Iatrogenic Reversible Hypofibrinogenemia in the Setting of Using a Direct Thrombin Inhibitor for Treatment for Recurrent Deep Vein Thrombosis

Abstract

Fibrinogen is an essential and abundant peptide synthesized by the liver. It is required for clot formation while providing a matrix and mesh network essential for clot strength. It is used in the diagnosis and monitoring of multiple coagulopathies. The gold standard for measuring fibrinogen is the Clauss method which uses citrated plasma to which thrombin is added, and the clot formation time is recorded via spectroscopic analysis. Hypofibrinogenemia is defined as fibrinogen of less than 150 mg/dL and is primarily treated with supplementation with cryoprecipitate, or a fibrinogen concentrate. Acquired hypofibrinogenemia may occur due to disseminated intravascular coagulopathy (DIC), liver failure, after cardiac surgery or after massive transfusions. There have also been reports of hypofibrinogenemia associated with the use of direct thrombin inhibitors and tPA. We present a case of acquired hypofibrinogenemia while being treated for recurrent deep vein thrombosis (DVT) which was able to be reversed with the cessation of the direct thrombin inhibitor. A 28-year-old female presented to the emergency department with left lower extremity pain, swelling and cyanosis. She was diagnosed with an extensive DVT of the left lower extremity and started on a heparin infusion. She subsequently underwent mechanical thrombectomy, IVC filter placement and iliac vein stenting due to extensive clot burden. She was transitioned to weight-based therapeutic enoxaparin and discharged home. However, despite her compliance, she continued to have worsening left lower extremity pain and swelling and was found to have a persistent DVT. She was then tried on apixaban but failed therapy and required a repeat thrombectomy due to clinical worsening of her lower extremity exam. Her initial hypercoagulability workup for anti-phospholipid syndrome was unremarkable. She then underwent catheter-directed tPA and was started on an argatroban infusion. She remained on the argatroban infusion for 7 days. While on argatroban infusion therapy, routine blood work noted her fibrinogen levels to be less than 50 mg/dL. Despite the initial concern for DIC, the hypofibrinogenemia was ultimately attributed to prolonged argatroban exposure after literature review. The decision was made to not replace the fibrinogen, but instead to transition the argatroban to fondaparinux. The repeat fibrinogen level one day after discontinuing argatroban was back to normal limits at 351 mg/dL and the patient was subsequently discharged on fondaparinux with subsequent clinical improvement. Multiple studies advocate for maintaining fibrinogen levels with supplementation for acquired coagulopathies. However, in this clinical situation, removing the offending agent was the key to correcting the patient's fibrinogen level. With the patient's history of recurrent DVTs, giving her fibrinogen replacement may have led to worsening thrombosis and adverse events. It is imperative that clinicians be aware of the many causes of hypofibrinogenemia. Before reflexively replacing fibrinogen, a physician must consider all reversible causes and make an informed clinical decision.