Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia

Abstract

In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott–Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.

A novel nonsense variant in TPM4 caused dominant macrothrombocytopenia, mild bleeding tendency and disrupted cytoskeleton remodeling

“…Although no patients with TPM4 ‐RT receiving thrombopoietin receptor agonists have been reported to date, the effectiveness of agents have been shown in other inherited thrombocytopenias with defects of the platelet cytoskeleton, such as MYH9 or DIAPH1 . 10 , 26 …”

“…The most common ITs are macrothrombocytopenia (MCT), characterized by reduced platelet count and increased platelet size or mean platelet volume (MPV). These MCTs are mainly caused by genetic defects affecting early megakaryopoiesis and proplatelet formation 7,10 . In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins 2,7,10,11 …”

“…These MCTs are mainly caused by genetic defects affecting early megakaryopoiesis and proplatelet formation 7,10 . In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins 2,7,10,11 6,12 .…”

“…These MCTs are mainly caused by genetic defects affecting early megakaryopoiesis and proplatelet formation. 7 , 10 In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins. 2 , 7 , 10 , 11 Thus, genetic changes affecting genes of the actomyosin cytoskeleton, such as MYH9 , ACTN1 , or in recent years, FLNA , DIAPH1 or TUBB1 associate with MCT.…”

“… 7 , 10 In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins. 2 , 7 , 10 , 11 Thus, genetic changes affecting genes of the actomyosin cytoskeleton, such as MYH9 , ACTN1 , or in recent years, FLNA , DIAPH1 or TUBB1 associate with MCT. 6 , 12 In 2017, the first five patients from two unrelated pedigrees with mild bleeding and TPM4 ‐related thrombocytopenia ( TPM4 ‐RT) due to the nonsense variant p.Arg69* (NM_003290.3) were identified.…”