Polycythemia Vera

Polycythemia vera is an uncommon neoplasm or blood cancer where the bone marrow produces too many erythrocytes, megakaryocytes, and granulocytes, resulting in panmyelosis. The cancer is caused by a mutation in the JAK2 gene. Janus Kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a role in signaling in the type II cytokine receptor family. Members of that family include interferon receptors, GM-CSF receptor family, gp130 receptors, and the single chain receptors (EPO-R, etc). The function of those receptors are not important. The most important receptor for this article is the EPO-R receptor. The erythropoietin receptor (EPO-R) is a protein encoded by the EPOR gene that pre-exists in a dimerized state. When the ligand erythropoietin binds to the EPO-R receptor it induces a conformational change that results in the autophosphorylation of the JAK2 kinases. This establishes the function of EPO-R which is to promote proliferation and the rescue of erythroid progenitors from apoptosis. EPO-R induces JAK2-STAT5 signaling and with help from the transcription factor GATA-1 induces the transcription of the protein BCL-XL which is anti-apoptotic and promotes red cell survival.

In polycythemia vera (PV) there is a JAK2V617F mutation that causes independent continuous expression of the JAK2 kinase without erythropoietin (EPO) that acts on signaling pathways involving the EPO-R or hyperexpression in the presence of EPO. This causes increased gene expression for erythroid precursor cell proliferation and differentiation. It up regulates BCL-XL, which as mentioned above is an anti-apoptotic. This causes an abnormal accumulation of red cells in the peripheral blood. Its important to note that the accumulation of the red cells is due to lack of apoptosis, NOT because they are dividing quicker. Also there is a difference between primary PV and secondary PV. In primary PV there is a decreased expression of EPO, this is a compensation method for the body. As there is autophosphorylation of the EPO-Receptor, the body tries to reverse the process by down regulating the expression of erythropoietin (EPO). In secondary PV, there is normal to increased expression of EPO.



Diagnosis of PV according to the World Heath Organization (WHO) has to satisfy both major and minor criteria. The major criteria that has to be observed is a hemoglobin higher than 18.5 g/dL in men, and greater than 16.5 g/dL in women. There also has to be the presence of the JAK2 mutation. Minor criteria include presence of bone marrow hypercellularity demonstrating panmyelosis, serum EPO levels decreased, and a demonstration of endogenous erythroid colony growth in vitro. Meaning that there is presence of red cell growth in the laboratory using EPO from the patient, which assumes there is an issue with the downstream signaling of EPO, not EPO itself.

Laboratory results illustrate an increased hemoglobin, hematocrit, and MCV. There is an increased red cell count, platelet count, and white blood cell count. The leukocyte alkaline phosphatase is also increased. Its important to know that although the platelet count is increased, there is also an altered function of the platelets. The erythrocyte sedimentation rate will be decreased due to the decrease in the zeta potential. The zeta potential is the electrokinetic potential between the red cells that stops them from stacking or from sticking to one another. One classic characteristic of PV is erythromelalgia. This is a burning sensation in the pain and feet, with a reddish or bluish discoloration. This is caused by an increased platelet agglutination, from being dysfunctional that results in microvascular blood clots.


If untreated, PV can be fatal. Although the disease can’t be cured, it can be controlled and the life expectancy has risen with modern advances in medicine. Phlebotomy is recommended to reduce the hemoglobin and hematocrit levels, but can induce iron deficiency anemia if not monitored. Low dose aspirin is prescribed to reduce the risk of thrombotic events. The accumulation of the red cells increases the risk for the patient to develop thrombotic events because the blood is “thick”. Chemotherapy can be used, but is not normally indicated, unless therapeutic phlebotomy is unable to maintain a normal hemoglobin or hematocrit or when there is significant thrombocytosis. It is dangerous because of the risk for transformation to acute myeloid leukemia (AML).

To recap; its important to know the mutation in the JAK2 kinase that induces polycythemia vera. Although this mutation is demonstrated in 90% of cases, its possible that its absent. Panmyelosis and elevation of RBC indices is a diagnostic finding. Its important to know the major and minor criteria for the diagnosis of PV. Treatment is therapeutic phlebotomy and chemotherapy in rare cases, only when prior treatment has failed.


Bloods Journey Through the Heart


The heart drives the circulatory system as it pushes blood through an intricate system of blood vessels including arteries, capillaries, and veins. Blood is essential as it carries oxygenated blood from the lungs to the tissues and transports waste products like carbon dioxide away where it is expelled from the body.

The heart is hollow and its strong musculature allows it to contract to pump blood to the arteries to be delivered to the rest of the body. One of the most fundamental aspects of the circulatory system is that veins deliver deoxygenated blood to the heart and arteries deliver oxygenated blood away from the heart. Within the heart there are four chambers; right atrium and ventricle, left atrium and left ventricle. These chambers are separated by valves. There are four valves that separate the different chambers; the mitral valve, tricuspid valve, aortic valve, and the pulmonary valve. The tricuspid valve separates the right atrium and right ventricle. The mitral valve separates the left atrium and left ventricle. The aortic valve is what separates the left ventricle and the aorta. The pulmonary valve separates the right ventricle and the pulmonary artery. Valves work to allow blood flow through into the following chamber while not allowing blood to flow back through. A reverse in the blood flow is called regurgitation and is a serious medical condition that should be addressed. Each valve has two cusps with the exception of the tricuspid valve as it has three.

