MYH-9 Related Platelet Disorders: Strategies for Management and Diagnosis

Abstract

MYH-9 related platelet disorders belong to the group of inherited giant platelet disorders. The MYH-9 gene encodes the non-muscular myosin heavy chain IIA (NMMHCIIA), a cytoskeletal contractile protein. Several mutations in the MYH-9 gene lead to macrothrombocytopenia, and cytoplasmic inclusion bodies within leukocytes, while the number of megakaryocytes in the bone marrow is normal. Four overlapping syndromes, known as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome and Sebastian platelet syndrome, describe different clinical manifestations of MYH9 gene mutations. Macrothrombocytopenia is present in all affected individuals, whereas only some develop additional clinical manifestations such as renal failure, hearing loss and presenile cataracts. The bleeding tendency is usually moderate, with menorrhagia and easy bruising being most frequent. The biggest risk for the individual is inappropriate treatment due to misdiagnosis of chronic autoimmune thrombocytopenia. More than 30 mutations within the 40 exons of the MYH-9 gene leading to macrothrombocytopenia have been identified, of which the upstream mutations up to amino acid ∼1400 are more likely associated with syndromic manifestations than the downstream mutations. Diagnosis is based on identification of the granulocyte inclusion bodies using blood smears and immunofluorescence and is finally confirmed by identifying the mutation. Treatment is supportive and should be aimed to prevent iron deficiency anemia. Beside renal failure, the biggest risk for patients affected by a MYH-9 disorder are the adverse effects resulting form treatment based on the misdiagnosis of immune thrombocytopenia.

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

“…Patient 60 did not complain of hearing loss and no proteinuria was detected. The 1841 variant is only rarely associated with renal problems; however, it is recommended to test renal function about once a year and to perform a hearing examination every 5 years in patients with MYH9‐associated thrombocytopenia (Althaus & Greinacher, 2010). …”

Thrombin generation in two families with MYH9-related platelet disorder

“…The bleeding tendency is mild to moderate and easy bruising, epistaxis and menorrhagia are the most prevalent symptoms [3].…”

“…Despite thrombocytopenia, episodes of thrombosis have been reported in a minor subset of patients [3,4]. In one systematic review seven patients with thrombotic events are described, four with myocardial infarctions, one with stroke and two with venous thrombosis (recurrent deep venous thrombosis and portal venous thrombosis respectively) [4].…”

“…In one systematic review seven patients with thrombotic events are described, four with myocardial infarctions, one with stroke and two with venous thrombosis (recurrent deep venous thrombosis and portal venous thrombosis respectively) [4]. Another review described two members of the same family with MYH9-RD who developed coronary artery disease and myocardial infarction requiring coronary artery bypass surgery [3].…”

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

“…In acquired thrombocytopenias, TPO-RAs could increase the risk of thromboembolic events (TEE) [96]. TEE have been reported in patients with ITs [97,98], and some authors hypothesized that the increased platelet size of some IT forms could favor these complications [99,100]. Thus, increased production of large platelets by TPO-RAs administration could particularly predispose to thrombosis.…”