Congenital Thrombocytopenia and CytochromecMutation: A Matter of Birth and Death

Abstract

Thrombocytopenia (TP) Cargeeg is a unique autosomal dominant disorder, affecting a seven-generation family, caused by cytochrome C (CYCS) mutation that dysregulates platelet formation. The CYCS mutation in this disorder is a glycine 41 replacement by serine, which yields a cytochrome C variant with enhanced apoptotic pathway activity in vitro. The deregulated apoptosis in this disorder affects megakaryocytes (MK) during platelet formation, leading to early and ectopic platelet release in the bone marrow (BM). Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome C activity is not a critical regulator of physiological apoptosis in most cells. The pathophysiology of this unique inherited TP, with unaltered platelet survival and normal MK content in the BM, has implications for physiological and pathological mechanisms altering MK apoptosis, with implications for other unexplained thrombocytopenic disorders.

Interspecies Variation in the Functional Consequences of Mutation of Cytochrome c

“…Analyses of bone marrow electron micrographs and in vitro platelet production suggest accelerated platelet production resulting in platelet release into the bone marrow space instead of the circulation [1,7]. Some evidence supports the role of the intrinsic apoptosis pathway in platelet formation [8,9], while others demonstrate that, at least in mice, the apoptotic pathway needs to be restrained for effective platelet formation [10–12].…”

Expert Approaches to Common Bleeding and Thrombotic Problems, Part II

“…6 The sixth article, by Balduini et al, presents an expert approach to the diagnosis and management of inherited, thrombocytopenic platelet disorders 7 -a topic that has been the focus of several articles recently published in Seminars in Thrombosis & Hemostasis. [13][14][15][16][17][18][19][20][21][22] In their contribution, Balduini et al provide an update on the characterized disorders associated with congenital thrombocytopenic with discussion of their pathogenesis, diagnosis, management, and prognosis. 7 They provide a helpful framework for exploring when a low platelet count might be due to an inherited cause and the tests that may be helpful in establishing a specific diagnosis, which is not always possible.…”

Thrombocytopenic Platelet Disorders

“…Together, the articles illustrate how a low platelet count can reflect defects in platelet birth or a reduced life span, and that some disorders uniquely alter the phenotype of circulating platelets. [4][5][6][7][8][9][10][11][12][13][14] The issue also reviews important acquired, immune thrombocytopenic disorders, including two fascinating but quite distinct immune-mediated thrombocytopenic disorders: immune thrombocytopenia (ITP) [4][5][6] and heparin-induced thrombocytopenia (HIT). 7 The article by Pels is focused on ITP diagnosis (including how to categorize ITP as newly diagnosed, persistent, or chronic) and treatment.…”

“…7 The remaining articles of this issue provide an update on several congenital disorders associated with reduced platelet numbers ( Table 1). [8][9][10][11][12][13][14] These inherited platelet disorders include rare, autosomal recessive conditions, 9,10,12,13 autosomal dominant conditions, 8,12,14 and X-linked disorders (Table 1). While gain-of-function defects are uncommon among platelet disorders, two conditions discussed in this issue, thrombocytopenia Cargeeg 8 and Quebec platelet disorder (QPD) 14 are due to unique, gain-of-function problems.…”

“…Bordé and colleagues provide an expert review on thrombocytopenia Cargeeg. 8 This intriguing thrombocytopenic disorder is associated with a point mutation in cytochrome c and the premature release and destruction of platelets in the bone marrow of affected heterozygous individuals. 8 The authors discuss the clinical manifestations and pathogenesis and also summarize current knowledge about the processes of megakaryopoiesis and platelet release.…”