The Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to: 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, Houston, TX 77030, USA

A 34-year-old woman with diffuse mediastinal B cell large cell lymphoma presented 60 days after high-dose chemotherapy and autologous stem cell transplantation, and post-transplant immunotherapy with interleukin-2, with skin necrosis in the ears and extremities. Extensive work-up revealed the presence of cryofibrinogenemia and associated thrombotic vasculopathy. The patient was successfully treated with corticosteroids and therapeutic plasma exchange. However, she had recurrence of large cell lymphoma a few weeks later and died of progressive disease. Cryfibrinogenemia and skin necrosis may have occurred secondary to the imminent relapse, or as a rare complication of high-dose chemotherapy or treatment with interleukin-2. Bone Marrow Transplantation (2000) 26, 1343-1345.

cryofibrinogenemia; lymphoma; stem cell transplantation; interleukin-2

A 34-year-old woman presented with chest pain and a mediastinal mass. An open biopsy showed diffuse B cell large cell lymphoma. The patient was treated with the CHOP regimen with an initial good response. However shortly after the last cycle, she developed fever, night sweats and recurrent chest pain. She had new axillary adenopathy, as well as re-growth of the mediastinal mass and 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 day 11 (with sustained ANC >1 ´ 10⁹/l for 3 consecutive days) and restaging tests on day 30 showed she was in complete remission. The patient completed the first maintenance course of IL-2 that was given in reduced doses (2 ´ 10⁶ U/m² daily by subcutaneous injection, 25% of planned dosing) due to fevers and pancytopenia.

She presented 2 weeks later, on day 56 of the transplant, with symptoms of an upper respiratory tract infection and was given oral antibiotics. A few days later she developed fever up to 38.2°C and then rapidly progressive large purpuric/necrotic lesions on her ears, and upper and lower extremities (see Figure 1). The WBC was 3.1 ´ 10⁹/l, hemoglobin 11.2 g/dl, and platelets 119 ´ 10⁹/l. A blood smear was normal with no evidence of microangiopathy. Electrolytes, creatinine, and liver function tests were within normal limits. Her LDH was 880 U/l (normal upper limit, 618). There was no laboratory evidence for disseminated intravascular coagulation (DIC). Chest X-ray showed a questionable 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 were negative. There was a low titer (1:256) of cold agglutinins. Assays of plasma for the presence of cryofibrinogen were found to be qualitatively positive on repeat testing. Antinuclear factor, rheumatoid factor, anticardiolipin antibody and Coombs' test were negative. Complement and immunoglobulin levels were within normal limits. Protein electrophoresis and immunofixation of serum and urine showed no monoclonal gammopathy. Levels of protein C and S, and antithrombin III were normal. A skin biopsy from the edge of a lesion showed numerous microthrombi in small dermal vessels, heavy fibrin deposits, and immunofluorescence detected trace deposits of IgM and C3. There was no inflammatory response surrounding the vessels.

The patient was initially treated with broad-spectrum antibiotics. With these findings she was diagnosed as having thrombotic vasculopathy and skin necrosis associated with cryofibrinogenemia. She was treated with high-dose methylprednisolone (2 mg/kg daily) and started therapeutic plasma exchange. She received 10 treatments over 2 weeks, with replacement of 1.5 of total plasma volume with each treatment. Her skin lesions healed promptly.

She subsequently developed low-grade fever and mild shortness of breath. Chest X-ray showed a left lower lobe infiltrate and CT scans showed several areas of consolidation at the left lung base and a new soft tissue mass in the retroperitoneum. Transbronchial biopsy of the area of pulmonary consolidation revealed recurrence of large cell lymphoma on day 82 after the transplant. The patient did not respond to a trial of rituximab (anti-CD20 monoclonal antibody) (Genentech, San Francisco, CA, USA) and expired of progressive disease on day 169. The skin lesions did not recur after completion of plasma exchange.

Discussion

Cryofibrinogenemia is defined by the presence of cold precipitable proteins in the plasma.^1,2 The cryoprecipitate is composed of fibrinogen, fibrin, fibronectin, and smaller amounts of other proteins. It dissolves when the plasma is re-warmed. The cold temperature-induced precipitation of protein from plasma but not from serum distinguishes cryofibrinogens from cryoglobulins, which are immunoglobulins that can precipitate in both cooled plasma and serum.

Cryofibrinogenemia may be associated with a variety of autoimmune, malignant, thrombotic, and infectious disorders, or may present as a primary disorder.^1,2 Cryofibrinogen may be detected in up to 3% of hospitalized patients who do not have related symptoms. The skin is the most common organ involved and cutaneous manifestations include cold sensitivity, purpura, livedo reticularis, Raynaud's phenomenon, and in the more severe forms, ulceration, gangrene and skin necrosis.^1,2 Lesions typically appear, as in our patient, on the distal extremities, buttocks, ears and nose.

