We present a patient who underwent urgent neurosurgery for acute onset paraplegia due to a spontaneous subdural spinal hematoma at the T11-L1 level less than 5 hours after she had taken rivaroxaban. Prothrombin complex concentrate (PCC, 50U/kg iv) and tranexamic acid (TA, 2x1g iv) were administered and perioperative hemostasis was good. There is scant data on neurosurgical procedures performed within 12 hours after the intake of a direct oral anticoagulant. With the hemostatic support of high dose PCC, early surgery after administration of rivaroxaban seems feasible in case of an emergency indication, but should only be considered when delaying surgery is esteemed hazardous to the patient. More experience is needed to allow balancing risks and benefits of urgent versus delayed intervention and on the optimal hemostatic support in the absence of a specific antidote.

Oral anticoagulants are the treatment of choice for the prevention of stroke in most patients with nonvalvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. Historically, vitamin K antagonists were the only oral anticoagulants for clinical use. Due to the unpredictable pharmacokinetics, regular monitoring of the anticoagulation effect using the International Normalized Ratio (INR) is required to ensure safe use. Due to its long half-life, the anticoagulant effect persists long after interruption of anticoagulation. Although administration of vitamin K reduces the time to INR normalization, this effect requires many hours. Therefore, complexes of clotting factors (prothrombin complex concentrate; PCC) have been used to quickly replenish the coagulation system and urgently restore coagulation in patients treated with vitamin K antagonists.

In the recent decade, new direct oral anticoagulant drugs (NOACs) were developed. Because they can be used without need for monitoring, the tests that measure their anticoagulant effect are less routinely available. Whereas the effect of the thrombin inhibitor dabigatran can be immediately reversed by a specific monoclonal antibody fragment (Idarucizumab)\cite{26095746}, antidotes for the factor Xa inhibitors are still under investigation and are not available for clinical use\cite{27573206,26911798}.

Therefore, patients taking oral factor Xa inhibitors requiring urgent surgery present a challenge where the urgency of the procedure has to be weighed against the bleeding risk of the residual anticoagulant effect.

Spontaneous subdural spinal hematoma is a rare complication in patients on anticoagulant treatment with vitamin K antagonists\cite{Jimbo_2006,Morandi_2001}, heparins[6] and NOACs[7-10]. Four cases of spontaneous spinal subdural hematoma in patients on rivaroxaban have been described: one was treated conservatively because of minimal neurologic deficit[7], in the remaining three surgery was delayed at least 48 hours after rivaroxaban intake and no important functional recovery was observed post-operatively.

An 80-year old Caucasian female, weighing 72 kg, with an estimated creatinine clearance 60 ml/min/1.73m², presented at our Emergency Department because of excruciating pain in the right leg, arisen abruptly seven days earlier while vomiting. She had a history of NVAF, for which she was started on rivaroxaban 15mg once daily three years earlier. At admission, a computed tomography (CT) of the thoracolumbar spine was performed, which was unremarkable. She was hospitalized on the geriatric department for intravenous analgesia. In the morning of the fourth day of hospitalization, rivaroxaban was administered at 8.08 a.m. During washing afterwards, she remarked not feeling the nurses’ touch on her legs and being unable to move her legs. An urgent neurological evaluation showed a flaccid paraplegia (Medical Research Council score of 0/5) with no sensation from below T10-T11 level. Magnetic resonance imaging scan revealed a T2 heterogenic mass at the level of T11-L1 (Fig. 1).

After multidisciplinary consulting, we decided to operate since we felt that this was the only treatment with realistic possibility of neurological recuperation. In a pre-operative blood sample, prothrombin time was 25 seconds (normal range 9.4 to 12.5 seconds; INR 2,1) and activated partial thromboplastin time was 34,9 seconds (normal range 25.1 to 36.5 seconds).

