Chou et al. Pediatric Rheumatology (2018) 16:31 https://doi.org/10.1186/s12969-018-0249-6 RESEARCH ARTICLE Open Access Clinical study of children with cryofibrinogenemia: a retrospective study from a single center Hsiao-Feng Chou1, Yu-Hung Wu2, Che-Sheng Ho3 and Yu-Hsuan Kao4* Abstract Background: This study aimed to evaluate the demographic, clinical features, laboratory data, pathology and other survey in pediatric patients with cryofibrinogenemia. Methods: A 12-year retrospective chart review identified eight pediatric patients at Mackay Memorial Hospital, Taipei, Taiwan. Results: The female-to-male ratio was 3:1. The mean age at symptom onset and of diagnosis was 10.3 ± 4.6 years and 12.3 ± 4 years, respectively. One child (12.5%) had primary cryofibrinogenemia. The common symptoms were purpura, arthralgia, and muscle weakness (100%). On laboratory examination, cryofibrinogen was positive in all patients. All patients had increased anti-thrombin III while 87.5% and 62.5% had abnormal protein S and protein C, respectively. All eight also complained of neurologic symptoms. One had vertebral artery narrowing, two showed increased T2-weighted signal intensity on the thalamus or white matter, and one had acute hemorrhagic encephalomyelitis on brain magnetic resonance imaging. Conclusions: This study reports on the presentations of cryofibrinogenemia, which is rare in children. Most cases are associated with autoimmune disease and have severe and complex presentations. Central nervous system involvement is common. Keywords: Cryofibrinogenemia, Children, Central nervous system Background thrombotic occlusions of medium and small vessels, Cryofibrinogenemia is a rare hematologic disorder wherein leading to amplified hyper-viscosity, reflex vasospasms, plasma forms a cryoprecipitate that consists of fibrinogen, and vascular stasis [2]. fibrin, fibronectin, factor VII, and smaller amounts of vari- The most common symptoms of cryofibrinogenemia ous plasma proteins. Cryofibrinogen precipitates at a low are due to cutaneous ischemia and include purpura, temperature (4 °C) and re-dissolves on warming to (37 °C) livedo reticularis, blisters, tissue necrosis, and ulceration. [1]. Its exact pathogenesis has not been elucidated. A first Systemic symptoms have been reported to be glomer- hypothesis is that there is a defect in the fibrinolytic ulonephritis and thrombophlebitis [3]. Cases involving process, with high plasma levels of α1antitrypsinandα2- children have rare been reported. This is a retrospective macroglobulin (protease inhibitors), and delayed lysis of review on pediatric patients diagnosed with cryofibrino- euglobulin. But since elevated plasma α1-antitrypsin and genemia in a tertiary medical center in Taiwan. α2-macroglobulin levels are not found in other studies, a second hypothesis favors an increased thrombin-binding capacity and clot formation. Both hypotheses lead to Methods After a review of the diagnostic criteria and clinical fea- * Correspondence: [email protected] tures, a medical chart review of eight patients younger 4 Section of Immunology, Rheumatology and Allergy, Department of than 18 years with a diagnosis of cryofibrinogenemia at Pediatrics, Mackay Memorial Hospital, No. 92, Sec. 2, Zhong-shan N. Rd, Taipei City 10449, Taiwan the pediatric department of Mackay Memorial Hospital, Full list of author information is available at the end of the article Taipei, Taiwan, between May 2010 and July 2015. The © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chou et al. Pediatric Rheumatology (2018) 16:31 Page 2 of 8 diagnostic criteria originally proposed by essential and involvement was indicated by proteinuria, hematuria, or el- supportive evidence. Essential evidence included: 1) ap- evated serum creatinine. propriate clinical presentation of sudden onset of skin Arterial thrombosis was confirmed clinically and by changes and constitutional symptoms, with or without angiogram of the lower limbs, superior mesentery artery, thrombosis, bleeding, or exposure to cold; 2) presence of and celiac artery. The associated autoimmune diseases cryofibrinogen in plasma; and 3) absence of cryoglobulins. were diagnosed based on the following criteria: systemic Essential cryofibrinogenemia meant no secondary causes of lupus erythematosus (SLE) was defined accorded to the cryofibrinogens and no evidence of other vaso-occlusive 1997 revised criteria of the American College of Rheuma- diseases. tology [4]; juvenile idiopathic arthritis (JIA) was