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Use of Prothrombin Complex Concentrate for Warfarin Reversal Before the Performance of an Epidural Blood Patch in a Patient With Cortical Vein Thrombosis and Subdural Hematoma: A Case Report

Chaudhuri, Kallol MD, PhD*; Phillips, Cooper W. MD; Chaudhuri, Swapna MD, PhD*; Wasnick, John MD, MPH*

doi: 10.1213/XAA.0000000000000417
Case Reports: Case Report
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Compared to conventional therapy, several studies with prothrombin complex concentrate (PCC) have recently demonstrated its superior efficacy in rapidly replacing vitamin K-dependent factors for patients with life-threatening hemorrhage. We present a novel use of PCC in a patient with intracranial hypotension, who had received warfarin for treatment of cortical vein thrombosis. However, after anticoagulation, she proceeded to develop bilateral subdural hematomas with descent of cerebellar tonsils. Given the possibility of an occult dural puncture during labor analgesia, an epidural blood patch was performed after administration of PCC and normalization of coagulation parameters, with prompt improvement of the patient’s headache.

From the *Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, Texas; and UT Southwestern Department of Anesthesiology and Pain Management, Dallas, Texas.

Accepted for publication July 29, 2016.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Kallol Chaudhuri, MD, PhD, Department of Anesthesiology, Texas Tech University Health Sciences Center, 3601 4th St, STOP 8182. Address e-mail to kallol.chaudhuri@ttuhsc.edu.

Prothrombin complex concentrate (PCC), a heterogeneous combination of several coagulation factors, has been effectively used for rapid and complete reversal of life-threatening hemorrhage induced by vitamin K anticoagulants (VKA) such as warfarin.1 Indeed, recent practice guidelines have recommended the use of 4-factor PCC rather than fresh-frozen plasma (FFP) for rapid anticoagulant reversal in patients with major VKA-associated bleeding.2 This case report describes a unique use of PCC after the failure of FFP to emergently reverse the anticoagulant action of warfarin in a parturient who had developed cortical venous thrombosis. Unfortunately, the patient proceeded to develop bilateral subdural hematomas, and an inadvertent dural injury resulting from labor epidural analgesia was considered to be a possible aggravating factor. To reduce the possibility of intracranial hypotension contributing to the expansion of her subdural hematoma, an epidural blood patch was performed after PCC administration and normalization of measures of coagulation.

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Consent for Publication

Before submission of the manuscript, the patient had the opportunity to review the case report and gave written permission to the authors for publication.

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CASE DESCRIPTION

A healthy 23-year-old gravida 2 para 1 parturient requested pain management for her active labor. After preanesthetic evaluation and informed consent, continuous lumbar epidural analgesia was successfully initiated at L3–L4 level after 2 attempts. There was no evidence of inadvertent dural puncture, and the catheter was used predictably for the duration of labor. The next day, the patient developed nonspecific neck pain that was treated with oral analgesics. After partial relief of her symptoms, the patient wished to be discharged; however, after discharge, she continued to note a variety of symptoms including postural headache that was relieved in the supine position, and neck pain.

Approximately 10 days after her initial discharge, the patient returned to the hospital with a throbbing headache, which was worse when standing and not completely relieved when recumbent. In addition, she had developed new complaints including photosensitivity, paresthesia of the left upper extremity, and left facial droop. Cranial imaging studies at this time revealed a cortical vein thrombosis in the right parietal region (Figure 1) with changes suggestive of intracranial hypotension—low-lying corpus callosum and compression of internal cerebral veins. The patient received a few doses of low-molecular-weight heparin (Lovenox®, enoxaparin; Sanofi-Aventis, US) by IM injection, and oral warfarin was initiated. She was also placed on levetiracetam (Keppra®, Gland Pharma, India, for Hospira, Inc, US), because the migrating paresthesia was postulated to be a manifestation of seizure activity. The patient was discharged home on these medications along with strict bed rest, caffeine, and analgesics. Her headache improved temporarily during the initial days after discharge.

Figure 1.

Figure 1.

Figure 2.

Figure 2.

Approximately a week later, the severe headache returned along with paresthesia of bilateral upper extremities. She was readmitted to the hospital, and head MRI revealed bilateral subdural hematoma with a midline shift (Figure 2). Also noted was diffuse patchy meningeal enhancement with extension of cerebellar tonsils (1 cm below the foramen magnum). An immediate evacuation of the subdural hematomas was considered by the neurosurgical service; however, because the patient’s initial international normalized ratio (INR) was 2.3, 3 units of FFP were infused over 5 to 6 hours, resulting in a repeat INR of 1.55. During this time, the neurosurgical team requested the obstetric anesthesiologist to consider performing an urgent epidural blood patch to treat possible intracranial hypotension. Because the INR remained persistently elevated even after the administration of several units of FFP, 4-factor PCC (Kcentra®, CSL Behring GmbH, Germany) was infused (25 units/kg) for rapid correction of the anticoagulant action of warfarin. Within half an hour, the INR decreased to a normal value of 1.07. Thereafter, an epidural blood patch was performed at the interspace of L4 and L5 using 20 mL of autologous blood. The patient’s headache improved immediately, but with minimal improvement of neck stiffness. Her other symptoms gradually improved over the next 48 hours, and a repeat CT of the head showed early resolution of the subdural hematomas. The patient was subsequently discharged home approximately a week after the epidural blood patch.

