The upper limit of the number of circulating platelets is usually admitted 450 109 / L. It is considered that the splenic platelet pool is one third of that value in the normal state and can reach considerable values in case of enlarged spleen in the myeloproliferative disorders. the term is reserved thrombocytosis thrombocytosis or to situations in which the number of circulating platelets is greater than 500,109 / L. The purpose is to distinguish in these thrombocytosis, the thrombocythemia, term applied to platelet number increases of integrating into the context of a myeloproliferative disorder. The term reserve of essential thrombocythemia or primitive to a particular variety of myeloproliferative disorder that presents itself as an almost exclusive proliferation of mégacaryoto platelet-line (see: to deepen / 1).
Secondary reaction thrombocytoses:
They are recognized most often on the clinical context, the discovery of an inflammatory syndrome clinical or laboratory, looking for iron deficiency, the notion of splenectomy or asplenia.
A- thrombocytoses passing:
Some thrombocytoses are transient and hard to classify mechanism. They are those imputed to the exercise, stress, trauma, especially if it is complicated fracture, or in the days following surgery or childbirth. The adrenaline was one of the first drugs known for its role in increasing the platelet count, probably démargination platelets, especially in the pulmonary circulation. Other thrombocytoses appear to be linked to a transient spinal cord stimulation. These are the ones which follow a bleeding episode or a hemolysis phase. Similarly thrombocytoses the interpreter is of so-called “rebound”, succeeding thrombocytopenia default production or excessive destruction. We observe in after acute alcohol intoxication, treatment of pernicious anemia, thrombocytopenia repairing a device or drug agranulocytosis. In fact, the most frequent succession to the use of chemotherapy causing transitory hypoplasia. Treatment with vincristine may induce thrombocytosis by a poorly understood mechanism. Thrombocytoses these are usually obvious cause because of the context. They are mild, asymptomatic, acute, and therefore have no practical risk of bleeding or thrombotic specific and do not require anticoagulant therapy unless the clinical context of those requiring preventive treatment of thrombosis.
B- sustainable thrombocytoses:
Durable reaction or side thrombocytoses meet in principle the same pattern. They are moderate, below 1 000 109 / L, but may especially when several causative factors are combined, exceed that figure. They are usually asymptomatic and hemorrhagic and thrombotic complications are rare in patients with no risk factor.
1- Splénectomie:
The post-splenectomy thrombocytosis is predictable but not constant (less than 1 in 2?) And not necessarily observed immediately after the procedure (from 1 to 10 days of onset time). The peak is reached in 1 to 3 weeks. The extent of thrombocytosis often exceeding 1 000 109 / L indicates that the mobilization of splenic pool is not the only cause.Return to normal may take weeks or months. Some, passing chronicity, are discussing the revelation by splenectomy of a latent myeloproliferative disorder. In fact, when splenectomy is for a condition responsible for chronic anemia, thrombocytosis is more pronounced. It persists more willingly if anemia is still present after splenectomy, especially if the anemia mechanism is hemolysis, reflecting a permanent spinal cord stimulation. In this case, despite his character reaction, some invoke the possibility of bleeding or thrombotic risk associated with this thrombocytosis in the long term.
2- Asplenia:
Asplenia is sometimes given explanation of the origin of chronic moderate thrombocytoses. Before the use of ultrasound, the presence on the Jolly body is likely to smear on track.
3- Iron deficiency:
The thrombocytoses of iron deficiency are now well known. They are not constant, almost always moderate, below 1 000 109 / L; they are likely to be observed even when the iron deficiency does not lead to significant anemia. This is particularly true of certain thrombocytoses accompanying polycythemia treated by bleeding or hemorrhage complicated. Their diagnosis is based on the determination of serum ferritin. The thrombocytoses of iron deficiency after restoration lend iron stocks. Some cases of thrombosis, including cerebrovascular, in patients whose only risk factor was the existence of iron deficiency, have recently been described. We lack depth pathophysiological studies on the mechanism thrombocytosis. They are not usually accompanied by an increased rate of CRP assays and rare events in these situations do not show either a clear elevation of thrombopoietin.
