de médecine interne et maladies infectieuses, Centre Haut-Rhinois de
compétence des maladies systémiques et auto-immunes rares, Hôpital
Pasteur, Hôpitaux civils de Colmar, 39 avenue de la liberté, 68024
2 Laboratoire d’hématologie et d’hémostase, Hôpital Pasteur, Hôpitaux civils de Colmar, 39 avenue de la liberté, 68024 COLMAR.
3 Faculté de médecine, INRA/UMR 1260; 27 boulevard J. Moulin, 13385 MARSEILLE.
4 Service d’hématologie biologique, Centre de référence des pathologies plaquettaires, Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, 26 avenue du Dr Netter, 75012 PARIS
Received: February 17, 2017
Accepted: May 15, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017038 DOI 10.4084/MJHID.2017.038
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thrombosis affecting thrombocytopenic patients is challenging. We
report the case of a woman affected by deep vein thrombosis and
pulmonary embolism in a thrombocytopenic context leading to the
discovery of a heterozygous mutation in the gene encoding ankyrin
repeat domain 26 (ANKRD26) associated with a heterozygous factor V (FV)
Leiden mutation. This woman was diagnosed with lower-limb deep vein
thrombosis complicated by pulmonary embolism. Severe thrombocytopenia
was observed. The genetic study evidenced a heterozygous FV Leiden
mutation. Molecular study sequencing was performed after learning that
her family had a history of thrombocytopenia. Previously described
heterozygous mutation c-127C>A in the 5′untranslated region (5′UTR)
of the ANKRD26 gene was detected in the patient, her aunt, and her
grandmother. ANKRD26-related thrombocytopenia and thrombosis are rare.
This is, to our knowledge, the first case reported in the medical
literature. This mutation should be screened in patients with a family
history of thrombocytopenia.
Taking into account the low platelet count, we used Fondaparinux (7.5 mg/day) for four days as an anticoagulant treatment, relayed by Rivaroxaban 30 mg/day for three weeks, then 20 mg/day for six months. Although the patient was asymptomatic, pulmonary scintigraphy showed a massive bilateral pulmonary embolism. Thrombophilia testing revealed a heterozygous R506Q FV Leiden mutation with no other abnormalities. Lupus anticoagulant, anti-β2GPI antibodies, and anticardiolipin were negative. Oxygen (2L/min) was provided for a total of 6 days. Finally, the diagnosis of inherited thrombocytopenia was suspected because there was a family history of unexplained thrombocytopenia with at least six members known to be thrombocytopenic (Figure 1): her two sisters (Figure 1; III-1 and III-2); her father (Figure 1; II-4); two aunts (Figure 1; II-2 and II-3), and her grandmother (Figure 1; I-2). About the grandmother, we managed to retrieve the platelet count in 2015; they were at 32 G/L at the time. Interestingly, she suffered from 6 pulmonary embolisms (and was treated from 1995 with anti-vitamin K anticoagulant), but never suffered from any bleeding complications.
Sanger sequencing of the 5′UTR part of the ANKRD26 gene demonstrated a previously described heterozygous c-127 C>A mutation. Knowing that result, we decided to conduct familial genetic investigations. Interestingly, the patient’s grandmother was affected by refractory cytopenia with multilineage dysplasia. We evidenced two family members positive for this mutation: the maternal grandmother (Figure 1; I-2) and one aunt (Figure 1; II-2). Nine days after admission, the patient was discharged. Six months after this thromboembolic event, anticoagulant treatment was stopped with no further complications. The patient was lost to follow-up after this last medical consultation, due to a job transfer. This observation is, to our knowledge, the first case of a pulmonary thromboembolic event in a patient with an ANKR26 inherited mutation and a factor V Leiden heterozygous mutation.
|Figure 1. Patient’s family tree|
Thrombotic events described in the literature are mostly arterial: nine MYH9 patients[1,4–5] and three BSS patients developed myocardial infarction, coronary arterial disease, and pons infarction stroke. In contrast, ten Glanzmann patients developed venous thrombosis,[1,6] mas did two MYH9 patients. Traditional risk factors (long flight immobilization, old age, surgery, treatment) associated with venous thrombosis are evidenced in 36% of the cases, other risk factors (V Leiden or JAK2 mutations) in 28%, unknown or undetected risk factors in 36%. In arterial thrombosis events, associated traditional risk factors (HTA, atrial fibrillation, hyperlipidemia, elevated levels of homocysteinemia or cholesterol, atherosclerosis, smoking) are present in 67% of the cases and undetected or absent in 33%. As in our patient, heterozygous FV mutation was detected in three Glanzmann patients with recurrent deep venous thrombosis[7,8] and a JAK2V617F mutation in an MYH9 patient with portal vein thrombosis.
