Hassan Fadi, Khoury Amir, Awad Jamal, Jeries Helana, Naffaa Mohammad E
The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Rheumatology Unit, Galilee Medical Center, Nahariya, Israel.
J Scleroderma Relat Disord. 2023 Oct;8(3):NP1-NP5. doi: 10.1177/23971983231162679. Epub 2023 Mar 26.
Cryofibrinogen is an abnormal, cold-insoluble protein composed of a combination of fibrinogen, fibrin, and fibronectin. Cryofibrinogenemia can be essential (e.g. primary) or secondary to various conditions. While low levels of cryofibrinogen can be seen in asymptomatic healthy individuals without evidence of clinical features typical of cryofibrinogenemia, cryofibrinogenemia associated with clinical features is considered very rare. The clinical features of cryofibrinogenemia ranges from skin manifestations, including Raynaud's phenomenon and livedo reticularis, to more severe organ-threatening manifestations such as tissue ischemia and gangrene.
We report a case of a 48-year-old male who presented with blue finger and palpable purpura on his distal extremities. Laboratory workup was positive for anti-nuclear antibodies, anti-double-stranded DNA, anti-ribonucleoprotein, and rheumatoid factor, while antineutrophil cytoplasmic antibodies and cryoglobulins were negative. Testing for hypercoagulable states and infectious etiologies was unrevealing. Later, angiographic computed tomography showed multiple pulmonary embolisms and disruption of blood flow to the left fifth digit. As the aforementioned workup could not explain the presence of the thrombus by a thromboembolic cause, a search for an in situ cause other than antiphospholipid syndrome was initiated and concentrated mainly on cryofibrinogenemia. Blood samples collected using prewarmed anticoagulant containing tubes were sent to central lab familiar with performing the test. Two weeks later, a positive result for the presence of cryofibrinogen confirmed the diagnosis of cryofibrinogenemia. Due to the presence of multiple signs compatible with mixed connective tissue disease, he was diagnosed with cryofibrinogenemia secondary to mixed connective tissue disease, and treatment with prednisone, low-molecular-weight heparin, prostacyclin and hydroxychloroquine was initiaed with favorable outcome.
Cryofibrinogenemia is a rare and underdiagnosed condition. Clinicians should be aware of this cryopathy especially in the cases of Raynaud's phenomenon and ischemic ulcers not explained by other causes. Precautions must be taken during the diagnostic process, and therapy should be given as soon as possible.
冷纤维蛋白原是一种异常的、冷不溶性蛋白质，由纤维蛋白原、纤维蛋白和纤连蛋白组合而成。冷纤维蛋白原血症可为原发性（例如特发性）或继发于各种疾病。虽然在无冷纤维蛋白原血症典型临床特征证据的无症状健康个体中可发现低水平的冷纤维蛋白原，但与临床特征相关的冷纤维蛋白原血症被认为非常罕见。冷纤维蛋白原血症的临床特征范围从皮肤表现，包括雷诺现象和网状青斑，到更严重的威胁器官的表现，如组织缺血和坏疽。
我们报告一例48岁男性，其远端肢体出现手指发蓝和可触及的紫癜。实验室检查抗核抗体、抗双链DNA、抗核糖核蛋白和类风湿因子呈阳性，而抗中性粒细胞胞浆抗体和冷球蛋白呈阴性。高凝状态和感染病因检测未发现异常。后来，血管造影计算机断层扫描显示多发性肺栓塞和左小指血流中断。由于上述检查无法用血栓栓塞原因解释血栓的存在，因此开始寻找除抗磷脂综合征以外的原位病因，主要集中在冷纤维蛋白原血症。使用预温含抗凝剂的试管采集的血样被送往熟悉该检测的中心实验室。两周后，冷纤维蛋白原检测呈阳性，确诊为冷纤维蛋白原血症。由于存在多种与混合性结缔组织病相符的体征，他被诊断为继发于混合性结缔组织病的冷纤维蛋白原血症，并开始使用泼尼松、低分子量肝素、前列环素和羟氯喹治疗，结果良好。
冷纤维蛋白原血症是一种罕见且诊断不足的疾病。临床医生应意识到这种冷冻病，尤其是在雷诺现象和缺血性溃疡无法用其他原因解释的情况下。诊断过程中必须采取预防措施，应尽快给予治疗。
