With chronic myeloid leukemia, essential thrombocythemia and primary myelofibrosis, polycythemia vera or polycythemia vera is one of the myeloproliferative disorders. It is therefore characterized by clonal expansion of a pluripotent hematopoietic stem cell, causing an unregulated proliferation of myeloid tissue predominant in the individual case, erythroid. Unlike secondary polycythemia, resulting from the normal hyperstimulation erythroblast progenitors by erythropoietin produced in excess, the progenitors in the deVaquez disease have the particularity of being able to differentiate regardless of erythropoietin or in the presence of minute amounts of erythropoietin, inhibiting the residual normal progenitors. It is therefore an intrinsic cellular defect. There is no in polycythemia vera mutation erythropoietin receptor and hypersensitivity progenitors to other growth factors suggests that erythropoietin an abnormality of a common transduction system of these factors. In fact, it probably develops in polycythemia vera several genetic abnormalities of the pluripotent stem cell involved, which have in common affect apoptotic pathways.The incidence of polycythemia vera disease is about 1 case per 100,000 inhabitants per year in France but the prevalence is not negligible because of the slow pace of change. It is a pathology of elderly with a mean age at diagnosis rather than 60, then the frequency increasing linearly. Very rare before age 40, it is quite exceptional in children. The sex ratio is close to 1.
Positive diagnosis:
A- Clinical signs:
• polycythemia vera The diagnosis is evoked more often in view of unforeseeable blood count.
• The mucous erythrose is rarely revealing.
• Functional signs reflecting the blood viscosity is to look at the examination but can meet in polycythemia: headache, dizziness, tinnitus, visual disturbances, paresthesia. They are found in about half the cases. Itching to the hot bathing is inconstant but highly evocative. The crisis érythromélalgiques feet are also very suggestive of myeloproliferative disorder.
• Vascular complications, mainly thrombotic and haemorrhagic much incidentally, can be revealing.
• Splenomegaly is present in two thirds of cases and is an essential part of the diagnosis. In moderate rule, it justifies the systematic implementation of an abdominal ultrasound. This review also has the merit of not misunderstand renal neoplasm, rare cause of secondary polycythemia.
B- biological signs:
1- Polycythemia vera Diagnosis:
• The essential orientation element is represented by the establishment, complete blood count, elevated red count, hemoglobin and hematocrit. In polycythemia vera (and most secondary polycythemia), this elevation in erythrocyte parameters is parallel except iron deficiency associated generator microcytosis and hypochromia (bleeding, gastrointestinal bleeding distillantes). The hematocrit is the key parameter. The upper limit of normal is 45% in women and 50% in men. In patients with moderate and isolated elevation between 45 and 47% in women and 50 to 52% in men, only one control is warranted. If the hematocrit is above 55% in women and 60% in men, polycythemia is certain and the isotopic determination of unnecessary blood volume. For intermediate figures, the latter exploration is required to eliminate false polycythemia by hemoconcentration. In polycythemia, the ESR is reduced or zero.
• The isotopic determination of blood volume, diluting the erythrocytes labeled with chromium 51 (51 Cr) coupled to the study of plasma volume expansion by dilution of the serum albumin labeled with iodine 125 (125I), not s’ expresses more depending on the weight (underestimation obese) but compared to theoretical values for a subject of the same weight and same size. A true polycythemia is defined by a globular total volume greater than 25% of the theoretical total erythrocyte volume, the total plasma volume is also within the limits of normal.
2- Elements for diagnostic polycythemia vera:
• At the CBC, the recognition of an inflation granulocyte colony and (or) in platelet lineage is a very strong argument.In about half the cases, there is a leukocytosis greater than 12,109 / L with neutrophilia. Figures above 20,109 / L are rare. It may be a discrete basophilia. Observing a myélémique reaction is suggestive of myélofibrosante evolution (along with anisopoïkilocytose with tears RBCs). The elevation of the leukocyte alkaline phosphatase score is devoid of interest. In half again, is found superior to thrombocytosis 450 109 / L. Figures above 800,109 / L is rare and encountered in cases of associated iron deficiency. As in other myeloproliferative disorders, thrombopathy can result in a hypoagrégabilité adrenaline and ADP (adenosine diphosphate)
• Bone marrow is of no diagnostic value, showing only a rich and well balanced marrow. However, it allows the removal of medullary karyotype, which can be a diagnostic aid.
