Современные подходы к лечению рефрактерной иммунной тромбоцитопении при беременности (на английском языке)

Рефрактерная иммунная тромбоцитопения (ИТП) является редким заболеванием и может быть «случайной находкой» во время беременности, но геморрагические осложнения несут угрозу для матери и для плода. Лечение рефрактерной ИТП должно осуществляться согласно Международным рекомендациям с использованием всех доступных препаратов.

Положительного результата лечения ИТП во время беременности удалось добиться благодаря использования правильной тактики родоразрешения и профилактике кровотечения. Включающей в себя 4T стратегию и адекватные дозы транексамовой кислоты (Сангера) и рекомбинантный тромбопоэтин (Емаплаг). Это был первый опыт применения рекомбинантного тромбопоэтина человека у рожениц с рефрактерной ИТП в Украине.

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

  • Imbach P., Crowther M. 2011. Thrombopoietin_receptor agonists for primary immune thrombocytopenia. N Engl J Med.365(8): 734_41.
  • 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.
  • Provan D., Stasi R., Newland A.C., Blanchette V.S., Bolton_Maggs P., Bussel J.B., Chong B.H., Cines D.B., Gernsheimer T.B., Godeau B., Grainger J., Greer I., Hunt B.J., Imbach P.A., Lyons G., McMillan R. et al. 2010. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 115: 168_186.
  • 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.
Автор: Давыдова Ю.1. Лиманская А.1. Клименко С.2. Мокрик А.1. Бутенко Л.1. Огородник А.1. 1 – ГУ «Институт педиатрии, акушерства и гинекологии Национальной академии медицинских наук Украины». 2 – ГУ «Украинский центр радиационной медицины Национальной академии медицинских наук Украины».
Опубликовано: журнал «Перинатология и педиатрия», № 4(68)/2016.
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