The discrepancy between the macrothrombocytopenia group and Glanzmann patients for thrombotic events remains unexplained because thrombosis may occur whether a functional platelet defect is present (BSS, Glanzmann) or not (MYH9, ANKRD26). In addition, functional defects in Glanzmann and BSS patients are distinct: it has been suggested that the defective binding of Von Willebrand factor (alteration present in BSS) can protect from venous thrombosis, whereas defective binding of fibrinogen (seen in Glanzmann) protects more from arterial thrombosis. This hypothesis could not be totally applied to MYH9 syndrome or our case because these two IPDs have no functional defect. A recent, interesting report found no difference in thrombin potential generation in MYH9 patients with or without arterial thrombotic events, indicating that other factors than the low platelet count might have contributed to the thrombosis. However, few patients were tested in this study. One should also keep in mind not only that few patients who developed thrombosis have been described, but also that the frequency of the different forms of IT is variable. We cannot exclude that in the present report, the risk factors themselves induced venous thrombosis and that the association made herein might be fortuitous.
The IT type diagnosed in this report should also be described. In our patient’s family, thrombocytopenia was a non-syndromic autosomal dominant form with an average MPV. In this disorder, morphologically platelets appeared normal but could be macrocytic,[9,10] sometimes demonstrated with optical microscopy. Electron microscopy studies identified the presence of particulate cytoplasmic structures in ANKRD26 platelets and megakaryocytes of patients with mutations reflecting dysfunctional proteasome pathways. In the group of IT patients with normal MPV, three genes must be sequenced first and foremost: the ANKRD26 gene (OMIM 188000), the RUNX1 gene mutated in the familial thrombocytopenic disorder with predisposition to myeloid leukemia (OMIM 601399), and a recently described gene, ETV6, which confers a predisposition to lymphoid leukemia and solid tumors (OMIM 6000618;). Platelet counts of different ANKRD26 patients published to date vary between 8 and 107 G/L, two patients having normal values.[9,10] There are reports of transient normalization of platelet counts in the setting of an acute infection, as observed in our patient, probably explained by the thrombopoietin level increase, usually found in inflammatory conditions. The bleeding syndrome is usually moderate, and numerous patients have undergone surgeries without platelet support and bleeding. No bone marrow analysis was performed for this diagnosis, but when previously performed, a dysmegakaryopoiesis is described, which contributes to the thrombocytopenia mechanism. Even if severe bleeding affects only a minority of patients, recent studies have pointed out the importance of IT genetic diagnosis.
The majority of the mutations identified are single nucleotide substitutions in the 5′UTR part of the ANKRD26 gene: the most frequent mutations described were c-127 A>T, c-128G>A, and c-134G>A.[9,10,14] One missense mutation in the coding region of the gene was also reported in one family. These mutations might result in the loss of two binding transcription factors that inhibit ANKRD26 expression in normal conditions and induce abnormal persistent activation of the ERK/MAP pathway, leading to the impaired pro-platelet formation and dysmegakaryopoiesis.
Today, it is well established that some ITs are characterized by increased risk of acquiring additional disorders over time that are much more relevant for patients than thrombocytopenia itself. Patients with ANKRD26-related thrombocytopenia have a propensity to develop myeloid malignancies.[17,18] Therefore, recognizing such patients is essential to provide genetic counseling and personalize follow-up, especially if hematological malignancies occur.
All the authors revised the manuscript and read and approved its final version.
AcknowledgementsThe authors would like to thank Ms. Christine Nguyen for her technical assistance.
