N D Khoroshko

Russian Academy of Medical Sciences, Moskva, Moscow, Russia

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Publications (100)41.19 Total impact

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    ABSTRACT: Chronic myelogenous leukemia (CML) is rare disorders with incidence about 1 : 100000 inhabitants yearly. In the whole Russian Federation there are nearly seven thousand CML patients. Introduction new innovative target drugs — tyrosine kinase inhibitors in routine clinical practice occurred in the last decade. This dramatically changed course of disease and fate of patients. The median survival had increased from 3–4 years to more than 15 years with full restoration of professional capabilities. There is perspective of therapy cessation in some patients. The present federal guidelines are evidence-based protocol and include all stages of CML patients management: diagnosis, treatment and minimal residual disease monitoring. The guidelines are intended to hematologists, oncologists, pediatricians, healthcare organizers.
    Full-text · Article · Jan 2013
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    ABSTRACT: Nilotinib (AMN 107, Tasigna*, Novartis Pharma, Switzerland), is 2-nd line Bcr/Abl-tyrosine kinase inhibitor (TKI2). Nilotinib is characterized by the highest selective activity in comparison with all TKI. Nilotinib has low active or inert towards other tyrosine kinases and involves a lesser risk of side effects associated with inhibition of non-target proteins. Clinically this is confirmed by the absence of life-threatening symptoms in the patients treated with nilotinib. Nilotinib are not cross-toxic wit imatinib. The strict adhering to the treatment protocol regulations - an obligatory condition to minimize the uncontrolled changes in plasma nilotinib concentrations, which can lead, in turn, to toxicity or reduction of the drug effect. These regulations are oral dose taken strictly after fasting, special care in combined treatment with the drugs modulating the cytochrome system activity and the drugs modulating the ECG QT interval. A characteristic feature of nilotinib toxicity profile is rare incidence of untoward phenomena, manifesting by clinical symptoms, and rather high incidence of deviations in laboratory values. Practical recommendations on the treatment strategy in patients with undesirable symptoms, such as rash, itching, hyperbilirubinemia, hyperglycemia, high amylase and lipase levels, QTcF interval prolongation, and in CML patients who wish to have children are presented.
    No preview · Article · Jul 2012 · Gematologiia i transfuziologiia
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    Preview · Article · Jun 2012 · Mediterranean Journal of Hematology and Infectious Diseases
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    ABSTRACT: Aim: To show distribution of the investigated patients into diagnostic groups, find out the diagnostic value of the levels of hemoglobin and packed cell volume as possible markers of absolute erythrocytosis in the group of patients with polycythaemia. Material and methods: We evaluated 61 patients, mean age was 46 years (18-82), 9 females and 52 males before treatment. Mean levels of hemoglobin infernales - 171g\l (143-190), packed cell volume 52% (49-61). Mean levels of hemoglobin and packed cell volume for males were 187 g/l(168-196) and 57,8% (49-65), respectively. All blood samples were taken in the morning. Full blood picture of venous blood was determined by Coulter principle on Gen S ("Beckman-Coulter", USA) blood analyzer with preserving agent (ethylene diamine tetraacetate, EDTA). Red cell mass and plasma volume were measured by the radionuclide method (Cr-51). Results were performed with an allowance for patient's surface area and were interpreted according to International Council for Standardization in Haematology guidelines (ICSH) (Pearson et al. 1995). Results: Polycythaemia vera was detected only in 19(31%) among 61 patients, 15 patients refused from further investigation. Among others. 46 patients 14 subjects had secondary erythrocytosis, among them 9 were diagnosed with absolute erythrocytosis (hypoxic) and 5 with idiopathic erythrocytosis. Relative ("apparent") erythrocytosis was detected in 13 cases. Measurement of red cell mass allowed us to divide patients into groups with absolute and relative erythrocytosis. Such laboratory parameters as hemoglobin, number of red blood cells and packed cell volume do not always completely show the level of red cell mass due to possible variations of the plasma volume and can not be the reason for diagnosis of haematological disorder. It is shown that hemoglobin level over 185 g/l confirms the presence of absolute erythrocytosis only in 50% of males with polycythaemia, 15% of males with secondary erythrocytosis might have incorrect diagnosis as though increased red cell mass. Statistically defined highly significant (p=0,001) difference of the level of red cell mass in males with polycythaemia and patients with "apparent" polycythaemia turned out to 166% and 111%, respectively. The levels of red cell mass in patients with polycythaemia confirm absolute erythrocytosis over superior normal limit (more then 25%) in comparison with secondary erythrocytosis where red cell mass rate remained normal. Average plasma volume measurements in the same groups of patients were at normal range - 95% u 81%, respectively. Difference between these mean values was authentically significant. Conclusion: Red cell mass and plasma volume measurement is easy and necessary procedure for estimation absolute and "apparent" polycythaemia. Rather common occurrence of different forms of erythrocytosis and in particular "apparent" erythrocytosis must determine certain diagnostic approach according to specific clinical case.