• The bone marrow biopsy is more contributory but is not performed routinely. Cell wealth is increased, affecting the three myeloid lineages. Hyperplasia of the megakaryocytic lineage, with dystrophies, is a characteristic sign. It exists in a quarter to half of the cases densification of reticulin fibrosis collagen network but the principle is absent in the diagnosis. He also noted a lack of hemosiderin in macrophages.
• Serum erythropoietin rate does not provide a really decisive diagnostic aid. Certainly, this rate is either decreased or normal when it should be increased in secondary polycythemia. There are however quite frequent overlap in the normal range.
• Cytogenetics on medullary karyotype can assist quite interesting to diagnosis by showing a non-specific clonal abnormality but very suggestive of myeloproliferative disorder. Nevertheless, these clonal abnormalities, which may also be observed in essential thrombocythemia and primary myelofibrosis, do see that in 15 to 20% of cases conventional cytogenetics. Detection rates are higher using the techniques of fluorescence in situ hybridization. The Philadelphia chromosome, specific for chronic myeloid leukemia, is never observed. The most frequent anomalies are represented by del 20q, 13q the del and trisomy 1, 8 and 9. The involvement of deletions suggests the gene inactivation of existence which could play an important pathogenic role.
• The in vitro culture of erythroblast progenitors is the most effective technique to confirm the diagnosis before myeloproliferation no obvious signs. The methods are now standardized but require the use of specialized laboratories. The test is most often performed on blood. The spontaneous growth of erythroblast progenitors in the absence of adding erythropoietin into the culture medium (endogenous erythroid colonies) is sensitive and specific.
• Further investigations have an interest entirely secondary. The serum iron is reduced tendency.There is frequently a discreet hyperuricemia. The vitaminémie B12 can be increased.
• Molecular techniques for the study of myeloid clonality in women are not available for diagnostic use.
Differential diagnosis:
A- False polycythemia:
These are situations where an increase in erythrocyte parameters does not match a true polycythemia. Some are obvious and do not require the use of an isotopic study of blood volume. Others require this investigation.
1- Thalassaemias heterozygous:
The ethnic group is evocative of course. The blood count is characteristic due to the formation of a very hypochromic and microcytic micropolycythémie. If the red count is increased, hemoglobin and hematocrit are decreased trend.The review to be favored in heterozygous b-thalassemia is the hemoglobin electrophoresis (increased hemoglobin levels A2). The only problem is a diagnostic polycythemia vera deep iron deficiency state but iron status and clinical circumstances will distinguish. Isotopic study of blood volume is useless (it would show a normal cell volume or decreased total).
2- acute Hémoconcentrations:
They are secondary to extensive burns, acute dehydration, excessive use of diuretics. Elevated red blood cell parameters is due to plasma hypovolemia. The obviousness of the diagnostic course not justify an isotopic study of blood volume.
3- Pseudo-polycythemia called “stress”
It is also known as syndrome Gaisbock. Unlike the previous two, this can pose a real diagnostic problem with polycythemia vera. It is not uncommon in humans mature, bloated and hypertensive. Isotopic study of blood volume is decisive in showing no polycythemia vera (cell volume normal or slightly increased total) but a decrease in plasma volume expansion. There is a risk of thrombosis.
B- secondary polycythemia:
These are true polycythemia due to excess production of erythropoietin. There are no signs of myeloproliferation.Their diagnosis is often obvious. Two main groups can be distinguished: polycythemia by tissue hypoxia, some causes are very common, and tumor polycythemia.
1- polycythemia by tissue hypoxia:
The overproduction of erythropoietin is compensatory or appropriate. The arterial blood gases is the key consideration. It is very rarely necessary to have to determine the carboxyhemoglobinemia, methemoglobinemia, the affinity of hemoglobin for oxygen (p50) or rate of 2,3 DPG intra-erythrocyte.
• The polycythemia arterial oxygen desaturation are characterized clinically by cyanosis and not by erythrose. They are affirmed before a SpO2 <92% and a PaO 2 <65 mmHg. The major cause is chronic respiratory insufficiency by obstructive pulmonary disease or bronchoemphysème. Next are pneumoconiosis and pulmonary fibrosis. The hypoventilations alveolar (Pickwick syndrome) may require continuous recordings of the gas analysis (nocturnal oxyhemoglobin desaturation episodes). Cardiovascular causes are represented by congenital heart defects with right-left shunt, the pulmonary veno-arterial fistula.
