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Rbc count in polycythemia vera: 10 High Red Blood Cell Count (Polycythemia) Symptoms & Treatment

Polycythemia Vera – Hematology and Oncology

  • Complete blood count (CBC)

  • Testing for JAK2, CALR, or LNK mutations (done sequentially)

  • Sometimes bone marrow examination and serum erythropoietin level

  • Sometimes RBC mass determination

Polycythemia vera is often first suspected because of an abnormal CBC (eg, hemoglobin > 16.5 g/dL [> 165 g/L] in men or >16.0 g/dL [> 160 g/L] in women). However, hemoglobin and hematocrit levels may be misleading. The hematocrit may be normal because of plasma volume expansion, and the hemoglobin may be normal if there is concurrent iron deficiency. Thus, an elevated red cell count is the most useful measure of erythrocytosis. Along with erythrocytosis, the neutrophil and platelet counts are usually, but not invariably, increased. In patients with only an elevated hematocrit, polycythemia vera may be present, but secondary erythrocytosis Secondary Erythrocytosis Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin… read more , a more common cause of elevated hematocrit, must be considered first. Polycythemia vera should always be considered in patients with a normal hematocrit but microcytic erythrocytosis and evidence of iron deficiency Diagnosis Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific… read more ; this combination of findings is a hallmark of polycythemia vera.

Polycythemia vera may also be suspected based on clinical findings, including thrombosis in an unusual site, such as Budd-Chiari syndrome in women or portal vein thrombosis in men.

The challenge in diagnosing polycythemia vera is that several other myeloproliferative neoplasms can have the same genetic mutations and bone marrow findings. Although the hallmark of polycythemia vera is erythrocytosis, some patients present with isolated leukocytosis or isolated thrombocytosis and do not initially manifest an elevated hematocrit level. Thus, multiple findings must be integrated.

Patients suspected of having polycythemia vera typically should have testing for JAK2V617F (exon 14) and JAK2 exon12 mutations. If these results are negative, testing for CALR and LNK mutations is done. The presence of a known causative mutation in a patient with clear erythrocytosis is strongly suggestive of polycythemia vera. If erythrocytosis is not clearly present, direct measurement of red cell mass and plasma volume (eg, with chromium-labeled RBCs, although this test is usually available only at specialized centers) is done to help differentiate between true and relative polycythemia and between polycythemia vera and other myeloproliferative disorders (which do not have an increased red cell mass). If erythrocytosis is present but secondary causes have not been excluded, serum erythropoietin level should be measured; patients with polycythemia vera typically have low or low-normal serum erythropoietin levels; elevated levels suggest secondary erythrocytosis.

Bone marrow examination is not diagnostic of polycythemia vera. When done, bone marrow examination typically shows panmyelosis, large and clumped megakaryocytes, and sometimes an increase in reticulin fibers. However, no bone marrow findings absolutely differentiate polycythemia vera from other disorders of excessive erythrocytosis (eg, congenital familial polycythemia) or from other myeloproliferative neoplasms, of which polycythemia vera is the most common.

Nonspecific laboratory abnormalities that may occur in polycythemia vera include elevated vitamin B12 and B12-binding capacity, hyperuricemia and hyperuricosuria (present in ≥ 80% of patients), and decreased expression of MPL (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.

The World Health Organization diagnostic guidelines are based on hemoglobin and hematocrit levels and red cell mass determination, but are limited because they ignore leukocytosis, thrombocytosis, and splenomegaly.

Time for revival of the red blood cell count and red cell mass in the differential diagnosis between essential thrombocythemia and polycythemia vera?

Haematologica. 2019 Nov; 104(11): 2119–2125.

Department of Hematology, Zealand University Hospital, Roskilde, Denmark

Red blood cell indices, red blood cell mass and bone marrow biopsy in the differential diagnosis between essential thrombocythemia and polycythemia vera?

The correct diagnostic classification of the Philadelphia-negative chronic myeloproliferative neoplasms (MPN) in the three subcategories, essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), relies upon diagnostic criteria that aim at minimizing misclassification. 1 Several reports have addressed the issue that JAK2V617F positive “ET” patients are frequently misclassified since they actually have a diagnosis of PV.28 This misclassification is partly based upon the use of the hemoglobin (Hb) concentration as a surrogate marker for the red cell mass (RCM), irrespective of the fact that the Hb concentration is influenced by iron deficiency, which is prevalent in PV patients. Indeed, these concerns have been addressed and confirmed in several studies showing that a high proportion of ET patients (approx. 45-65%) did not meet the World Health Organization (WHO) diagnostic criterion of an elevated Hb, despite an increased Cr-51 RCM.57 However, despite the convincing data published in 2005 by Johansson et al.,5 these concerns were not translated into the revised 2007 WHO diagnostic recommendations. These recommendations, therefore, remained unchanged9 and were addressed and met by alternative diagnostic approaches in ET, PV and PMF patients. 2 In their 2013 study,3 Silver et al. for the first time prospectively evaluated the accuracy of the 2007 WHO criteria for diagnosing PV, especially in “early-stage” patients. This and other studies support the latest updated WHO criteria (2016) for diagnosing MPN,1,9 which included these novel data with regard to the inaccuracy of the Hb-concentration, and even the hematocrit (HCT), in the differential diagnosis between ET and PV patients by lowering the Hb/HCT thresholds (> 16.5 g/dL/0.49 in men and > 16 g/dL/0.48 in women).1 Thus, the 2013 Silver study in a prospective setting and with a median 5-year follow up time convincingly demonstrated that the surrogate markers Hb and HCT are inadequate in the assessment of an increased RCM for early PV cases, since 64.3%, 28.5%, and 28.5% of their patients would not have been diagnosed as PV using Hb, HCT, and either Hb or HCT values, respectively. 3 Importantly, of the 28 patients with an increased RCM in their study, 18 did not meet the WHO 2007 criteria for an increased Hb value. For the four women, the median Hb count was 15.2 g/dL (range: 14.4-16.4 g/dL) and for the 14 men 17.2 g/dL (range: 15.6-18.1 g/dL), respectively. Similarly, eight patients (1 woman and 7 men) did not meet the WHO criteria for an increased HCT value, being 44.3% for the woman, and for the seven men the median HCT was 48.5% (range: 45.7-49.4 %).3 Silver et al. also highlighted the value of bone marrow (BM) morphology3 as emphasized in the WHO classification. Accordingly, this study supported previous reports by Johansson et al.,5 Cassinat et al.,6 and Alvarez-Larran et al.7 which all revived ancient knowledge, written by the Polycythemia Vera Study Group (PVSG), and underscoring the inaccuracy of the Hb and the HCT values for diagnosing PV and the need for RCM measurement instead. 10 This has since fostered intense debate in several reviews and perspective papers expressing conflicting opinions. On the one hand, some authors believe that only RCM measurements can reliably distinguish PV from other MPN,24,11 while others would disregard RCM measurements,1215 arguing that Hb/HCT thresholds should be used as surrogate markers for RCM measurements. This lively debate has recently been further fueled by a comprehensive and scholarly review on MPN, emphasizing the urgent need for RCM investigations to distinguish PV from other MPN,16 adding that BM morphology has no place in the distinction of PV from other MPN subtypes.16 Others have highlighted the importance of BM morphology in PV and its usefulness in distinguishing between ET and PV.3,1721 A very recent study has established a clear-cut distinction between ET and PV, and, therefore, also the reproducibility of BM morphology in so-called masked polycythemia vera (mPV) and its differentiation from ET. 21 The disease entity mPV will be further addressed below.

Do the revised and lowered thresholds for Hb/HCT levels unmask undiagnosed PV patients in the general population when “potential PV patients” are being referred?

In 2014, the issue as to which of the three red cell parameters, Hb, HCT or RCM, to use as the diagnostic hallmark of PV was thoroughly reviewed by Barbui et al. They also critically addressed the validity and applicability of the three major diagnostic classification systems for PV as proposed by the PVSG, the British Committee for Standards in Hematology (BCSH), and the WHO.13 It was suggested either to reduce the thresholds for the Hb-concentration, or to include the HCT as a major diagnostic criterion in association with the JAK2V617F mutation. In this review, the existence of prodromal (latent PV-disease), named “masked” PV and defined by Barbui et al.,13 was also addressed, covering patients not meeting the required Hb or HCT threshold levels as defined in the WHO and BCSH criteria. 22,23 With regards to the impact of lowering the Hb and the HCT thresholds for PV, influenced by the above studies,3,58,22,23 the 2016 revised WHO criteria have not resolved the conflicting opinions,24,25 as recently addressed and discussed in depth.26,27 However, very interestingly, applying the lower Hb thresholds as reported by the WHO 2016 criteria in the Canadian population, Ethier et al. found an Hb value at or above the threshold in 4.1% of all complete blood counts from unselected males and in 0.35% of females. These figures increased the incidence of “potential PV patients” by up to 12-fold in males and 3-fold in females. The same pattern was demonstrated when including the neutrophil and platelet count, implying that up to 60 times more males and three times more women would be suspected of suffering from MPN and would accordingly require diagnostic investigations. 24 According to the screening procedure in clinical practice as described by Rumi and Cazzola,25 the best compromise between the need for an early diagnosis of PV patients and the risk of excessively expanding the number of potential PV patients would be a threshold of 17 g/dL in men. Applying this Hb cut-off value, Barbui et al. found that 14% of their 375 patients presenting with WHO-defined PV did not meet the 2016 criteria.26 In the context of screening procedures in clinical practice and which blood cell counts to use, according to the Canadian data, the Hb/HCT thresholds as defined in the 2016 WHO criteria will markedly increase the number of individuals with suspected PV in the general population.24 Given this, it is important to note that a very recent Danish study has found MPN to be massively underdiagnosed with an estimate of 10,000 undiagnosed MPN in Denmark, corresponding to approximately 550,000 US citizens having an undiagnosed MPN and accordingly being at a considerable risk of thrombosis. 28 In this perspective, it might be much more cost-effective to screen high-risk MPN individuals and obtain a diagnosis earlier rather than later when the individual has already suffered one or more potentially life-invalidating thrombotic events before being diagnosed with ET or PV.28

Consequences of misclassification of PV as ET

There are several consequences of misclassifying PV patients as ET.

