Patients with MYH-9 mutation related macrothrombocytopenia are often misdiagnosed as having immune thrombocytopenia, which then prompts ineffective and even potentially harmful treatments like intravenous IgG, immunosuppressive therapy and splenectomy. As the disease is dominantly inherited all first-degree relatives should be assessed for macrothrombocytopenia as the bleeding history alone is not sensitive enough. If the platelet count is normal, MYH-9 disease is excluded, and this individual person cannot pass the mutation. Usually, the history of older affected relatives provides an estimate of the risk to develop premature cataract, hearing loss and renal dysfunction. However, some individuals are more affected than others, even within the same family. We therefore recommend testing of renal function about once a year and performing a hearing test every 5 years.
Corticosteroids, intravenous IgG, and splenectomy are ineffective in increasing platelet counts or reducing bleeding tendency in these patients. Patients with MYH-9 related disorders usually do not have life-threatening bleeding, and in general the recommendations for other bleeding disorders such as mild von Willebrand syndrome also apply for MYH-9 disorders. Patients should avoid any medications that impair platelet function, e.g. aspirin and other non-steroidal anti-inflammatory drugs unless there is symptomatic arterial disease which mandates secondary prophylaxis. If these patients require a coronary stent, bare metal stents might be better suited than drug eluting stents, as they require a shorter duration of double antiplatelet therapy.
The most important preventive measure is to avoid iron deficiency anemia, especially in women at childbearing age. A low hematocrit will exacerbate the impaired platelet-subendothelial interactions (impaired primary hemostasis) even in patients with normal platelets [32
]. Giant platelets tend to localize more into the middle of the blood flow and need the red blood cells to be shifted towards the vessel wall, thus enhancing their potential for subendothelial interaction [31
] Hormonal contraceptives can reduce menorrhagia as well as tranexamic acid at a dose of 3 × 1 g/day during the first 3 days of the menses. Desmopressin given as nose spray is little effective in MYH-9 related menorrhagia.
As inflamed and hyperemic gingival tissues are a risk factor for gum bleeding, regular dental care can help to avoid this additional cause of chronic blood loss.
Until now there is no known treatment to prevent the non-hematopoietic manifestations of NMM-IIA
mutations. NMM-IIA is important in stabilizing the cilia in the inner ear. Avoiding very loud noise at younger age might slow down the process of hearing loss, and cochlear implant should be an option to improve hearing in patients with deafness. In recent studies individuals with renal involvement had their proteinuria reduced by treatment with angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors [33
]. In MYH-9 related disease pharmacological blockade of the renin-angiotensin system reduced proteinuria in 4 individuals [34
]. This treatment should be offered to patients who show first symptoms of renal affection. However, it remains unclear whether this therapeutic approach prevents or delays the development of renal failure.
Pregnancy and childbirth do not appear to be associated with a major increase in bleeding complications in women with MYH-9 disorders. Furthermore, family histories suggest that spontaneous delivery do not put newborns with MYH-9 mutation at increased risk for intracerebral hemorrhage. MYH-9 macrothrombocytopenia by itself does not mandate cesarean section. However, in case of prolonged labor, cesarean section might be less traumatic than other obstetrical interventions for affected children. If the mother or the father has an MYH-9 disorder, the platelet count of the newborn should be assessed directly after delivery, and in case of a low platelet count a cranial ultrasound should be performed to exclude intracranial hemorrhage which might require platelet transfusion.
We recommend all routine vaccinations, especially vaccinations for pertussis to avoid cough induced hemorrhage and for measles to prevent viral megakaryotoxicity. There are no data indicating that routine vaccination is associated with relevant intramuscular bleeding, but if the vaccine is approved for subcutanous application this route should be preferred.
Perisurgery major hemorrhage is rare in patients with MYH-9 disorders, and prophylactic platelet transfusions are not indicated even if the platelet count is low. We have managed individuals with MYH-9 disorders through a wide variety of surgical interventions, including dental extraction, tonsillectomy and adenectomy, cataract lens replacement, cesarean section, orthopedic joint replacement, cardiopulmonary bypass surgery as well as neurosurgical interventions. Our standard protocol is to give desmopressin 0.3 μg/kg body weight before surgery and 24 h later, and to combine this with tranexamic acid 0.5 g orally three times a day for 5 days after surgery (local application by mouth rinse after dental extraction). When the platelet counts of individuals with MYH-9 disorders are monitored, e.g. before and during interventions, it is important to use always the same counting machine as different machines show different error rates with giant platelets and a large unexpected decrease in platelet counts may simply result from using another machine.
While the literature does not report on increased bleeding after surgical interventions in MYH-9 disorders, we are aware of patient histories of major bleeding after tonsillectomy. Sehbai et al. [35
] reported a neurosurgical intervention in an individual with MYH-9 with administration of desmopressin without bleeding complications. McBane et al. [36
] reported hip arthroplasty in a patient with MYH-9 giant platelets without abnormal bleeding. At least 2 patients with MYH-9 related disorders are reported who developed thrombosis following surgery [37
]. Therefore thrombosis prophylaxis should be given in situations with a high risk of thrombosis. This is especially important if also antifibrinolytic agents are given to prevent bleeding after surgery.
Very recently thrombopoietin receptor analogues have been approved (Romiplostim (Nplate®) and eltrombopag (Revolade®, Promacta®)). We recommend to be very careful in applying these drugs to patients with MYH-9 disorders. MYH-9–/–
deficient stem cells differentiate into megakaryocytes that are fully capable of proplatelet formation, and thrombocytopenia in MYH-9 disorders results from ineffective platelet maturation due to the cytoskeletal abnormalities rather than from impaired megakaryopoiesis [39
]. It is therefore likely that the thrombopoietin receptor agonists increase production of even larger platelets because the fragmentation defect is still present. These giant platelets are larger than the diameter of capillaries in the microcirculation and increasing the number of giant platelets may worsen the microcirculation because of the changed rheologic situation.