Bone Marrow Transplantation (2000) 26, 1343–1345 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Cryofibrinogenemia and skin necrosis in a patient with diffuse large cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation A Shimoni, M Ko¨rbling, R Champlin and J Molldrem The Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Summary: day 11 (with sustained ANC Ͼ1 × 109/l for 3 consecutive days) and restaging tests on day 30 showed she was in A 34-year-old woman with diffuse mediastinal B cell complete remission. The patient completed the first mainte- large cell lymphoma presented 60 days after high-dose nance course of IL-2 that was given in reduced doses (2 × chemotherapy and autologous stem cell transplantation, 106 U/m2 daily by subcutaneous injection, 25% of planned and post-transplant immunotherapy with interleukin-2, dosing) due to fevers and pancytopenia. with skin necrosis in the ears and extremities. Extensive She presented 2 weeks later, on day 56 of the transplant, work-up revealed the presence of cryofibrinogenemia with symptoms of an upper respiratory tract infection and and associated thrombotic vasculopathy. The patient was given oral antibiotics. A few days later she developed was successfully treated with corticosteroids and thera- fever up to 38.2°C and then rapidly progressive large peutic plasma exchange. However, she had recurrence purpuric/necrotic lesions on her ears, and upper and lower of large cell lymphoma a few weeks later and died of extremities (see Figure 1). The WBC was 3.1 × 109/l, hem- progressive disease. Cryfibrinogenemia and skin oglobin 11.2 g/dl, and platelets 119 × 109/l. A blood smear necrosis may have occurred secondary to the imminent was normal with no evidence of microangiopathy. Electro- relapse, or as a rare complication of high-dose chemo- lytes, creatinine, and liver function tests were within normal therapy or treatment with interleukin-2. Bone Marrow limits. Her LDH was 880 U/l (normal upper limit, 618). Transplantation (2000) 26, 1343–1345. There was no laboratory evidence for disseminated intrava- Keywords: cryofibrinogenemia; lymphoma; stem cell scular coagulation (DIC). Chest X-ray showed a question- transplantation; interleukin-2 able left lower lobe infiltrate. Blood cultures were negative; serology for acute infection with EBV, CMV, hepatitis viruses and Mycoplasma was negative. PCR for hepatitis C virus RNA was negative. Repeat assays for cryoglobulins A 34-year-old woman presented with chest pain and a were negative. There was a low titer (1:256) of cold agglu- mediastinal mass. An open biopsy showed diffuse B cell tinins. Assays of plasma for the presence of cryofibrinogen large cell lymphoma. The patient was treated with the were found to be qualitatively positive on repeat testing. CHOP regimen with an initial good response. However Antinuclear factor, rheumatoid factor, anticardiolipin anti- shortly after the last cycle, she developed fever, night sweats and recurrent chest pain. She had new axillary aden- opathy, as well as re-growth of the mediastinal mass and a b a left lower lobe lung infiltrate. She received a partial course of mantle radiation therapy with prompt resolution of symptoms. She was then given two courses of ifosfamide and etoposide, and achieved a partial response. Peripheral blood stem cells were collected after the second course. The patient proceeded to high-dose chemotherapy with the BEAM regimen. The stem cells were incubated with interleukin-2 (IL-2) prior to infusion and the patient also received IL-2 (1 × 106 U/m2) by continuous intravenous infusion on days 1 to 21 after transplant. She engrafted on Correspondence: Dr J Molldrem, Section of Transplant Immunology, Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 24, Hous- ton, TX 77030, USA Received 19 May 2000; accepted 20 August 2000 Figure 1 Purpuric lesions on right ear and upper right arm. Cryofibrinogenemia post autologous transplant A Shimoni et al 1344 body and Coombs’ test were negative. Complement and toclasis,6 immunoglobulin and complement deposits7 have immunoglobulin levels were within normal limits. Protein also been documented, although these are unusual. Under- electrophoresis and immunofixation of serum and urine lying thrombosis is the dominant feature, but immune showed no monoclonal gammopathy. Levels of protein C mechanisms may be contributing since some patients and S, and antithrombin III were normal. A skin biopsy respond to immunosuppression, such as corticosteroids from the edge of a lesion showed numerous microthrombi and/or cytotoxic therapy. in small dermal vessels, heavy fibrin deposits, and immuno- The treatment of cryofibrinogenemia includes avoidance