    No preview · Article · Jan 2012 · Terapevticheskii arkhiv
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    ABSTRACT: To define an association of bone marrow microvessel density (MVD) with histological properties (the magnitude of fibrosis and quantification of megakaryocytes (MGKC)) in patients with Ph-negative chronic myeloproliferative diseases (CMPD). MVD was analyzed in 93 patients with different forms of CMPD, by estimating histological parameters. True polycythemia (TP) was present in 28 patients; 20 patients had essential thrombocythemia (ET), 36 had subleukemic myelosis, out them 6 were in a prefibrotic stage, and 9 with diagnosed post-TP (ET) myelofibrosis. The grade of myelofibrosis was estimated from the degree of bone marrow fibrosis as 0, 1, 2, and 3 and the clusters of MGKC were in accordance with degrees: 0, 1, and 2. MVD was studied from the absolute number of CD34-positive vascular structures. In patients with TP, fibrosis was defined as grade 0 and 1 in 23 (82%) and 5 (18%) cases, respectively. The content of reticulin fiber was in the normal range in 19 (95%) of the 20 patients with ET. The clusters of MGKC of grades 1 and 2 showed an even distribution among patients with ET and those with TP. Fibrosis was absent in all the patients (n = 6) with prefibrotic-stage primary myelofibrosis (PMF). The patients with PMF had high MVD values [6.5 (range 2.8-22)] than those with TP [4.0 (range 1.76-10.2)] or ET [3.7 (range 2-8.5)] and the controls [3.2 (range 2-4.1)] (p < 0.001) confirming that angiogenesis is uninvolved at the onset of disease in patients with ET and those with TP. The patients with prefibrotic-stage PMF had higher values [6.0 (range 4.8-10.6)] than those with ET [3. 7 (range 2-8.5)] (p < 0.001). This suggests that angiogenesis is an early sign preceding the development of fibrosis. Bone marrow angiogenesis assessment (from MVD measurements) may be an additional criterion for the diagnosis of disease evolution and an additional criterion between ET and PMF in a prefibrotic stage.
    No preview · Article · Jan 2010 · Terapevticheskii arkhiv
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    ABSTRACT: The efficiency of rituximab (MabTera®, "F.Hoffimann-La Roche Ltd.", Switzerland; a chimeric monoclonal antibody to CD20 B-lymphocytes) is evaluated in 8 patients with the refractory autoimmune hemolytic anemia (AIHA) with heat agglutinins with positive Coombs direct test. The disease duration was 6-68 months. Rituximab was injected in a dose of 375 mg/m2. If B-lymphocytes with the CD20+, CD19+, CD22+ immunophenotype disappeared from circulation on day 7 of the course, the patients received just two drug doses. The maximum effect was observed after 3-16 weeks without maintenance therapy. Complete remission was achieved in 4, partial in 4 patients. The remission stability was evaluated by normalization of erythrocyte distribution by compactness and by the mean creatinine content in erythrocytes. Monitoring of these parameters in 2 patients detected the starting relapse and helped to prolong the remission. Four patients developed AIHA relapses after 2,8,9, and 17 months. Repeated courses of rituximab led to restoration of the remission. In addition, the third course was effective in 2 patients. No episodes of clinically significant infections, including herpes virus, were recorded. By the present time the duration of remission is 16-55 months.
