Perioperative Eltrombopag in Patients With Inherited Thrombocytopenia

The objective of the study is to estimate the response to eltrombopag based on platelet count increase above a safety level of 80 G/L and lack of requirement for pre-, per- and post-operative administration of platelet concentrates (PC) for performing elective invasive acts at mild or high bleeding risk,in selected patients with inherited thrombocytopenia (IT).

The hypothesis of the trial is that preoperative treatment by a thrombopoietin mimetic (eltrombopag) will be effective and safe and will avoid requirement of PC administration in a majority of IT patients Eltrombopag is a thrombopoietin mimetic available orally, not licenced for the treatment of IT. Preliminary data in short series of IT patients indicate that eltrombopag, at the doses used in primary immune thrombocytopenia, increases the platelet counts after 2-4 weeks of treatment and reduces spontaneous bleeding in a significant proportion of subjects. The tolerance of short-term treatment is good. The experience of eltrombopag for the management of perioperative thrombocytopenia in IT is anecdotic. Avoiding the administration of platelet concentrates in these patients, especially children, would represent a direct benefit by preventing adverse reactions to transfusion of blood products and human leukocyte antigen (HLA) immunisation.

Eltrombopag will be prescribed after the inclusion visit at the standard dose of 50 mg/day with dose adjustment on the platelet count (+/- 25 mg) after 2 weeks, for a maximum of 4 weeks before the invasive procedure. If the predefined safety level of platelet count required for the procedure is reached, the treatment will be discontinued and the patient operated without prophylactic administration of PC. In case of bleeding of undetermined cause per-and post-operatively, rescue PC will be given.

Clinical and biological follow-up will be performed until the end-of-study visit, 4 weeks after the intake of the last tablet of eltrombopag.

Eligibility Criteria:
Inclusion Criteria:

* Symptomatic patients with bleeding history and chronic thrombocytopenia with strong presumption of constitutional origin on the basis of

  * the identified mutation and/or
  * a combination of the following criteria: familial antecedent with Mendelian transmission, duration of thrombocytopenia, suggestive syndromic presentation, and evidence against primary or secondary immune thrombocytopenia, especially absence of immunologic markers and failure of previous conventional or immunosuppressive therapies.
* Averaged platelet counts during the last five years below the safety level required for the procedure.
* Scheduled (\>4 weeks) surgery or invasive procedure with anticipated risk of bleeding: e.g. needle biopsy of solid organ (liver, kidney....etc.), interventional endoscopy, major surgeries, or surgery without possibility of mechanical control of haemostasis (e.g. tonsillectomy). Written informed consent of the patient or his (her) parents or tutors (patients \< 18 yrs).

Patients included in the French national registry of rare platelet disorders

* Patient with social insurance coverage

Exclusion Criteria:

* questionable constitutional origin;
* definite platelet dysfunction associated to thrombocytopenia (eg: gray platelet syndrome, NBEAL2 and related gene mutations, homozygous Bernard-Soulier Syndrome);
* thrombocytopenia with predisposition to hematologic malignancies (e.g; RUNX1, ETV6 or ANKRD26 gene mutations).
* amegakaryocytic thrombocytopenia resulting from mutations in the thrombopoietin (TPO) TPO-Mpl receptor, supposed, by definition, to be hardly responsive to receptor agonists.
* questionable requirement of prophylactic PC transfusions;
* procedure usually associated with platelet consumption requiring transfusions of PC (e.g.: cardiac surgery), making difficult the evaluation of success or failure;
* procedures at risk of bleeding with immediate vital or functional consequences (e.g.: intra cranial surgery);
* personal history of arterial or venous thromboembolic events or known familial thrombophilia;
* association with another acquired or constitutional hemorrhagic diathesis;
* chronic hepatitis, cirrhosis, with moderate to severe liver failure (Child-Pugh score ≥5);
* previous or concurrent myeloid malignancy, including myelodysplastic syndrome;
* alanine aminotransferase (ALT) or bilirubin levels 2 times the upper limit of normal (ULN);
* altered renal function (creatinin clearance \<30 ml/min);
* pregnancy (negative test required before inclusion in fertile women) or lactating women;
* refusal of safe contraception;
* ocular lenses opacity;
* hypersensitivity to eltrombopag or one of excipients;
* previous participation to the present study;
* current treatment with antiplatelet drugs, anticoagulants or direct acting antiviral agents approved for treatment of chronic hepatitis C infection;
* psychiatric, social or behavioral condition judged to be non-compatible with the respect of the protocol, including good observance of treatment and compliance to follow-up;
* adult protected by the law.