Treatment of inherited thrombocytopenias

Abstract

The new techniques of genetic analysis have made it possible to identify many new forms of inherited thrombocytopenias (IT) and study large series of patients. In recent years, this has changed the view of IT, highlighting the fact that, in contrast to previous belief, most patients have a modest bleeding diathesis. On the other hand, it has become evident that some of the mutations responsible for platelet deficiency predispose the patient to serious, potentially lifethreatening diseases. Today's vision of IT is, therefore, very different from that of the past and the therapeutic approach must take these changes into account while also making use of the new therapies that have become available in the meantime. This review, the first devoted entirely to IT therapy, discusses how to prevent bleeding in those patients who are exposed to this risk, how to treat it if it occurs, and how to manage the serious illnesses to which patients with IT may be predisposed.

Figure 1.

Inherited thrombocytopenias (IT) predisposing to other disorders. Based on personal experience (303 consecutive families with IT), 45% of patients with known IT have one of the forms that predispose to additional disorders, including glomerulonephritis, bone marrow aplasia, leukemia and myelodysplastic syndromes. Recognizing patients with the IT highlighted in the figure is important because they need a specific follow-up and can benefit from effective treatments. The prevalence of the forms of IT mentioned in this manuscript are given in Table 1.

Figure 2.

Risk of death in hereditary thrombocytopenias (IT). The collection of large series of patients with IT revealed that the majority of patients have modest to no bleeding diathesis. In addition, available therapies are often able to reduce the risk of bleeding in those with severe forms of IT. The greatest risk is, therefore, that deriving from the possible development of further diseases to which some IT predispose; BM: bone marrow.

Figure 3.

First clinical study with eltrombopag in inherited thrombocytopenias. This figure shows the effect of eltrombopag in 12 patients with MYH9-related disease. Most of them had a clinically relevant increase in platelet count after a few weeks of treatment. (From Pecci et al. with permission.)

Figure 4.

Eltrombopag for preparation for surgery in IT patients. Thrombopoietin receptor agonists is an advantageous alternative to platelet transfusions in the preparation for surgery of patients with forms of IT who respond to this treatment. The figure shows the trend of the number of platelets in one representative patient reported in the study by Zaninetti et al. who used eltrombopag to prepare for 11 surgical interventions. This was an adult subject with severe MYH9-related disease who received eltrombopag in preparation for orthopedic surgery and a rapid normalization of platelet count was achieved. This avoided excessive bleeding during surgery and safe administration of antithrombotic prophylaxis. (From Zaninetti et al. with permission.) LMWH: low molecular weight heparin.

Figure 5.

Romiplostim in patients with a form of inherited thrombocytopenia due to mutation in the gene for thrombopoietin (congenital amegakaryocytic thrombocytopenia [CAMT] variant due to THPO mutation). The figure is from an article reporting an Egyptian family with 4 siblings suffering from this recently identified form of inherited thrombocytopenia. The patient described in the figure is the one with the most severe clinical manifestations. He was born with thrombocytopenia but later developed pancytopenia from bone marrow aplasia. The administration of small doses of romiplostim rapidly increased the values of platelets, neutrophils and hemoglobin. The infections and bleeding stopped, and the patient no longer needed red blood cell transfusions. Of note, the treatment was still effective and well tolerated after 7 years. (From Pecci et al. with permission.) ANC: absolute neutrophil count; HgB: hemoglobin; PLT: platelets.

Figure 6.

Hematopoietic stem cell transplantation (HSCT) in Wiskot-Aldrich syndrome (WAS). Patients with WAS on average die in early adulthood from infections or bleeding. HSCT cures this disease in the vast majority of cases. The best results are obtained when the procedure is performed early. (From Burroughs et al. with permission.) OS: overall survival.