defined Supportive evidence was non-specific and not compul- by the International League of Associations for Rheuma- sory. However, when present along with essential evidence, tology criteria [5]; juvenile dermatomyositis (JDM) was supportive evidence improved diagnostic accuracy. Sup- according to the criteria of Bohan and Peter in 1975 [6]; portive evidence included: 1) angiogram with abrupt Behcet’s disease was diagnosed according to the Inter- occlusion of small to medium sized arteries; 2) typical national Study Group for Behcet’s disease in 1990 [7]and skin biopsy findings of cryofibrinogen plugging vessels, leu- cutaneous mastocytosis was according to the criteria of a kocytoclastic vasculitis, or dermal necrosis; and 3) elevated consensus proposal of Valent et al. in 2001 [8]. serum levels of α1-antitrypsin and α2-macroglobulin [3]. Data were collected and charted in terms of sex, age at onset, initial complaints, presenting features, laboratory Results values, electrophysiologic examinations, imaging studies The female-to-male ratio was 3:1. The mean age at (i.e., angiography and magnetic resonance imaging [MRI]), symptom onset was 10.3 ± 4.6 months (range, 2.5–18. and skin biopsy. 5 years). The mean age at diagnosis was 12.3 ± 4 months The clinical symptoms evaluated were defined as fol- (range, 4–18.6 years). Based on the symptoms identified, lows: 1) skin manifestations, including purpura, Raynaud the most common initial symptoms were arthralgia and phenomenon, skin necrosis or ulceration, livedo reticularis, myalgia. The most common symptoms were purpura, urticaria, gangrene, sensitivity to cold, and ecchymosis; 2) muscle weakness, and arthralgia (Table 1). The skin neurologic involvement (e.g. muscle weakness, numbness, manifestations were shown in Fig. 1. headache, vertigo, dizziness, seizures, dysuria, and dyspho- On laboratory examination, cryofibrinogen was positive nia); 3) arthralgia, fever, and myalgia; and 4) other systemic and cryoglobulin was negative in seven children (87.5%). symptoms like dyspnea, chest pain, abdominal pain, hema- Three patients with α1 anti-trypsin checked had negative tochezia, menorrhea, bone pain, or insomnia. results (Table 3). In addition, anti-thrombin III was in- The laboratory examinations included platelet count, creased in all patients. The other frequent laboratory abnor- Prothrombin time (PT), activated partial thromboplastin mality was abnormal protein S (87.5%), increased protein C time (aPTT), von Willebrand factor (vWF), serum im- (5/8, 62.5%), decreased C3 (4/8; 50%), and abnormal C4 (4/ munoglobulin A (IgA), cryofibrinogen, cryoglobulin, α1 8; 50%). Other immunologic results had relatively lower anti-trypsin, and other immunological examinations. Hepa- proportion of abnormal values. None of the eight children titis C virus (HCV) antigen, anti-HCV, hepatitis B virus had hepatitis B or C virus infection (Table 2). (HBV) surface antigen (HBsAg), and anti-HBV antibodies Four patients received skin biopsy and one revealed were measured. Proteinuria, hematuria, and serum creatin- micro-thrombi on small arterioles (Fig. 2). Angiograms inewerealsorecorded. were performed on four patients and all revealed abnor- Systemic involvements were evaluated by several ex- mal findings that included vessel narrowing or decreased aminations. Skin biopsy was performed for establish the arterial flow rate on the lower extremities, renal arteries, diagnosis. Arthritis indicated joint swelling with two or or celiac trunks (Table 3, Fig. 3). more of erythema, local heat, tenderness, or limited All eight patients had neurologic symptoms, the most range of motion. In the peripheral and central nervous common of which was muscle weakness (Table 1). On system (CNS), neuritis indicated peripheral neuropathy electro-physiologic examinations, NCV revealed neuro- on nerve conduction velocity (NCV), while patients pre- pathic change on three of seven (42.9%) patients, com- sented with numbness, weakness, or pain. Brain and spine patible with multi-neuritis. The VEP showed prolonged MRI, electromyogram (EMG), somato-sensory evoked po- P100 in two patients who complained of blurred vision tential (SSEP), brainstem auditory evoked potential (BAEP), or diplopia. The EEG showed spikes or cortical dysfunc- andvisualevokedpotential(VEP)wereperformedaccord- tion on three of four patients (75%) who presented with ing CNS symptoms and signs. chronic headache or consciousness disturbance. Three In the respiratory system,