Eltrombopag in preparation for surgery in patients with severe <i>MYH9</i>‐related thrombocytopenia
Authors: Carlo Zaninetti, Serena Barozzi, Valeria Bozzi, Paolo Gresele, Carlo L. Balduini, Alessandro Pecci
Journal: American Journal of Hematology (2019)

Patients with inherited thrombocytopenias often require platelet transfusions prior to surgery if their platelet count is severely reduced. However, platelet transfusions have several drawbacks, as they expose patients to the risk of acute reactions, transmission of infectious diseases, and alloimmunization with consequent refractoriness to subsequent platelet transfusions.1 The latter is a particularly critical event in these patients with lifelong thrombocytopenia. Moreover, the availability of platelet units is affected by the scarceness of blood donors. MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene encoding the non-muscle myosin heavy chain IIA, and represents the most frequent form of inherited thrombocytopenia.2 In 2010, a phase 2 clinical trial reported that the oral thrombopoietin-mimetic eltrombopag is effective in raising platelet count in most patients with this disorder. Eltrombopag was given to 12 patients with platelet counts below 50 × 109/L: 11 subjects obtained a significant increase in platelet count.3 The authors therefore suggested that a short-term course of eltrombopag could be used to prepare patients with MYH9-RD and severe thrombocytopenia for elective surgery, thus avoiding perioperative platelet transfusions. However, clinical evidence on this matter is still scarce: only three single case reports have described successful surgery after eltrombopag administration.4 Since 2010, we proposed short-term eltrombopag to all patients with MYH9-RD who needed elective surgery and had a platelet count too low for a safe procedure according to the current guidelines.5 All patients accepted this treatment. Here, we report the outcome of the 11 consecutive surgical procedures carried out at our institution after eltrombopag administration in five patients with severe thrombocytopenia caused by MYH9 mutations. The main features of patients at presentation are reported in Table S1. Platelet counts ranged from 5 to 25 ×109/L. All subjects presented with spontaneous mucocutaneous hemorrhages. Their ISTH Bleeding Assessment Tool scores ranged from 3 to 22. Three patients had previously undergone major and/or minor surgeries: in all cases, the procedures were prepared with prophylactic platelet transfusions. One patient had always been hospitalized to perform dental extractions or periodontal surgery: some of these procedures were complicated by significant bleeding despite prophylactic platelets (Table S1, patient 3). Another patient had developed refractoriness to platelet transfusions. In fact, she had previously been transfused with platelets before surgery (Table S1, patient 2). Later, she needed hysterectomy due to a rapidly growing uterine mass, but the scheduled surgery was shelved because her platelet count remained around 15 × 109/L despite preoperative transfusion of apheresis platelets. Subsequent investigations detected the presence of alloantibodies against the platelet glycoprotein Ia-IIa complex. Patients 1 and 3 had previously received eltrombopag within the abovementioned clinical trial.3 Preoperative eltrombopag administration and surgical procedures are described in Table 1 and Figure S1. Eltrombopag was started 3 weeks before the procedure. We used the dose of 75 mg/day, as this dosage was associated with a better platelet response compared to 50 mg/day within the previous clinical trial, without any significant safety issues.3 The only exception was patient 1, who had shown a good response to 50 mg/day within the trial and was then treated again with this dose. Easy bruising Gum bleeding Menorrhagia Easy bruising Gum bleeding Menorrhagia Easy bruising Gum bleeding Menorrhagia Easy bruising Menorrhagia Easy bruising Petechiae Gum bleeding Epistaxis Easy bruising Petechiae Gum bleeding Epistaxis Easy bruising Petechiae Gum bleeding Epistaxis Easy bruising Petechiae Gum bleeding Epistaxis Easy bruising Gum bleeding Easy bruising Bleeding from tonsillar tumor In 10 cases (patients 1-4), eltrombopag induced an increase in platelet count that allowed to carry out surgery without the need of platelet transfusions and without any bleeding complications. Procedures included five major surgeries (two orthopedic, one gynecologic, and two cochlear implantations), four dental surgeries, and a percutaneous kidney biopsy. Preoperative platelet counts ranged from 75 to 180 ×109/L. The study of in vitro platelet aggregation in response to collagen, ADP, and ristocetin (Supplementary Methods) showed normal findings, or a slightly reduced response to the lowest ADP concentration in patient 3 (Table S2). All patients reported the disappearance of bleeding symptoms 7 to 10 days after starting treatment. In the patients treated more than once, platelet responses were reproducible over time: for instance, patient 3 received four eltrombopag courses over a 10-year period with very similar results. Eltrombopag was continued 3 to 7 days after surgery: in all the cases, we obtained a stable platelet count up to 5 to 7 days after drug discontinuation (ie, up to 14 days after surgery) (Figure S1). Whenever indicated (major orthopedic and gynecologic surgery), standard antithrombotic prophylaxis with heparin was administered. Of note, patient 3 no longer required hospitalization for dental surgery. Conversely, eltrombopag induced a very slight increase of platelet count in patient 5 (from 5 to 11 ×109/L). In this case, transfusion of apheresis platelets was deemed necessary before the biopsy of a tonsillar tumor. This patient too experienced remission of spontaneous bleeding from the tonsillar lesion following the mild increase of platelet count during eltrombopag treatment. Of note, this patient presented at baseline with a massive splenomegaly of unknown cause, which could have contributed to the failure to significantly increase platelet count through a mechanism of platelet splenic sequestration. Concerning adverse events, patient 3 referred mild headache at the beginning of two eltrombopag courses, which resolved spontaneously after 2 to 3 days. No other adverse events were observed during eltrombopag treatment or at the follow-up visits routinely performed 30 days after surgery. As eltrombopag has been associated with occurrence of cataracts in patients with immune thrombocytopenia, and MYH9-RD is a syndromic disorder predisposing to cataracts,2, 3 ophthalmological evaluation was carried out at every follow-up visit. None of our patients showed occurrence or worsening of cataracts, not even patients 1 to 3 who already presented cataracts at baseline and received repeated eltrombopag courses. In summary, eltrombopag successfully replaced platelet transfusions in preparation for surgery in 10 of 11 cases. Importantly, this drug provided a simple and safe option for increasing platelet count in case of refractoriness to platelet transfusions. Another advantage of eltrombopag compared to prophylactic platelet transfusions is that the drug induced a stable increase of platelet count throughout the perioperative period, thus also allowing the safe administration of a standard antithrombotic prophylaxis, and, in some cases, avoiding hospitalization. In our real-life setting, short-term eltrombopag was safe with no significant adverse events reported. However, since thrombopoietin-mimetics have been associated with potentially severe adverse events in acquired thrombocytopenias, including thrombosis, the risk-benefit ratio of eltrombopag administration should be always carefully assessed for each MYH9-RD patient. In conclusion, our data suggest that short-term eltrombopag should be considered as the first-line treatment to prepare MYH9-RD patients with severe thrombocytopenia for elective surgery. The work of A.P. is supported by a grant from the IRCCS Policlinico San Matteo Foundation and the Fondazione Telethon (GGP17106). There are no conflicts of interest to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.