Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease

Abstract

Glanzmann thrombasthenia is a rare autosomal recessive inherited bleeding disorder characterized by the lack of platelet aggregation, caused by deficiencies and/or abnormalities of platelet GPIIb-IIIa receptor. We report a case of Glanzmann thrombasthenia combined with type 2N von Willebrand disease (VWD), a variant characterized by an impaired capacity of FVIII to bind von Willebrand factor (VWF), which results in an autosomally transmitted reduction in circulating FVIII levels. Glanzmann thrombasthenia stems from compound T1214C and G1234A mutations in the ITGA2B gene; the type 2N VWD is due to a heterozygous G2561A mutation in the VWF gene (R854Q). The haemostatic phenotype of a 48-year-old female patient was unusually characterized by a severe chronic arthropathy with loss of cartilage and the presence of subchondrial cysts involving both ankles. The arthropathy was quantified with the compatible MRI scoring system (currently used to assess arthropathy in haemophilia), reaching almost the highest score. These haemorrhagic complications are very rare in Glanzmann thrombasthenia and resemble those seen in severe haemophilia; for such, a reason we decided to explore the patient's FVIII and VWF parameters. Our findings suggest that the type 2N R854Q mutation, which is normally asymptomatic at the heterozygous level, may be expressed in the presence of a combined impairment of primary haemostasis.

Type 2N von Willebrand disease: Characterization and diagnostic difficulties

“…We surmise from these findings that an associated haemostatic defect, even a mild decrease in VWF levels, can increase the expression of the type 2N VWF defect. This hypothesis is supported by our recently reported findings in a patient with Glanzmann thrombasthenia carrying the p.R854Q mutation, 26 this approach seems to have enabled us to avoid any false negatives.…”

Coincidence of Glanzmann's thrombasthenia with hereditary haemorrhagic telengiectasia in a man with gastrointestinal bleeding

“…Glanzmann's thrombasthenia is an autosomal recessive bleeding diathesis with variable haemorrhagic pattern [4,5]. Whereas some affected individuals have severe, frequent and potentially fatal bleeding, others may experience minimal bruising [6].…”

Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation

“…In fact, platelet disorders can sometimes coexist with coagulation factor defects or von Willebrand disease (VWD) that can determine bleeding manifestations such as deep muscle hematomas or hemartrosis. 3,18,19 Moreover, some specific IPFDs show unusual clinical features: for example, the Quebec platelet disorder is associated with delayed bleeding, typically starting 12 to 24 hours after surgery or trauma, that can be controlled with antifibrinolytics but not with platelet transfusions 20 ; in the Scott syndrome, affected persons have mild postoperative or postpartum bleeding, trauma-related hematoma, and bleeding after tooth extraction but rarely spontaneous hemorrage. 21 The use of a bleeding assessment tool is strongly encouraged to standardize the evaluation of bleeding severity, improve diagnostic accuracy and sensitivity, and possibly predict the future risk of bleeding.…”

“…However, excluding the forms for which a candidate gene is known, the identification of new genetic defects underlying an IPFD is challenging and made particularly difficult by the complexity of the mechanisms regulating platelet activation, with many proteins not yet known to be involved in platelet function. Moreover, platelet disorders are heterogeneous and sometimes are coinherited with other genetic defects, such as the association of VWD and Glanzmann thrombasthenia, 18,52 or VWD and heterozygous mutations in platelet proteins (P2Y 12 , TP, and GPVI). 19 Finally, complex genetic conditions such as compound heterozygosity, large chromosome deletions (del11q23-ter in Paris Trousseau syndrome), and compound inheritance of a null allele and one point mutation (the 1q21.1 deletion associated with a point mutation in RBM8A described in thrombocytopenia absent radii 53 ), render the unraveling of an underlying genetic defect particularly complex.…”