  1. Misclassification of JAK2V617F positive ET patients as ET instead of PV implies that these patients are not phlebotomized and are, therefore, exposed to an increased risk of potentially life-invalidating or life-threatening thrombotic complications due to the increased RCM. This is not a trivial risk, in particular in those patients aged <60 years without a prior thrombosis but with leukocytosis and platelet counts < 1500 × 109/L since these patients are categorized as “low-risk” according to international guidelines and are not offered cytoreductive treatment, irrespective of the fact that both leukocytes and platelets are deeply involved in the development of atherothrombosis,2933 the JAK2V617F mutation promotes atherothrombosis, being associated with e. g. transitory cerebral ischemia, completed stroke and ischemic heart disease, and leukocytosis per se is considered a risk factor for thrombosis in the background population,34 and a causative factor for thrombosis in ET and PV patients.35 Importantly, the most recent studies, including a meta analysis study, have provided evidence that leukocytosis is a risk factor for thrombosis in the MPN-population as well.36,37

  2. Misclassifying JAK2V617F positive “ET” patients as “ET” instead of PV has a huge impact on any prognostic model that compares the prognosis of ET and PV patients, the potential outcome being that JAK2V617F positive ET patients have an inferior prognosis as compared to those who are JAK2V617F negative or CALR-positive.38 In several published studies these differences might be explained by the fact that PV patients not being phlebotomized have been included in the ET-cohorts. This may also hold true for mPV patients who have an increased risk of thrombosis (young patients)39 and poorer survival than PV patients. This is likely explained by the fact that several mPV patients have not been phlebotomized despite an expanded RCM.

  3. Results from studies on safety and efficacy of any drug, both those conventionally used [e.g. hydroxyurea (HU), interferon-α2 (IFN) and anagrelide] and novel agents such as ruxolitinib or experimental drugs (in clinical trials for future approval for the indication of ET or PV) may be severely undermined, impossible to interpret, and therefore not credible.

  4. Building future therapeutic recommendations and prognostic models on a diagnostic platform that does not take into account the true nature of a disease (e.g. a higher rate of thrombosis in PV than ET, a higher rate of transformation to myelofibrosis and acute myelogenous leukemia in PV than in ET, a reduced life expectancy in PV as compared to ET) due to diagnostic misclassification undermines our current understanding and concepts on MPN in highly important issues. These include pathogenetic mechanisms for disease evolution both in terms of molecular phenotypes, clinical phenotypes and associations between them, diagnostic classification in the biological continuum from early cancer stages (ET, PV) to the advanced myelofibrosis stage, and, not least, when and how to treat MPN. The cornerstone treatment of PV is phlebotomies, carried out to alleviate the hyperviscosity state due to an expanded RCM and thereby to reduce the risk of the deadly thrombosis seen in median survival figures for PV patients of 18 months without such treatment. This approach may, however, be misguided by using only the Hb concentration and the HCT as these are profoundly influenced by the iron-deficient state in patients with PV and also in JAK2V617F positive ET patients in whom erythropoietin (Epo) and ferritin levels and the mean corpuscular volume (MCV) values have been repeatedly reported to be lower than in JAK2V617F negative ET patients.40

  5. Without an estimation of RCM and plasma volume in the diagnostic setting of JAK2V617F positive ET and PV, the transitional stage between ET and PV may be wrongly described as a new disease entity within MPN. 22 Thus, it is tempting to speculate whether the “novel” disease entity (mPV) would ever have been born, if arguing that a large proportion of these mPV patients are only “masked” as long as RCM is not being estimated. As discussed above, reports on masked PV22,23 were influential in lowering the Hb/HCT thresholds in the 2016 WHO classification of MPN.1,27 This was defined as a new JAK2V617F-positive entity with a phenotype mimicking ET (isolated thrombocytosis) but, as in PV, associated to endogenous erythroid colony formation (EEC) or the BM features of PV, which had previously been described as latent or inapparent PV.41,42 The revised WHO 2016 classification was, among others, based upon the mPV studies, which defined threshold values as optimal cut-off levels for distinguishing JAK2V617F ET from mPV (Hb 16.5 g/dL/HCT 0.49 in men and 16 g/dL/HCT 48 % in women, respectively)43 and were subsequently validated in larger cohort studies. 15,44

Very recently, the notion that mPV may not be a novel disease entity but has emerged consequent to the inaccuracy of diagnosing PV in the absence of an estimation of RCM has been supported by a large French single center study of 2,480 RCM estimations in patients with JAK2V617F positive ET, “masked PV”, and PV.45 This study showed that patients with mPV actually have an increased RCM and are, therefore, easily “unmasked and revealed to be true PV once RCM is estimated.45 Thus, these mPV patients share clinical and biological features with both ET and PV, with a median age, platelet, Hb and leukocyte levels comparable to those of ET patients, and at the same time classic PV features, (which, in addition to the increased RCM, also include lower Epo level and lower MCV), and have splenomegaly more frequently than ET patients.45 Accordingly, patients being described as mPV nicely present a picture of a diagnosis of MPN as a moving target that is highly dependent on the time point for diagnosis in the biological continuum from early JAK2V617F positive ET to overt PV.

The mPV story underscores the urgent need for a renaissance of the RCM and plasma volume assessment in these patients, since otherwise JAK2V617F positive “ET” patients and mPV patients will not receive adequate treatment by phlebotomies and so will obviously also have an increased risk of thrombosis.38,39 The French and other studies, including those pioneered by Silver and Spivak, also put into perspective the view that it is indeed possible to incorporate RCM estimations into ‘good clinical practice’ in the differential diagnosis between JAK2V617F positive ET and PV.28,16,45 However, as noted above, there are still conflicting opinions as to the need for RCM measurements in distinguishing between patients with JAK2V617F positive ET, mPV and overt PV.24,1115 Of note, a very recent study showed that when applying the 2016 WHO criteria, increased RCM was significantly associated with increased Hb/HCT (93. 8%/94.6%),15 thus supporting the 2016 WHO criteria for PV, implying Hb/HCT values should be used as surrogate markers for RCM measurements.15 In this study, the importance of BM morphology for a diagnosis of PV was also highlighted.15

Red blood cell count as a surrogate marker for red cell mass?

Recently, Michiels et al. underscored the importance of RBC count in addition to a BM biopsy as a powerful tool to differentiate between ET and PV.8 In their study, the diagnostic value of RCM in relation to RBC count, Hb and HCT in discriminating between JAK2V617F ET and PV was assessed. The best correlation was found between RBC count and RCM. Thus, at RCM above 30 mL/kg the RBC count was above 5.8×1012/L, and this diagnosed PV in all their patients. All JAK2V617F ET patients had a normal RCM and a RBC count below 5.8×1012/L. It was concluded that a RBC count within the normal range (< 5. 8×1012/L in males and < 5.6×1012/L in females) enables JAK2V617F ET to be distinguished from prodromal PV and overt PV. Thus, they also concluded that the RBC count and a BM biopsy might obviate the need for RCM measurement.8

Are hemoglobin and hematocrit values imperfect surrogate markers for red cell mass?

In this issue of Haematologica, Silver et al. convincingly confirm the urgent need to investigate JAK2V617F positive ET patients using RCM estimations,46 repeating the important message that a normal Hb or HCT value does not signify a normal RCM in MPN.28,10,11,16 Based upon JAK2V617F positivity, chromium-51 RCM, and BM biopsy morphology, 83 and 39 patients were diagnosed with PV and ET, respectively. Chromium-51 RCM separated PV from ET JAK2V617F, whereas red cell values (Hb, HCT, RBC count) overlapped in 25. 0-54.7%. The authors concluded that a significant proportion of PV patients may be underdiagnosed by using only red cell values. Of note, using ROC analyses, the authors found threshold values for the Hb HCT coincidentally similar to the WHO 2016 criteria. Furthermore, it was concluded that (without isotope studies) BM biopsies and serum erythropoietin values should become mandatory since they improve diagnostic accuracy. In this perspective, the paper by Silver et al. is highly relevant and timely. It carries a novel approach into the future and will hopefully promote an optimal classification of MPN by a renaissance of the use of RCM estimations (the “gold standard” for discriminating JAK2V617F ET from PV) as a highly important tool to ensure a correct diagnostic classification of MPN. This will be a major scientific step forward in improving good clinical practice in MPN patients. It will reintroduce RCM and plasma volume estimations as essential for correct diagnostic classification of MPN, at least in JAK2V617F positive “ET” patients. In patients with huge splenomegaly but still a low normal or even lowered HCT, in the transitional stages between PV and post-polycythemic myelofibrosis, a RCM estimation may reveal the true nature of the disease as PV and accordingly a need for phlebotomies due to an expanded RCM in patients who still present a normal Hb-concentration and normal HCT consequent to hemodilution due to an expanded plasma volume. As previously noted, RCM estimation in JAK2V617F positive ET patients will likely reduce the risk of thrombosis in a substantial proportion of “ET” patients since they will be correctly classified as PV and will, therefore, receive treatment with phlebotomies. Additionally, these patients will then also have the opportunity to be treated with IFN in cases in which the institution does not include ET patients as an indication for being treated with IFN but does so if the patient has PV. This will be even more important when the new IFN-drug, ropeginterferon α-2b, has been licensed for use in newly diagnosed PV in Europe, and hopefully soon in the US as well. 47 Based upon the above considerations, the paper by Silver et al. is also of utmost importance since by diagnosing many more JAK2V617F ET patients correctly as PV, their findings may offer more patients the opportunity to be treated with IFN, which is the only agent that has shown to be disease modifying. In fact, in a subset of patients with early MPN disease (ET and PV), after approximately five years of IFN therapy it was seen that this approach may induce minimal residual disease (MRD), with normal cell counts, normal spleen size, a normal BM, and no detectable JAK2V617F mutation, representing an MRD stage that may even be sustained after interrupting IFN for up to three years.48

Considering the findings by Silver et al. and Michiels et al., in some of their previous papers the RBC count is the most valuable parameter and is better than Hb-concentration and hematocrit when considering the equation: HCT= RBC count x MCV, and taking into account that several PV patients have lowered MCV which accordingly lowers the HCT and wrongly dictates that a phlebotomy is not needed, irrespective of the fact that the RBC count is increased49 (). In this context, it is also important to note that erythrocytosis in PV usually induces plasma volume expansion4,16,50 which may mask the true HCT, implying that the HCT in many PV patients, especially women, appears to be normal.2,4,16,41,50

Association between the hemoglobin (Hb)-concentration, hematocrit, red blood cell (RBC) count and mean corpuscular volume (MCV) values in a 76-year old woman with polycythemia vera. The Figure illustrates that: (i) the RBC count is a a more accurate indicator of erythrocytosis than the Hb-concentration and the hematocrit; (ii) that this dissociation is consequent to iron deficiency as evidenced by a lowered MCV; and (iii) the hyperviscosity state due to the raised RBC count is reflected in a low erythrocyte sedimentation rate (SR) (< 1 or 2 mm/h) (normal range: 2-20 mm/h). The need for phlebotomies in this patient was monitored by the elevated RBC count and the lowered SR, and tightly associated with the emergence of headache, which immediately resolved after phlebotomy.

These considerations are not only relevant at the time of diagnosis but also during the course of PV when several patients may not be phlebotomized when only using HCT and elevated RBC count is not taken into consideration (). On the contrary, hydroxyurea (HU)-treated patients may be unnecessarily phlebotomized due to an HU-induced increase in MCV and accordingly also an increase in the HCT, although the RBC count is normal.