    No preview · Article · Sep 2009 · Gematologiia i transfuziologiia
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    ABSTRACT: Clinical manifestations of subleukemic myelosis, which debuted with Budd-Chiari syndrome in a young female patient, are presented. The cytoreductive therapy should be spent simultaneously with anticoagulant therapy.
    No preview · Article · Mar 2008 · Gematologiia i transfuziologiia
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    ABSTRACT: Increased PRV-1 mRNA expression and the presence of Jak2(V617F) mutation in peripheral blood granulocytes are specific markers for chronic myeloproliferative disorders (MPD), which facilitate the differential diagnosis between polycythemia vera (PV) and secondary erythrocytosis (SE) and may be helpful for monitoring treatment efficacy in MPD patients. We evaluated the presence of the Jak2V617F mutation and increased PRV-1 mRNA expression along with previously established markers - erythropoietin (EPO) independent colony formation (EEC) and erythropoietin level for diagnosis of PV and assessment of treatment efficiency. Increased PRV-1 expression was found in 37 out of 46 patients diagnosed with PV (80%), in 4 out of 15 patients diagnosed with essential thrombocythemia (ET) (27%) and in 4 out of 8 patients with chronic idiopathic myelofibrosis (CIMF) (50%), and increased PRV-1 expression plus EEC formation was observed in 19 of 36 examined MPD patients indicating the superiority of PVSG and WHO bone marrow criteria for the diagnosis of ET, PV and CIMF. We could confirm a very high sensitivity, specificity and utility of the Jak2(V617F) mutation for differential diagnosis between PV and SE. Spontaneous EEC, serum EPO levels, PRV-1 expression was evaluated in 22 PV patients who carried the Jak2(V617F) mutation. A concordance of increased PRV-1 expression and presence of Jak2(V617F) mutation in 19/22 (85%); of increased PRV-1/Jak2/EEC in 14/22 (63%); and of Jak2/PRV-1/EEC/low Epo level in 10/22 (45%) patients was found indicating the superiority of the presence of Jak2(V617F) mutation for the diagnosis of PV. IFN-alpha therapy in patients with PV was more effective then hydroxyurea treatment and significantly reduced increased PRV-1 expression together with higher levels of Jak2(V617F) mutation (50-100%) in PV patients treated with hydroxy urea (HU) and lower levels of Jak2(V617F) mutation (35-90%) in PV patients treated with IFN-alpha. Normal PRV-1 expression level was observed in 44% of PV patients who achieved clinical remission and only in 3% of patient who did not. These preliminary observations indicate that the Jak2(V617F) mutation in particular and PRV-1 overexpression appear to be suitable markers for monitoring treatment efficiency in prospective randomised clinical studies comparing pegylated interferon and hydroxyurea in well defined PV patients with a clear indication for cytoreductive therapy.
    Full-text · Article · Jan 2008 · Hematology (Amsterdam, Netherlands)
  • N.D. Khoroshko · O.Yu. Vinogradova · A.G. Turkina
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    ABSTRACT: Drugs with antityrosine kinase activity, primarily imatinib mesylate, are the first-line therapy for chronic myeloid leukemia (CML) today. However 19% patients receiving imatinib exhibit drug resistance or intolerance. Dasatinib is characterized by high antityrosine kinase activity and by a wide spectrum of effects on various tyrosine kinases. Dasatinib suggests using it in therapy of CML in patients with imatinib resistance caused by high activity of BCR-ABL, presence of imatinib stable mutations, and by non-BCR-ABL-dependent mechanisms. Side effects of dasatinib consist in its hematological and other than hematological toxicity, which can be arrested in the majority of cases by intervals in the therapeutic course, reduction of dasatinib dose, and symptomatic therapy.
