Bleeding diathesis in patients with mast cell activation disease

Abstract

Supplementary Material to Seidel et al. "Bleeding diathesis in patients with mast cell activation disease" (Thromb Haemost 2011; 106.5) Definition of mast cell activation disease The term mast cell activation disease (MCAD) denotes a collection of disorders characterized by accumulation of pathological mast cells in potentially any or all organs and tissues and/or aberrant release of variable subsets of mast cell mediators (1, 2). A classification has been proposed which differentiates several types and subclasses of MCAD. The traditionally recognized subclass termed systemic mastocytosis (SM) includes disorders characterized by certain pathological immunohistochemical and mutational findings (the WHO criteria; [3]) which are divided into several subtypes. On the other hand, mast cell activation syndrome (MCAS) presents a complex clinical picture of multiple mast cell mediator-induced symptoms, failure to meet the WHO criteria for diagnosis of SM, and exclusion of relevant differential diagnoses (1, 2, 4-7). Mast cell activation disease in general has long been thought to be rare. However, although SM is truly rare, recent findings suggest MCAS is a fairly common disorder ([2], further references therein). Symptoms observed in patients with MCAS are little, if any, different from those seen in patients with SM ([2], further references therein). The clinical manifestation results from episodic release of both preformed and newly-synthesized mast cell mediators either in response to trigger stimuli or spontaneously. The clinical presentation of MCAD is very diverse, since due to both the widespread distribution of mast cells and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues. Moreover, symptoms often occur in a temporally staggered fashion, waxing and waning over years to decades. Patients often have a history of chronic and acute mediator

Familial Occurrence of Systemic Mast Cell Activation Disease

“…In previous studies we have presented indirect evidence for a potentially high prevalence of MCAD in the general population: (1) In human tissues, mast cells are the principal source of heparin. We found increased heparin levels in blood indicating a pathological increase in mast cell activity in approximately 50% of MCAD patients and and in 17% of the control subjects ([21] and references therein; unpublished data). (2) In our comparative analysis of KIT mutations in mast cells from patients with MCAD and control subjects we detected potentially functionally activating genetic alterations in 13 of 20 patients (65%) and in 3 of 20 control subjects (15%) [22].…”

An update on the new classification of Ehlers‐Danlos syndrome and review of the causes of bleeding in this population

“…In patients with MCAD and EDS, it is imperative for the clinician to recognize that ensuring adequate haemostasis may require mast cell mediator blockers, stabilizers and steroids for acute bleeding. Maintenance treatment with these agents requires careful titration in the chronic setting to prevent reocurrence …”

“…Degranulation releases histamine, heparin, vasoactive intestinal polypeptide, prostanoids, chymase, antithrombin III, tissuetype plasminogen activator, factor VIII and tryptases, which can act as pro-inflammatory mediators and also play a role in bleeding. [48][49][50] Excess production and accumulation of mast cells characterize a wide range of disorders, broadly termed mast cell activation disease (MCAD), which occurs from a pathologic and potentially clonal accumulation of mast cells in various organs and tissues. Organs such as the bone marrow, spleen, liver, GI tract and skin can be involved.…”

Characterization of Mast Cell Activation Syndrome

“…Work was funded by a grant from The Mastocytosis Society and by the University of Minnesota Clinical and Translational Science Institute. All diagnoses met published criteria [history consistent with chronic/recurrent aberrant MC mediator release affecting two or more organ systems, absence of any other evident disease (including mastocytosis) better accounting for all symptoms/findings in the case, and at least two elevated levels of mediators relatively specific to MCs (serum tryptase [12], serum chromogranin A (absent confounders of heart or renal failure or recent proton pump inhibitor use or neuroendocrine cancer) [13,14], plasma prostaglandin D 2 [15,16], plasma histamine [12,16], plasma heparin [16,17,18], urinary prostaglandin D 2 [15,16], urinary N-methylhistamine [19,20], urinary leukotriene E4 [21,22], urinary 11-β-prostaglandin-F 2α [15,16]) and/or increased MCs identified in extracutaneous tissue] [23] and were made at age 16 or older. For purposes of follow-up, data cut-off was June 30, 2014.…”