Hopefully, based upon previous reports on the need of the RCM in the diagnosis of MPN,27,10,11,16,49,50 and the most recent studies by Silver et al. and the French study discussed above, consideration of the RCM will be revived at many more MPN centers worldwide. Such efforts are not only expected to improve quality of life of the large proportion of undiagnosed PV patients amongst JAK2V617F positive ET patients, but likely prognosis as well, since they will be correctly diagnosed as PV and accordingly receive the cornerstone treatment of PV (phlebotomy) to reduce the HCT <0. 42 in women and <0.45 in men.24,11,16,5053

The important distinction between different HCT levels for women and men when deciding the need for phlebotomies has been addressed in several papers.2,4,16,5053 The rationales for this distinction are several and obvious, including the simple fact that women and men have different red blood cell volumes as reflected in different ranges for red cell indices. This common knowledge dictates that a woman’s normal RCM is approximately 600 mL lower than that for men.4,53 Accordingly, a female patient with a hematocrit of 45% has at least an excess of approximately 600 mL blood4 which associates with an increased risk of major thrombosis.54 Indeed, the study by Marchioli et al. clearly showed that allowing HCT between 0. 45 and 0.50 is associated with a significant risk of death from cardiovascular causes or major thrombotic events54 also in the general population.55 These are lessons that we learnt from Pearson 30 years ago51,52 and which have been repeated since then in several other studies: an elevated HCT is associated with an increased risk of thrombosis. In fact, in the general population the risk of thrombosis at elevated HCT values has previously been reported to be driven by smoking,56 which has recently been associated with an increased risk of MPN.57

The excess blood volume is even larger in PV-patients with hepatic vein thrombosis,16 who often have a normal HCT due to an expanded plasma volume.4 Importantly, the thrombosis risk in JAK2V617F positive “ET” patients will likely be markedly reduced simply due to normalization of the expanded RCM by phlebotomies. Additionally, without a RCM estimation, some patients with JAK2V617F positive “ET” may be erroneously classified as “early prefibrotic myelofibrosis” while actually having undiagnosed PV for several years and then being referred with an enlarged spleen, a normal Hb-concentration and a normal HCT, red cell values that are in the normal range due to hemodilution consequent to the expanded plasma volume associated with the enlarged spleen. Accordingly, in such patients, a RCM estimation may reveal an expanded RCM requiring phlebotomies to omit thrombotic complications, often at unusual sites such as portal thrombosis, mesenteric thrombosis and thrombosis of hepatic veins.58 Indeed, similar to mPV as a transitional stage in the biological continuum from ET to overt PV, one might speculate as to whether a proportion of JAK2V617F positive patients with a normal Hb/HCT and splenomegaly classified as “early prefibrotic myelofibrosis” may actually have PV with an expanded RCM and expanded plasma volume in a transitional stage towards classic myelofibrosis.

Today, we still need to go over the important lessons from the history of MPN. Back in 1908, Osler taught us that the RBC count is superior to the Hb concentration as an indicator of erythrocytosis.2,4,16,50,59,60 This should, therefore, be used in the diagnosis of PV, and the lesson from the PV study group and from several authorities thereafter is that the RCM is “the gold standard” for an accurate diagnosis of PV in patients with mPV and its precursor stage: JAK2V617F positive ET.28,16 In the paper by Silver et al. in this issue of Haematologica and in other papers, the importance of these lessons have been repeatedly highlighted. These will hopefully stimulate research into MPN towards additional comparative and correlative studies on the value of RCM estimations, the RBC count, and BM morphology in the diagnosis of MPN. Such studies are even more urgent taking into consideration a most recent review challenging and critically discussing the role of the hematocrit as a determinant risk factor for thrombosis in erythrocytosis. 61 It is to be hoped that such studies may promote a consensus amongst MPN experts that the RCM is essential for a correct classification of JAK2V617F positive ET patients, mPV and PV patients.

This will ensure timely treatment with phlebotomies in those patients who otherwise will be classified as ET and who would then carry an increased risk of potentially life-threatening or life-invalidating thrombotic complications. Future studies should also address whether the RBC count in addition to the erythrocyte SR may be simple but highly robust and reproducible indicators of an increased RCM and the hyperviscosity state, respectively, to be used in the diagnosis of PV and when monitoring PV patients for the need for phlebotomy.62


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What is the role of blood count studies in the diagnosis of polycythemia vera (PV)?

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  • High Red Blood Cell Count: Causes & Symptoms


    What is high red blood cell count?

    Red blood cells are one of the major components of blood, along with white blood cells and platelets. Red blood cells help carry oxygen throughout the body.

    Doctors measure your red blood cell count to help diagnose medical conditions and learn more about your health. A high red blood cell count means the number of red blood cells in your bloodstream is higher than normal. Normal red blood cell counts are:

    • For men, 4.7 to 6.1 million red blood cells per microliter of blood
    • For women, 4.2 to 5.4 million red blood cells per microliter of blood
    • For children, 4.0 to 5.5 million red blood cells per microliter of blood

    Doctors typically find a high red blood cell count during tests for another health issue. You may need more tests to determine what’s causing the higher levels. These may include tests to look for conditions that cause your body to produce too many red blood cells, such as heart failure, or disorders that restrict your oxygen supply, such as sleep apnea.

    Possible Causes

    What causes a high red blood cell count?

    A high red blood cell count may be a symptom of a disease or disorder, although it doesn’t always indicate a health problem. Health or lifestyle factors can cause a high red blood cell count.

    Medical conditions that can cause an increase in red blood cells include:

    Lifestyle factors that can cause a high red blood cell count include:

    • Smoking cigarettes
    • Living at a high altitude
    • Taking performance-enhancing drugs such as anabolic steroids (for example, synthetic testosterone) or erythropoietin

    Care and Treatment

    How is a high red blood cell count treated?

    If a medical condition is causing a high red blood cell count, your doctor may recommend a procedure or medication to lower it.

    In a procedure called a phlebotomy, a health professional inserts a needle into your vein and drains blood through a tube into a bag or container. You might need to have this procedure on a repeated basis until your red blood cell level is close to normal.

    If you are diagnosed with the bone marrow disease polycythemia vera, your doctor may also prescribe a medicine called hydroxyurea to slow your body’s production of red blood cells. You’ll need to see your doctor regularly while taking hydroxyurea to be sure your red blood cell level does not drop too low.

    POLYCYTHEMIA VERA (PV) – MPN Research Foundation

    What Are the Available Treatments for PV?

    Many of the treatment options for PV are designed to manage the disease by returning hematocrit levels to normal values. However, the circumstances are different for every PV patient and asymptomatic patients may not require treatment for extended periods of time. Routine monitoring by a physician is recommended for all PV patients, regardless of symptoms.

    When treatment is required, common treatment options for PV include:

    Phlebotomy is the removal of blood to reduce the number of blood cells. With fewer blood cells, the blood is thinner and flows more easily, improving symptoms and reducing the risk for blood clotting. This procedure is typically done to meet target blood count goals that are determined by the physician, taking into consideration the patient’s sex and other factors. 

    Low-Dose Aspirin
    Most, if not all PV sufferers are prescribed a low-dose aspirin treatment. Since aspirin prevents platelets from sticking together, it reduces the occurrence of blood clots that can cause life-threatening heart attacks or strokes.

    Combined with low-dose aspiring, the regular maintenance of a hematocrit below .45 for men and .42 for women is currently accepted as a non-leukomegenic approach and a first choice treatment for recently diagnosed, low-risk PV patients.

    If phlebotomy and low-dose aspirin are not effective or appropriate, or if a patient is consider higher risk for blood clotting, physicians may prescribe medicine to lower red blood count and relieve symptoms, including:

    Hydroxyurea is often prescribed for PV patients at high risk for blood clots, based on age and prior history of blood clotting.

    Jakafi (ruxolitinib)
    Jakafi is the first FDA-approved treatment for PV patients who have an inadequate response to or cannot tolerate hydroxyurea. Jakafi inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. It also helps decrease the occurrence of an enlarged spleen (splenomegaly) and the need for phlebotomy. Patients do not need to be JAK2 positive to take Jakafi, though the great majority with PV harbor this mutation.

    Some PV patients have experienced anemia with or without splenomegaly while on Jakafi. Please discuss in depth with your doctor upon making any treatment decisions. 

    Pegylated Interferon
    Younger patients who require treatment and women of childbearing age are often treated with pegylated interferon because it has not been shown to cause birth defects. Since Pegasys was developed for Hepatitis C and not MPN, it is considered an “off-label” medication. There are several clinical trials currently being conducted to evaluate Pegasys in people with MPNs.

    It’s Time to Change Your PV Prognosis

    The MPN Research Foundation is committed to providing education and support to PV patients and their families. In the fight against PV, information is power. Sign up to receive news and updates about the latest PV treatment options and other resources to change your PV prognosis.

    Symptoms, Causes, Diagnosis, and Treatment

    SPEAKER: Sure, the smell

    of bacon in the morning

    is great and all.

    But nothing beats coffee.

    But is it good for you?

    Well, let’s get to the truth

    about coffee.

    Can you get addicted to coffee?


    Now, if you’ve been hopped up

    on caffeine for years,

    and one day you suddenly switch

    to decaf, your head’s

    going to hurt.

    But the withdrawal is only


    And most experts don’t think

    caffeine addiction is

    a big problem.

    It’s not like you’re going

    to need rehab.

    Does decaf mean it has

    no caffeine?

    Not quite.

    A regular cup of coffee

    has around 130 milligrams

    of caffeine.

    A cup of decaf has about five


    That’s about the same amount

    as a cup of hot cocoa or half

    of a bar of chocolate.

    Should I ever cut back

    on coffee?


    If you have osteoporosis,

    keep your intake to three cups

    a day.

    And cut out the caffeine if you

    have insomnia.

    Also, while caffeine can get rid

    of headaches, bigger coffee

    drinkers have a bigger chance

    of getting migraines.

    So if you drink another cup,

    that relief might only

    be temporary.

    And finally, here

    is the big one.

    Is drinking coffee every day OK?


    It turns out if you drink up

    to three eight-ounce cups

    of coffee every day,

    you actually get a lot of health


    And we’re not talking

    little things.


    Coffee drinkers seem more

    protected against big things

    like diabetes, Alzheimer’s

    disease, Parkinson’s disease,

    liver disease, and gout.

    The truth is, coffee is good.

    So go ahead and fill her up.

    How is Polycythemia Vera Diagnosed?

    Polycythemia vera (PV) may not cause signs or symptoms for years. The disease often is found during routine blood tests done for other reasons. If the results of your blood tests aren’t normal, your doctor may want to do more tests.

    Your doctor will diagnose PV based on your signs and symptoms, your age and overall health, your medical history, a physical exam, and test results.

    During the physical exam, your doctor will look for signs of PV. He or she will check for an enlarged spleen, red skin on your face, and bleeding from your gums.

    If your doctor confirms that you have polycythemia, the next step is to find out whether you have primary polycythemia (polycythemia vera) or secondary polycythemia.

    Your medical history and physical exam may confirm which type of polycythemia you have. If not, you may have tests that check the level of the hormone erythropoietin (EPO) in your blood.