fluorescence detected trace deposits of IgM and C3. There of cold exposure. Primary cases have been treated with was no inflammatory response surrounding the vessels. anticoagulation,6 and corticosteroids and immunosuppres- The patient was initially treated with broad-spectrum sive agents have been used with variable success.4,5,7 Stano- antibiotics. With these findings she was diagnosed as hav- zol (Sanofi Winthrop Pharmaceuticals, New York, NY, ing thrombotic vasculopathy and skin necrosis associated USA), an androgen steroid with fibrinolytic activity has with cryofibrinogenemia. She was treated with high-dose also been used successfully in the treatment of this syn- methylprednisolone (2 mg/kg daily) and started therapeutic drome.8 There are a few reports of therapeutic plasma plasma exchange. She received 10 treatments over 2 weeks, exchange in refractory patients.5 Our patient had prompt with replacement of 1.5 of total plasma volume with each resolution of symptoms with plasma exchange and corticos- treatment. Her skin lesions healed promptly. teroids suggesting that this is a useful treatment modality She subsequently developed low-grade fever and mild in severe cases. shortness of breath. Chest X-ray showed a left lower lobe Cryofibrinogenemia should be differentiated from other infiltrate and CT scans showed several areas of consoli- causes of thrombotic coagulopathy such as TTP, DIC, cou- dation at the left lung base and a new soft tissue mass in marin necrosis, protein C deficiency, antiphospholipid syn- the retroperitoneum. Transbronchial biopsy of the area of drome and some forms of cryoglobulinemia.4,9 Cryofibrin- pulmonary consolidation revealed recurrence of large cell ogenemia should also be differentiated from the lymphoma on day 82 after the transplant. The patient did inflammatory vasculitides. The diagnosis relies on the not respond to a trial of rituximab (anti-CD20 monoclonal detection of cryofibrinogen in addition to the characteristic antibody) (Genentech, San Francisco, CA, USA) and skin biopsy showing thrombotic vasculopathy in the expired of progressive disease on day 169. The skin lesions absence of other diagnoses. Blood obtained for detecting did not recur after completion of plasma exchange. cryofibrinogen should be anticoagulated and the sample maintained at 37°C until it is centrifuged immediately after collection. The separated plasma should be kept at 4°C for Discussion at least 72 h since late precipitates may form. Extensive work-up in our patient did not disclose any Cryofibrinogenemia is defined by the presence of cold pre- thrombotic abnormality other than cryofibrinogenemia. We cipitable proteins in the plasma.1,2 The cryoprecipitate is have not identified any infection or serologic evidence for composed of fibrinogen, fibrin, fibronectin, and smaller autoimmune disorder. A few weeks after the occurrence of amounts of other proteins. It dissolves when the plasma is skin necrosis the patient was found to have relapsed with re-warmed. The cold temperature-induced precipitation of large cell lymphoma in her lung and abdomen. Cryofibrin- protein from plasma but not from serum distinguishes cry- ogenemia heralded this early post-transplant relapse and is ofibrinogens from cryoglobulins, which are immunoglob- known to occur secondary to malignant disorders. The ulins that can precipitate in both cooled plasma and serum. patient responded to therapeutic plasma exchange directed Cryofibrinogenemia may be associated with a variety of against cryofibrinogenemia and not to treatment targeted to autoimmune, malignant, thrombotic, and infectious dis- her lymphoma. Furthermore, the lymphoma progressed orders, or may present as a primary disorder.1,2 Cryofibrin- after completion of plasma exchange but the skin lesions ogen may be detected in up to 3% of hospitalized patients did not recur, which suggested that these processes may who do not have related symptoms. The skin is the most not be closely correlated. An alternative possibility is that common organ involved and cutaneous manifestations the episode of cryofibrinogenemia-induced skin necrosis include cold sensitivity, purpura, livedo reticularis, Ray- was related to other complications of the transplant, such naud’s phenomenon, and in the more severe forms, ulcer- as an unrecognized infection or toxicity related to high- ation, gangrene and skin necrosis.1,2 Lesions typically dose chemotherapy or to the treatment with IL-2. Cryofib- appear, as in our patient, on the distal extremities, buttocks, rinogenemia-induced skin necrosis is a rare entity, that has ears and nose. not been previously reported in association with high-dose The pathogenesis