    No preview · Article · Jan 2008
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    ABSTRACT: We evaluated the content of early and late cobblestone area-forming cells, immediate progeny of hemopoietic stem cells, and committed precursor cells in the bone marrow and peripheral blood of patients with chronic myeloproliferative diseases and healthy donors. In patients with essential thrombocythemia, the number of late cobblestone area-forming cells in the peripheral blood decreased, while other parameters did not differ from those in healthy donors. In patients with idiopathic myelofibrosis, we found a decreased number of late and early cobblestone area-forming cells in the bone marrow and late cobblestone area-forming cells in the peripheral blood, while the count of early cobblestone area-forming cells in the peripheral blood increased. In patients with chronic myeloid leukemia, the number of early cobblestone area-forming cells in the bone marrow decreased, but the count of late and early cobblestone area-forming cells in the peripheral blood increased. The number of endogenous committed precursor cells in the peripheral blood increased in all groups of patients with chronic myeloproliferative diseases and, particularly, in patients with idiopathic myelofibrosis and chronic myeloid leukemia. Functional characteristics of immediate descendants of hemopoietic stem cells probably reflect the level of damage and attest to the existence of various mechanisms underlying the defect of the hemopoietic stem cell during chronic myeloproliferative diseases.
    No preview · Article · Sep 2007 · Bulletin of Experimental Biology and Medicine
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    Preview · Article · Aug 2007 · Blood Reviews
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    M.A. Sokolova · N. D. Khoroshko · N. V. Tsvetaeva · M. D. Sanatko

    Preview · Article · Aug 2007 · Blood Reviews
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    ABSTRACT: Philadelphian (Ph) chromosome is the specific cytogenetic marker of chronic myeloid leukemia (CML). It emerges as a result of t(9;22)(q34;q11) reciprocal translocation. Ph-chromosome is a genetic abnormality, most fully analyzed at a molecular level. Southern blot hybridization is the first method which was effectively used for the molecular diagnosis of CML. This method was replaced by the polymerase chain reaction (PCR) and real time PCR, due to which the molecular diagnosis of CML transformed from an almost artistic manipulation into a routine method of laboratory analysis. Due to this the routine protocols for examination of CML patients in complete remission were appreciably simplified. CML patients can develop resistance to gleevek during therapy with this drug; one of the causes of this resistance is emergence of tumor cell clones carrying mutations at the BCR/ABL gene site determining the tyrosine kinase activity. Molecular methods detect these mutations.
    No preview · Article · Mar 2007 · Gematologiia i transfuziologiia
  • A.G. Turkina · O.Yu. Vinogradova · N.D. Khoroshko · A.I. Vorobyov
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    ABSTRACT: Progress in the treatment of chronic myeloid leukemia (CML) is due to clinical use of imatinib mesylate drug (Gleevek®, "Novartis Pharma AG", Switzerland). This agent blocks the oncoprotein BCR-ABL. BCR-ABL plays the key role in the development of leukemia. High efficiency of the drug leads to a pronounced decrease of Ph-positive hemopoiesis in the bone marrow. Treatment by imatinib mesylate allows increasing survival of patients with complete cytogenetic response to 95% over 5 years. The new therapeutic method necessitates significant changes in organization of care of this patient population: introduction of cytogenetic and molecular methods for the diagnosis and monitoring of treatment efficiency. During 2 recent years the cytogenetic laboratories working heretofore have been additionally equipped and 5 new cytogenetic centers for studies of the karyotype of leukemia patients appeared. Creation of the Russian Register can help to evaluate the prevalence of the disease in various regions of the country and the requiremen in new therapeutic methods.