4- inflammatory disease and infection:
The thrombocytoses chronic inflammatory syndromes or acute or chronic infections are usually recognized on clinical infectious or inflammatory context (fever, sweats, weight loss), or on biological data (sedimentation rate, fibrinogen assay). They can also benefit from the CRP, reflecting the production of IL6, indirect stimulating factor thrombopoiesis.The list of inflammatory diseases or infections for these thrombocytoses can not be exhaustive. It has been reported with particular frequency: rheumatoid arthritis, bowel, etc.
5- Cancer:
Thrombocytoses The accompanying various forms of cancer are probably only a particular aspect of these thrombocytoses of inflammatory origin. Epithelial cancers most frequently cited are the bronchial cancers of the kidney, breast. It is likely that cancers that involve chronic bleeding and peritumoral inflammatory syndrome are prime sources of thrombocytosis. An isolated thrombocytosis accompanied by an inflammatory biological syndrome is one of the classic modes of discovery of Hodgkin’s disease and certain non-Hodgkin lymphoma. The thrombocytosis, in cases where it is secondary to a malignant disease, may have a double interest: to bring to suggest the diagnosis of tumor and, to some extent, to follow the evolution after treatment. Little is known about the actual consequences, in terms of the risk of thrombosis, such thrombocytoses, regardless of the role that already plays favoring the development of the tumor.
Primary thrombocytoses:
A- Myelodysplastic syndrome:
primary thrombocytoses observed in the course of myelodysplastic syndromes are rare and usually easily recognized because of haematological context.
1- sideroblastic anemia:
The thrombocytosis that occurs during sideroblastic anemia acquired is inconstant, moderate, generally observed in adults, sometimes older. It is accompanied in a third of cases of moderate splenomegaly. The normo- progressive anemia or macrocytic accompanying actually contains a double red cell population, including hypochromic red cells despite the rise in serum ferritin. Myelogram shows a red cell hyperplasia, the ringed sideroblasts in all stages of erythroid maturation. The elevation of free erythrocyte proto- porphyrins may be an orientation element. The evolution is threatened primarily by hemochromatosis favored by transfusions that quickly become necessary.
2- Other myelodysplastic syndromes:
Other myelodysplastic syndromes usually have thrombocytopenia that thrombocytosis. The 5q syndrome, readily observed in an elderly woman, also includes a refractory macrocytic anemia, splenomegaly, an inconstant elevation in platelet number and common dystrophy of the megakaryocytic lineage made of small elements whose nucleus shows failure to net lobation.
B- Myeloproliferative:
The thrombocytoses myeloproliferative disorders in fact constitute the crucial time of diagnosis of thrombocytosis primitive. This diagnosis is extremely easy when thrombocytosis is part of a typical picture of chronic myeloid leukemia with a predominant leukocytosis on neutrophils, eosinophils and basophils more rarely, a myelemia and splenomegaly.The thrombocytosis especially has prognostic significance. Indeed, it is recalled that between thrombocytosis in determining the Sokal score and secondary occurrence of thrombocytosis during the evolution of chronic myeloid leukemia is often synonymous with impending acute transformation. The association of thrombocytosis and high hematocrit is a good orientation element in favor of polycythemia vera. also be sought in its favor splenomegaly, leukocytosis, we will proceed with the study of blood supply. The thrombocytosis therefore of unquestionable diagnostic value (minor criterion PVSG (polycythemia vera study group), but not within the framework of the predictors of risk of thrombosis that are contrary correlated with the age and history of thrombotic patients. Finally, thrombocytosis is more rare in the typical myelofibrosis recognized on érythromyélémie, erythrocyte deformation, splenomegaly and bone marrow fibrosis. in fact, the difficulty of diagnosis of thrombocythemia is that although a thrombocytosis can appear totally isolated, previous diagnoses should be carefully disposed of:
• primitive polyglobuline, conducting a systematic study of globular volume when Hb exceeds 13 g / dL; It is essential, then, to interpret the results of this review to ensure the absence of iron deficiency. The dosage of ferritin is the basic criterion on which that assessment is based;
• some isolated thrombocytoses similar in all respects to those observed in essential thrombocythemia may be the first sign of chronic myeloid leukemia. Besides the systematic search of the Philadelphia chromosome, essential given the very high risk of acute rapid transformation in this variety of primary thrombocytosis, it recommends more systematic research of the transcript bcr / abl. Finally, careful analysis of the bone marrow biopsy shows in that event megakaryocytic hyperplasia small megakaryocytes made no particular tendency to group in clusters. It is more difficult to establish the exact classification of apparently isolated thrombocytoses but with a degree of érythromyélémie, a small splenomegaly and debutante myelofibrosis as reticulin densification. The problem they pose is whether he is a beginner myelofibrosis or fibrotic changes that sometimes occur in the long term in the evolution of an authentic essential thrombocythemia. The degree of fibrosis, the extent of clinical and hematological abnormalities, including research of erythrocyte deformation, are used to make this distinction which perhaps is only a theoretical interest.
