Рефрактерна імунна тромбоцитопенія (ІТП) є рідкісним захворюванням і може бути «випадковою знахідкою» під час вагітності, але геморагічні ускладнення несуть загрозу для матері і для плода. Лікування рефрактерної ІТП повинно здійснюватися відповідно до Міжнародних рекомендацій з використанням всіх доступних препаратів.
Позитивного результату лікування ІТП під час вагітності вдалося досягнути завдяки використанню правильної тактики розродження і профілактиці кровотечі, що включає в себе 4T стратегію і адекватні дози транексамової кислоти (Сангера) і рекомбінантного тромбопоетину (Емаплаг). Це був перший досвід застосування рекомбінантного тромбопоетину людини у породіль з рефрактерною ІТП в Україні.
MODERN APPROACHES FOR MANAGEMENT OF REFRACTORY THROMBOCYTOPENIA IN PREGNANCY
Davydova Iulia, Limanskaya Alice, Klimenko Sergiy, Mokrik Alexandra, Butenko Ludmila, Ogorodnyk Artem.
SI “Institute of Pediatrics, Obstetrics and Gynecology National Academy of Medical Sciences of Ukraine”.
Thrombocytopenia is one of the hematological diseases, which demands the repeated thrombocytes infusion. The last tendencies in the management of this disease show the enhanced amount of the necessary thrombocytes doses for treatment and the worldwide trend for the declining of donors.
Considerably to these facts the new approaches for the thrombocytopenia treatment have been organized within last two decades. One of them is the finding of the safe, appropriate and effective growth factor for platelets, which could significantly improve the level of thrombocytes.
The thrombopoietin (TPO), the c-Mpl ligand, the primary natural regulator for megakaryocyte and platelets development was purified in 1994, and since that two recombinant forms rh(TPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) have passed through the clinical investigation.
The efficacy of both of them have been proved in different hematological protocols, but showed no benefit in stem cells transplantation and in leukemia chemotherapy.
There are some serious cautions for platelet infusion therapy (PIT) in pregnancy. We do consider two main protocols for PIT in gestation and postpartum period: acute (after bleedings, PPH, postoperative blood loss) and repeated (in patients with comorbidities- leukemia, SLE, ITP, TTP, HUS etc.). In the second situation we have to consider the possible refractoriness and alloimmunization and in both situations we have to assume the possibility of the transmission of the infectious agents (viruses of hepatitis B,C, HIV) and, of course, the transfusion reactions. There is one more important factor for the limitation of platelet infusion – the limited supply of the products and significantly high cost of them. The main consequent approaches for ITP management in pregnancy are represented in the table 1.
In the table 2 we represent the data concerning the PIT and rhTPO usage in pregnancy and postpartum.
Table 1
The main consequent approaches for ITP management in pregnancy
First line therapy | ||||
Initial response | Peak response | Level of evidence | ||
Oral corticosteroids | 2-14 days | 4-28 days | C, D | |
Intravenous immunoglobulins | 1-3 days | 2-7 days | C | |
Second line therapy (for refractory ITP) | ||||
Combined corticosteroids and intravenous immunoglobulins | ||||
Splenectomy (second trimester) | ||||
Third line therapy | ||||
Relatively contraindicated | Anti-D immunoglobulin
Azathioprine |
C
D |
||
Not recommended, but use in pregnancy described
|
Cyclosporine
Dapsone Thrombopoietin receptor agonists Campath-1H Rituximab |
A(C)
C C C C |
||
Contraindicated | Mycophenolate mofetil Cyclophosphamide
Vinca alkaloids Danazol |
C
C D X |
Table 2
Platelet infusion therapy and rhTPO use in treatment of thrombocytopenia during pregnancy
Platelet infusion therapy | rhTPO | ||
Pregnancy
specific causes |
Gestational thrombocytopenia | – | – |
HELLP syndrome | + | n.s. | |
AFLP | + | n.s. | |
Severe preeclampsia | + | n.s. | |
Non- pregnancy specific causes
and thrombocytopenia associated with systemic disorders |
Primary ITP | + | + |
Secondary ITP | + | + | |
TTP/HUS | + | n.s. | |
von Willebrand disease type IIB | + | n.s. | |
Systemic lupus erythematosus | + | n.s. | |
Antiphospholipid syndrome | – | – | |
Viral infections | – | – | |
Drug induced thrombocytopenia | – | – | |
Bone marrow disorders | + | + | |
Splenic sequestration | + | – |
The case of refactory ITP management in pregnancy.