    People who have PV have very low levels of EPO. People who have secondary polycythemia usually have normal or high levels of EPO.

    Specialists Involved

    If your primary care doctor thinks you have PV, he or she may refer you to a hematologist. A hematologist is a doctor who specializes in diagnosing and treating blood diseases and conditions.

    Diagnostic Tests

    You may have blood tests to diagnose PV. These tests include a complete blood count (CBC) and other tests, if necessary.

    Complete Blood Count

    Often, the first test used to diagnose PV is a CBC. The CBC measures many parts of your blood.

    This test checks your hemoglobin (HEE-muh-glow-bin) and hematocrit (hee-MAT-oh-crit) levels. Hemoglobin is an iron-rich protein that helps red blood cells carry oxygen from the lungs to the rest of the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A high level of hemoglobin or hematocrit may be a sign of PV.

    The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results may be a sign of PV, a blood disorder, an infection, or another condition.

    In addition to high red blood cell counts, people who have PV also may have high white blood cell and/or platelet counts.

    Other Blood Tests

    Blood smear. For this test, a small sample of blood is drawn from a vein, usually in your arm. The blood sample is examined under a microscope.

    A blood smear can show whether you have a higher than normal number of red blood cells. The test also can show abnormal blood cells that are linked to myelofibrosis and other conditions related to PV.

    Erythropoietin level. This blood test measures the level of EPO in your blood. EPO is a hormone that prompts your bone marrow to make new blood cells. People who have PV have very low levels of EPO. People who have secondary polycythemia usually have normal or high levels of EPO.

    Bone Marrow Tests

    Bone marrow tests can show whether your bone marrow is healthy. These tests also show whether your bone marrow is making normal amounts of blood cells.

    The two bone marrow tests are aspiration (as-pi-RA-shun) and biopsy. For aspiration, your doctor removes a small amount of fluid bone marrow through a needle. For a biopsy, your doctor removes a small amount of bone marrow tissue through a larger needle. The samples are then examined under a microscope.

    If the tests show that your bone marrow is making too many blood cells, it may be a sign that you have PV.


    Polycythemia is a chronic disease in which the bone marrow produces an excess of red blood cells. Many patients also have an increase in the number of platelets and leukocytes in the blood. As a result, the blood becomes thicker, more viscous, blood flow in small vessels is disturbed and the likelihood of blood clots – blood clots that clog the lumen of blood vessels and disrupt the blood supply to organs – increases.

    Polycythemia vera is rare and develops slowly.Most often it occurs in people over 40-50 years old, but there are isolated cases in younger people and even in children. In the initial stages, it is asymptomatic, therefore it is often diagnosed by chance, during an examination associated with another disease.

    Polycythemia can be life threatening if left untreated. However, modern approaches to therapy allow achieving very good results: patients get rid of most of the negative manifestations of the disease.

    Synonyms Russian

    Polycythemia vera, polycythemia vera, polycythemia primary, erythremia, Vakez disease, Osler-Vakez disease.

    English synonyms

    Erythremia, Osler-Vaquez Disease, primarypolycythemia, splenomegalicpolycythemia, polycythemiarubravera, erythrocytosismegalosplenica, cryptogenicpolycythemia.


    • Weakness.
    • Shortness of breath.
    • Headaches.
    • Frequent bleeding.
    • Heaviness in the abdomen.
    • Pain in muscles and joints.
    • Skin redness.
    • Itching, especially after taking a warm shower or bath.

    General information about the disease

    All blood cells are formed in the bone marrow from a single blood stem cell. It gives rise to the lymphoid stem cell and the myeloid stem cell. From the lymphoid stem cell, lymphocytes are formed, from the myeloid stem cells – the rest of the types of leukocytes, platelets and erythrocytes.Mature erythrocytes are biconcave cells that do not have a nucleus. The main function of red blood cells is to carry oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs. This function is carried out at the expense of hemoglobin, which occupies most of the red blood cell and gives this cell its characteristic red color. In addition to the respiratory function, erythrocytes are involved in maintaining acid-base balance, and also transfer amino acids, fats, proteins and toxins to their surface. Red blood cells last 120 days and then are destroyed in the liver and spleen.

    Erythropoiesis (formation of erythrocytes) is a complex multistep process, the main regulator of which is the protein erythropoietin. It is produced in the kidneys and partly in the liver, and its amount increases with a decrease in the level of oxygen in the blood (hypoxia). Normally, with hypoxia, the amount of erythropoietin increases, which activates the formation of red blood cells in the bone marrow. However, in polycythemia vera, the level of erythropoietin not only does not increase, but can even be reduced.An increase in the formation of red blood cells is associated with an increase in the sensitivity of bone marrow cells to erythropoietin. The reasons for such changes have not been completely elucidated, however, it is known that in polycythemia vera there are abnormalities in the Janus kinase-2 gene and the EpoR gene, which carry information about the number of erythropoietin receptors and their sensitivity.

    Thus, with polycythemia, an excessive amount of red blood cells is formed, the blood volume increases, it becomes thicker. Disrupted blood flow in small vessels.As a result, blood pressure rises, frequent bleeding occurs, in particular bleeding of the gums. Due to impaired blood circulation, the tips of the fingers, nose, mucous membranes acquire a bluish-red tint. The supply of oxygen to tissues is impaired, which negatively affects the functioning of the whole organism. A change in blood viscosity increases the likelihood of thrombosis – blockage of blood vessels by blood clots, which leads to disruption of organs and tissues. This can manifest itself as a heart attack, stroke.The liver and spleen are enlarged, foci of hematopoiesis appear in them.

    Along with true, primary polycythemia, the cause of which is unknown, secondary polycythemia is isolated, in which an increase in the production of red blood cells is caused by an increased level of erythropoietin in response to a lack of oxygen in the tissues, for example, in chronic bronchitis or heart disease. In this case, polycythemia is only a consequence and disappears with the treatment of the underlying disease.

    Who is at risk?

    • Men.
    • People over 40 years old.
    • Representatives of the Caucasian race.
    • Patients with family history of polycythemia.


    Laboratory diagnostics

    • Complete blood count (without leukocyte count and ESR)
    • Erythrocytes. Their level is usually significantly increased.
    • Leukocytes. Their concentration can be increased mainly due to neutrophils.
    • Platelets.Platelet counts may also be elevated.
    • Hemoglobin is a protein that is part of erythrocytes and is involved in the transfer of oxygen. With polycythemia, it is usually increased.
    • Hematocrit. This is the ratio of red blood cell volume to total blood volume. With polycythemia, it is usually increased.
    • Reticulocytes are immature erythrocytes. They enter the bloodstream from the bone marrow and mature within 2-3 days, turning into mature erythrocytes. With polycythemia, their excess may be observed, which indicates their accelerated formation in the bone marrow.
    • Erythropoietin. In polycythemia vera, it is usually greatly reduced.
    • Vitamin B 12 . Plays an important role in the synthesis of nucleic acids (compounds involved in the storage and transmission of hereditary information) necessary for the formation of red blood cells. An increase in its level with polycythemia indicates the intensity of the formation of red blood cells.
    • Basic blood electrolytes – sodium, potassium, calcium,

    Microcirculatory and hemorheological disorders in patients with polycythemia vera




    14.00.29 – hematology and blood transfusion


    dissertation for the degree of candidate of medical sciences

    Moscow, 2004

    Work performed at the Military Medical Institute of the Federal Border Service of the Russian Federation at the Nizhny Novgorod State Medical Academy

    Scientific advisers Doctor of Medical Sciences, Professor L.G. Kovaleva Doctor of Medical Sciences, Associate Professor V.I. Andryukhin

    Official opponents Doctor of Medical Sciences, Professor N.A.A. Gorbunova Doctor of Medical Sciences, Professor A.K. Golenkov

    Leading scientific institution Russian Cancer Research Center, Russian Academy of Medical Sciences

    Defense will take place “_” _ 2004 at_hour on

    meeting of the dissertation council D 001.042.01. at the State Institution Hematological Research Center of the Russian Academy of Medical Sciences (Moscow, 125167, Novozykovsky proezd, 4 a).

    The dissertation can be found in the library of the State Scientific Center of the Russian Academy of Medical Sciences. The abstract was sent out in 2004.

    Scientific Secretary of the Dissertation Council, Candidate of Biological Sciences, Senior Researcher

    V.D. Reuk

    Urgency of the problem. Patients with polycythemia vera constitute one of the largest groups among patients in hematology clinics. This pathology is based on a defect at the level of a polypotent stem cell with increased production of an abnormal clone with a predominant growth of erythroid progenitor cells [Demidova AV, 1986; Wasserman L.P., 1971; BerkP.D. et all, 1986]. The incidence of the disease is 0.6-1.8 per 100 thousand population [AV Demidova; 1986]. The average age of patients is 40-60 years, young people rarely get sick [Kotsyubinsky NN, Dygin VP, 1979; Melikyan A.L., 1984]. According to the modern concept, polycythemia vera (PI) refers to the group of hematogenous thrombophilia or pre-thrombotic conditions with a threat to the development of both acute and recurrent thrombosis in vessels of various localization and caliber [Barkagan Z.S.,

    An indispensable companion of polycythemia vera is hyper-coagulation syndrome.The latter is a coagulopathy, which is characterized by all clinical and laboratory signs of increased blood coagulation [Vorobiev AI, 1997; Vorobiev A.I. et al., 2001]. Most often, there is thrombosis of peripheral veins of the extremities, cerebral, coronary and, less often, own veins of the liver with the development of Budd-Chiari syndrome [Arkhipov NV. et al., 2002; Barbui T., Finazzi G. 1997; Landofi R. 1998].

    Cytostatic therapy with hydrea and myelosanom allows to achieve remission in 81-95% of patients and contributes to an increase in life expectancy (median survival -8-16 years).It is far from always possible to carry out a complete correction of rheological disorders and associated vascular complications, including thrombosis and bleeding [Kovaleva L.G. et al., 1984, 1989; Wasserman L.P. et all, 1981; Berg P.D. et all, 1986; Barbui T., Finazzi G., 1998]. A rational approach to the treatment of polycythemia vera requires a thorough and multifaceted assessment of clinical manifestations and targeted correction of the identified disorders [Chernukh A.M. et al., 1984; Mikhailova L.G. et al., 1984; Gorbunova N.A. et al., 1989].

    According to modern concepts, peripheral circulation disorders play an important role in the development of the pathological process in polycythemia vera [Kozinets GI, Makarov VA, 1997; Likhovetskaya Z.M. et al., 1989]. We are talking not only about violations of the transport function in the microvasculature, but also about changes in transcapillary metabolism, which represent an interconnected process. It is known that blood flow in the microcirculation system depends both on the vascular tone and on the rheological properties of blood.


    Hemorheological disorders are most often universal in nature, and this determines their important role in the development of a wide variety of pathological conditions, incl. with polycythemia vera [Likhovets-kaya Z.M. et al., 1989; Mchelishvili G.I., 1986].