C- essential thrombocythemia:
Essential thrombocythemia currently appears as one of the most common myeloproliferative disorders. Its frequency is higher than that of the myelofibrosis and chronic myeloid leukemia. It is probably higher than that of polycythemia vera.The distribution by age and sex is one of the first features of this myeloproliferative disorder. The average age is 60 years, there globablement a female predominance (sex ratio: 1.67). It actually exists in this disease a second peak incidence around 30 years, mainly affecting female population. This explains why problems of pregnancy and contraception often arise acutely in this disease. The usual mode of discovery of the disease is a systematic count revealing thrombocytosis and corresponds to at least half of the cases of essential thrombocythemia. The circumstances of discovery are divided under three headings.
1- Thrombosis:
Arterial thrombosis are much more common than venous thrombosis (about 6 times). They interest the coronary circulation, brain areas responsible for irreversible strokes, members peripheral arteries. Venous thrombosis may affect the deep venous territories, not complicated or pulmonary embolism. Superficial vein thrombosis is sometimes confused with érythromélalgiques events. Some locations deserve special mention: thrombosis of the cavernous bodies with priapism or especially thrombosis of the splanchnic territory.
2- Events vascular microcirculation interesting:
Transient ischemic attacks, linked to a temporary obstruction of microcirculation, gathered at diagnosis in about a third of symptomatic forms of essential thrombocythemia. These events are attributed to in vivo activation of platelets within the arterioles, not irrevocably leading to thrombosis, which explains their spectacular reversal thanks to the use of aspirin. Of these accidents, those observed in the extremities, appointed Erythromelalgia, are considered by some as pathognomonic of thrombocytosis in myeloproliferative disorders. Usually observed in the toes, the erythromelalgia crises are characterized by pain, burning, increased local heat and a change in skin color occur in the same territory as pain and often predominant in the plant feet or toes pulp. At a minimum, it is tingling sensations or skin burns soles with a purplish, mottled skin. Sometimes the redness dappled way to a érythrocyanose then necrosis area, usually limited, which can still surrender and heal spontaneously by mummification of the skin at the price of a small umbilicated scar. It can, conversely, result in gangrene, more or less limited, a toe. The most striking feature is when the gangrene occurs in a patient’s peripheral pulses which are found and that the arterial vascular system can be perfectly atherosclerotic event. These transient ischemic events are likely to hit the cerebral vasculature. Sometimes these events not involving any signs of localization: headaches, balance disorders, dysarthria, bilateral obscuring the view. The existence of seizures was reported. It can be rather localized events (mono- or hemiparesis), transient unilateral eye disorders, scintillating scotoma, diplopia access. Others affect mesenteric vascular territories (angina small bowel).
3- hemorrhagic events:
They have long been used to name the disease: hemorrhagic thrombocythemia. In fact they are far less common than vascular events as revealing circumstance and more like evolutionary complication of the disease being treated.Sometimes it is spontaneous bleeding, usually mucocutaneous and moderate. The heavier or gastrointestinal bleeding are more likely caused by a local cause or a surgical procedure.
4- Splenomegaly:
Clinical examination shows an enlarged spleen in a small percentage of cases (less than 50%). The spleen is still moderate in size.
5- Laboratory tests:
• The hemogram: increasing the platelet number is on average between 1 000 to 1 500 109 / L, which corresponds to a small number of patients with platelet numbers are very high, exceeding 2 000 or 3 000 109 / L and a high frequency of patients with platelet count is between 600 and 1 000 109 / L. Hemoglobulin rate averages around 13.8 g / dL.Sometimes it is initially lowered due to microcytic iron deficiency anemia. It is then necessary to use an iron treatment followed by a study of cell volume to eliminate polycythemia vera.