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DISCUSSION

Accidental dural puncture is a well-known complication of epidural catheter placement; however, it may not always be evident during the procedure if there is absence of cerebrospinal fluid (CSF) flow through the epidural needle or via the catheter. The incidence of unrecognized accidental dural puncture among patients with postdural puncture headache (PDPH) widely varies in the published literature, ranging from as low as 10.5% to as high as 33%.3 Possible mechanisms of unrecognized dural puncture are thought to be (1) a tear in dural fibers only, leaving the arachnoid membrane intact, with subsequent rupture of the “weakened” portion of the membrane; or (2) a torn flap of dural ligament acting as a wedge, closing the punctured hole temporarily, which becomes displaced later. In our patient, there was no evidence of CSF leak during the performance of labor epidural analgesia. Because of the persistent nature of her headache, without relief in the recumbent posture, brain imaging was performed, which provided a tentative diagnosis of cortical vein thrombosis (CVT).

Cerebral venous thrombosis is reported to have an incidence of 8.9 cases per 100,000 deliveries.4 Non-PDPH, which may be difficult to differentiate from PDPH, is usually continuous and not positional; it may be accompanied by neurologic symptoms, for example, seizures, hemiparesis, etc. An association between CVT and intracranial hypotension has been suggested. Decreased CSF volume and pressure can lead to increased volume of venous blood (Monro-Kellie doctrine) and dilation of sinuses, decreased flow and stasis. Intracranial hypotension also causes downward migration of the brain, causing distortion of cerebral veins (more stasis) and traumatic injury of the endothelial cells, which promotes thrombosis.5

Subdural hematoma (SDH) is reported after dural puncture; intracranial hypotension causing venous stasis and weakened vasculature has been speculated to precipitate the subdural hematoma. Downward sagging of the brain increases the wall tension of the bridging veins, which may also add to this complication. Failure to diagnose a dural puncture, because of the absence of flow of CSF and/or definitive symptoms, may delay suggested treatment, for example, with an epidural blood patch. This can allow continuous loss of CSF from the subarachnoid space and increase the severity of intracranial hypotension, potentially resulting in CVT.7 Diagnosis of subdural hematoma in the majority of reported cases after neuraxial anesthesia was made approximately a week after dural puncture, which suggests that a delay in prompt diagnosis of accidental puncture after the procedure may increase the incidence of SDH.

Anticoagulation is an accepted practice for treatment of CVT; however, its use can potentiate the development of SDH. This combination of possible intracranial hypotension secondary to occult dural puncture and the use of anticoagulants may have played a dual role in the development of SDH in our patient.

PCC is primarily a mixture of vitamin K procoagulant factors (factors II, VII, IX, and X), and depending on the formulation, it contains either 3 (3F-PCC, without factor VII) or 4 (4F-PCC, with factor VII) factors. The currently US Food and Drug Administration-approved PCC, a 4F-PCC (proprietary name Kcentra®), is a nonactivated lyophilized mixture prepared from pooled human plasma. PCC also contains some anticoagulant factors, including proteins C and S, antithrombin III, and heparin. Warfarin is one of the most commonly prescribed anticoagulants, and its use for the prevention of thromboembolism has increased in recent years. However, inadvertent bleeding episodes are more frequent with warfarin, because higher than the desired level of anticoagulant activity occurs more commonly. The long half-life (60–72 hours) of the drug can pose an additional challenge in these situations. A 4-factor PCC, rather than FFP, is currently recommended for rapid reversal of anticoagulant activity in patients with warfarin-induced major hemorrhage.1

Compared with FFP, 4-factor PCC is reported to reverse VKA-induced anticoagulation more effectively and more rapidly, and with a comparable safety profile, in patients who need surgical or invasive intervention urgently (or within 24 hours).6 PCC was shown to normalize the INR faster than FFP in patients with VKA-related intracranial hemorrhage. Acute expansion of hematoma was a major cause of mortality in these patients, and earlier normalization of INR appeared to be advantageous in limiting the expansion of hematoma.7 Clinically significant improvement in coagulation was also reported with PCC in retrospective studies in patients with surgical bleeding not associated with oral anticoagulant therapy.8

In addition to better efficacy and rapid reversal of anticoagulation, the advantages of PCC include a lower volume of infusion, faster administration (no need of thawing), and better safety profile. Limitations of PCC include its expense and its association with thromboembolic complications, for example, myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, etc. In addition, for elective situations, vitamin K should be considered as the primary agent for warfarin reversal.

In an earlier report, PCC was used for warfarin reversal to perform spinal anesthesia in an 87-year-old patient scheduled for the removal of malignant melanoma.9 PCC was also reported to be effective in helping to perform emergency lumbar puncture in patients on oral anticoagulants.10 To our knowledge, this is the first case report of PCC administration to reverse the anticoagulant action of warfarin to perform an epidural blood patch. Our case demonstrates that PCC can be a safe and useful compound when effective reversal of warfarin effect is required for safe administration of neuraxial anesthesia/analgesia, surgical anesthesia, or for epidural blood patch in obstetric patients.

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ACKNOWLEDGMENT

The authors gratefully acknowledge Alan Santos, MD, MPH, Professor and Medical Director, Department of Anesthesiology, TTUHSC-Lubbock, Texas, for his expert advice during the preparation of the manuscript.

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DISCLOSURES

Name: Kallol Chaudhuri, MD, PhD.

Contribution: This author helped prepare the manuscript.

Name: Cooper W. Phillips, MD.

Contribution: This author helped prepare the manuscript.

Name: Swapna Chaudhuri, MD, PhD.

Contribution: This author helped prepare the manuscript.

Name: John Wasnick, MD, MPH.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: Hans-Joachim Priebe, MD.

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REFERENCES

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7. Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566573.
8. Schick KS, Fertmann JM, Jauch KW, Hoffmann JN. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care. 2009;13:R191.
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