The authors present the case of an 80-year-old woman with myelodysplastic syndrome treated with chemotherapy and apixaban, a direct oral anticoagulant, victim of an intracranial hemorrhage. She presented to the emergency room with an altered mental state and was found to have a large intraparenchymal hematoma with significant mass effect. Our patient received FEIBA (Factor Eight Inhibitor Bypass Activity) to reverse the bleeding. Bleeding reversal strategies related to anticoagulants are discussed.
Intracerebral hemorrhage (ICH), of which intraparenchymal hematomas are a subtype, accounts for less than 20% of all stroke cases, but is associated with 30% to 40% early mortality . Mortality remains high despite declining incidence . Among survivors, less than 50% are able to regain their previous level of activity.
Risk factors for ICH include history of ICH, hypertension, hyperlipidemia, diabetes, metabolic syndrome, myeloid angiopathy, and many medications. Medications that increase the risk of ICH include vasoconstrictor agents such as triptans and selective serotonin reuptake inhibitors, decongestants, stimulants, phentermine, and sympathomimetic drugs. Oral contraceptives containing estrogen may cause bleeding due to cerebral venous sinus thrombosis. Additionally, drugs of abuse such as tobacco, marijuana, cocaine, alcohol, and amphetamines also increase the risk of ICH. .
The traditional presentation of ICH is sudden onset of focal neurological deficits, which progress rapidly within minutes to hours . Deficits are often accompanied by nausea, headaches, decreased consciousness and high blood pressure.
The main goals of the emerging management of ICH are to prevent further bleeding and to assess whether surgical intervention is beneficial. To this end, the focus is on blood pressure control and agents to reverse any underlying coagulopathy. Our patient was on direct oral anticoagulant (DOAC) for her myelodysplastic syndrome and received FEIBA (Factor Eight Inhibitor Bypass Activity) to reverse the bleeding.
Presentation of the case
An 80-year-old woman presented to the emergency room with a deteriorating mental state. The patient’s son reported that she had full cognitive function the previous night. She started to feel sick the morning of the ER presentation and vomited several times. A few hours later, she was unable to drink water through a straw and could only answer questions with “gibberish”. Her symptoms progressed until she could no longer open her eyes or speak. His medical history was extensive for myelodysplastic syndrome which was being treated with chemotherapy and apixaban, a DOAC. She had taken her medication within the previous 12 hours. Her son said she does not smoke or use recreational drugs or alcohol.
His vital signs included a temperature of 98.5°F, blood pressure of 138/81 mmHg, pulse of 100 beats per minute, respiratory rate of 16 breaths per minute, and oxygen saturation of 96% on air. ambient. Physical examination showed multiple areas of bruising of different ages, including periorbital bruising, but no eye lesions. She also had scattered petechiae. The patient only opened her eyes to noxious stimuli and moaned a few times. She was, however, able to protect her airways. His coma score in Glasgow was 9 (E2V2M5). Her cardiopulmonary and abdominal examinations were unremarkable. Laboratory analysis was significant for severe thrombocytopenia, anemia, hyperglycemia, mild hypokalemia, and hyponatremia (Table 1).
Non-contrast cerebral CT showed a large left frontal intraparenchymal hematoma with significant mass effect, resulting from an anterior midline shift from left to right of approximately 11 mm. Extra-axial hemorrhage was also present in the parafalcine region as well as anterior to the bilateral frontal lobes and in the basal cisterns. In addition, there was intraventricular extension of the hemorrhage, relative effacement of the left lateral ventricle, and bilateral hemorrhage into the occipital horns of the lateral ventricles. The left parietal parenchyma showed a rounded focus approximately 1.4 cm in diameter, and a small-volume subarachnoid hemorrhage is observed near the left parietal cortex (Figure 1).
Her ICH score was 4, with 1 point each for age 80, GCS between 5 and 12, ICH volume >30 cubic centimeters, and intraventricular blood present. The patient received FEIBA for reversal of anticoagulation and platelet transfusion. An ICH score of 4 is generally associated with 97% mortality. Given his poor prognosis, the family opted for palliative care.
ICH associated with coagulopathy is an additional risk factor for mortality and poor functional outcome with hematoma expansion that can occur within one hour in up to 25% of patients and within four hours in 88% patients. Anticoagulant-related ICH is a medical emergency that requires urgent reversal . The use of oral anticoagulants is increasing due to the aging of the population and the associated increase in the number of patients with cardiovascular comorbidities. There are several reversal agents available, with availability varying by institution. Current anticoagulation options include vitamin K antagonists (VKAs) such as warfarin and DOACs. DOACs are divided into two classes; direct thrombin inhibitors and factor Xa inhibitors. Treatment should be initiated based on neuroimaging and clinical information such as type and time of anticoagulant administration rather than waiting for laboratory results .
Warfarin interferes with the production of vitamin K-dependent clotting factors II, VII, IX, and X by depleting the vitamin K store . Warfarin-related coagulopathy is usually treated with prothrombin complex concentrate (PCC) which corrects the coagulopathy by replacing the four vitamin K dependent factors. It can be administered in a small rapid volume for which it is considered the preferred treatment. Fresh Frozen Plasma (FFP) is derived from whole blood products and works by replacing plasma proteins with complete clotting factors. FFP is ineffective in the acute setting because reversal of INR (international normalized ratio) with FFP can take up to 24 hours. Additionally, FFP requires high volumes and can worsen fluid balance, which can lead to pulmonary edema in patients with heart failure.
Heparin-induced coagulopathy is treated with protamine sulfate. Dosage may vary depending on length of last dose and route; subcutaneous or intravenous route . DOACs have been shown to be safer than warfarin in terms of the risk of stroke or systemic embolism, intracranial hemorrhage, and all-cause death compared to warfarin . Given their safety, effectiveness and ease of use, their use has increased.
Andexanet alfa is a factor Xa inhibitor reversal agent and is currently the only FDA-approved agent for apixaban and rivaroxaban. The single-arm ANNEXA-4 study reported that 82% of patients had excellent or good hemostatic efficacy at 12 hours after administration of andexanet alfa . Given its cost and limited availability, PCC is still commonly used. There is insufficient evidence on the risks and benefits to strongly favor 4-factor PCC or andexanet over the other; these reversal agents have not been compared to each other directly in a randomized trial. Data comparing outcomes in patients receiving andexanet alfa or PCC are limited by baseline imbalances between groups attributable to selection bias .
Factor VIII Inhibitor Bypass Activity (FEIBA), an activated prothrombin protein complex concentrate, is also used as an off-label factor Xa inhibitor reversal agent. It controls bleeding by induction and facilitates the generation of thrombin . A few studies report good hemostasis with FEIBA in bleeding associated with DOACs. A case series of 104 patients who used FEIBA specifically for bleeding secondary to apixaban or rivaroxaban achieved hemostasis in 89% of patients .
A study of 64 consecutive patients on DOACs found low-dose (<20 Units/kg) and moderate-dose (20-30 Units/kg) FEIBA to be an effective management strategy to achieve hemostasis in the 'ICH linked to the AOD. . Despite a handful of studies reporting that FEIBA is a safe and effective agent for apixaban and rivaroxaban reversal, it is still considered off-label for DOAC-associated bleeding at the time of writing.
There are several ways to manage ICH associated with coagulopathy, such as PCC, andexanet alfa, and FEIBA. Overall, there have been significant advances in management options for ICH in patients on oral anticoagulation. Failure to treat coagulopathy can result in delay of neurosurgery, increased hematoma size, and increased risk of mortality.
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