Elevated levels of serum IgM anti‐phosphatidylserine‐prothrombin complex antibodies in patients with cancer‐associated vasculitis

prothrombin complex antibodies in patients with cancerassociated vasculitis Cancer-associated vasculitis has been included in the category of vasculitis associated with probable etiology by the CHCC 2012. Among the many clinical manifestations of cancer-associated vasculitis, cutaneous signs represent earlier and informative diagnostic signs. Antiphospholipid (aPL) antibodies are a group of autoantibodies directed against membrane phospholipids such as phospholipid-binding proteins. Our previous studies have suggested that IgM anti-phosphatidylserineprothrombin complex (aPSPT) antibodies could play a significant role in the pathogenesis of cutaneous vasculitis. We also found that serum IgM aPSPT antibody levels in model rats with cutaneous vasculitis were significantly higher than those of wild-type rats. We retrospectively investigated three patients with cancerassociated vasculitis in the Department of Dermatology at our university. All patients were diagnosed as having cancer-associated vasculitis according to criteria established by McLean et al. aPL antibodies, including aPSPT antibodies, anticardiolipin antibodies, as well as anti-b2-glycoprotein I-dependent cardiolipin (ab2GPI/CL) antibodies, were measured as previously reported. A 65-year-old woman (Patient 1) had small cell lung carcinoma associated with cutaneous vasculitis. She presented with a mildly painful purpuric rash accompanied by swelling and redness on her lower extremities and swollen ankle joints. A 74-year-old woman (Patient 2) had liver cancer associated with cutaneous vasculitis. She showed diffuse palpable purpuric lesions on her swollen lower extremities (Fig. 1a). A 79-year-old woman (Patient 3) had malignant brain tumor associated with cutaneous vasculitis. She presented with painful purpuric rash and edematous erythema in a livedoid pattern on her lower extremities. We detected elevated serum IgM aPSPT antibody levels (18 U/ml) in Patient 1. Patient 2 demonstrated elevated serum IgM aPSPT antibodies (35 U/ml). Patient 3 had elevated serum IgM aPSPT antibodies (22 U/ml). No aCL antibodies or ab2GPI/ CL antibodies were detected in the serum of any of the patients. Antineutrophil cytoplasmic autoantibodies, antinuclear antibody, cryoglobulins, and lupus anticoagulant were negative in all three patients. Complement values were normal in all patients. Histopathological findings of skin biopsies were consistent with necrotizing vasculitis and thrombosis in all patients (Fig. 1b). Direct immunofluorescence studies of skin biopsies revealed IgM deposits within the affected vessel walls of the necrotizing vasculitis (Fig. 1c). The association between aPLs and cancer has been previously reported. Some of these reports have suggested that phosphatidylserine is segregated to the internal leaflet of the plasma membrane in vascular endothelial cell. Loss of asymmetry has been described under different pathological and physiological conditions, including apoptosis and malignant transformation. In fact, Ran et al. demonstrated that anionic phospholipids become exposed on the vascular endothelium of blood vessels in mice bearing malignant tumors. The tumor cells can secrete procoagulants and inhibit anticoagulant properties of endothelial cells. However, it remains unclear whether aPL antibodies, including aPSPT antibodies, have a pathogenic role in the development of thrombosis or, in contrast, these antibodies are an epiphenomenon in cancer patients. The following etiopathogenic hypotheses of cancer-associated vasculitis have recently been discussed: an immunologic dysregulation with a circulating immune complex; handling, production, or elimination of circulating immune complexes; and an immunogenetic abnormality with autogenes and oncogenes with upand/or downregulation of cell proliferation through abnormal apoptosis. In our patients, direct immunofluorescence studies revealed IgM deposits within the affected vessel walls of the