    A number of works have been devoted to the study of hemorheology and microcirculation in patients with PI. Currently, hemorheology is being enriched with modern methods, which penetrate deeper into the essence of biophysical processes [Bessmeltsev S.S. et al. 1989; Gorbunova N.A. et al., 1989; Gertz M. A., Kyle B. A. 1995]. In this regard, the data obtained earlier need to be clarified from the standpoint of modern rheology. Taking into account the complexity of the whole complex of rheological parameters of blood, it can be assumed that in patients with PV, changes in homeostasis can be multidirectional and some can compensate for others. In this situation, a comprehensive study of these parameters will be of great diagnostic value, i.e. hemorheological profile. It seems relevant to determine the hemorheological profile at different stages of the development of the disease, to identify the role of these disorders in the clinical picture of the disease and to optimize the therapy programs for polycythemia vera with targeted pharmacological regulation of rheological properties on this basis.

    Purpose of the work: determination of microcirculatory and hemorheological parameters in patients with polycythemia vera at various stages of the disease, the role of microcirculation and hemorheological disorders in the clinical course of the disease.

    Research objectives

    1. To study the state of the microvasculature at various stages of polycythemia vera.

    2. Determine the dynamics of changes in blood viscosity depending on the stage of the disease and stages of treatment.

    3.To reveal the degree of aggregation and disaggregation disorders of erythrocytes, their shape and deformability in patients with true polycythemia at various stages of the disease.

    4. To reveal the relationship between the initial data of hemorheology and the lipid spectrum of plasma in patients with polycythemia vera.

    5. Determine the effect of exfusion, disaggregating and cytostatic therapy on the parameters of hemorheology and microcirculation.

    Scientific novelty

    Based on the results of a comprehensive study of hemorheological parameters (using various research methods) and microcirculation, as well as the plasma lipid spectrum in comparison

    with clinical features of the course of the disease, new data were obtained that made it possible to assess the state of the microcirculatory bed, intravascular disorders and viscous-dynamic properties of blood, their relationship and role in the pathogenesis of polycythemia vera.

    The conducted research has revealed new features of hemorheological disorders in patients with polycythemia vera, characteristic of various stages of the disease.

    The dynamics of disorders of hemorheological properties of blood under the influence of various treatment regimens has been studied.

    Practical significance of the work.

    The use of examination methods used in the work for diagnostic purposes allows, based on the results of assessing the parameters of microcirculation and hemorheology, to predict clinical disorders in patients with polycythemia vera.

    The features of rheological and microcirculatory disorders, as well as shifts in the plasma lipid spectrum in patients with polycythemia vera, established in the course of the study, make it possible to expand the diagnostic capabilities, more accurately assess the risk of complications and optimize the treatment of patients.

    The use of the methods used by the author for assessing the state of hemorology allows for targeted correction of the identified disorders, preventing vascular complications and further progression of the disease.

    Implementation in practice

    1. The complex of methods for diagnostics of hemorheological and microcirculatory disorders proposed in the work has been used since 1998 in the city hematology department of the clinical hospital №12 in Nizhny Novgorod when examining patients with true polycytemia and other hematological malignancies.

    2. The method of planning treatment of patients with polycythemia developed by the author on the basis of data on the state of hemorheology and microcirculatory bed has been introduced into clinical practice since 1998 in the city hematology department of clinical hospital No. 12.Nizhny Novgorod.

    3. The main provisions of the dissertation have been used since 2001 in the process of teaching at the Department of Hospital and Military Field Therapy with a course of toxicology and medical protection of the Military Medical Institute of the Federal Border Service of the Russian Federation at the Novosibirsk State Medical Academy.

    Provisions for defense:

    1. In polycythemia vera, there are pronounced microcirculation disorders with systemic and generalized lesions of microvessels with a change in their number, tone, impaired vascular wall permeability, slowing blood flow velocity.These disorders are aggravated by disorders of hemorheology with an increase in the dynamic viscosity of blood at all shear gradients, a change in the aggregation of erythrocytes and, to a greater extent, disaggregation, a decrease in the deformability of erythrocytes, as well as a decrease in the number of discocytes and an increase in the percentage of pathological forms (spherocytes, ecchinocytes, stomatocytes ).

    2. The nature, intensity of microcirculatory and rheological disorders depend on the stage of the disease and, to a large extent, determine the clinical picture.

    3. In the development of vascular complications in patients with true polycytemia, an important role belongs to changes in the lipid spectrum due to an increase in atherogenic fractions.

    4. Three-component therapy with the inclusion of antiplatelet agents, hemo-exfusion with replacement with rheopolyglucin, cytostatic agents leads to a significant improvement in hemorheology and microcirculation indices, which is an integral part of the therapeutic effect.

    Approbation of work

    The results of the work carried out were reported at conferences of the Department of Hospital Therapy of the Nizhny Novgorod State Medical Academy, the Department of Hospital and Military Field Therapy with a course of toxicology and medical protection of the Military Medical Institute of the Federal Border Service of the Russian Federation at the Novosibirsk State Medical Academy, the Dispensary and Polyclinic Department of the Hematological Scientific Center …Moscow, the II International Conference on Microcirculation and Hemorheology in 1999 (Yaroslavl), the International Conference on Hemorheology in 2001 (Yaroslavl), at the Scientific and Practical Conference of the Military Medical Institute of the Federal Border Service of the Russian Federation at the Novosibirsk State Medical Academy, dedicated to Science Day in 2002, at an expanded meeting of the Department of Hospital and Military Field Therapy with a course of toxicology and medical protection, the Department of Internal Medicine of the Military Medical Institute of the Federal Border Service of the Russian Federation at the Novosibirsk State Medical Academy, the Department of Ambulance and Emergency Aid with a course of anesthesiology and resuscitation of the Nizhny Novgorod State Medical Academy, the Department of Radiation Diagnostics of the Nizhny Novgorod State Medical Academy, Department of Military Field Therapy of the Russian Military Medical Academy (St. Petersburg) in 2003.

    On the topic of the dissertation, 14 papers have been published, in which its main provisions are stated.

    Volume and structure of the thesis

    The work consists of an introduction, a review of the literature, materials and research methods, the results of their own research and their discussion, conclusions, conclusions, practical recommendations and a list of references. …

    The text part of the thesis is presented on / D> pages of typewritten text, illustrated with 22 tables and 33 figures.

    The list of literature includes 164 domestic and foreign sources.


    The author expresses his deep gratitude to those who took part in the work, Dr. med. Professor of the State Scientific Center of the Russian Academy of Medical Sciences Kovaleva L.G. Associate Professor Andryukhin V.I., Ph.D. Associate Professor Mikhailova E.V., Ph.D. Associate Professor Shabanov V.A., employee of the Department of Internal Diseases of the IUI FPS RF at the Novosibirsk State Medical Academy, Ph.D. Associate Professor Lapshina L.A., Head of the Department of Hemosorption and Hyperbaric Oxygenation, NIITO, MD Professor Levin G.Ya., employees of the clinical hospital No. 12 of Nizhny Novgorod VV Muravyov, Murygina SV, Strelkovaya O.Yu., hematologist of the Nizhny Novgorod Regional Diagnostic Center V.A. Parfentiev.


    In the course of this work, in the city hematology department of Clinical Hospital No. 12 in Nizhny Novgorod, inpatient and outpatient examination of 160 patients with polycythemia vera was carried out.Among them there were 90 women, 70 men. The average age of patients was 51 years.

    The diagnosis was verified on the basis of general clinical and hematological studies, confirmed by trepanobiopsy data, dynamic observation from 2 to 20 years.

    Patients with symptomatic erythrocytosis were excluded from the study.

    Laboratory and instrumental research methods included methods for studying microcirculation, methods for studying the hemorheological properties of blood, as well as the lipid spectrum of plasma.Microcirculation was studied by biomicroscopy of the vessels of the conjunctiva of the eyeball using a capillaroscope brand “M-70A” (total magnification * 60). For a quantitative summary assessment

    of all characteristics of microcirculation, the total conjunctival index (OCI) was used, which was determined by the addition of pathological changes in all components of microcirculation.

    Spontaneous aggregation (AGE) and hydrodynamic disaggregation of erythrocytes (DHE) at a constant hematocrit of 0.30 g / L were studied using a rheoscope designed according to the method of H.Schmid-Schonbein (1973) modified by G.Ya. Levin et al. (1984). The rate of spontaneous aggregation of erythrocytes was assessed (T XA – the time to reach half of the maximum aggregation amplitude). Disaggregation of erythrocytes at a shear rate of -2 s “1.4 s” ‘and 8 S’1 was determined as a percentage in relation to the maximum amplitude of erythrocyte aggregation. The deformability of erythrocytes (DE) was studied under conditions of artificial shear flow using a rigidometer device, by the method proposed by Levin GL. et al (1989), in which erythrocytes were stretched in artificial laminar shear flow; the deformability was expressed as a percentage of elongated (deformed) cells.The dynamic viscosity of whole blood (DVK) was studied on a VIR-75 M rotary viscometer designed by A.N. Sundukov (1978) with two coaxial cylinders at 5 fixed shear rate gradients from 1 to 43 The geometry (shape) of erythrocytes was determined using phase contrast microscopy …

    Laboratory and instrumental research included a blood test with counting erythrocytes, leukocytes, platelets, hematocrit, measuring the mass of circulating erythrocytes (MCE) and circulating blood volume (BCC), assessment of lipid metabolism (cholesterol, triglycerides, lipoproteins), uric acid levels as well as some indicators of the coagulation and anticoagulation system (prothrombin index, APTT, ATV, TPVR, FMK, ethanol test, fibrinolytic activity, antithrombin III, factor XIII, platelet aggregation with ADP, adrenaline and ristomycin), fibrinogen level.

    All obtained data were subjected to statistical processing using the “MED STAT” and “MICROSOFT EXCEL” software package with the calculation of the arithmetic mean (M), the mean error of the arithmetic mean (m). The criteria for the reliability of the Student (t), Fisher, levels of significance (P) by the difference method were used.


    The paper analyzes the rheological status in 160 patients with polycythemia vera (the number of erythrocytes, hematocrit, dynamic blood viscosity), microrheological disorders of erythrocytes

    (shape, deformability, aggregation and disaggregation of erythrocytes) and indicators of microcirculation (background, morphological structure of blood vessels, the number of functioning capillaries, the state of tone and blood flow, the presence of aggregates of erythrocytes).As a control of the norm, 65 practically healthy persons were used, comparable in age and sex (structurally) – employees of medical institutions and a military medical institute. An integrated approach made it possible to determine the hemorheological profile in patients with polycythemia vera, the changes of which were characterized by general trends (see Fig. No. 1).

    — o — Control – ■ —1st —D — 1GA “st

    —1-II “B” st —o — 1 || st

    Figure # 1. Hemorheological profile in patients with polycythemia vera.