• The isotope corpuscular volume is by definition never rose above the range considered those of polycythemia (more than 130% of the theoretical cell volume). The plasma volume is however very variable, often increased. Normality of Hb and hematocrit is not a sufficient argument to eliminate polycythemia and the systematic study of globular volume is recommended above 13 g / dL Hb. Leukocytosis is moderately high, greater than 12,109 / L in 40% of patients. A very limited scale érythromyélémie can be observed in a small number of cases.
• The bone marrow aspiration is essential for cytogenetics but brings only rarely the case for diagnosis because of frequent dilution of samples.
• Bone marrow biopsy confirmed marrow megakaryocytic hyperplasia. Megakaryocytes are large, their ploidy is high, their grouping into clusters is characteristic. The overall cell density of the marrow is not always frankly increased and essential thrombocythemia of diagnosis is compatible with a cell density close to normal. A reticulinic hyperplasia was observed in approximately 20% of the initial bone marrow biopsy. This is a densification diffuse non mutilating, without disruption of the cord and without collagen fibrosis.
• Cytogenetic study is essential for the diagnosis of essential thrombocythemia to eliminate the presence of a Philadelphia chromosome. No cytogenetic abnormality can not be held for specific essential thrombocythemia. The frequency of finding such abnormalities is low, on the order of 5 to 6% of cases.
• Systematic research of bcr / abl is desirable to eliminate chronic myeloid leukemia afterthought. Highlights to include:
• The generalization of automatic and systematic count of circulating platelets highlighted the frequent finding of thrombocytosis in blood count.
• Unlike anemia or thrombocytopenia, it is rare that thrombocytosis is suspected on clinical grounds.
• The development of a diagnostic strategy is of paramount importance to distinguish the reaction thrombocytoses those who translate a primitive disorder of the spinal cord, that is to say, a myeloproliferative disorder or myelodysplasia.
• This step is essential etiological to assess the extent of bleeding or thrombotic risk that this excess platelets involves short-term and vital potential risk that the discovery of a hematologic disease is long run.
Strong Points to remember:
• The diagnostic strategy of thrombocytosis is to eliminate successively:
– The reaction or secondary thrombocytoses; – Within primary thrombocytoses, witnessed a proliferation of autonomous mégacaryocyto-platelet elements, we will then remove those who witness a Myelodysplastic Syndrome: sideroblastic anemia, 5q syndrome;
– Retaining only primitive myeloproliferative disorders differentiating revealing thrombocytoses chronic myeloid leukemia or – and this is the most delicate point – of polycythemia vera, or, more rarely, those witnessed a myelofibrosis;
– To finally retain the essential thrombocythemia diagnosis after removal of the previous contingencies.
• This is to change the strategy of diagnosis by elimination we are trying to explore and assess the positive arguments for diagnosis as the analysis of the bone marrow biopsy, cultures megakaryocytic progenitors, determining the clonality hematopoietic proliferation.
FOR FURTHER:
1 / megakaryopoiesis and regulation:
Platelet production involves differentiation from multipotent stem cells, cell only for the production of platelets. This first stage of differentiation is that of progenitors and corresponds, in vitro when cultured megakaryocytes in semi-solid medium, the BFU-MK (burst forming units) and CFU-MK (forming unit megakaryocyte colonies). From a certain point of differentiation, megakaryocytic precursors stop dividing and follow an endo-replication process of DNA resulting in polyploid megakaryocytes. The ploidy of megakaryocytes normal individuals can reach 64 N but the majority of magacaryocytes have ploidy of 16 N or 32 N. Along this polyploïdisation, megakaryocytes undergo a maturation process before producing platelets. Platelet production depends on three independent parameters: the number of megakaryocytes in the marrow, the megakaryocyte volume that is directly related to their level of ploïdisation, the degree of cytoplasmic maturation of megakaryocytes. platelet depletion experiments or thrombocytosis creation of transfusion in animals have concluded that megakaryopoiesis was subject to regulation at different levels. Factors exerting their proliferative action, especially in the early stages, mitotic have an activity called MK-CSA (megakaryocyte- colony stimulating activity) directly stimulated megakaryocytic depletion. Further, conversely, to delayed action, would act in the maturation phase; by analogy with the regulation erythrocyte this activity is called “thrombopoietin”.
