Romiplostim (Nplate®) and Oprelvekin (Neumega®) Correct Thrombocytopenia in TAR Syndrome (Thrombocytopenia with Absent Radii)

TAR Syndrome is characterized by absence of radii with preservation of thumbs and thrombocytopenia. It is caused by a microdeletion on 1q21.1 that encodes RBM8A gene, leading to deficiency of RNA binding protein Y14, involved in the nuclear export of transcripts and translational enhancement in all hematopoietic linages. Inheritance is generally autosomal recessive but up to 25% of cases are of de novo pattern. Thrombocytopenia is commonly detected at birth and platelet counts in most cases increase by the age of 2, but not reaching to normal levels in adulthood. Bone marrow characteristically show low number of megakaryocytic progenitors, although thrombopoietin (TPO) levels are elevated and corresponding receptors are expressed on cells without mutations on coding exons. (Semin Hematol. 2013 Oct;50(4):333-47)

TPO signaling via Jak2 phosphorylation has been reported abrogated in childhood with progressive restoration in adulthood. Despite the latter, platelet counts do no normalize, suggesting that that biogenesis is not reconstituted. Dysmegakaryopoiesis in early stages of megakaryocyte maturation is considered the primary cause of thrombocytopenia. Functionality can be impaired due slightly reduction of CD42b/CD42a (GPIX/GP1BA), CD29 (integrin B1) and CD49e (fibronectin receptor). (Haematologica. 2012 Jan;97(1):73-81)

We report the case of a 43 year-old female from Cuba with TAR syndrome. Due religious beliefs, she refused blood products. Thrombocytopenia was discovered at the age of 2 with a self-reported platelet count was 3 000/μL. Over childhood and youth she had multiple episodes of thrombocytopenia with easy bruising, diffuse petechiae and menorrhagia. Patient was treated in country of origin with prolonged courses of high dose steroids without success.

She was referred to us in 1999 for management of thrombocytopenia during pregnancy. Platelet counts ranged from 10 000/μl to 19 000/μl while pregnant. She underwent caesarian section with a platelet level of 12 000/μl without bleeding complications. Bone marrow biopsy while pregnant was reported as normocellular with decreased numbers of megakaryocytes.

Overtime multiple unsuccessful therapies have been tried including steroids and danazol. Platelet have oscillated in between 30 000/μl to 101 000/μl without correlation with any intervention. Laboratory investigation were non-suggestive of immune thrombocytopenic purpura, as antiplatelet antibodies to glycoproteins IIb/IIIa, Ib/IX, IV were negative. Platelet activation markers such as CD62P fluorescence index, platelet microparticles and circulating activated platelet aggregates were normal. Electronic microscopy showed a larger cluster of glycogen and microtubular banding. Her TPO level was found elevated on 336pg/ml when her platelet count was of 30 000/μl.

Patient had a major episode of gynecological hemorrhage with hemodynamic compromise in 2007 due to bleeding from uterine fibroids that required emergent embolization. She responded well to Oprelvekin (Neumega) 50 mcg/Kg subcutaneous daily for 3 days. Platelet count was increased from 40 000/μl to 189 000/μl in 72 hours. Platelet counts slowly decreased to a baseline of 60 000/μl over a period of 4 months after discontinuation.

She required an elective maxillofacial surgery in 2016. Patient was treated with Romiplostim (Nplate) 2mcg/Kg subcutaneously weekly. After 3 doses, platelet counts rose from 30 000/μL to 160 000/μl. The procedure underwent without any bleeding complications. Platelet count dropped to 60 000/μl after discontinuation of Romiplostim over a period of 3 months were have remained stable.

We report here that Oprelvekin and Romiplostim corrected thrombocytopenia in TAR syndrome. The first, a recombinant Interleukin-11 that induces megakaryocytic fragmentation and maturation. The second, a synthetic thrombopoiesis stimulating protein with a different structure than recombinant TPO, that has shown in vitro to promote maturation via jak2 phosphorylation. In view of high TPO levels in this case, synthetic peptidase appears more potent than recombinant TPO in promoting megakaryocyte maturation and platelet production. Both medications are complementary in platelet biogenesis but effective in improving platelet counts when used independently. The molecular mechanisms underlying such responses to these agents remain to be elucidated in the future studies.