therapy, primarily based on the trial conducted by the Polycythemia Vera Study Group (PVSG). The study found that, compared to the use of chlorambucil or radioactive phosphorous, treatment with phlebotomy alone was associated with a longer median survival.[rx]
The rationale behind repeated phlebotomies was that cytoreduction would reduce hyper-viscosity. Additionally, it would induce a state of iron-deficiency that would help retard red-cell proliferation.
In practice, weekly sessions are conducted, during which approximately 500 mL of blood is removed, provided the hemodynamic status permits this.
This is continued weekly until a target hematocrit of under 45% is obtained. This target was determined based on the findings of the CYTO-PV trial conducted in Italy. Investigators observed significantly lower rates of cardiovascular deaths and major thrombotic episodes in patients kept under this threshold.[rx]
For secondary polycythemias, phlebotomy is usually reserved for the following conditions[rx]:
Chronic lung diseases
Cyanotic heart diseases
Post-renal transplant patients with hypertension and erythrocytosis, not responding to optimal doses of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)
Hydroxyurea is usually considered second-line therapy. Evidence of benefit came from, among others, a study by the Polycythemia Vera Study Group (PVSG)[rx] that showed lower rates of thrombosis compared to a historical cohort treated with phlebotomy alone. Despite theoretical concerns, studies[rx] have not found a significant association between the use of hydroxyurea and an increased risk of leukemic transformation. Indications for use include:
Poor venous access
High phlebotomy requirement
When phlebotomy is not possible due to logistic reasons
The standard daily doses range from 500 to 1500 mg per day.
Doses are adjusted to target platelet counts below 500,000/mcL. However, it is necessary to adjust doses such that the absolute neutrophil count remains above 2000/microliters.
The JAK2 inhibitor ruxolitinib is used when patients are intolerant or unresponsive to hydroxyurea.
Evidence supporting the use of Ruxolitinib in myeloproliferative disorders came from the COMFORT trials. The COMFORT-I study compared the efficacy of Ruxolitinib with placebo therapy, whereas COMFORT-II compared it with “best available therapy.” Both trials showed a significant reduction in splenomegaly, improvement in symptoms, and better survival.[rx]
However, despite this enhanced benefit, the use of ruxolitinib was associated with increased risks of anemia, often dose-limiting, and thrombocytopenia.
The standard recommended dose for polycythemia vera is 10 mg, twice a day.
Dose reduction is required if hemoglobin drops to below 12 gm/dl.
A fall in hemoglobin to below 8 gm/dl is an indication for dosing is to be temporarily interrupted.
The original PVSG trial showed that, despite greater longevity, patients treated with phlebotomy alone were at a greater risk of developing thrombosis during the first 3 years of therapy. This seemed to suggest a potential benefit to the use of antiplatelet or anticoagulant agents concurrently. Initial trials using higher doses of aspirin or dipyridamole showed unsatisfactory gastrointestinal hemorrhage. However, subsequent studies[rx] found that lower doses of aspirin could be safely used.
Currently, aspirin is indicated when there is inadequate control of microvascular symptoms after achieving the target hematocrit, or in the presence of other cardiovascular risk factors.
Aspirin, when indicated, is recommended to be used at low doses, ranging from 40 to 100 mg daily.
Agents such as allopurinol and febuxostat may be required in cases with significant hyperuricemia. Recent studies indicate that, between them, allopurinol may be a safer alternative with respect to all-cause and cardiovascular mortality.[rx]
Management of Pruritus
Depending on the severity of pruritus and the clinical response to therapy, therapeutic modalities available for symptomatic relief include antihistamines[rx] and selective serotonin reuptake inhibitors (SSRIs).[rx]
Management of Polycythemia Vera in Pregnancy
The standard therapeutic measures of phlebotomy and low dose aspirin are appropriate in most cases. Certain high-risk women may require the addition of pegylated interferon (IFN)-alpha.
Secondary polycythemia is associated primarily with complications arising from hyperviscosity. Polycythemia vera is associated with progression to malignant conditions.
Commonly encountered complications include:
Bleeding – Recurrent epistaxis or GI bleed are often seen, that may lead to iron deficiency anemia, potentially confounding clinical findings, including bone marrow appearance.
Thrombosis – Due to hyperviscosity, there is a preponderance of both arterial and venous thrombosis. Manifestations of arterial thrombosis include digital infarcts, cerebral ischemic infarcts, particularly in watershed territories. Venous thrombosis such as Budd-Chiari syndrome is also seen.
- Blood clots – Increased blood thickness and decreased blood flow, as well as abnormalities in your platelets, raise your risk of blood clots. Blood clots can cause a stroke, a heart attack, or a blockage in an artery in your lungs or a vein deep within a leg muscle or in the abdomen.
- Enlarged spleen – Your spleen helps your body fight infection and filter unwanted material, such as old or damaged blood cells. The increased number of blood cells caused by polycythemia vera makes your spleen work harder than normal, which causes it to enlarge.
- Problems due to high levels of red blood cells – Too many red blood cells can lead to a number of other complications, including open sores on the inside lining of your stomach, upper small intestine or esophagus (peptic ulcers) and inflammation in your joints (gout).
- Other blood disorders – In rare cases, polycythemia vera can lead to other blood diseases, including a progressive disorder in which bone marrow is replaced with scar tissue, a condition in which stem cells don’t mature or function properly, or cancer of the blood and bone marrow (acute leukemia).
Progression to leukemia, particularly acute myeloid leukemia (AML) is seen in approximately 5% of cases and is often refractory to treatment. Studies have implicated the use of chlorambucil, pipobroman, or radioactive phosphorous as factors that increase the likelihood of progression.
Lifestyle and Home Remedies
You can take steps to help yourself feel better if you’ve been diagnosed with polycythemia vera. Try to:
- Exercise – Moderate exercise, such as walking, can improve your blood flow. This helps decrease your risk of blood clots. Leg and ankle stretches and exercises also can improve your blood circulation.
- Avoid tobacco – Using tobacco can cause your blood vessels to narrow, increasing the risk of heart attack or stroke due to blood clots.
- Avoid low-oxygen environments – Living at high altitudes, skiing or climbing in mountains all reduce the oxygen levels in your blood even further.
- Be good to your skin – To reduce itching, bathe in cool water, use a gentle cleanser and pat your skin dry. Adding starch, such as cornstarch, to your bath might help. Avoid hot tubs, heated whirlpools, and hot showers or baths. Try not to scratch, as it can damage your skin and increase the risk of infection. Use lotion to keep your skin moist.
- Avoid extreme temperatures – Poor blood flow increases your risk of injury from hot and cold temperatures. In cold weather, always wear warm clothing, particularly on your hands and feet. In hot weather, protect yourself from the sun and drink plenty of liquids.
- Watch for sores – Poor circulation can make it difficult for sores to heal, particularly on your hands and feet. Inspect your feet regularly and tell your doctor about any sores.