    Thus, the indices of red blood (hemoglobin and erythrocyte count), hematocrit and platelet count, dynamic blood viscosity at all shear gradients were significantly higher than the indices

    control groups already in patients with the initial stage of polycythemia vera. As the disease progressed, the above indicators gave the maximum deviations from the norm. Significant changes in these parameters took place in patients without signs of exacerbation of the disease, which confirms their role in the pathogenesis and progression of polycythemia.

    In the terminal stage, a decrease in red blood counts in combination with a significant decrease in blood viscosity were recorded. At the same time, other indicators such as the general conjunctival index, deformability and shape of erythrocytes had the same tendency to increase as the disease progressed, with maximum deviations in the expanded stage; in the terminal stage, these parameters remained reduced by 1.5-2 times. This was especially true of the shape of erythrocytes: the number of discocytes sharply decreased, the percentage of pathological forms increased, in addition, the deformability of erythrocytes decreased.

    In the peripheral blood of the examined patients with true polycythemia, there was an increased hematocrit already at the initial stage of the disease. The maximum rise in this parameter took place in the expanded stage, reaching 0.7-0.72 g / l in some patients. In the terminal stage, this indicator decreased. The increase in hematocrit was primarily associated with high erythrocytosis. In the examined patients, the number of erythrocytes was increased already in the initial stage, the maximum increase was noted in patients in the expanded stage.In the terminal stage, the number of erythrocytes was below normal, and 8 patients developed anemia of varying severity. An increase in the mass of circulating erythrocytes with erythremia has a certain effect on blood flow. In addition, with a hematocrit of more than 0.4 g / l, blood viscosity is in a logarithmic relationship to this indicator [Stone O.H., 1968]. In patients with polycythemia vera, we noted an increase in the actual mass of circulating erythrocytes by 33% of the calculated at the initial stage.The maximum deviation took place in patients with stage P “B”. This, in turn, led to an increase in globular mass with an increase in the volume of circulating blood (1.5-1.7 times higher than it should be).

    To study microcirculation in patients with polycythemia vera, the method of biomicroscopy of the vessels of the conjunctiva of the eyeball was used using a capillaroscope of the brand “M-70A” (total magnification X60). The information obtained as a result of the study allows one to judge the state of the microcirculation as a whole, and not by individual parameters.Distinct microcirculatory disorders were revealed.

    according to the general conjunctival, perivascular, vascular and intravascular indices.

    Patients with the initial stage of PI showed a 2.4-fold increase in OCI. As the progression progressed, the total conjunctival index increased with its maximum increase in the advanced stage of the disease with myeloid metaplasia of the spleen (see Fig. 2). At the same time, it was found that the proportion of different microcirculatory disorders is not the same at different stages of the disease.So at the early stages, functional disorders prevailed in the form of an increase in the number of functioning capillaries, a violation of vascular tone, which can be interpreted as an adaptive mechanism at the level of microcirculation due to an increase in the volume of circulating blood. The slowdown in blood flow velocity was moderate. The presence of aggregates of erythrocytes in the capillaries was observed only in the CA part of the patients. In the unfolded stage, the maximum deviations reached disturbances in blood flow up to stasis, aggregation of erythrocytes took place in arterioles, capillaries, and venules, and morphological changes in the vessels increased, which determined in the complex pronounced disturbances of microcirculation as a whole.In the terminal stage, the microcirculatory picture had its own characteristics. The background was usually cloudy, in 50% of patients the presence of hemorrhages, perivascular edema and hemorrhages was noted. Increased vascular disorders in the form of aneurysmal dilatations.

    Figure # 2. Dynamics of the general conjunctival index in patients with polycythemia vera.

    In addition, it was noted that different types of microcirculation corresponded to different stages of polycythemia. In the initial stage, there were mainly hyperemic (80%) and normo-circulatory (20%) types of microcirculation.In the expanded stage

    28% of the surveyed had hyperemic and 32% hyperemic-ski-stasic types of microcirculation. In the terminal stage, 2/3 of the patients had a spastic-stasis type of microcirculation due to pronounced rheological disorders with the development of III degree microcirculation disorders (Fig. No. 3).

    Figure No. 3. Distribution of microcirculation types in patients with polycythemia vera.

    Patients with PI revealed distinct microcirculation disorders according to the data of the general conjunctival (OCI), perivascular (RCI), vascular (SKI) and intravascular (ICI) indices (see.table No. 1)

    When analyzing the quantitative results of rheological parameters, it was found that patients with polycythemia vera had pronounced hemorheological disorders. They primarily concerned macro-rheological characteristics – the dynamic viscosity of blood.

    Significant changes were also noted in the state of microrheological characteristics of erythrocytes, such as shape, deformability and aggregation, which have the most pronounced effect on microcirculation [Dintenfass b, 1981; Freitas J., 1983].

    Table No. 1

    Indicators of hemorheology in patients with PV (M ± m)

    Indicators Control n = 65 Stage I n = 10 II “A” st. n = 75 1GB “st. n = 60 III st. n = 15

    Erythrocytes, x10, 2 / L 4.52 ± 0.1 6.72 ± 0.14 * 6.62 ± 0.14 * 6.95 ± 0.27 * 3.1 ± 0.15 *

    Hematocrit, g / L) 0.43 ± 0.03 0.62 ± 0.02 * 0.66 ± 0.03 * 0.63 ± 0.01 * 0.42 ± 0.02

    Fibrinogen, g / L ‘0.37 ± 0.01 0.41 ± 0.02 * 0.38 ± 0.03 * 0.29 ± 0.02 * 0.37 ± 0.04

    DVK, mPa s 1s1 43 s1 22.0 ± 2.5 5.4 ± 0.1 40.2 ± 2.4 * 8.4 ± 0.4 * 41.6 ± 2.2 * 8.75 ± 0.5 * 44.2 ± 1.9 * 10.4 ± 0.4 * 25.1 ± 2.3 * 5.10 ± 2 *

    DE,% 73, b ± 4.9 43.5 ± 2.1 * 41.2 ± 3.3 * 35.1 ± 2.2 * 65.2 ± 1.8 *

    SSAE, (T1 / 2) s 56.1 ± 4.2 45.4 ± 3.1 * 46.8 ± 3.2 * 46.6 ± 3.2 * 49.2 ± 2.1 *

    Disaggregation,% 2 s “1 4 s” 1 8 s-1 24.1 ± 1.5 47.5 ± 2.6 59.8 ± 1.9 20.1 ± 1.1 32.75 ± 1, 5 * 51.2 ± 1.9 * 18.5 ± 1.2 25.1 ± 1.1 * 35.6 ± 1.9 * 17.9 ± 1.1 23.5 ± 3.2 * 31, 2 ± 1.6 * 13.2 ± 1.2 21.1 ± 2.1 * 43.5 ± 1.4 *

    Erythrocytes (%) Discocytes Pathological forms 91, b ± 2, b 9.4 ± 2.7 88.75 ± 2.4 13.5 ± 2.6 81.4 ± 3.5 * 19.7 ± 2 .8 * 72.4 ± 4.8 * 23.5 ± 3.1 * 67.3 ± 3.6 * 28.9 ± 2.9 *

    * – reliable data compared with control at p <0.05)

    When analyzing the deformability of erythrocytes in patients with various stages of polycythemia vera, 90% of this indicator was below normal.The deformability of erythrocytes with IP was significantly reduced already in the initial stage with a maximum deviation in the expanded stage, and the violation of this function of erythrocytes persisted in the terminal stage as well. The studies have revealed a significant decrease in the number of discocytes and an increase in the percentage of pathological forms of erythrocytes, mainly due to echinocytes. These violations bore the same pattern as DE, i.e. maximum disturbances were observed in the expanded stage, pronounced disturbances persisted in the third, terminal stage of the disease.

    In the analysis of the initial aggregatograms of patients with polycythemia vera in vitro by the method of rheoscopy, a moderate increase in the rate of spontaneous aggregation of erythrocytes was shown. A third of patients in the expanded stage showed a significant increase in the rate of spontaneous aggregation of erythrocytes. This category of patients had a history of vascular complications and, in addition, there were clear changes in the plasma lipid spectrum with an increase in total cholesterol and triglycerides, as well as a moderate increase in fibrinogen.

    The most significant violations were identified from the side of hydrodynamic disaggregation. The strength of erythrocyte aggregates was on average 20% higher at different shear gradients and at different stages of polycythemia vera. In 12% of patients, disaggregation did not occur at all.

    Figure №4. Variants of changes in aggregation and disaggregation in patients with polycythemia vera.

    Indicators of dynamic blood viscosity, which is an integral function of blood plasma viscosity, hematocrit, deformability and aggregation of erythrocytes, also undergoes significant changes in patients with polycythemia vera.

    It was noted that changes in viscosity are the same pattern as disturbances in microcirculation. In patients with PI, an increase in the dynamic viscosity of blood at different shear gradients was reliably established as compared with the control group. DVK was significantly higher, starting from the initial stage of the disease, with maximum deviations in the expanded stage, followed by a decrease in the terminal stage. The predominant increase in blood viscosity was observed at low shear gradients.Thus, the blood viscosity at a shear gradient of 1 s “1 was 1.5-2 times higher. At the same time, at a shear gradient of 43 s” 1, the blood viscosity increased to a lesser extent – by 1.5 times compared to the control. … In the terminal stage, in the absence of erythrocytosis, an increase in blood viscosity by 11.3% persisted. This phenomenon can be explained by the revealed by us a decrease in the deformability of erythrocytes, a decrease in the number of discocytes and violations of erythrocyte disaggregation. This is consistent with modern scientific ideas about the syndrome of high blood viscosity [G.I., Makarov V.A., 1997].

    Aggregation Disaggregation

    We analyzed the state of microcirculation and hemorheology, some parameters of hemostasis and lipid metabolism in patients with polycythemia vera with complications of a predominantly vascular nature (myocardial infarction, acute cerebrovascular accidents, thrombophlebitis of the leg vessels, erythromelalgia). Patients in whom the course of PV was not accompanied by complications were selected as a comparison group.

    The results of the study showed that a number of parameters (VKI, disaggregation, shape of erythrocytes, DE) in patients with complications of PI are not only pathologically altered, but also significantly differ from those in patients with uncomplicated forms of PI (see Table 2) …

    Table No. 2

    Laboratory characteristics of patients with polycythemia vera with uncomplicated and complicated course of the disease.

