OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press23910.17650/1818-8346-2017-12-2-30-38HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯTHROMBOTIC AND BLEEDING RISK FACTORS IN ESSENTIAL THROMBOCYTHEMIAФАКТОРЫ РИСКА РАЗВИТИЯ ТРОМБОТИЧЕСКИХ И ГЕМОРРАГИЧЕСКИХ ОСЛОЖНЕНИЙ ПРИ ЭССЕНЦИАЛЬНОЙ ТРОМБОЦИТЕМИИZhernyakovaA. A.ЖерняковаА. А.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

Контакты: Анастасия Андреевна Жернякова

191024 Санкт-Петербург, 2-я Советская ул., 16

zhernyakova.a@mail.ruMartynkevichI. S.МартынкевичИ. С.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

ShuvaevV. A.ШуваевВ. А.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

PolushkinaL. B.ПолушкинаЛ. Б.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

FominykhM. S.ФоминыхМ. С.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

Udal’evaV. Yu.УдальеваВ. Ю.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

ZotovaI. I.ЗотоваИ. И.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

ShiсhbabaevaD. I.ШихбабаеваД. И.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

VoloshinS. V.ВолошинС. В.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

БессмельцевS. S.БессмельцевС. С.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

ChechetkinA. V.ЧечеткинА. В.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

AbdulkadyrovK. M.АбдулкадыровК. М.
Russian Federation

16 2-ya Sovetskaya Str., Saint Petersburg 191024

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological AgencyФГБУ «Российский НИИ гематологии и трансфузиологии» ФМБА РоссииRussian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological AgencyФГБУ «Российский НИИ гематологии и трансфузиологии» ФМБА России,2706201712230382706201727062017https://oncohematology.abvpress.ru/ongm/article/view/239

Background. Thrombosis and hemorrhage are the main category of complications, that affects the overall survival (OS), quality of life and therapy option choice in essential thrombocythemia (ET). Molecular marker presence (JAK2V617F (JAK2+), MPL (MPL+), CALR (CALR1+-type 1, CALR2+-type 2) or its absence (triple-negative status (TN)) in ET supposed to impact on the clinical course, thrombosis rate and ET prognosis.

The aim of this study was to investigate interactions between the presence of molecular marker, thrombosis/bleeding rates and the OS in ET.

Methods. Outpatient’s charts of 240 ET patients, who had been diagnosed with ET at our institution according to WHO 2008 criteria. The following data were assessed: complete blood count, bone marrow biopsy results, bone marrow cytogenetic, the restriction fragment length polymorphism (RFLP) results used for JAK2V617F detection, in case of JAK2V617F-negative status the PCR-RFLP results (MPL detection) and the direct sequencing results (CALR detection). Different thrombotic/bleeding complications rates were analyzed. The OS in ET patients was compared according to complications and IPSET-thrombosis groups.

Results. Among 240 pts 183 (76.3 %) hadn’t any thrombotic complication or bleeding event (no complications/NC), 57/240 (23.7 %) had complications: 49/57 (85.9 %) reported arterial or/and venous thrombosis, stroke or heart failure (thrombosis+) and 11/57 (19.3 %) had bleeding events (hemorrhage+). Thrombotic complications in JAK2+ had 27.4 % (50/182) pts, in TN – 30.7 % (8/26) pts, in CALR1+ – 18.2 % (2/11) pts and no cases of thrombosis were detected in CALR2+ and MPL+ subgroups (p < 0,001). There were significant statistical differences in median platelet count as follows: 742 . 10 9/L (thrombosis+) and 937 . 10 9/L (hemorrhage+) (p = 0.003). No significant statistical differences in median hemoglobin and leukocyte count (р = 0.75 and р = 0.47) were detected. There were more than a half pts older than 60 years in groups NC (51 %) and thrombosis+ (59 %) and in group hemorrhage+ only 36 % (p < 0,001). Cardiovascular risk factors were reported in 24 % pts (NC), 69 % pts (thrombosis+) and 36 % pts (hemorrhage+) (p < 0,001). There were no significant statistical differences in follows risk factors as platelets count > 1000 . 10 9/L and leukocytosis > 11 . 10 9/L (р = 0.85 and р = 0.72). No significant differences in OS among groups NC, thrombosis+ and hemorrhage+ (р = 0.21) and IPSET-thrombosis groups (р = 0,068) were found.