    No preview · Article · Mar 2007 · Gematologiia i transfuziologiia
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    ABSTRACT: The aim of this study was to evaluate the incidence of additional chromosome aberrations and their relationship with gleevek resistance. We analyzed clinical and laboratory findings in 116 Ph+ and BCR-ABL+ patients with chronic myeloid leukemia (CML) in the acceleration phase. All patients received therapy with BCR-ABL tyrosine kinase inhibitor Gleevek(r) ("Novartis Pharma AG", Switzerland) in a daily dose of 600 mg. Complete recovery of Ph-negative hemopoiesis was attained in 36.2% patients and was associated with 93% 4-year survival vs 30% in patients without cytogenetic response. The notions of hematological and cytogenetic resistance are formulated and the terms for its diagnosis are determined. Different approaches to drug resistance control are demonstrated (increase of gleevek dose, chemotherapy, combined therapy). The significance of additional chromosome aberrations, detected in Ph-positive and Ph-negative cells by the beginning and during gleevek therapy, is evaluated. Unfavorable prognostic clinical hematological signs, significantly related to treatment resistance and low survival, are detected.
    No preview · Article · Mar 2007 · Gematologiia i transfuziologiia
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    ABSTRACT: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007. Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation. A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme. The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.
    No preview · Article · Feb 2007 · Terapevticheskii arkhiv
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    ABSTRACT: To quantitatively determine minimal residual disease (MRD) by real-time polymerase chain reaction (PCR) in patients with a chronic phase (CP) of chronic myeloid leukemia (CML). A molecular response was analyzed in 53 CML CP patients with incomplete and complete cptogenetic response (ICR and CCR) during imatinib therapy (median follow-up 36 months). BCR-ABL gene type p210 expression was quantitatively determined by real-time PCR under the TaqMan technology (an ICycler IQ device). The beta2 microglobulin (beta2M) gene was used as a reference gene. The results were expressed as the ratio: the number of BCR-ABL copies to that of beta2M x 10(5), as well as the difference of the common logarithm (lg) of the baseline expression level (BEL) and the result obtained: CEL lg-result lg. The study revealed a correlation of the results of real-time PCR with those of cytogenetic analysis and showed it possible to study not only bone marrow, but also peripheral blood. Some negative real-time PCR results were checked using more sensitive PCR techniques. MRD was identified in most CML patients showing ICR and CCR during imatinib therapy. The reduction in BCR-ABL transcript levels by less than 2 lg (as compared to BEL) was associated with a cytogenetic recurrence and that by less than 3 lg was associated with a permanent high cytogenetic response. In patients with a cytogenetic recurrence, the median of BCR-ABL transcript levels was higher than that in patients with a permanent stable or unstable cytogenetic response. An elevation of BCR-ABL transcript levels over time antedated the development of a cytogenetic recurrence. Quantitative monitoring by real-time PCR gives additional information on the dynamics of MRD in CML patients treated with glivec and permits improvement of study protocols for patients with CML at complete clinicohematological and cytogenetic remission.
    No preview · Article · Feb 2007 · Terapevticheskii arkhiv
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    ABSTRACT: To assess incidence of hyperhomocysteinemia (HHC) in patients with chronic myeloproliferative diseases (CMPD) and to analyse possible correlation between an elevated concentration of plasma homocystein (HC) and thrombotic complications. The trial enrolled 61 patients: 39 CMPD patients with thrombotic complications and free of them, 22 nonhematological patients with thrombosis. The control group consisted of 40 healthy donors. The examination protocol included determination with standard methods of HC plasma concentration, platelet and plasma components of hemostasis, mutation of factor V Leiden gene, prothrombin and methylenetetrahydrofolate reductase (MTHFR). Mean HC concentration in the serum in CMPD patients was 19 +/- 1.7 mcmol/l which appeared higher than in healthy donors (12 +/- 1.3 mcmol/l). The highest HC was in patients with subleukemic myelosis (SLM)--23 +/- 2.3 mcmol). No difference in HC concentration in plasma was observed in CMPD carriers of homo- or heteroxygous mutation of C667T gene or CMPD patients without the mutation. In CMPD content of factor VIII was higher in HHC than in normal HC (222 +/- 26.5 and 116 +/- 20%, respectively, p = 0.002). For von Willebrand factor 202 +/- 15.6 and 120 +/- 14.6%, respectively (p < 0.003). HC reduction in response to vitamin therapy was the greater the higher its initial level was. There is correlation between HHC and thrombosis in CMPD patients. HC concentration may depend on the proliferative stage of CMPD. As HC is a significant independent factor of thrombotic complications risk, it is necessary to detect and treat HHC.
