Chronic isolated macrothrombocytopenia with autosomal dominant transmission: a morphological and qualitative platelet disorder

Abstract

We studied 47 subjects belonging to 13 unrelated families with a history of mild haemorrhagic diathesis and chronic thrombocytopenia. 36 patients presented some degree of thrombocytopenia: 7/36 (19%) had slight thrombocytopenia (100–150×109/L); 26/36 (72%) had mild thrombocytopenia (50–100×109/L) and 3/36 (8%) had severe thrombocytopenia (<50×109/L). No correlation was observed between platelet count and the degree of haemorrhagic diathesis, which was mild in the majority of patients. Transmission was autosomal dominant. Platelet anisocytosis, increased percentage of large platelets and absence of leukocyte inclusions were observed in 26/30 (87%) of the examined blood smears. The ultrastructural appearance of platelets was normal. Megakaryocytes appeared normal in number in 10/10 patients, but showed asynchronous nuclear‐cytoplasm maturation and mainly nonlobulated nuclei. Platelet aggregation was studied in 26 patients and either increased or decreased curves were variably observed in response to different aggregating agents. Platelet‐associated IgG (PAIgG) was increased in 18/31 (58%) patients, while serum autoantibodies against platelet glycoproteins Ib/IX or IIb/IIIa were demonstrable in only 1 case. An increased expression of platelet surface glycoproteins Ib and IIb/IIIa, as studied by murine monoclonal antibodies binding in 17 cases, was observed. Platelet survival performed by 111In‐oxine‐labelled autologous platelets was normal in the 3 studied patients. Congenital macrothrombocytopenia confirms to be a distinct clinical disorder for which the name of “chronic isolated hereditary macrothrombocytopenia” is proposed.

Novel point mutation in a leucine-rich repeat of the GPIb chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant

“…Patients who did not fit the above classification have been assigned to the group of chronic isolated macrothrombocytopenia (CHMT) or Mediterranean thrombocytopenia. 3,4 This form included defects with a similar phenotype, i.e. mild or no hemorrhagic diathesis, autosomal dominant inheritance of the trait, mild thrombocytopenia, variable percentages of giant platelets and a variable aggregation response to 1.5 mg/mL ristocetin.…”

Megathrombocytes and spurious thrombocytopenia

“…A very mild form of ITP, where the platelet destruction is “compensated” by a stimulated thrombopoiesis, could present with a normal or nearly normal platelet count and a high percentage of megathrombocytes. Alternatively, the presence of large platelets could be due to a primary disturbance of haemopoiesis, as happens in chronic myeloproliferative disorders (6), or could have a genetic basis, being included in the large and poorly understood spectrum of familiar disorders of platelet size and number, such as hereditary macrothrombocyto‐penia (7). Megathrombocytes are indeed a well recognised finding of various genetic disorders, such as the Bernard–Soulier syndrome and the May–Hegglin anomaly.…”