The heart works like machine constantly pumping blood that is fed to it. There are two venous systems that dump into the right atrium; the inferior vena cava and the superior vena cava. The inferior vena cava carries deoxygenated blood from the lower body back to the heart and conversely the superior vena cava carries deoxygenated blood back to the heart from the upper body and head. The right atrium contracts and pumps blood through the tricuspid valve into the right ventricle. When the right ventricle is filled the tricuspid valve closes off preventing regurgitation.

The right ventricle then contracts that pushes blood through the pulmonary valve and into the pulmonary artery to be carried to the lungs. once inside the lungs blood flows the tiny capillary vessels in the lungs where there is exchange of carbon dioxide and oxygen. Oxygen from the alveolar air sacs diffuses through the capillaries into the blood while at the same time carbon dioxide passes from the blood into the air sacs. The carbon dioxide is then exhaled as one respirates normally. The blood is now oxygenated and travels back through the pulmonary veins where it dumps into the left atrium.

As the left atrium contracts blood is pushed through the mitral valve into the left ventricle. When the ventricle has reached capacity the mitral valve closes, again blocking regurgitation. The left ventricle then contracts and the blood is pushed through the aortic valve into the aorta and the coronary arteries. The aorta supplies the rest of the body with oxygenated blood. The coronary arteries is actually what supplies the heart with oxygen to keep the tissue alive.

There is a right coronary artery and a left coronary artery. The right coronary artery supplies the right atrium and right ventricle. It branches into the posterior descending artery. The left main coronary artery branches into the circumflex artery and the left anterior descending artery. It supplies oxygenated blood to the left atrium and the left ventricle.

Acid-Base Balance

An acid is any compound that can donate H+ when dissolved in water. A base is any compound that can donate OH- ions. A buffer system is a combination of a weak acid or base and its salt or conjugate that resists changes in pH. The human body has incredible mechanisms to maintain an acid-base balance. Changes in pH put the body in different physiological states that can cause an array of problems. Acidosis is when the pH falls below the reference range of 7.34. Alkalosis is when the pH increases above the reference range of 7.44.


The most important buffer system in the body is the bicarbonate (HCO3)/carbonic acid (H2CO3) system. Carbonic acid works to allow the human body to rid of toxic CO2 via respiration to maintain a normal pH of 7.4. There normally is a 20:1 ratio of bicarbonate to carbonic acid.

The red cells pick up CO2 from tissues and throughout its travel through the blood vessel its converted to carbonic acid. That carbonic acid is then broken down into bicarbonate and hydrogen. The excess hydrogen ions are buffered by hemoglobin. Bicarbonate leaves the red cell and goes into circulation. Bicarbonate enters the plasma through an exchange mechanism with chloride to maintain a state of electroneutrality in the cell. When the red cells reach the lung the hemoglobin will release the excess hydrogen ions by the binding of oxygen to hemoglobin. The excess hydrogen ions bind to bicarbonate to form carbonic acid. Carbonic acid then dissociates into H20 and CO2 which is expelled.

As mentioned above, an individual can be in a state of acidosis or alkalosis. This can be caused by ventilation and is called respiratory acidosis or respiratory alkalosis or it can either be caused by HCO3-. This is called metabolic acidosis or alkalosis.

Respiratory acidosis is an increase in PCO2. Conversely respiratory alkalosis is a decrease in PCO2. Metabolic acidosis is a loss of HCO3- or an addition of H+. Metabolic alkalosis is a loss of H+ or an increase of HCO3-. The body will naturally compensate for the pH changes. Some of the compensatory mechanisms are increasing respiration in metabolic acidosis. Hyperventilation increases the amount of CO2 that is expelled and raising the pH. In respiratory acidosis the kidney will increase its reabsorption of HCO3-.

Metabolic acidosis can be caused by multiple different disease states. Excessive loss of HCO3- by diarrhea can cause metabolic acidosis. Diabetic ketoacidosis can cause it. Other causes are ingestion of acids or renal tubular failure where there is no renal reabsorption of HCO3-.

Metabolic alkalosis is caused by excess or an overdose of HCO3-. Excessive vomiting causes a loss of hydrochloric acid with the stomach contents. Vomiting also results in hypokalemia and hyponatremia which are both positively charged ions (acids) leading to an increase in the pH. Excessive diuretic use can sometimes initially cause an increase in chloride, but most commonly results in hyponatremia and causing a contractile alkalosis.

Respiratory acidosis is most commonly caused by CO2 retention usually due to ventilation failure. Decreased cardiac output and hypotension also cause acidosis. Less blood is pumped to the heart so less CO2 is getting transported to the lungs to be expelled. Chronic lung conditions such as COPD result in an inability to ventilate properly and to expel CO2. Certain drugs cause depression of the respiratory center in the brain and can cause respiratory acidosis. Some of these drugs are barbiturates, opiates and ethanol (alcohol).

Respiratory alkalosis is primarily caused by hyperventilation (increased alveolar ventilation). This results in a decreased arterial PCO2. Any condition which decreases pulmonary compliance causes a sensation of dyspnea. Dyspnea is not a single sensation and there are at least three distinct sensations including air hunger, work/effort, and chest tightness. These sensations cause a state of hypoxia which is caused by the hyperventilation.