Pre-operatively 50 units/kg of PCC were administered, as well as 2 x 1 g of tranexamic acid. At 12.40p.m. laminectomy and durotomy at the level T11-L1 were performed, demonstrating a subdural hematoma which was evacuated (Fig 2). After closure of the wound, total blood loss was 100cc. No additional administration of prothrombin complex concentrate (PCC) was required during surgery. Tranexamic acid (6 x 1 g was continued for 24 hours postoperatively).

Rivaroxaban blood levels were 440ng/mL (chromogenic anti-factor Xa assay, pre-operative sample processed post-operatively), confirming peak levels at the time of surgery.

Immediately post-operatively, the excruciating pain was greatly reduced, but neurological function did not recover. She was transferred for geriatric rehabilitation. Thromboprophylactic enoxaparin was resumed 1 day postoperatively. At time of submission, 30 days after operation, there was no neurological recovery, nor any thromboembolic complications.

Intracranial and intraspinal hemorrhaghe is a rare but devastating complication of anticoagulation therapy. Although novel oral anticoagulants significantly reduce the risk of intracranial bleeding compared with vitamin K antagonists, there is less experience with the management in case of urgent surgery.

While specific tests that allow the assessment of anticoagulant status are available for all NOACs, they are not routinely performed at all laboratories. Given their predictable pharmacokinetics, time since last intake is the most important factor to determine the residual anticoagulant effect. In an emergency situation, identification of the type of anticoagulant, the dose, and the time since last intake is therefore important. As renal insufficiency can prolong the half-life of NOACs, an assessment of renal function is also helpful.

Typical routine coagulation assays such as the prothrombin time and activated partial thromboplastin time are influenced by NOACs, but are not linearly correlated with NOAC levels.

In our patient, the prolonged prothrombin time was compatible with the recent intake of rivaroxaban, which was confirmed by the rivaroxaban level using an anti-factor Xa-chromogenic assay. However, in case of an urgent surgical indication, in most centers quantitative measures of drug levels will not be readily available and hence do not guide the peroperative hemostatic management.

Vitamin K has no effect on hemostasis in patients treated with NOACs. However, in vitro and preclinical studies have shown that the use of prothrombin complex concentrate, which contain coagulation factor II, VII, IX, and X, can counteract the effect of NOACs, especially when administered in a high dose (50 U/kg). PCCs were effective in reducing bleeding in animal models of severe trauma during NOAC treatment[11]. In healthy volunteers who received rivaroxaban or apixaban, PCCs (50 U/kg) reversed the effects on coagulation tests and biopsy-induced bleeding[12, 13]. Therefore, PCCs are recommended as a prohemostatic agent in patients treated with a factor Xa inhibitor who present with severe or life-threathening bleeds not responding to conservative measures[14]. For patients treated with the thrombin inhibitor dabigatran, the specific reversal agent idarucizumab can rapidly and completely reverse the anticoagulant effect. Idarucizumab is approved by the FDA and EMA in patients with recent intake of dabigatran requiring urgent surgery or presenting with life-threatening bleeding.

In this case, the patient treated with rivaroxaban presented both with an acute bleeding complication in a critical organ and with the need for an urgent intervention. Diagnosis of the bleeding and indication for surgery was made at the time of expected peak rivaroxaban levels (3 to 4 hours after intake). Administration of PCCs is therefore recommended. In patients without a bleeding but requiring an urgent procedure, an analogous strategy has been proposed.

In conclusion, we performed an urgent laminectomy and durotomy with evacuation of the subdural hematoma after administration of PCCs and TA less than five hours after rivaroxaban intake. Per- and postoperative hemostasis was assessed as normal, which supports the suggested approach. Early surgery after administration of rivaroxaban seems feasible in case of an emergency indication, but more experience is necessary on the hemostatic effects and the thrombotic risk of such strategy, and it should only be considered when delaying surgery is esteemed hazardous to the patient.

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Fig 1. T2 spine

Fig 2. Perop image

Table.