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Inherited thrombocytopenias
study of pregnancy, the risk of bleeding was greater when mothers had a severe bleeding history and a platelet count below 50x109/L. Platelet count appeared more important as a parameter than the genetic cause of the inherited thrombocytopenia.133 Clearly, studies support the classic theory that a primary role of platelets is to maintain vas- cular integrity.135 Nevertheless, many subjects with new forms of inherited thrombocytopenias have modest reductions in platelet count and will bleed rarely or not at all in normal life. Bleeding in such patients depends not only on the extent of the fall in platelet count but also on the nature of accompanying functional defects. Furthermore, much evidence has accumulated on the non- hemostatic roles of platelets.136 Using mouse models, Goerge et al. observed that thrombocytopenia rapidly leads to bleeding in inflamed skin and brain due to the loss of vascular integrity.137 Much needs to be learned on how the genetic defects described in our review influence the non-hemostatic roles of platelets.
Managing bleeding in inherited thrombocytopenia is much the same as in all inherited platelet disorders, with platelet and red blood cell transfusions being the first options. The use of recombinant activated factor VII is especially recommended in BSS in which the absence of a major surface constituent (GPIb-IX-V) makes isoanti- body formation likely and platelet transfusion ineffective.138 Tranexamic acid or local measures are the most frequent options for mild bleeding and tranexamic acid is counseled prior to surgery or childbirth if the thrombocytopenia is severe, with platelet concentrates on standby. A quantitated bleeding score, such as the International Society of Thrombosis and Haemostasis Bleeding Assessment Tool, is useful for assessing disease severity but will not predict bleeding risk.139-141 Curing the disease is still at its debut for inherited thrombocytope- nia. Human stem cell and allogeneic bone marrow trans- plants have been used very successfully in children with WAS in whom the immunodeficiency is accompanied by a major bleeding risk.53 It has also been used in congenital amegakaryocytic thrombocytopenia and more recently in gray platelet syndrome, in which a positive effect was noted on myelofibrosis, but each procedure has its com- plications in terms of donor matching and the choice of conditioning regime.21,48,142 Lentivirus-based gene therapy is already a proven therapy in WAS when donor-match- ing for HSC transplantation is a problem, although restoration of the platelet count remains incomplete.54 Clearly the gain versus risk profile for the patient must be evaluated case-by-case and current gene therapy proce- dures can only be considered when a patient’s long-term survival is in question or perhaps when CRISPR-Cas gene editing becomes available. One highly promising, non- invasive approach to raising the platelet count is the use of the thrombopoietin-mimetics, eltrombopag or romi- plostim.143 Although bleeding is generally mild in MYH9- related disease, eltrombopag was first used successfully prior to surgery in a case with aggravated thrombocy- topenia over 10 years ago.144 Thrombopoietin-mimetics have more recently been used for a patient with a DIAPH1 mutation prior to hip arthroplasty and as a “bridge” for a child with WAS and severe thrombocytope- nia awaiting HSC transplantation.145,146 The goal in such situations is to transiently increase the platelet count to >50x109 platelets/L. Romiplostim has been successful in correcting the platelet count resulting from mutations in
THPO in congenital amegakaryocytic thrombocytopenia in which the patient’s own thrombopoietin is absent or non-functional.147 Overall, a careful and complete diagno- sis is essential for the optimal management of patients, not only for those in need of special care but also to avoid over-reacting for patients with little risk of bleeding.
Perspectives
It is clear that we have entered a new era in the diagno- sis of inherited thrombocytopenias with the arrival of WES, whole genome sequencing and selected high- throughput sequencing platforms. A feature of the reports so far is the large genetic heterogeneity. Crucial for the future will be a better understanding of regulatory DNA elements and untranslated regions, a new science that will include epigenomic profiling.148 The challenges of whole genome sequencing are great but the potential to identify possible pathological traits hidden up to now, including difficult copy number variations and sequence variations deep within introns, is vast. The study of RNA sorting during platelet biogenesis and of the modulating influence of miRNA is also important.149 Despite current technolog- ical advances, a high proportion of new cases of inherited thrombocytopenia remain without diagnosis; this propor- tion is often estimated to be around 50% but can be as high as 70% or more depending on the extent to which patients with easily identified disorders have been pre- screened.127 128, 150,151 Assigning a significance to the variants is key, because in the absence of confirmation with fol- low-up biological studies, including the use of mouse, zebrafish or Drosophila models or site-directed mutagen- esis in megakaryocyte-related cells, the alternative is to use sophisticated bioinformatics; new variants are being variously graded as highly significant and likely pathogen- ic to those of unknown significance.126,131 An early meta- analysis of genome-wide association studies identified 68 common single-nucleotide variants that influenced platelet count or platelet volume; genes already linked to inherited thrombocytopenia, such as THPO, GPIBA, TUBB1 and the pro-survival gene, BAK, were included, but the majority involved genes with no known link to megakaryopoiesis.152 Evaluating the sum of the effects of large combinations of single nucleotide variants and of novel gene variants of unknown significance has barely started yet and they may be disease-modulating, particu- larly if including heterozygous variants of known causal genes.153 Their identification will require large study groups and high-powered bioinformatics beyond the scope of most individual laboratories.
A major challenge posed by inherited thrombocytope- nia is identifying how patients, sometimes within the same family, with an identical genotype can vary so much clinically. In a GAPP study, there were descriptions of patients with excessive bleeding, mild thrombocytopenia and platelet dense granule secretion but with an enrich- ment of heterozygous FLI1 and RUNX1 hypomorphic mutations that were proposed to modulate phenotype.154 On the basis of data from the ThromboGenomics project, we identified a disease-modifying TUBB1 mutation in a patient with classic type I Glanzmann thrombasthenia who, confusingly, also had giant platelets and macrothrombocytopenia.155 Such studies must be just the tip of the iceberg but the benefit of screening against large
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