Conclusion. Along with common thrombotic risk factors (age > 60 and cardiovascular risk factors) mutational status may help to identify ET course. Leukocytosis > 10 . 10 9/L and thrombocytosis > 1000 . 10 9/L cannot be assessed as independent thrombosis risk factors in ET. The JAK2V617F mutation was associated with increased risk of thrombotic complications in ET. CALR mutations were associated with lower thrombosis risk, comparing to JAK2+ status despite the fact of CALR+ patients had higher platelets level.

Введение. Молекулярно-генетический фенотип (носительство одной из мутаций JAK2V617F (JAK2+), MPL (MPL+), CALR (CALR1+ – 1-й тип, CALR2+ – 2-й тип), его отсутствие – тройной-негативный (ТН) статус при эссенциальной тромбоците- мии (ЭТ) рассматриваются в качестве фактора, влияющего на развитие тромбогеморрагических осложнений.

Цель исследования – оценить наличие и характер взаимосвязей между молекулярно-генетическими нарушениями, клинико-лабораторными параметрами и развитием осложнений, прогнозом течения ЭТ.

Методы. Проанализированы данные, полученные на этапе диагностики и последующего динамического наблюдения за 240 пациентами с ЭТ (критерии ВОЗ 2008 г.). Исследовались показатели гемограммы, результаты молекулярно-генетических методов: полиморфизма длин рестрикционных фрагментов (ПДРФ) для определения мутации JAK2V617F, полимеразной цепной реакции с последующим анализом ПДРФ (ПЦР-ПДРФ) для выявления мутаций MPL и прямого секвенирования для обнаружения CALR. Регистрировались тромботические и/или геморрагические осложнения: артериальные/венозные тромбозы, острый инфаркт миокарда (ОИМ), острое нарушение мозгового кровообращения (ОНМК) и кровотечения. Проведен анализ общей выживаемости (ОВ) у пациентов с наличием/отсутствием осложнений, различных групп риска развития тромботических осложнений по шкале риска тромбозов при ЭТ (ВОЗ-ЭТ IPSET-thrombosis).

Результаты. Среди 240 пациентов у 183 (76,3 %) наблюдалось состояние без осложнений (БО), у 57 (23,7 %) развились осложнения, из них у 49 (85,9 %) больных – артериальные / венозные тромбозы, ОНМК и ОИМ (тромбозы+), у 11 (19,3 %) – кровотечения (геморрагии+). Тромботические осложнения в JAK2+ были у 50 / 182 (27,4 %) больных, TН – у 8 / 26 (30,7 %) пациентов, CALR1+ – у 2 / 11 (18,2 %). При CALR2+ и MPL+ тромбозов не отмечено (p < 0,001). Выявлено наличие статистически значимых различий по уровню тромбоцитов между пациентами групп «тромбозы+» и «геморрагии+» (р = 0,003), по уровню гемоглобина и лейкоцитов таковых отмечено не было (р = 0,75 и р = 0,47). Пациентов старше 60 лет было более половины в группах пациентов БО (51 %) и «тромбозы+» (59 %), а в группе «геморрагии+» – значительно меньше (36 %, р<0,001). По наличию сердечно-сосудистых факторов риска в анамнезе (БО – 24 %, «тромбозы+» – 69 % и «геморрагии+» – 36 %) подгруппы также значимо отличались (р<0,001). Различий по гипертромбоцитозу (более 1000.10 9 / л) и лейкоцитозу (более 11.10 9 / л) не получено (р = 0,85 и р = 0,72 соответственно). При анализе ОВ не выявлено статистически значимых различий между подгруппами с осложнениями и без них (р = 0,21) и группами по шкале ВОЗ-ЭТ (IPSET-thrombosis) (р = 0,068).

Заключение. Лейкоцитоз и гипертромбоцитоз не являются тромбогенными факторами. Мутация JAK2V617F ассоциирована с увеличением риска и частоты тромбозов, мутации CALR (вне зависимости от типа) не увеличивают риск и частоту тромбозов, но увеличивают частоту кровотечений.

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