    Indicators. Control n = 65 Patients with PI without complications, n = 3b Patients with PI with complications n = 35

    Hemoglobin, g / L 123.1 ± 2.1 196.47 ± 3.3 * 191.7 ± 3.2 *

    Erythrocytes 1012 / L 4.52 ± 0.1 6.69 ± 0.11 * 6.63 ± 0.13 *

    Platelets 109 249.3 ± 21.4 458.7 ± 28.5 * 503.03 ± 24.9 *

    Hematocrit, g / L 0.43 + 0.03 0.66 ± 0.21 * 0.67 ± 0.2 *

    OKI VKI 17, b ± 3.2 5.3 + 1.8 67.03 ± 1.8 * 1 41.3 ± 2.2 * 81.7 ± 2.1 * 48.6 ± 2.9 *) **

    DVK (mPa) 1 s1 43s1 22.0 ± 2.5 5.4 ± 0.1 54.85 ± 1.68 * 8.4 ± 0.9 * 59.8 ± 1.8 * 10.4 ± 036 *

    SSAE (T! L) p.56.1 ± 4.2 46.1 + 1.6 * 47.3 ± 1.8 *

    Disaggregation,% 2 s’1 4 s-1 8s- ‘24.1 ± 1.5 47.5 ± 2.6 59.8 ± 1.9 22.3 ± 1.1 * 28.3 ± 1 , 2 * 50.2 ± 2.2 * 20.2 ± 1.1 *) ** 23.5 ± 1.2 ** 41.4 ± 1.9 **

    Form of erythrocytes (%) Discocytes Pathological forms 91.6 ± 2.6 9.4 ± 2.7 76.6 ± 1.9 * 22.3 ± 2.1 * 71.1 ± 1.8 *) * * 28.8 ± 2.7 *) **

    Total cholesterol (mmol / l) ipoproteins (mmol / l) triglycerides (mmol / l) 4.8 ± 0.10 7.30, ± 0.21 1.0 ± 0.05 6.2 ± 0.2 * 7.5 ± 0.62 * 1.2 ± 0.06 * 7.5 + 0.15 *) ** 7D ± 0.07 1.57 + 0.16 *) **

    Fibrinogen, (g / l) 0.37 ± 0.1 0.33 ± 0.2 * 0.49 + 0.2 *) **

    ♦ – significant differences (p <0.05) with control

    *) ** – significant differences (p <0.05) with the first group

    Thus, hemorheological disorders (a decrease in the deformability of erythrocytes, an increase in the aggregation properties of erythrocytes with a decrease in the disaggregation of the latter, a change in the shape of erythrocytes), found in patients with polycythemia vera, lead to a violation of microcirculation with corresponding clinical manifestations.In addition, an increase in the mass of circulating erythrocytes, an increase in the dynamic viscosity of blood at all shear gradients, a violation of the “aggregation-disaggregation” process, together with an increase in the number of platelets with their hyperaggregation, play an important role in the occurrence of thrombotic complications. The revealed changes in the plasma lipid spectrum with an increase in atherogenic fractions in patients with polycythemia vera, especially in the group with a complicated course, suggest their definite role in the development of hemorological disorders.The results obtained indicate that patients with PI experience regular disturbances in the rheological properties of blood and microcirculation, the main of which are a decrease in the deformability of erythrocytes, a violation of the shape, an increase in their aggregation properties, an increase in blood viscosity, the appearance of stasis at the level of microcirculation, and a violation of vascular tone. These disorders correlate to a certain extent with the stage of the disease, the severity of clinical manifestations, the presence of vascular complications, and the severity of biochemical studies, and, therefore, can be considered as factors in the pathogenesis of both the PI itself and its progression.

    In patients with PI, the relationships were determined between indicators of microcirculation and hemorheology, hemorheology and plasma lipid spectrum, hemorheology and hemostasis.

    Quantitative indicators of macro – and microhemorheology, microcirculation and hemostasis were subjected to correlation analysis. In addition, correlations between the parameters of the lipid spectrum of plasma (total cholesterol, triglycerides, – whether

    by proteids).

    Analysis of the data obtained allowed us to come to the following basic principles.The most pronounced effect on microcirculation with an increase in OCI is exerted by the dynamic viscosity of blood at a shear gradient of 1 s “1 (r = 0.40, at p <0.05), the number of discocytes (r = 0.42, at p <0.05) and platelet aggregation (r = 0.31, at p <0.05). A positive high correlation was found between the intravascular conjunctival index and the level of fibrinogen (r = 0.67, at p <0.05). Revealed dyslipidemia in patients with polycythemia vera was accompanied by a positive correlation between

    content of total cholesterol and triglycerides of plasma and dynamic viscosity of blood at 1c “1 (r = 0.31, at p <0.05; r = 0.52, at p <0.05).

    Evaluation of the correlation between blood counts, microcirculation and hemorheology showed a closer positive correlation between the number of erythrocytes and disaggregation at 4 s “1 (r = 0.63, at p <0.05), a negative relationship between the level of hemoglobin and'din -mic viscosity of blood at a shear gradient of 43 s "1 (r = -0.40, at p <0.05).

    Correlations between the number of platelets and the deformability of erythrocytes (r = 0.40, at p <0.05), the rate of spontaneous aggregation of erythrocytes (r = 0.63, at p <0.05) were found.

    The obtained interrelationships in patients with PIs make it possible to judge about the mutual influence of hemorheological parameters, microcirculation, hemostasis, as well as the plasma lipid spectrum.

    To clarify the possibility of using indicators of hemorheology and microcirculation to assess the effectiveness of therapeutic effects in patients with polycythemia vera when using various treatment regimens.

    The studies were carried out in three groups of patients: Group I (n = 36) received only hemoexfusion; Group II (n = 40) – hemoexfusion and antiplatelet agents; Group III (n = 42) – hemoexfusion, antiplatelet agents and cytostatics.

    When using the first treatment regimen, the hemoglobin parameters, the number of erythrocytes and hematocrit were normalized. All this led to the normalization of the dynamic blood viscosity at all shear gradients, a slight decrease in the rate of spontaneous aggregation of erythrocytes by (2%), and a decrease in the strength of aggregates with an improvement in disaggregation.

    Improvement of these parameters of hemorheology was accompanied by a significant improvement in microcirculation indices with a decrease in OCI by 25%.As a result of treatment, a good clinical effect was obtained in the main part (58%) of patients of the first group, in 37% it was satisfactory and in 5% of patients there was no clinical effect (See Fig. No. 5).

    However, the patients of this group retained thrombocytosis and leukocytosis, such indicators as the deformability of erythrocytes and the content of discocytes remained without significant dynamics.

    Figure 5. Clinical effect of the first treatment regimen for patients with polycythemia vera.

    In group II, positive changes were revealed in all indicators of hemorology and microcirculation with a significant improvement in indicators of aggregation and disaggregation. However, DE indices and the content of discocytes did not improve. A more significant improvement was noted in terms of the parameters of hemorheology and microcirculation. In the second group, the number of patients with a good clinical effect increased to 64%, in 23% of cases the effect was regarded as satisfactory, and in 13% of patients there was no clinical effect (Fig.No. 6).

    □ good

    □ satisfactory ■ no effect


    Figure 6. Clinical effect of the second treatment regimen for patients with polycythemia vera.

    As the studies have shown, the most pronounced clinical effect (79%) was achieved in the III group of patients (Fig. №7).

    □ good

    □ satisfactory ■ no effect


    Figure №7. Clinical effect of the third treatment regimen for patients with polycythemia vera.

    Positive clinical dynamics in this group with a significant decrease or disappearance of complaints was accompanied by a distinct improvement in blood parameters and rheological properties of blood: normalization of the hematocrit index, dynamic blood viscosity at all shear gradients, a decrease in the rate of spontaneous aggregation of erythrocytes and an improvement in the process of disaggregation of the latter. In this group, there was a significant improvement in the indicators of erythrocyte deformability and an increase in the number of discocytes with a decrease in pathological forms.

    However, it was not possible to completely normalize the indicators of erythrocyte deformability, their shape, and aggregation properties. The data obtained indicate the known limits of the hemorheological effectiveness of the applied traditional therapeutic programs of polycythemia vera. In this regard, in case of pronounced disorders of hemorheology, with a complicated course, in the complex treatment of patients with polycythemia vera, methods of more powerful rheological action should be used.

    The results of the study indicate a significant contribution of microcirculation and hemorheological disorders to the clinic of polycythemia vera.Disorders of the hemorheological profile and microcirculatory parameters are an integral part of the entire large complex of pathological changes at the cellular-tissue level that form the picture and outcome of this disease. An interesting and extremely important fact is that the blood parameters studied in the work can serve not only as diagnostic markers, but also as prognostic indicators: it is the success (or failure) of correction of the latter that gives rise to the assumption that the treatment is successful (or unsuccessful) in polycythemia vera.


    1. Patients with polycythemia vera have microcirculatory disorders revealed by an increase in the general conjunctival index; these changes increase as the disease progresses. There was a generalized lesion of microvessels of the conjunctiva of the eyeball with a change in the number, permeability of the vascular wall, tone, slowing down of blood flow and the appearance of aggregation of erythrocytes of varying degrees.

    2. The hemorheological profile in patients with polycythemia vera is characterized by: an increase in the dynamic blood viscosity at all shear gradients, a decrease in the deformability of erythrocytes, hyperaggregation of erythrocytes with a decrease in their disaggregation, a decrease in the number of discocytes and an increase in

    the number of discocytes and an increase in the number of pathological forms of erythrocytes.

    3. Changes in hemorheology correlated (r = + 0.31 and 0.52 at P <0.05) with shifts in lipid metabolism, which makes it possible to use the results of cholesterol and triglyceride analysis as functional tests in polycythemia vera.

    4. Indicators of the hemorheological profile reflect the severity of the pathological process: the number of discocytes, deformability of erythrocytes, disaggregation decrease as the disease progresses, reaching critically low values ​​in the expanded stage; aggregation of erythrocytes, dynamic viscosity of blood, microcirculum mountain disturbances increase as the disease progresses; in the terminal stage of the disease, the value of these values ​​decreases, approaching the norm, at the same time, a sharp decrease in the percentage of discocytes remains.

    5. The dynamics of microcirculation and hemorheology indices correspond to the clinical effect of the ongoing therapy of true polycytemia with exfusion, antiplatelet and cytostatic therapy. The greatest correction of microcoagulation and hemorheological deviations is observed in the group of patients with three-component complex therapy.

    6. The use of hemorheological profile indicators for diagnostics and monitoring of the body condition in polycythemia vera allows better planning of a targeted treatment program and prevention of thrombosis and other complications.


    1. In a comprehensive examination of patients with polycythemia vera, it is advisable to use indicators of the state of the microvasculature and the hemorheological profile as additional research methods.

    2. Indicators of the state of the microvasculature and hemorheological profile can serve as a prognostic criterion in assessing the risk of thrombotic and other complications of polycythemia vera: an increase in the value of the markers under study by 2 or more times indicates a high risk of complications.

    3. If it is impossible to study the hemorheological profile, the level of triglycerides in the blood plasma can be used as an indicator that indirectly characterizes the blood viscosity in patients with polycythemia vera: an increase in the latter by 1.5 times or more corresponds to a clinically significant increase in blood viscosity.

    4. When prescribing treatment for patients with polycythemia vera, preference should be given to three-component therapy with the inclusion of hemoecfusions, antiplatelet agents and cytostatic drugs.


    1. Muravyova L.P. Microcirculatory disorders in patients with polycythemia // Clinical aspects, microcirculation disorders and blood rheology. – Gorky: GMI, 1984 .– S. 84-88.

