Cryoglobulinaemic vasculitis, cryofibrinogenaemia and low-grade B-cell lymphoma
Authors: A.L. Krunic, M.M. Medenica, A.E. Laumann, J.C. Shaw
Journal: British Journal of Dermatology (2003)

Sir, Cryoglobulins and cryofibrinogen are cold‐precipitable proteins that can occur without an identifiable underlying condition (‘essential’ cryopathies) or in association with infectious, autoimmune or lymphoproliferative diseases (secondary cryopathies).1, 2 Cryoglobulinaemic vasculitis (CV) is an immune‐complex‐mediated vasculitis that clinically presents as palpable purpura precipitated by cold exposure.3 It is associated with type II mixed cryoglobulinaemias (MC) (monoclonal component, usually immunoglobulin (Ig)M, polyclonal component, usually IgG) or type III MC (one or more polyclonal components). Chronic hepatitis C (HCV) infection is present in 42–98% of affected individuals with CV.2 Chronic antigenic stimulation may eventuate in mono‐ and oligoclonal expansion of B lymphocytes producing low‐grade lymphoma of the CD5‐positive phenotype.4 Cryofibrinogen consists of aggregates of fibrin, fibrinogen and fibronectin that precipitate at 4 °C and resolubilize on rewarming.5 Cutaneous manifestations of cryofibrinogenaemia (CF) include purpura, livedo and ulcerations.6 An 83‐year‐old white woman presented with a 1‐year history of lower extremity palpable purpura aggravated by cold exposure. Treatment with prednisone and azathioprine produced some remission of symptoms. Six weeks later she developed a fever (38·1 °C) and several large haemorrhagic ulcers covered with black eschar on her lower limbs. Examination at her first visit revealed purpuric macules in a livedo‐like pattern on both legs with larger confluent purpuric patches on the shins and ankles (Fig. 1a). Several, large ulcerations with violaceous borders and necrotic centres were present on the posterior calves, shins and medial malleoli (Fig. 1b). Both index fingers were violaceous with small fingertip ulcers. Blood results showed elevated cryoglobulins 20% by volume (0–0·5%), cryofibrinogen 5% by volume (< 1%), rheumatoid factor 1158 IU mL−1 (< 20 IU mL−1), C3 70 mg dL−1 (83–188 mg dL−1), C4 2 mg dL−1 (18–45 mg dL−1), total haemolytic complement < 100 U mL−1 (180–320 U mL−1), C‐reactive protein 2·2 mg dL−1 (< 0·6 mg dL−1), IgG 612 mg dL−1 (800–1700 mg dL−1), IgM 623 mg dL−1 (60–370 mg dL−1), serum protein electrophoresis showed monoclonal IgMκ, and separate monoclonal free κ and polyclonal IgG. Serum viscosity was 2·3 cp (1·5–1·9 CP). Urinary protein electrophoresis demonstrated monoclonal IgMκ and monoclonal free κ. Bone marrow biopsy revealed atypical CD20 and CD5‐positive lymphoid aggregates (Fig. 2a). The flow immunophenotyping/cytochemistry of the peripheral blood was consistent with low‐grade B‐cell lymphoproliferative disorder. Protein C, protein S, anticardiolipin antibodies, lupus anticoagulant, prothrombin time, partial thrombin time, international normalized ratio, antinuclear antibodies, antineutrophilic cytoplasmic antibodies, HCV antibodies (× 3), HBV surface antigen were normal or negative. Polymerase chain reaction for HCV RNA was negative (< 600 IU mL−1). Radiological studies did not show evidence of multiple myeloma. Biopsy from an area of palpable purpura demonstrated a dense perivascular infiltrate comprising extravasated red blood cells, neutrophils and nuclear dust. Biopsy from the edge of an ulcer revealed thrombi within the vessel wall and evidence of recanalization with minimal inflammation (Fig. 2b). Direct immunofluorescent testing demonstrated perivascular deposits of IgG, IgM and C3.