• stimulating factors The physiological regulator of megakaryocytopoiesis is thrombopoietin (TPO), also called ligand Mpl receptor (Mpl-L) or growth factor and development of megakaryocytes (MGDF) (megakaryocyte, growth and development factor). Mpl receptor of this growth factor was first described. It is expressed primarily on the surface of cells of the platelet lineage mégacaryocyto- and early hematopoietic progenitors. Thrombopoietin plays a direct role in the proliferation, ploïdisation and terminal differentiation of megakaryocytes from stem cells. It therefore has activity both MK-CSA and TPO. In addition to its essential effect on megakaryocytopoiesis, thrombopoietin has a modulating action on the proliferation of the progenitors of the various hematopoietic lineages. The level of physiological secretion thrombopoietin appears fixed and circulating blood levels seems determined by what remains after its absorption at the surface of platelets. The in vitro and in vivo humoral regulation Megakaryocytopoiesis has also highlighted the challenging role of hematopoietic growth factors, none of which is specific to the megakaryocytic lineage. We distinguish three categories:
– A cytokine acting as a powerful synergistic factor in the formation of megakaryocytic colonies but did not influence in isolation: the stem cell factor (SCF), which acts in particular in vitro synergy with IL-3 and GM-CSF;
– Several cytokines can induce the proliferation of megakaryocytic progenitors and the formation of megakaryocytic colonies IL3, GM-CSF;
– Finally, cytokines acting at the post-mitotic phase and playing a role in megakaryocytic maturation. It is essentially IL6 and incidentally cytokines of the same family, including the IL11. The IL6 is the most powerful factor stimulating the hepatic synthesis of CRP (C-reactive protein). Other cytokines generally act on megakaryopoiesis as erythropoietin;IL1 whose action is indirectly inducing the production of IL6, GM CSF and SCF and fibroblast growth factor (bFGF) whose receptor is present on the surface of megakaryocytes.
• inhibitors Factors Recently, it has emphasized the role of inhibitors of megakaryopoiesis contained in circulating platelets and may play a role in the feedback of platelet production. This is for example platelet factor 4 (PF4) and TGFb, the inhibitory effect is exerted on all myeloid lineages and not exclusively on the mégacaryocyto-platelet lineage.
• Determination of thrombopoietin One would have thought that the dosage of thrombopoietin would establish a pathophysiological opposition between primitive and secondary thrombocytosis. In the current state of the dosing thrombopoietin, we never found a significant association between circulating levels of thrombopoietin and numbers of platelets, whether normal or secondary hyerplaquettose individuals. Even more, perhaps for the reasons stated above (fixed secretion and absorption of thrombopoietin on platelets), it seems that the primary thrombocytoses, at least those of essential thrombocythemia and polycythemia vera, do not cause no significant decrease in circulating thrombopoietin rate witnessed a feedback (feed back) on the contrary. The role of a decrease in the thrombopoietin receptor in these conditions is a hypothesis that has been advanced to the origin of this finding.
2 / Positive Case for diagnosis of essential thrombocythemia:
Besides the characteristic appearance of the bone marrow biopsy described above, two diagnostic methods are currently being evaluated to make positive arguments for the diagnosis of essential thrombocythemia:
– The culture of hematopoietic progenitors may bring direct positive arguments for the diagnosis of primary thrombocytosis; the image of the spontaneous growth of erythroid progenitors in the absence of erythropoietin in polycythemia vera, was highlighted in essential thrombocythemia spontaneous growth of megakaryocytic progenitors in the absence of stimulating factors; this spontaneous pushes lack in secondary thrombocytoses;
– Looking for arguments in favor of monoclonality hematopoiesis is based on the study of polymorphism of different genes related to X; by definition it is applicable only in the female population; the combination of genes it is now possible to study (Humara, G6PD, IDS and P55) has dramatically expand the percentage of women informative, that is to say having a heterozygous for one of the genes studied. One difficulty is the existence in the normal female population of apparent excessive lyonization monoclonality related phenomenon. This pitfall can be avoided by studying separately circulating granular elements and T cells as witnesses to the polyclonality residual normal hematologic cell population. This study finds its main application especially in young women because of possible monoclonality acquired without proof of myeloproliferative disorder of some older women.