    No preview · Article · Feb 2007 · Terapevticheskii arkhiv
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    ABSTRACT: To reveal prognostically significant factors affecting efficacy of glivek therapy in untreated (duration of the disease < or = 6 months) and pretreated (duration of the disease > 6 months) patients with chronic myeloid leukemia (CML) in a chronic phase. A total of 338 patients (64 untreated and 274 pretreated) with a chronic-phase CML on glivek therapy entered the trial. Five-year survival on glivek was high (89, 98 and 88% in untreated and pretreated patients, respectively). Incidence of transformation in the acceleration phase and blast crisis was low both in untreated and pretreated patients (1.6 and 11%, respectively) and correlated with the rate of a complete cytogenetic response (CCR). Untreated patients had no factors affecting treatment efficacy negatively, CCR probability was 96%. Blastemia, thrombocytosis and splenomegaly reduced CCR probability significantly in pretreated patients. Slow reduction of the tumor mass, late achievement of a complete hematological response and a cytogenetic response decreased probability of CCR. Glivek is a drug of choice for patients with chronic-phase CML. High probability of CCR both in untreated and pretreated patients lowers the risk of the disease transformation into the phase of acceleration/blast crisis and raises overall survival in both groups.
    No preview · Article · Jan 2007 · Terapevticheskii arkhiv
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    ABSTRACT: To analyse the course of pregnancy in chronic myeloproliferative diseases (CMPD) with hyperthrombocytosis, primarily, essential thrombocytemia. The analysis of thrombogenic risk factors covered literature data and 8 cases observed by the authors. Six pregnant women received long-term treatment with preparations of interferon-alpha in a dose 9-20 million IU a week (both before and during pregnancy). Rapid reduction of hyperthrombocytosis (1100-4000 x 10(9) l) and the absence of a negative effect on development of the fetus were seen in all the cases. Normal delivery on week 37-39 was in 4 patients, spontaneous abortion on week 24 was provoked by a car accident. Three gravidas (gestational week 28, 33 and 34) are still under observation. Lupus anticoagulant or elevation of anticardiolipin antibodies level was detected in 4 of 8 patients, 2 patients had heterozygous mutation of methylentetrahydrofolatereductase genes and factor V (Leiden). These patients were given lannacher, faxiparine, folic acid and discrete plasmapheresis (in 2 cases). Gravidas with hyperthrombocytosis, if not contraindicated, must be treated with aspirin and interferon-alpha preparations at any gestational term. Moreover, it is necessary to exclude additional most prevalent causes of thrombophilia for adequate prevention of thromboses.
    No preview · Article · Feb 2006 · Terapevticheskii arkhiv

Publication Stats

82 Citations
41.19 Total Impact Points

Institutions

  • 1998-2010
    • Russian Academy of Medical Sciences
      Moskva, Moscow, Russia
    • N.N. Blokhin Cancer Research Center
      Moskva, Moscow, Russia
  • 1998-2008
    • National Research Center for Hematology
      Moskva, Moscow, Russia
  • 2005
    • Russian Academy of Sciences
      Moskva, Moscow, Russia
  • 1987
    • Kirov Research Institute of Hematology and Blood Transfusion
      Khlynov, Kirov, Russia