Abstract
Low platelet count is rarely caused by inherited thrombocytopenia. May–Hegglin anomaly is an uncommon condition that falls under the umbrella of familial thrombocytopenia. The condition is under-reported in Saudi Arabia; therefore, we report the current case. This is a 24-year-old Saudi lady, presented to the emergency room with vaginal bleeding. No bleeding occurred at any other sites. She has a positive family history of thrombocytopenia among her father and 2 of her siblings. Her platelet count was 16 × 103/µL with normal other blood count as well as renal and liver panels. She was admitted to the regular bed for investigation as sever thrombocytopenia with suspicion of either familial or immune thrombocytopenia. Further studies showed normal hemostatic, virology, and connective tissue disease markers. Peripheral blood film showed low platelet distribution with occasional large/giant platelets and basophilic inclusion bodies in some neutrophils (Dohle body-like). A picture suggestive of May–Hegglin related thrombocytopenia that was confirmed by the presence of a positive myosin heavy chain 9 (MYH9) gene mutation. In conclusion, there are many difficulties in diagnosing and treating May–Hegglin disorders in females of reproductive age. More research and guidelines are needed to manage inherited thrombocytopenia before and throughout pregnancy.
Introduction
A platelet counts of less than 150 per microliter of blood is known as thrombocytopenia. This may be the result of acquired or inherited factors. 1 Acquired thrombocytopenia can be caused by immune system problems, drug side effects, exposure to toxins, infections, nutritional deficiencies such as vitamin B12 insufficiency, hypersplenism, or decreased platelet production from marrow failure, as in hematologic malignancies. 1 However, hereditary thrombocytopenia, which frequently begins in childhood, accounts for only a small proportion of the etiology of thrombocytopenia. An inherited form of thrombocytopenia includes May–Hegglin anomaly (MHA), Wiskott–Aldrich syndrome, Alport syndrome, Bernard–Soulier syndrome, Fanconi syndrome, and thrombocytopenia-absent radius syndrome.1,2 MHA is an autosomal dominant disease that can present with bleeding tendency, giant thrombocytopenia, and an inclusion body in the granulocyte cytoplasm, the so-called “Dohle” body.2,3 MHA etiology has been attributed to a single-gene mutation that causes deficiency in myosin heavy chain 9 (MYH9).4,5 Furthermore, May–Hegglin thrombocytopenia was first discovered by a German doctor in 1909, with less than hundred reported cases since then. 5 Due to the rarity of the condition and underreporting of its occurrence, the exact epidemiological features of MHA have not been thoroughly established. We describe the case of a newly diagnosed woman of reproductive age who arrived at an emergency hospital with severe thrombocytopenia and per-vaginal hemorrhage. Following a thorough study, a diagnosis of May–Hegglin abnormality with thrombocytopenia was made. This case report aimed to synthesize the current knowledge on MHA and explore its clinical implications, genetic underpinnings, and management strategies.
Case Report
A 24-year-old female, married P0+0, with no previous operation, visited the emergency room complaining of per-vaginal bleeding and was told to have a low platelet count. No bleeding was observed on the other side. She denied a history of a low platelet count before the current onset. She had 2 brothers and 1 sister, and has a positive family history of low platelet counts among her younger sister and 1 of her brothers, as well as, her father. She has no history of bleeding or current bruising. There was no history of thrombosis or B symptoms. The patient denied using any types of herbal medication or other medical therapy for any reason. There was no history of fever, rash, joints pain or fatigue. She was admitted to the regular bed for investigation of suspected familial versus immune thrombocytopenia (ITP). Unfortunately, she refused further management as inpatient care and left against medical advice after extracting all laboratory test including bone marrow biopsy.
Upon examination, the patient appeared healthy, had no palpable lymphadenopathy, a normal ocular examination, a soft abdomen, and no organomegaly. Furthermore, respiratory, cardiovascular, and neurological examinations were unremarkable.
The investigation showed white blood cell count of 7.2 × 103/µL, platelet count of 16 × 103/µL, hemoglobin 13.3 g/dL, and mean platelet volume of 14.9. Furthermore, vitamin B12 levels of 259 IU/L, partial thromboplastin time 30.1 seconds, prothrombin time 10.6 seconds, international normalized ratio 0.96 IU, Von Willebrand activity, and antigen levels were normal. The renal and liver panels were within the normal ranges. Additionally, virology tests, including hepatitis B/C, human immune deficiency virus, cytomegalovirus, and Epstein–Barr virus, were all nonreactive. An extended workup to include connective tissue disease markers and antiphospholipid workup was performed and showed negative results (Table 1).