Patient Ch., 25 years of age, diagnosed for ITP at 26 weeks of gestation, the platelet number at the time of diagnostics 20000. The other bone marrow disorders excluded by bone marrow biopsy. The in-patient of the High Risk Pregnancy Department (Obstetric Issues of the Extragenital Pathology) from the 28 weeks of pregnancy. The therapy on the regional level started by oral corticosteroids. The therapy details and platelet response are represented in the Table 3.
Table 3
The management of refractory ITP in pregnancy
Week of gestation | Line of therapy | Dosage | Platelets level | Hemorrhagic signs | |||
28 | 1 line | Prednisone of 1mg/kg daily | 20000 | – | |||
29 | 1 line | IVIg 1 g/kg | 5000 | – | |||
30 | 2 line | Combined corticosteroids and intravenous immunoglubulins | 5000-12000-5000 | – | |||
31 | 2 line | Combined corticosteroids and intravenous immunoglubulins
rh TPO (revalade) Tranexamic acid infusions (Sangera) |
3000-5000 | + | |||
32 | 2 line | rhTPO (revalade)
Tranexamic acid infusions (Sangera)
|
2000-single platelets in blood smear | + | |||
33 | 2 line | rhTPO (revalade)
Azathioprine |
Single platelets in blood smear | + | |||
Pregnancy termination – elective caesarean section (female 2300 g-44 sm)
Prophylactics of hemorrhage (total blood loss 700,0 ml |
|||||||
Tonus | Tissue | Thrombin | Trauma | ||||
Carbetocin after the cord clamping | Argon-plasma coagulator | Platelets infusion – 4 doses of afferent PIT
Octaplex (according to weight in kg) Octagam (according to weight in kg) Erythrocytes infusion |
Low segment incision
Extraction of child in the intact amniotic membranes |
||||
Postpartum period | |||||||
Therapy | Platelets level | Hemorrhagic signs | |||||
PIT + Sangera
Pulse –therapy + Sangera Emaplug s.c. (300 units/kg) + Sangera Rituximab (1 per week) |
Single in blood smear
Single in blood smear Single in blood smear- absent in blood smear-30000 |
+
No major bleeding from the wound by caesarean section performed + No major bleeding from the wound by caesarean section performed – |
Conclusions.
The refractory ITP is a rare disease and could be occasionally seen during pregnancy, but the hemorrhagic complications could be extremely harmful for both mother and child and demand the preterm pregnancy termination. The management of refractory ITP during pregnancy should be performed according to the International recommendations for the thrombocytopenia treatment with all the reserve of the medications. The positive result of the ITP management and perinatal and obstetric outcomes has been achieved through the use of the entire arsenal of drugs, correct tactics of delivery with hemorrhage prevention be using the 4 T strategy and the adequate doses of the tranexamic acid (Sangera) and rhTPO (Emaplug) (Yuriya-Pharm, Ukraine). It was the first implementation of the subcutaneous rhTPO in parturient with refractory ITP in Ukraine.
References
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- Neunert C., Lim W., Crowther M., Cohen A., Solberg L., Jr, Crowther M.A. 2011. The American Society of Hematology 2011 evidence_based practice guideline for immune thrombocytopenia. Blood. 117(16): 4190_207.
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- Xu Zhang,Yajing Zhao, Xiaoqing Li et al. 2016, Feb. 16. Trombopoietin: a potential diagnostic indicator of immune thrombocytopenia in pregnancy. Oncotarget. 7(7): 7489_7496.