• The polycythemias by default oxygen transport to the tissues have a predominant cause: smoking. If tobacco consumption, it is frequently found a polyglobulique trend, combined with a discrete neutrophilia could cast doubt on polycythemia vera beginner. The cause of polycythemia is, at least in part, by an excess of carboxyhemoglobin.Other causes are also classical than exceptional: hyperaffine hemoglobinopathies with hemoglobin for oxygen (familial) deficiency 2, 3 DPG, methemoglobinemia.
2- tumor polycythemia:
There inappropriate overproduction of erythropoietin tumor tissue in the most common etiology is renal clear cell carcinoma, where the rule before any polycythemia, performing an abdominal ultrasound to assess the volume of spleen and not to disregard renal neoplasm. Polycythemia disappears after resection of the tumor tissue and reappears when metastases. Benign kidney tumors have also been implicated. The second cause is tumor typically represented by cerebellar hemangioblastoma, where we could also demonstrate an inappropriate secretion of erythropoietin. We will only mention the hepatoma cirrhosis, some large uterine fibroids. Pheochromocytomas, some adrenal tumors can cause false polycythemia by hemoconcentration. Mention, finally, polycythemia trends that can lead to prolonged androgen taken in high doses.
C- Other myeloproliferative disorders:
Even if they are very close to the nosological terms of polycythemia vera, presentation is very different.
• The forms of chronic myeloid leukemia polycythemia are quite exceptional. The picture is that of chronic myeloid leukemia in her usual variety and there is therefore no diagnostic problem. Search Philadelphia chromosome or its molecular equivalents is positive.
• There are forms of overlap between essential thrombocythemia and polycythemia vera: a patient with an array of essential thrombocythemia with polycythemia affirmed by the isotopic study of blood volume, possibly after correction of iron deficiency associated, is ranked in the part of polycythemia vera.
• The existence of polycythemia forms of primary myelofibrosis is very controversial. There are actually very few diseases vera accompanied outset a significant splenomegaly and a net myelofibrosis, partly collagen. These forms are long and stable near polycythemia vera vector.
D- pure Érythrocytoses:
It is a diagnosis of exclusion become very rare. They are defined by the existence of a true polycythemia strictly isolated, without arguments for a secondary polycythemia and do not fulfill the criteria for polycythemia vera. Some pure érythrocytoses correspond to a myeloproliferative disorder such as show evolution. The assumptions do not fail to try to explain the mechanism of others but none is conclusive. Note the existence of exceptional benign familial érythrocytoses characterized by a truncated erythropoietin receptor in its cytoplasmic site.
Evolution:
The evolution of polycythemia vera is threatened by two types of complications: vascular, linked to the lack of effective control of polycythemia;hematological, partly related to the treatments used. However, if the treatment is appropriate expectancy and quality of life have become, in the usual age ranges, similar to those of a population-control.
A- vascular complications:
1. Bleeding complications:
They are primarily due to platelet dysfunction, sometimes increased by the inadvertent use of salicylates in high doses. This is especially section of bleeding or gastrointestinal which then will find a local cause of bleeding.
2- thrombotic complications:
They are much more formidable. They can be venous or arterial.
• Venous thrombosis may interest the lower limbs and be complicated by pulmonary embolism. Very specific and poor prognosis are the thrombosis of hepatic veins (Budd-Chiari) and portals. These can complicate a typical polycythemia vera. They may also be indicative of an atypical myeloproliferative disorder in young women with a little evocative blood picture. The diagnosis is based largely on the growth of spontaneous erythroblast precursors.
• Arterial thrombosis are represented by strokes, arterial occlusions of the lower limbs, myocardial infarction, more rarely mesenteric infarction or thromboses of the central retinal artery. The pathogenesis of thrombotic complications of polycythemia vera is imperfectly understood. Age, thrombotic antecedents, associated risk factors play a supporting role. The hyperviscosity correlated to hematocrit, thrombocytosis and platelet activation are directly implicated factors. It might also be important to look for these patients deficient in natural anticoagulants.
