Mast Cell Disease and Blood Coagulation Abnormalities: Discussion on 14 Cases and Review of the Literature

INTRODUCTION

Mast cell disease is a clonal haematological disorder resulting in organ infiltration by mast cells and uncontrolled degranulation (mast cell activation syndrome, MCAS). Although not characteristic and poorly explained, both primary (platelet’s adhesion and aggregation) and secondary (coagulation cascade leading to thrombin formation) clotting abnormalities are observed among some patients.

METHODS

We retrospectively identified patients with established diagnosis of mastocytosis and related clotting abnormalities (clinical and/or biological) using the French National Reference Centre for Mastocytosis database.

RESULTS AND DISCUSSION

Our cohort included 14 adult patients (median age of 42 [range 26-78] years, sex ratio 3.7, CKIT D816V in 13/14 cases, median tryptase of 200 [4-1240] ng/mL).

Four patients had typical symptoms and/or clotting tests (PFA, von Willebrand’s disease [vWD] screening) indicating abnormalities of primary haemostasis [Table, patient 1], with n=1 confirmed and n=2 highly suspicious of vWD. They presented with either nil (n=1) or mild (n=3) mucocutaneous bleeding. This could be due to heparin binding to von Willebrand’s factor, therefore preventing platelet aggregation.

Ten patients had abnormalities of coagulation cascade (prolonged PT, aPTT, reduced clotting factors II, V, VII, X), usually transient but with bleeding in 7 cases (severe/life-threatening in 5 of them ) [Table, patient 3]. Clotting abnormalities were typically accompanied by anaphylactoid symptoms of MCAS and increased by the presence of hematopoietic organ infiltration [Table, patients 2-4]. Haemostatic management (red blood cells and platelets transfusion, fresh frozen plasma, vitamin K, antifibrinolytic) was unsuccessful, while control of mast cell activity (e.g. with and steroids) would achieve haemostasis, indicating the crucial role of mast cell mediators. These mainly include tryptase and heparin, which inhibit the intrinsic pathway, inducing an anticoagulant state.

The exact prevalence of clotting abnormalities in mastocytosis remains unclear and probably underestimated. However, we found a predominance of aggressive types of mastocytosis in the population with coagulation cascade abnormalities: 50% had aggressive systemic mastocytosis associated or not with a clonal haematological non mast cell lineage disease (ASM/AHNMD), 30% had mast cell leukaemia (MCL). All deceased patients (n=5, 36% of the overall population) belonged to this group. In contrast, mastocytosis was indolent in 75% of cases in the group with primary haemostasis abnormalities.

AHNMD: associated clonal haematological non mast cell lineage disease; aMCL: acute mast cell leukemia; aPTTr: activated partial thromboplastin time ratio;CM: cutaneous mastocytosis; H/SMG: hepato or splenomegaly; GI: gastrointestinal; ISM: indolent systemic mastocytosis; N: normal; SSM: smouldering systemic mastocytosis; PLT: platelet, in x10³/µL; PTr: prothrombin time ratio; SDH: subdural haematoma. Reference values are indicated below PLT, PTr, aPTTr. ^†: patient deceased from the disease or complications of the latter. *6 months later.

CONCLUSIONS AND PERSPECTIVES

Blood coagulation abnormalities in mastocytosis appear secondary to a hyperactivity of the clonal mast cell, resulting in an anticoagulant state and typically presenting in the context of MCAS and/or significant mast cell proliferation. They are particularly prevalent in aggressive types of mastocytosis, and are only successfully controlled by mast cell inhibitors, notably steroids. More data are required to better correlate clinical and biological pictures, and to assess whether standard or specific clotting tests could be used as a marker of mast cell activity and potentially of poor prognosis in patients with systemic mastocytosis.