Blood Counts, Chemistry, Virology, and Serology Test Done for the Patient.
Abbreviations: aCL Ab, anti-cardiolipin antibody; ALT, alanine transaminase; ANA, antinuclear antibody; Anti Beta2GP1, anti beta2 glycoprotein 1 antibody; Anti CCP, anticyclic citrullinated peptide; aPTT, partial thromboplastin time; AST, aspartate transaminase; BUN, blood Urea Nitrogen; CMV, cytomegalovirus; Cr, creatinine; CRP, C-reactive protein; EBV-G, Epstein–Barr virus antigen; ESR, erythrocyte sedimentation rate; HBsAb, hepatitis B virus service antibody; HBsAg, hepatitis B virus service antigen; HEP, hepatitis; Hgb, hemoglobin; HIV, human immune deficiency virus ; IGG, immunoglobulin G; IGM, immunoglobulin M; INR, international normalized ratio; LDH, lactate dehydrogenase; MPV, mean platelet volume; PT, prothrombin time; RF, rheumatoid factor; WBC, white blood cell.
Peripheral blood film (PBF) showed marked thrombocytopenia with rare clumps and occasional large/giant platelets, and no blast or red blood cell fragmentation was observed. Re-examination of PBF showed a basophilic inclusion body in some of the neutrophils (Dohle body), which is suggestive of MHA (Figure 1A-D). Furthermore, a normal bone marrow (BM) biopsy done which was performed. Genetic testing of a BM biopsy revealed a positive MYH9 mutations variant c.5521G>A p. (Glu1841Lys) Chr22:26680520 indicative of MYH9-related thrombocytopenia.
Peripheral blood film (A-D): (A) Low-power view of peripheral blood film, showed low distribution of the platelet. (B) A high-power view of the peripheral blood film, showed giant platelets (blue arrows) and neutrophils with basophilic inclusions (Dohle bodies; orange arrow). (C) Peripheral blood film showing giant platelets (blue arrows) and neutrophils with inclusions (Dohle bodies; orange arrow). (D) Peripheral blood film showing magnified view of neutrophils with inclusions (Dohle body; orange arrow).
Ultrasound abdomen showed an average liver size with homogeneous echo texture and no focal lesions or intrahepatic radicle dilatation. No obvious surface irregularities are observed. The spleen was normal in size measuring (8.1 cm).
The patient continued regular follow-up in the hematology clinic’s outpatient setting and consistently maintained a low platelet count (less than 80) without any bleeding. In spite of this, she considered herself ready to get pregnant and asked for advice on prenatal, antenatal, and postnatal care for her condition.
Discussion
MHA is a rare hematologic disorder characterized by macrothrombocytopenia, fewer platelets than normal, and the presence of Dohle-like bodies in granulocytes, which result from mutations in the MYH9 gene. 5 Most of the reported cases were discovered accidentally with no bleeding tendency; some cases presented with mild-to-moderate bleeding tendency, such as easy bruising, nose or gum bleeding, heavy menstrual cycle or prolonged bleeding postinjury, cut wounds, and postsurgical procedures.5 -7 However, mutations in MYH9 can also be linked to other inherited macrothrombocytopenia diseases, such as Alport syndrome, Fechtner syndrome, Sebastian syndrome, and Epstein syndrome. These disorders (especially Alport syndrome, Epstein syndrome, and Fechtner syndrome) are more associated with hearing loss, renal disease, and cataracts than MHA.5,6 In contrast, Sebastian syndrome has a manifestation similar to MHA but can be differentiated between both conditions by studying the ultrastructural features of inclusion bodies using electron microscopy. 5
The diagnosis of MHA was based on a positive family history of thrombocytopenia, as in our case. Excluding other acquired causes of thrombocytopenia, presence of a low platelet counts in most of cases ranged between 40 and 80 × 109/L, giant platelets and Dohle-like bodies in peripheral blood smear, as well as, genetic testing that confirms mutations in MYH9.5,6,8 Mutated MYH9 is present on chromosome 22q12–13 and encodes nonmuscle myosin heavy chain class IIA (NMMHC-IIA), which leads to defective megakaryocytic maturation and fragmentation.5,6 There is no role of other hematologic tests/investigations, such as bone marrow biopsy (will show normal morphology with no dysplasia or evidence of malignancy) or platelet aggregation (normal). However, the bleeding time can be prolonged in proportion to the degree of thrombocytopenia. 5
Moreover, the work of De Rocco et al advanced our knowledge of MYH9-related illnesses by demonstrating that isolated instances without a family history might make identification more difficult. Their results highlight the need to closely examine blood smears to detect Dohle-like inclusions and large platelets, which are essential for the precise diagnosis of thrombocytopenia associated with MYH9 mutations. 9 Other conditions that could have a Dohle-like body in the PBF, such as pregnancy, postadministration of granulocytic colony stimulating factor, inflammation, burns, sepsis, and myeloproliferative disorders. 10