    2. Muravyova L. P., Kovaleva L. G. Microcirculatory disorders in the clinic of polycythemia // Mater. II All-Union Congress of Hematologists and Transfusiologists October 15-18, 1985 – Lvov, 1985. – P. 226.

    3. Muravyova L.P., Parfentiev V.A. Differential diagnosis of erythrocyte globules // Diagnostic and medical errors of a doctor. – Gorky: GMI, 1985 .– S. 118-122.

    4. Muravyova L. P., Shabanov V.A. Clinical significance of hemorheologin disorders in patients with polycythemia vera // Mater. Int. conf. “Experimental and clinical aspects of microcirculation adaptation.” – Yaroslavl, 1995. – S. 48-51.

    5. Murav’eva LP, Shabanov VA, Murav’ev VV, Murygina SV. Violations of the rheological properties of blood and microcirculation in polycythemia vera // Mater.Int. conf. “Microcirculation” -Moscow – Yaroslavl, 1997. – S. 192-193.

    6. Muravyova LP, Muravyov VV, Shabanov VA Diagnostics and treatment of cardiovascular complications in patients with true polycythemia // Mater. I reg. cardiological conf. “Actual problems of practical cardiology.” – N. Novgorod, 1997 .– P. 80.

    7. Muravyov LP, Shabanov VA, Muravyov VV Rheological approaches in the treatment and prevention of acute and cardiovascular disorders in polycythemia vera // Mater.And region. cardiological conf. “Actual problems of practical cardiology.” -N. Novgorod, 1999.-S. 78.

    8. Muravyov LP, Muravyov VV, Murygina SV. Factor analysis of the rheological properties of blood and microcirculation in patients with polycythemia vera // Mater. II Int. conf. “Microcirculation and hemorheology”. – Yaroslavl-Moscow, 1999 .– S. 206-207.

    9. Murav’eva LP, Shabanov VA, Levin G.Ya., Muravyov VV, Murygina SV, Mikhailova EV Rheological risk factors for acute thrombotic cardiovascular complications in true polycythemia // Mater.All-Russian scientific. – practical. conf. “Thrombosis, hemorrhages, disseminated intravascular coagulation, treatment problems.” – Moscow, 2000. – S63-64.

    10. Murav’eva LP, Muravyov VV, Mikhailova EV, Murygina SV. The role of rheological blood disorders in the development of cardiovascular complications in true polyditaemia // Diagnostics, treatment and prevention of arterial hypertension and coronary heart disease in military personnel. – N. Novgorod, 2000 .– S. 63-64.

    11. Muravyov L. P., Muravyev V. V., Mikhailova E.V., Murygina SV. Experience of using therapeutic plasmapheresis in hematology // Mater, nauch. – practical. conf. “Blood and aging.” – Samara, 2001. – pp. 31-32.

    12. Murav’eva LP, Muravyov VV, Shabanov VA, Murygina SV, Mikhailova EV. Features of hemorheological disorders in patients with polycythemia vera and symptomatic erythrocytosis // Mater. Int. conf. on hemorheology. – Yaroslavl, 2001 .– p. 95.

    13. Mikhailova E.V., Levin GL., Shabanov V.A., Strelkova O.Yu., Muravyova L.P.Investigation of the deformability of erythrocytes in arterial hypertension using rigidometry and morphological analysis // Ibid. – S18-19.

    14. Muravyov V.V., Murav’eva L.P., Andryukhin V.I. Clinical and hemorheological efficacy of erythrocytapheresis in patients with polycythemia vera // Nizhny Novgorod honey. zhurn. – Appendix to NMF. Ozone therapy. – 2003. – S. 279-280.

    Circulation 100 copies. Risograph 011-3750

    Nizhny Novgorod Research Institute of Traumatology and Orthopedics Nizhny Novgorod, Verkhne-Volzhskaya emb., 18 License of the Republic of Latvia No. 020899 dated 14.07.1999

    * – 289 G

    The appearance of normoblasts in the general blood test.

    In today’s article, we have important hematopoietic cells – normoblasts (NRBCs – nucleated red blood cells). Normoblasts, also called erythroblasts, are young erythrocytes with a nucleus. They arise from pro-erythroblast progenitor cells. When normoblasts mature, they lose their nucleus – the part of the cell where DNA is stored and converted into reticulocytes and then into red blood cells.This allows you to carry more hemoglobin (and therefore more oxygen) and become very flexible in shape.

    Blood microscopy. Normoblasts. Sometimes you can find normoblasts with 2 nuclei.

    Contents of the article:

    1. Classification normoblasts

    2. Terminology

    3. Methods for the detection of normoblasts

    4. Errors in the analysis

      0 blood test.Norms

    5. Reasons for the presence of nucleated erythrocytes in the blood

    1. Classification normoblasts

    According to maturity and morphology, normoblasts are divided into: polychromatophilic 10 and basophilic

    2. Terminology

    In Russia, doctors got confused with the name of these cells, due to the fact that different names were assigned to normoblasts in different textbooks on hematology.Abroad, normoblasts are usually called erythroblasts. Some practicing hematology consultants, due to confusion in terminology, cannot understand what kind of cells appeared in the patient’s blood, and even classify normoblasts as leukocyte cells, which is fundamentally wrong. So, let’s list all the synonyms for young nuclear erythrocytes: normoblasts, NRBC (Nucleated red blood cells), erythroblasts, normocytes.

    The photo shows normoblasts with internuclear bridges. A sign of dyserythropoiesis is a violation of the maturation of erythroid cells.

    3. Methods for detecting normoblasts

    With the advent of modern hematological analyzers, it became possible to detect 1 normoblast per 1000 leukocytes in the blood. This sensitivity allows one to suspect the disease at the earliest stages. A doctor of clinical laboratory diagnostics using a microscope can also find these cells in a blood smear with greater certainty, but with less sensitivity: 1 normoblast per 200 leukocytes.

    Scatterograms of the Sysmex-XN hematology analyzer.Differentiation of normoblasts from basophils occurs in the WNR channel.

    4. Errors in the analysis

    During long-term transportation of blood to the laboratory, normoblasts may appear falsely in your analysis in rare cases. This is due to the fact that with prolonged standing of blood, leukocytes begin to break down into the so-called “apoptotic bodies”. Apoptotic leukocytes can be attributed to the hematological analyzer as normoblasts. But in fact, they are not in the blood. Therefore, when normoblasts appear in the general blood test, the doctor of clinical laboratory diagnostics must evaluate their presence microscopically and calculate the leukoformula.

    Blood microscopy. Apoptotic leukocytes are shaped like normoblasts. Therefore, the hematology analyzer may be wrong.

    5. The appearance of normoblasts in the general blood test. Norms.

    Normoblastemia (erythroblastemia) – the appearance of normoblasts in the peripheral blood.

    Modern hematology analyzers have an NRBC counting function.

    In healthy adults and older children normoblasts are found only in the bone marrow, where they develop and mature.NRBCs do not appear in the blood of a healthy adult. Therefore, the presence of NRBC in the analysis of peripheral blood (complete blood count) is an important sign that deserves attention when assessing pathological conditions. Normoblasts are normal in newborns (0-2%). In adults, the appearance of 0.1% normoblasts gives the doctor a reason for further diagnostic search and collection of anamnesis. It will be desirable to conduct a general blood test with mandatory microscopy of the leukocyte formula. An entry in the comments to the analysis: “Normoblasts – 1/100 or 1: 100” will mean that the doctor under a microscope in a blood smear found 1 normoblast per 100 leukocytes.If normoblasts are found in the blood, a consultation with a hematologist is necessary.

    6. Reasons for the presence of nucleated erythrocytes in the blood

    There are many reasons for the appearance of normoblasts in the general blood test, I will try to list all kinds:


    Most often normoblasts are found in patients suffering from anemia.

    • Anemia (at the beginning of treatment for iron deficiency anemia, megaloblastic anemia, hemolytic anemia)

    • Thalassemia

    • Crisis of sickle cell anemia

    • Bleeding of the patient (blood loss)A characteristic feature is erythrocytes with Jolly bodies (remnants of the nuclei of normoblasts) and target erythrocytes. It is necessary to differentiate with hemolytic anemias of other origins and with MDS.


      Conditions that reduce the amount of oxygen transported to tissues (hypoxia) cause an increase in red blood cell production, which in turn leads to the presence of nucleated red blood cells in the blood.

      Removal of the spleen

      The spleen “removes” nucleated red blood cells that leave the bone marrow.Removal or dysfunction of the spleen can lead to the presence of nucleated red blood cells in the blood – normoblasts.

      Diseases of the bone marrow

      • Myeloproliferative diseases, leukemias (for example, chronic myeloid leukemia )

      • Myelofibrosis

      • Myeloid anemia as a result of cerebral insufficiency 9000 )

      • Vakez’s disease (polycythemia vera, primary erythrocytosis)

      Blood microscopy using an automatic Hema Vision scanner.Normoblasts (erythroblasts). A large increase in normoblasts in the blood indicates a serious health problem. Most often, a significant increase in normoblasts in the blood occurs in hemolytic disease of newborns, myeloproliferative diseases and leukemia.

      The video below is recommended for viewing only by doctors.

      Other causes of NRBC in the blood

      It is unclear why some of these develop normoblastemia, but disruption of the blood-bone marrow barrier in some of these conditions may play a role:

      • Sepsis (severe reaction to infection )

      • Chemotherapy

      • Liver disease

      • Diabetic ketoacidosis

      • Neuroblastoma, a form of cancer that develops from immature nerve cells

      • Disease characterized by Gaucher substances, a condition, accumulation of fat , especially in the spleen and liver

      • Granuloma (in tuberculosis)

      • Collagen vascular diseases (eg lupus)

      • Histiocytosis, a group of syndromes characterized by an abnormal increase in the number of certain immune cells called histi ocytes

      • Sarcoidosis, a disease that causes inflammation of the lungs, skin, eyes and lymph nodes

      • Osteopetrosis (marble disease), a rare bone disease that makes bones abnormally dense and prone to fracture

      • Kidney transplant

      • Burns

      • Lead poisoning

      • Pregnancy

      • Uremia (a condition in which urea in the blood increases sharply)

      Normoblasts with a cytoplasmic bridge in myelodysplastic syndrome.

      Normoblasts are almost never detected in aplastic anemia. The detection of normoblasts in the peripheral blood casts doubt on this diagnosis. The presence of normoblasts in certain clinical conditions may indicate the need for bone marrow examination to exclude hematological malignant neoplasms or other blood diseases. Detection of one harmless normoblast can lead to timely medical intervention and increase the chance of recovery.

      If you have any difficulties in interpreting a complete blood count or questions about the article, you can ask here.


      • Constantino, B. T., & Cogionis, B. (2000). Nucleated RBCs — significance in the peripheral blood film. Laboratory Medicine , 31 (4), 223-229.

      • Lewis, S., Bane, B., & Bates, I. (2009). Practical and laboratory hematology.

      • Lugovskaya, S.A., & Pochtar, M.E. (2016). Hematological atlas. 4th ed., Add. Tver: Triad .