B- hematological complications:
1- Secondary Myelofibrosis:
This is the natural evolution of polycythemia vera, delayed installation, and half of those enjoying a prolonged survival, that is to say 20 years or more, have developed this complication . It occurs very gradually. Before the formation of the characteristic picture of myelofibrosis, superimposed on that of the primary myelofibrosis (voluminous splenomegaly, anemia anisopoïkilocytose including erythrocytes in tears érythromyélémie, marrow fibrosis collagen, hepatosplenic myeloid metaplasia demonstrated by scintigraphy-111) s ‘sometimes installs an intermediate phase (Spent phase) marked by an increase in volume of the spleen and a reduction of plasma polycythemia by hypervolemia. At the stage of myelofibrosis incorporated, the therapeutic possibilities are limited, as in the primary myelofibrosis, and terminal complications are the same as in this condition. Prolonged iron deficiency, such as that induced by bleeding in the long term for therapeutic use, plays a role in promoting undeniable on early development of secondary myelofibrosis. It seems also important that the treatment myélofreinateur permanently normalize platelet counts, the role of cytokines leached by megakaryocytes in the genesis of myelofibrosis is well established.
2- acute leukemic transformation:
It occurs in large polycythemia vera series, in 10 to 15% of patients in the 10th year after diagnosis, and this risk continues to steadily increase with time. This complication appears dependent on the delivered treatment to control polycythemia vera. The risk is very low among patients treated with exclusive bleeding, even if it is not nonexistent.Promoting the role and alkylating radiophosphorus is unmistakable. This has led to extensive use in recent years, products supposed leukaemogenic little as hydroxyurea (Hydrea) and pipobroman (Vercyte), especially among relatively young (under 65). In fact, the observation periods are now sufficient to conclude the non triviality of these agents. As with hydroxyurea pipobroman that the leukemia risk is about 10% in the 13th year. Acute leukemias finish from the evolutionary course of the disease polycythemia vera treated myélofreination have all the features of acute leukemia induced. They are usually preceded by a phase and myelofibrosis (or) myelodysplasia. It is difficult to classify acute myeloid leukemia. The unfavorable karyotype says: complex karyotypes with -5 / del 5q and (or) -7 / del 7q in patients previously submitted to radiophosphorus or alkylating, del 17p if pretreatment with hydroxyurea or pipobroman (new concept). Once installed, the acute leukemic transformation of polycythemia vera is fatal in a very short period and does not recognize any treatment. It is exceptional, because of age, an allogeneic bone marrow can be proposed.
Treatment:
Its goal is the permanent normalization of hematocrit (which should be as close as possible to 45%) and platelet count (which should not surpass the 500,109 / L) to reduce vascular risk. It must also play a role inducer lowest possible regarding hematological complications.
A- bloodletting:
Exclusive treatment attempts, the long course of polycythemia vera by bleedings cause disadvantages such that half of the patients have given up to 5 years and almost all 10 years. This lack of compliance is due to constraints related to the gesture but also the development of a deep iron deficiency and often poorly tolerated, yet it should be respected. In fact, the only benefit of bloodletting is to accompany a leukemia risk very low. By cons, they poorly controlled vascular risk because of the often random nature of their achievement after a while, and also due to the exacerbation of thrombocytosis by iron deficiency. Finally, they facilitate rapid progression to myelofibrosis. The grooves are no longer reserved only emergency treatment of polycythemia vera, to quickly normalize hematocrit when it is above 55% in women and 60% in men. They are made at a rate of 300 mL / d or 1 day to 2.
B- myélofreinateur Treatment:
1- radiophosphorus or 32P:
It has long been the benchmark. It is delivered intravenously, at 0.1 mCi / kg to a maximum dose of 7 mCi. Perfectly tolerated, it results in a complete response after 3 to 4 months. The duration of the complete response is of the order of 3 years. Repeated 32P cures results in increasingly short answers but the radiation resistance is rare.
The satisfactorily control 32P vascular risk. He did not particularly facilitates myélofibrosante natural evolution. By cons, its inducer leukemia is well established. It has been shown recently that the implementation of hydroxyurea after 32P, maintenance, was more leukemia that only 32P. 32P should now be reserved for the most elderly. Given the steady increase in general life expectancy, it is not illogical to set the bar at 70 years.
2- alkylating agents:
It is essentially busulfan (Misulban). This product is hardly used because it is considered of an induction leukemia risk identical to that of 32P, which is superadded severe aplastic risk.
