Argatroban Resistance and Successful Adjunctive Anticoagulation for Cerebral Venous Sinus Thrombosis With SERPINC1 Mutation

Case Description

We report the case of a 19-year-old 85-kg young man who was admitted to the hospital with sudden headache, nausea, and vomiting for 3 days. He had a significant history of DVT in the left lower limb a year earlier. He had taken dabigatran for only 6 months after this. Brain magnetic resonance black blood thrombosis imaging (MRBTI) on admission showed multiple sinus thrombi, which indicated cerebral venous sinus thrombosis (CVST) (Figure 2, A–C). Ultrasonography of the optic nerve sheath showed widening.

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Figure 2 Cranial MRI and DSA Images and Anticoagulation Treatment During Hospitalization

(A–C) After admission, MRBTI revealed thrombosis in the left transverse sinus (A), left sigmoid sinus (B), and superior sagittal sinus (C). (D) Twelve days after admission, DSA before surgery showed occlusion of the superior sagittal sinus and left transverse sinus. (E) DSA after surgery showed recanalization of the posterior half part of the superior sagittal sinus and left transverse sinus. (F–H) Fifteen days after admission, MRBTI revealed that there was still a thrombus in the left transverse sinus (F), left sigmoid sinus (G), and superior sagittal sinus (H). (I, J) At the 3-month follow-up, MRBTI suggested the thrombus in the left transverse sinus (I), left sigmoid sinus, and superior sagittal sinus (J) were absorbed more obviously than before. (K) Coagulation indexes include APTT level, INR, and AT activity. The dosing of LMWH was adjusted according to the patient's weight and liver function. The LMWH used was enoxaparin with 8,000–10,000 IU every 12 hours by hypodermic injection and argatroban (manufactured in Tianjin Pharmaceutical Research Institute; initiated with an intravenous drip of 60 and 20 mg/d after 2 days) was used by intravenous infusion at a speed of 2.4–9 mg/h. Oral rivaroxaban (15 mg) was administered twice a day, and 1 week later, it was decreased to 15 mg every day. Oral warfarin (6 mg) was administered every day. APTT = activated partial thromboplastin time; DSA = digital subtraction angiography; INR = international standard ratio; LMWH = low-molecular-weight heparin; MRBTI, magnetic resonance black blood thrombosis image.

On admission, the D-dimer level was 7,276 μg/mL (reference range: 0–24 μg/mL). The level of AT activity was 50% (reference range: 80%–120%). The level of factor VIII activity was 100.70% (reference range: 50%–150%). The lumbar puncture showed an increased intracranial pressure of 330 mmH₂O. Family SERPINC1 gene analysis identified the frameshift mutations in exon 1 (c.40delA: [p.R14Gfs*17]) in him and his father.

After admission, 8,000 IU LMWH (enoxaparin) was injected subcutaneously every 12 hours to prevent thrombus expansion and accelerate thrombolysis. His headache was not relieved. On the sixth day after admission, we changed LMWH to argatroban. The baseline level of APTT was 37.4 seconds in this patient (Figure 2K). During the first 5 days of argatroban administration, although the rate of argatroban gradually increased from a speed of 2.4 to 9 mg/h, it failed to achieve a target range of APTT. The main complaint of headache was still not significantly relieved. Thereafter, we chose combined anticoagulation (pumping argatroban 5.6 mg/h and LMWH: 8,000–10,000 IU twice a day), and the APTT gradually reached a target level. On the thirteenth day after admission, he received endovascular treatment and several thrombi were removed from the venous sinus (Figure 2, D and E). However, his symptoms were not relieved after the thrombectomy. In select refractory cases such as this one, owing to the dangerous course of acute CVST, a dynamically observed thrombosis and absorption by serial imaging indicators were necessary. The thrombi on recurrence appeared the same as those observed at the beginning of admission on the first day after surgery (Figure 2, F–H). Continuing the abovementioned enhanced anticoagulation, the headache was relieved and the thrombus load significantly lessened on the twentieth day after admission. After that, we changed the anticoagulant treatment to 15 mg of rivaroxaban every 12 hours. On the 25th day after admission, we added LMWH (8,000–10,000 IU twice for 1 day) and warfarin combined with rivaroxaban to enhance the anticoagulant therapy. His headache gradually resolved. After 5 days, his international normalized ratio (INR) improved to the standard level (between 2 and 3), and he discontinued LMWH and rivaroxaban and was discharged with oral warfarin. The anticoagulation treatment process during hospitalization is shown in Figure 2K.

At the 3-month follow-up, he had no recurrence of headache or any systemic hemorrhage and the ultrasonography of the optic nerve sheath showed normal. MRBTI suggested thrombus absorption (Figure 2, I and J).