Chronic myeloproliferative syndromes

What are they?

Red blood cells, the different kinds of leukocytes, and platelets all originate in the bone marrow, from immature cells called blasts that differentiate until the various cell types are created. Within these initial cells two large types differentiate: lymphoblasts, the precursors of lymphocytes, and myeloblasts, from which red blood cells, platelets and the rest of leukocytes develop.

When, due to different causes, there is a loss of the control mechanisms of the proliferation of myeloid germ cells in their most primitive state, the so-called pluripotent cells, all the cells derived from these altered blasts begin to reproduce excessively and occupy the bone marrow slowly and steadily. Diseases that respond to these characteristics, that is, those pathologies in which there is a proliferation of immature cells of the bone marrow in a chronic way, are called chronic myeloproliferative syndromes.

How are they produced?

Most chronic myeloproliferative syndromes are of unknown origin. When one of these syndromes occurs, there is usually a proliferation of all cell lines that derive from the altered blasts, but with a predominance of one of them. Depending on the predominant line, a difference is made between:

• polycythemia vera, in which the red series (red blood cells) predominates
• thrombocythemia or essential thrombocytosis, with a predominance of proliferation of megakaryocytes (platelets)
• agnogenic myelofribrosis, with formation of fibrous tissue in the bone marrow
• chronic myeloid leukemia, in which the dominant line is the white series (leukocytes)

Polycythemia vera occurs when the bone marrow is excessively sensitive to erythropoietin, so that at very low levels of erythropoietin there is an excessive proliferation of red blood cell precursors, erythroblasts. It occurs mainly in middle-aged men and must be differentiated from polyglobulia secondary to an increase in erythropoietin due to other causes (tumors, high height, cardiopulmonary diseases, kidney diseases,…).

Essential thrombocytosis is due to excessive proliferation in the bone marrow of megakaryocytes, the precursors of platelets. As in all myeloproliferative syndromes, the other cell lines also reproduce in greater numbers than usual, but the predominant line is that of platelets.

Agnogenic myelofibrosis occurs when megakaryocytes reproduce excessively in the bone marrow but die inside the marrow, so that upon their death factors are released that make the fibroblasts of the intramedullary connective tissue proliferate. Other substances prevent this tissue from degenerating, so that slowly this tissue occupies the entire marrow and the precursor cells of red blood cells, leukocytes and platelets migrate to the liver and spleen, where they create colonies.

In chronic myeloid leukemia, there is an excessive proliferation of leukocytes derived from myeloblasts. Given that this entity has special characteristics, it is explained in another section of this hematology section, within the one corresponding to leukemias.

Symptoms

In polycythemia vera there are two phases:

• proliferative phase, in which the red blood cell precursors reproduce at the spinal level and symptoms such as facial flushing, headache, dizziness, tinnitus, paresthesia, neuropathies, thrombosis, bleeding, weight loss, diaphoresis or itching on contact with water appear ( aquagenic itching). Splenomegaly also occurs in 3 out of 4 patients and a third have hepatomegaly.
• metamorphosis phase, in which the rate of proliferation slows and in the long run anemia may occur, with symptoms derived from it such as pale skin and mucous membranes, asthenia, dyspnea, palpitations, headache, lack of concentration, irritability, insomnia or low libido.

In essential thrombocytosis, due to the excess of platelets in the blood, different pictures of arterial or venous thrombosis occur, especially at the neurological level, as well as erythromelalgia, which consists of burning pain in both hands and feet, or priapism. Splenomegaly occurs in less than 20% of cases, and occasionally there may be hemorrhagic phenomena.

Agnogenic myelofibrosis, due to the replacement of blood blasts by connective tissue, produces a decrease in all cell lines, with which patients affected by it suffer anemia and its consequences, recurrent infections secondary to the lack of leukocytes and hemorrhagic processes due to the decrease in the number of platelets in the blood. Likewise, as blood cell-forming colonies are created in the viscera, they undergo an increase in size, so that patients suffer from splenomegaly and hepatomegaly, as well as bone lesions secondary to fibrosis. There is also an increase in uric acid, which can lead to episodes of gout or kidney stones.

Diagnosis

The diagnosis of chronic myeloproliferative syndromes will be based mainly on laboratory tests and the study of the bone marrow.

In the analysis of a patient with polycythemia vera, an increase in the number of red blood cells will be appreciated, which will be smaller than normal, so the mean corpuscular volume (MCV) will be decreased. Likewise, there will be an increase in both platelets and neutrophil-type leukocytes (which present high alkaline phosphatase levels), an elevation in vitamin B12 levels and a decrease in erythropoietin levels in the blood.

There are major diagnostic criteria for polycythemia vera (elevated erythrocyte mass, elevated blood oxygen saturation, and the presence of splenomegaly) and minor factors (elevated white blood cell, platelet, alkaline phosphatase, and vitamin B12 levels). All the majors or the first two majors are required together with the presence of two minors in order to make the diagnosis of polycythemia vera.

The diagnostic criteria for essential thrombocytosis are the presence of more than 600,000 platelets / mm3 in the blood, a normal or decreased number of red blood cells, the presence of accumulated iron in the bone marrow and the absence of myelofibrosis, of the Philadelphia chromosome (characteristic of the chronic myeloid leukemia) and other causes of thrombocytosis. Vitamin B12 and alkaline phosphatase are normal.

In the blood test of patients with agnogenic myelofibrosis, a decrease in all cell lines will be seen, as well as the presence of dacryocytes, tear-shaped red blood cells. The diagnosis will be given by the bone marrow aspirate, in which nothing will be obtained due to the occupation of the same by fibrous tissue, which will be appreciated in the bone marrow biopsy.

Treatment

The only definitive treatment for polycythemia vera would be bone marrow transplantation. If this is not possible, bleedings can be done to try to keep the hematocrit below 45%. Other therapeutic options are radiation therapy and chemotherapy.

Treatment of essential thrombocytosis, if feasible, is also bone marrow transplantation. If the patient is not a candidate for it, palliative treatments will be given, such as chemotherapy or antiplatelet drugs.

The treatment of agnogenic myelofibrosis would ideally be bone marrow transplantation again. If this is not possible, palliative treatments with chemotherapy and transfusions will be given.

Precautionary measures

Given the unknown origin of chronic myeloproliferative syndromes, there are no preventive measures against them.