The pathogenesis of cryofibrinogenemia is not well defined. Rarely, antibodies directed against fibrinogen have been detected.³ The cutaneous lesions are related to skin ischemia, due to the cold-induced deposition of fibrin in small dermal arteries. Interestingly, our patient first developed skin eruptions on the exposed surface of her body after prolonged exposure to air-conditioning. Skin biopsy typically shows eosinophilic fibrin thrombi in the superficial and deep dermal blood vessels with minimal inflammation and no vasculitis.^4,5 In a few cases leukocytoclasis,⁶ immunoglobulin and complement deposits⁷ have also been documented, although these are unusual. Underlying thrombosis is the dominant feature, but immune mechanisms may be contributing since some patients respond to immunosuppression, such as corticosteroids and/or cytotoxic therapy.

The treatment of cryofibrinogenemia includes avoidance of cold exposure. Primary cases have been treated with anticoagulation,⁶ and corticosteroids and immunosuppressive agents have been used with variable success.^4,5,7 Stanozol (Sanofi Winthrop Pharmaceuticals, New York, NY, USA), an androgen steroid with fibrinolytic activity has also been used successfully in the treatment of this syndrome.⁸ There are a few reports of therapeutic plasma exchange in refractory patients.⁵ Our patient had prompt resolution of symptoms with plasma exchange and corticosteroids suggesting that this is a useful treatment modality in severe cases.

Cryofibrinogenemia should be differentiated from other causes of thrombotic coagulopathy such as TTP, DIC, coumarin necrosis, protein C deficiency, antiphospholipid syndrome and some forms of cryoglobulinemia.^4,9 Cryofibrinogenemia should also be differentiated from the inflammatory vasculitides. The diagnosis relies on the detection of cryofibrinogen in addition to the characteristic skin biopsy showing thrombotic vasculopathy in the absence of other diagnoses. Blood obtained for detecting 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 at least 72 h since late precipitates may form.

Extensive work-up in our patient did not disclose any thrombotic abnormality other than cryofibrinogenemia. We have not identified any infection or serologic evidence for autoimmune disorder. A few weeks after the occurrence of skin necrosis the patient was found to have relapsed with large cell lymphoma in her lung and abdomen. Cryofibrinogenemia heralded this early post-transplant relapse and is known to occur secondary to malignant disorders. The patient responded to therapeutic plasma exchange directed against cryofibrinogenemia and not to treatment targeted to her lymphoma. Furthermore, the lymphoma progressed after completion of plasma exchange but the skin lesions did not recur, which suggested that these processes may not be closely correlated. An alternative possibility is that the episode of cryofibrinogenemia-induced skin necrosis was related to other complications of the transplant, such as an unrecognized infection or toxicity related to high-dose chemotherapy or to the treatment with IL-2. Cryofibrinogenemia-induced skin necrosis is a rare entity, that has not been previously reported in association with high-dose chemotherapy and autologous transplantation.

1 Smith SB, Arkin C. Cryofibrinogenemia: incidence, clinical correlations, and a review of the literature. Am J Clin Pathol 1972; 58: 524-530, MEDLINE

2 Mckee PA, Kalbfleisch JM, Bird RM. Incidence and significance of cryoglobulinemia. J Lab Clin Med 1963; 61: 203-210,

3 Euler HH, Zeuner RA, Beress R et al. Monoclonal cryo-antifibrinogenemia. Arthritis Rheum 1996; 39: 1066-1069, MEDLINE

4 Beightler E, Diven DG, Sanchez RL et al. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 1991; 24: 342-345, MEDLINE

5 Young GD, Clealand LG, McNeil JD. Cryofibrinogenemia: a case report. Aust NZ Med 1991; 21: 444-446,

6 Jantunen E, Soppi E, Neittaanmaki H, Lahtinen R. Essential cryofibrinogenemia, leukocytoclastic vasculitis and chronic purpura. J Intern Med 1993; 234: 331-333, MEDLINE

7 Zouboulis CC, Gollnick H, Weber S et al. Intravascular coagulation necrosis of the skin associated with cryofibrinogenemia, diabetes mellitus, and cardiolipin autoantibodies. J Am Acad Dermatol 1991; 25: 882-888, MEDLINE

8 Falanga V, Kirsner RS, Eaglstein E et al. Stanozolol in treatment of leg ulcers due to cryofibrinogenaemia. Lancet 1991; 338: 347-348, MEDLINE

9 Cohen S, Pittelkow MR, Su D. Cutaneous manifestations of cryoglobulinemia: clinical and histopatologic study of seventy-two patients. J Am Acad Dermatol 1991; 25: 21-27, MEDLINE

Figure 1 Purpuric lesions on right ear and upper right arm.