- Girolami A, Sambado L, Bonamigo E, Vettore S,
Lombardi AM. Occurrence of thrombosis in congenital thrombocytopenic
disorders: a critical annotation of the literature. Blood Coagul
Fibrinolysis 2013 Jan;24(1):18-22. https://doi.org/10.1097/MBC.0b013e3283597634
- Sinzinger H, Kaliman J, O'Grady J. Platelet lipoxygenase defect (Wien-Penzing defect) in two patients with myocardial infaction. Am J Hematol 1991;36(3):202-205. https://doi.org/10.1002/ajh.2830360308 PMid:1899965
- Kubisz P, Stanciakova L, Stasko J, Dobrotova M, Sterenova M, Ivankova J, Holly P. The sticky platelet syndrome: an important cause of life-threatening thrombotic complications. Expert Rev Hematol 2016 Jan;9(1):21-35. Epub 2015 Dec 9. https://doi.org/10.1586/17474086.2016.1121095
- Althaus K, Greinacher A. MYH-9 related platelet disorders. Strategies for management and diagnosis. Transfus Med Hemother 2010;37(5):260-267. Epub 2010 Sep 15. https://doi.org/10.1159/000320335 PMid:21113248 PMCid:PMC2980510
- Zetterberg E, CarissonAlle MS, Najm J, Greinacher A. Thrombin generation in two families with MYH9 related platelet disorder. Platelets 2016;27(3):264-7. Epub 2015 Aug 6 https://doi.org/10.3109/09537104.2015.1064882
- Nurden AT, Fiore M, Nurden P, Pilois X. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability and animal models. Blood 2011 Dec 1;118(23):5996-6005. Epub 2011 Sep 13. https://doi.org/10.1182/blood-2011-07-365635
- Ten Cate H, Brandjes DPM, Smits PHM, Van Mourik JA. The role of platelets in venous thrombosis: a patient with glanzmann's thrombasthenia and a factor V Leiden mutation suffering from deep venous thrombosis. J ThrombHaem2003; 1:394-395. https://doi.org/10.1046/j.1538-7836.2003.00041.x PMid:12871523
- Rezende SM. Secondary prohylaxis with warfarin for recurrent thrombosis in a patient with Glanzmannthrombastenia and F5 G1691A. Br J Haematol 2012;156:144-145. https://doi.org/10.1111/j.1365-2141.2011.08821.x PMid:21848888
- Pippucci T, Savoia A, Perrotta S, Pujol-Noix N, Noris P, Castegnaro G, et al. Mutations in the 5' UTR of ANKRD26, the ankyrin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet 2011;88(1):115-120. https://doi.org/10.1016/j.ajhg.2010.12.006 PMid:21211618 PMCid:PMC3014357
- Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G et et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia analysis of 78 patients from 21 families. Blood 2011;117(34):6673-6680. https://doi.org/10.1182/blood-2011-02-336537 PMid:21467542
- Necchi V, Balduini A, Noris P, Barozzi S, Sommi P, Di Buduo C et al. Ubiquitin/proteasome rich particulate cytoplasmic structures (PaCs) in the platelets and megakaryocytes of ANKRD26-related thrombocytopenia. Thromb Haemost 2013;109 :263-71. https://doi.org/10.1160/TH12-07-0497 PMid:23223974
- Balduini CL, Savoia A, Seri M. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 2013;11(6):1006-19. https://doi.org/10.1111/jth.12196 PMid:23510089
- Cerutti A, Custodi P, Duranti M, Cazzola M, Balduini CL. Circulating thrombopoietin in reactive conditions behaves like an acute phase reactant. Clin Lab Haematol 1999;21(4):271-275. https://doi.org/10.1046/j.1365-2257.1999.00226.x PMid:10583330
- Marquez R, Hantel A, Lorentz R, Neistadt B, Wong J, Churpek JE et al. A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies. Leuk Lymphoma 2014;55:2945-6. https://doi.org/10.3109/10428194.2014.903476 PMid:24628296 PMCid:PMC4206674
- Al Daama SA, Housawi Y, Dridi W, Sager M, Otieno FG et al. A misssense mutation in ANKRD26 segregates with thrombocytopenia. Blood 2013;122:481-2. https://doi.org/10.1182/blood-2013-03-489344 PMid:23869080
- Bluteau D, Balduini A, Balayn N, Currao M, Nurden P, Deswarte C et al. Thrombocytopenia associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 2014;124(2):580-91. https://doi.org/10.1172/JCI71861 PMid:24430186 PMCid:PMC3904625
- Noris P, Favier R, Alessi MC, Geddis AE, Kunishima S, Heller PG, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood 2013;122(11):1987-9. https://doi.org/10.1182/blood-2013-04-499319 PMid:24030261
DV, Bessler M and Olson T. Genetic predisposition to myelodysplastic
syndrome and acute myeloid leukemia in children and young adults. Leuk
Lymphoma 2016; 57(3):520-36 https://doi.org/10.3109/10428194.2015.1115041 PMid:26693794 PMCid:PMC4798888
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