Most patients with malignant tumors have abnormalities in one or more coagulation indicators, such as a shortened prothrombin time (PT), an increased plasma FIB level, or an increased D-dimer level [5]. FIB and D-dimer are specific indicators of hypercoagulability. Hypercoagulability in patients with malignant tumors can promote the formation of tumor thrombi and cause secondary hyperfibrinolysis [6]. FIB is the main coagulation factor in plasma, and its normal concentration is about 2 to 4 g/L [7]. A high level of plasma FIB in patients with lung cancer, ESCC, gastric cancer, colorectal cancer, ovarian cancer, and other cancers is independently associated with poor prognosis [8–11]. A reduced FIB level occurs in disseminated intravascular coagulation (DIC), severe hepatitis, cirrhosis, thrombolytic therapy, primary fibrinolysis, and several other diseases. Primary hypofibrinogenemia is an autosomal genetic disease and identification of the mutant gene is the gold standard for diagnosis, but this is difficult in clinical practice [12]. Secondary hyperfibrinolysis is a thrombo-hemorrhage syndrome that is the consequence of a primary disease and manifests as local or diffuse intravascular coagulation [13].
Plasma fibrin precipitates in blood vessels, thereby promoting the release of plasminogen activator in the circulating blood, leading to hyperfibrinolysis and an increased level of D-dimer. Several factors, such as severe trauma, postpartum hemorrhage, and liver transplantation, can lead to hyperfibrinolysis, and administration of tranexamic acid to these patients can reduce the risk of bleeding and death [14]. A multi-center study by Hagemo et al. [15] showed that various factors, such as hyperfibrinolysis, severe blood loss, blood dilution after rehydration, acidosis, and hypothermia, could lead to a decreased FIB level, and that the most direct and effective treatment was intravenous infusion of plasma, cryoprecipitate, and FIB. In addition, Hess et al. [16] reported that hypofibrinogenemia caused by trauma was related to a more favorable patient prognosis.
Hypofibrinogenemia secondary to a malignant tumor is rare, and there are only a few case reports with this finding. Rapaport et al. [17] reported a patient who had prostate cancer with concurrent hypercoagulability and hypofibrinogenemia. Libek et al. [18] reported a patient who had prostate cancer and a subcutaneous hematoma due to hyperfibrinolysis, and they considered this to be paraneoplastic syndrome (PNS). Aulmann et al. [19] reported a patient who had metastatic breast cancer combined with thrombocytopenia and hyperfibrinolysis, and they also considered this to be PNS [19]. Recently, Ma et al. [20] reported hypofibrinogenemia in patient who had relapsed gastric cancer after surgery. Hunault-Berger et al. [21] examined 214 patients with acute T lymphoblastic leukemia and T lymphoblastic lymphoma, and reported that administration of L-asparaginase chemotherapy inhibited the biosynthesis of liver L-asparagine-dependent protein, leading to acquired hypofibrinogenemia. Acute promyelocytic leukemia (APL) can also cause secondary hypofibrinogenemia [22]. These patients have increased levels of urokinase-type plasminogen activator, tissue-type PA, and annexin-α2 in APL cells, leading to synthesis and activation of plasminogen, metabolism of FIB, and hypofibrinogenemia. Liu et al. [23] studied patients with APL and reported that administration of all-trans retinoic acid (ATRA) induced APL cell differentiation, down-regulated annexin-α2, and corrected the hyperfibrinolysis [23]. The main supportive treatments for these patients are infusion of fresh frozen plasma (FFP), cryoprecipitate, and/or concentrated FIB to maintain an FIB level above about 1.0 to 1.5 g/L [24].
Our patient had ESCC combined with hypofibrinogenemia. After fresh plasma infusion, FIB supplementation, and cryoprecipitate, his FIB level increased slightly to about 1 g/L. The patient accepted radical RT as treatment for the ESCC. His FIB level gradually rose during the RT period, and reached a maximum of 2.20 g/L. After the RT period, the patient’s symptoms gradually resolved, and we evaluated the patient’s status as SD. One month after RT, the patient had a status of PR, and he maintained this status for more than 10 months. The FIB level was 0.97g/L at the last follow-up. The patient had no increased tendency for bleeding during the entire course of disease, treatment, and recovery. We therefore considered the hypofibrinogenemia in this patient to be a consequence of PNS, although the exact mechanistic relationship of PNS with ESCC remains unknown.