Hydroxyurea 3- and pipobroman:
These two non radiomimetics drugs without cross-resistance, are currently the most popular products. Their handling is stackable (see for detail). Obtaining a complete response is almost constant. This should be maintained by a maintenance treatment at the lowest possible dose. The tolerance of the two products is good; cytopenias are rare and quickly resolvent. Hydroxyurea may cause mucocutaneous disorders such leg ulcers or stomatitis. Pipobroman in dosage of attack, can lead to digestive disorders such epigastralgia and diarrhea. The occurrence of a large sub hydroxyurea macrocytosis is constant and devoid of pathological significance. It is now established that the risk of leukemia induction is real with these drugs, even if it is probably smaller than 32P and alkylating. The risk of facilitating the evolution myélofibrosante appears high with hydroxyurea, probably because the permanent normalization of platelet count is more difficult to obtain than pipobroman. Stable control hematocrit is sometimes more difficult to obtain with hydroxyurea with pipobroman. This product therefore deserves to be favored.
C- Interferon alpha:
They are often effective in controlling the disease and polycythemia vera may be free of leukemia induction effect.However, their numerous manifestations of intolerance make their exceptional use. They may have a place in the very rare forms refractory to hydroxyurea and pipobroman. They have the particularity of well control the itching and can be prescribed for pregnant women.
D- Salicylates:
Their interest in low doses (100 mg / d) in combination with myélofreinateur treatment for better control of the thrombotic risk is evident.
Highlights to include:
• A diagnosis of polycythemia vera or polycythemia vera proceeds from a rational approach that is far from always having to resort to highly specialized further investigations.
• There must be early to avoid the occurrence of vascular complications, the cause of mortality and especially significant morbidity.
• With a vascular risk driven this treatment will be controlled, thus allowing patients to benefit from a hope and a quality of life close to those of a control population, at least in the usual high age groups .
• This treatment aims to minimize as much as possible the risk of late complications Hematologic: myélofibrosante evolution and acute leukemic transformation.
FOR FURTHER:
Hydroxyurea administration regimen or pipobroman in polycythemia vera disease Both products devoid of cross-resistance are identical in operation.
• Hydroxyurea (Hydrea) is dosed in capsules of 500 mg, pipobroman (Vercyte) tablets containing 25 mg.
• The dosage of attack is 25 mg / kg / day for Hydrea and 1.25 mg / kg / day for the Vercyte or 3-4 capsules (Hydrea) or tablets (Vercyte) per day.
• Weekly monitoring of blood count is held until normalization of hematocrit (about 45%). This result is generally obtained within 1 month to 6 weeks. The normalization of platelet count usually goes along with that of hematocrit.
• In the absence of normalization of hematocrit to 6 weeks, the dosage of Hydrea is increased or Vercyte capsule or tablet a day for 15 more days.
• If, after 2 months, hematocrit is still not standardized (very rare circumstance), the dose of Hydrea or Vercyte may still be increased by a capsule or tablet a day for 15 additional days (maximum 6 capsules or tablets a day).
• Once normalized hematocrit, Hydrea or Vercyte must be brought to maintenance to maintain the result. The maintenance dose is usually half the starting dose but can be much lower. A monthly monitoring of the blood count is now sufficient.
• If hematocrit new increase beyond 48% in women and 50% in men, the maintenance dose will be slightly increased in order to standardize constantly hematocrit.
• Both the Hydrea Vercyte are very aplasiants. These products will nonetheless interrupted when it drops in hematocrit below 36% in women and 38% in men and (or) for neutropenia below 1,2.109 / L and (or) cases of thrombocytopenia less than 100,109 / L.
• The occurrence of Hydrea as macrocytosis is constant. She is fickle and then accented with little Vercyte.
Strong Points to remember:
• In the majority of cases of polycythemia vera, the diagnosis may be placed before the association to a real signs of polycythemia myeloproliferation drawn from the clinical examination and blood count: splenomegaly and (or) and leukocytosis with neutrophilia (or) thrombocytosis.
• This proves nevertheless sometimes necessary to seek, to a compatible table with a pure erythrocytosis, and after eliminating secondary polycythemia, more elaborate signs for the myeloproliferative disorder, the first of which is pushing up the spontaneous in vitro erythroblast progenitors.
• Treatment of polycythemia vera is to permanently normalize hematocrit and platelet count, to control vascular risk. It is based on myélofreinateurs agents, bloodletting was no longer used only in emergency situations.
• Because of its role leukemia inducer, radiophosphorus should be reserved for older individuals or unable to comply with regular monitoring.
• Hydroxyurea and pipobroman became reference products although they are far from being devoid of risk of leukemia induction. Pipobroman is probably preferable because it facilitates unless the hydroxyurea myélofibrosante evolution.
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