Hereditary platelet diseases, such as MHA, are thoroughly discussed by Homan et al, who highlighted the difficulties in diagnosing them because of the variation in clinical presentation and genetic etiology. This study emphasizes the importance of comprehensive genetic screening in patients suspected of having inherited platelet abnormalities. 8
In rare situations, MHA may be associated with other diseases, indicating a potential genetic link between MHA and other diseases. Fattizzo et al and Veiga et al explored the broader context of myelodysplastic syndromes and hematopoiesis, indirectly linking insights from these studies to the understanding of MHA. Their findings on genetic mutations and hematologic characteristics provide a backdrop for the complexities involved in diagnosing and managing disorders such as MHA.11,12 Ikawa et al presented a teen-aged case linking MYH9 mutations to both cardiomyopathy and macrothrombocytopenia, suggesting a multifaceted relationship between different genetic disorders. 13
Gülen et al documented a pair of cases: a 14-year-old male who presented with recurrent epistaxis and easy bruising, and a 5-year-old daughter who was unintentionally diagnosed with thrombocytopenia without any bleeding. 6 In a group of 3 cases, Kamath et al reported 2 males and 1 female, all between the ages of 20 and 25 years. One male patient was symptomatic, but the other 2 individuals had mucosal bleeding at presentation, with platelet counts ranging from 14 to 38 × 109/L. This indicates that bleeding with MHA is not predicted to occur with any of the following characteristics: sex, age, or platelet level. 14
Regarding the treatment of MHA, most symptomatic cases require no management, unless active bleeding or prior to surgical intervention are platelet transfusion, desmopressin (DDAVP), or antifibrinolytics (tranexamic acid) is recommended.5,6,14,15 Since it is not an immune condition, studies have shown no benefit of using corticosteroids, intravenous immunoglobulin, plasmapheresis, or splenectomy in MHA.5,14,15 The most important step in management is to avoid platelet dysfunction, as in nonsteroidal anti-inflammatory drug use and some herbal medications. In addition, iron deficiency anemia should be avoided to prevent platelet subendothelial dysfunction.15,16 In cases of prevaginal bleeding in nonpregnant women, hormonal contraceptives and/or tranexamic acid are administered during the first 3 days of menses. If a patient with MHA has coronary artery disease, bare metal stents should be inserted with a short duration of double antiplatelet therapy. 15 Furthermore, a thrombopoietin receptor agonist has been proven effective in these patients; however, it should be used cautiously because the increased production of giant platelets could increase the risk of thrombosis.15,17,18 Ensuring good oral hygiene, gingival examination, vaccination, and genetic counseling are often recommended.
ITP and gestational thrombocytopenia are the most common causes of thrombocytopenia during pregnancy. Hematologists should consider the diagnosis of MHA in pregnant women who do not respond to ITP management. 5 Ultimately, in pregnancies with MHA, there is no significant increase in the risk of bleeding or cesarean section. There is no clear risk of intracranial hemorrhage in infants with MHA9 mutations after vaginal delivery. 15 Genetic mutation tests for MHA have been performed if the baby is born with a low platelet count or bleeding, and a product of 1 parent with MHA as the fetus has a 50% chance of inherited the disease.5,15,19
By sharing our case scenario, we focused on a hidden, yet significant cause of thrombocytopenia. Unfortunately, an examination of the literature reveals few or unreported instances from Saudi Arabia, which suggests that the disease is either underreported or overlooked and that awareness of it has to be increased. Finally, there is a dearth of evidence regarding MHA during pregnancy, which calls for further research in this area.
Conclusion
Hereditary thrombocytopenia, such as MHA, is rare and can be easy to be misdiagnosed as ITP. The diagnosis and treatment of May–Hegglin thrombocytopenia in females of reproductive age present significant challenges for both prenatal and antenatal care. Further studies are required to address the management of hereditary thrombocytopenia before, during, and after pregnancy.
Footnotes
Acknowledgements
We would like to thank the patient for her cooperation and support in the current case report.
Ethical Considerations
Our institution does not require ethical approval for reporting individual cases or case series.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
All the data already involved within the manuscript, there is no additional data.
Informed Consent
Written informed consent was obtained from patients (s) for their anonymized information to be published in this article.
Declaration
This report follows the CARE guidelines for reporting research by applying the CARE checklist.20