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1. Bleeding on Anti-Xa Drugs: “Does All Bleeding Really Stop?”
Keywords
Anti Xa inhibitorRivaroxabanApixabanEdoxabanBetrixabanAndexanetKcentraFour-factor PCCProthrombin complex concentrateFEIBAThrombosisCase
Pertinent History
A 57-year-old male presents as a trauma alert following a rollover MVC. The patient was pulled from the driver’s seat by a good Samaritan who stopped at the crash site. The patient has been disoriented since EMS arrived and throughout transport by the aeromedical crew. On arrival to the Emergency Department (ED), the patient had a Glasgow Coma Score (GCS) of 13 and was repetitive with questions. He admits to being on blood thinners, but does not know the name of the drug or when he took his last dose.
PMH, SH, FH
Unknown
Medication
Unknown, possibly a blood thinner.
Pertinent Physical Exam
BP 105/62, HR 112, temperature 98.2 °F, RR 18, SpO2 98% on room air
Except as noted below, the findings of the complete physical exam are within normal limits.
Constitutional:
Alert, confused male who appears to be in moderate distress.
Head:
Contusions to the face and scalp with a scalp laceration and hematoma. The laceration is actively bleeding.
Eyes:
Pupils are equal and reactive at 4 mm bilaterally.
Neck/Spine:
Midline c-spine tenderness is noted. No thoracic or lumbar spine tenderness was noted.
Cardiovascular:
S1/S2, increased rate with an irregularly irregular rhythm.
Pulmonary/chest:
Clear bilaterally. Bruising was noted on the lower right chest wall.
Abdomen:
Soft, with abdominal tenderness in the right upper quadrant.
Musculoskeletal:
Extremities appear intact with good distal pulses.
Neurologic:
He is alert but confused and repetitive (GCS +4), he opens his eyes to verbal command (GCS +3), and he obeys commands (+6). His total GCS = 13.
ED Management (21:14)
The patient was a level 2 trauma activation. On arrival his GCS was 13. A FAST (focused assessment with sonography for trauma) exam was performed and showed no free fluid. Direct pressure on the scalp laceration was applied, and bleeding was slowed but not completely stopped. The wound was stapled closed to help control immediate bleeding, but oozing continued. Chest and pelvis X-rays were performed. The pelvis was normal, but the chest X-ray revealed right-sided rib fractures in ribs 10, 11, and 12. With concerning exam findings, a head, cervical spine, and abdominal CT were ordered.
Pertinent Results
Lab results | |||
|---|---|---|---|
Test | Results | Units | Normal range |
WBC | 15.4 | K/uL | 3.8–11.0 103/mm3 |
Hgb | 11.8 | g/dL | (Male) 14–18 g/dL (Female) 11–16 g/dL |
Platelets | 162 | K/uL | 140–450 K/uL |
Sodium | 143 | mEq/L | 135–148 mEq/L |
Potassium | 4.9 | mEq/L | 3.5–5.5 mEq/L |
Chloride | 110 | mEq/L | 96–112 mEq/L |
Bicarbonate | 22 | mEq/L | 21–34 mEq/L |
BUN | 13 | mg/dL | 6–23 mg/dL |
Creatinine | 1.3 | mg/dL | 0.6–1.5 mg/dL |
Glucose | 140 | mg/dL | 65–99 mg/dL |
Lactate | 1.4 | mmol/L | <2.0 |
INR | 3.2 | – | ≤1.1 |
PTT | 28 | seconds | 21–35 seconds |
Published with kind permission of © Colin G. Kaide 2019. All Rights Reserved
Published with kind permission of © Colin G. Kaide 2019. All Rights Reserved
Update 1 on ED Course (21:53)
The patient returned from CT scan , and initial ED physician interpretation of the head CT showed bilateral frontal contusions (left > right). The abdominal CT shows what appeared to be a grade 1 liver laceration (ED attending interpretation). Given the findings in the face of a reported “blood thinner” and elevated INR, anticoagulant therapy was presumed. Initially, the surgery attending wanted to give 4-factor prothrombin complex concentrate (4F-PCC), assuming the patient was on warfarin. The ED attending concurred initially but raised concern for the possibility that the patient could be on a factor Xa inhibitor (FXaI), because the INR was very elevated without a concomitant rise in PTT (which is normally slightly elevated with warfarin due to its effects on the common pathway). Kcentra® (4F-PCC) was ordered.
Update 2 on ED Course (22:05)
While the team was assessing the patient, a social worker obtained contact information for the patient’s wife and called to provide an update to her. During the phone call, the patient’s wife reported the patient is very good at taking his prescription medications and he took his evening medications with dinner 4 hours ago. She also added the following information:
PMH
Atrial fibrillation, HTN
Medications
Lisinopril 20 mg daily
Carvedilol 6.25 mg BID
Aspirin 81 mg daily
Rivaroxaban 20 mg daily with evening meal
Acetaminophen PRN
Because of the new information confirming the patient was on an FXaI, rivaroxaban (Xarelto®), the decision was made to hold the 4F-PCC and start andexanet (Andexxa®), a specific reversal agent for bleeding on that drug.
Update 3 on ED Course (2230)
Just as andexanet was started, the patient began to show signs of deterioration in mental status with his GCS falling to 9. With this change, expansion of the contusion was suspected. The patient was intubated using rapid sequence intubation (etomidate and succinylcholine). He was taken for a repeat head CT, which showed a significant enlargement of the contusion on the left side of the brain. He was admitted to the surgical ICU for monitoring and possible intervention if further expansion was seen.
Published with kind permission of © Colin G. Kaide 2019. All Rights Reserved
Learning Points
Priming Questions
- 1.
What strategies can you use to determine if the patient is on an anticoagulant when that information is not readily available?
- 2.
What additional information do you need to know to help decide whether to reverse the anticoagulation, or to watch and wait?
- 3.
If the patient is on an FXaI anticoagulant, how should their coagulopathy be managed?
- 4.
Does andexanet work to stop bleeding from FXaI drugs?
- 5.
In the absence of availability of andexanet, what other drugs could be used and do they work?
Introduction/Background
- 1.
Millions of people in the United States are taking an anticoagulant medication for treatment or prevention of venous thromboembolism (VTE) or prevention of thromboembolic complications from diseases such as atrial fibrillation (AF) or a mechanical valve. Of those, a significant proportion are on FXaIs, one type of direct oral anticoagulant (DOAC).
Frequency of FXaI use is on a trajectory to increase significantly as there is a desire in the medical community to move away from warfarin. This is further fueled by the FDA approval of a reversal agent that specifically targets FXaIs.
- 2.
Rivaroxaban (Xarelto®) was the first FXaI approved by the FDA in 2011, shortly followed by apixaban (Eliquis®) in 2012. More recently, edoxaban (Savaysa®) and betrixaban (Bevyxxa®) also became available in 2015 and 2017, respectively.
- 3.
As with older anticoagulant medications such as warfarin, DOAC use is associated with an increased risk of bleeding. Clinical trial data indicates annual major bleeding rates range between 2% and 4% with FXaIs [1, 2], and reported mortality rates are as high as 20% [3]. When DOACs first became available, many providers were initially resistant to prescribing them (rather than warfarin) for their patients due to the lack of an FDA approved reversal strategy. Nevertheless, despite this concern, DOAC use has continued to grow. The introduction of idarucizumab (Praxbind®) allayed some of the fears of using the antifactor II agent, dabigatran (Pradaxa®). Availability of a FXaI-specific reversal agent had been an ongoing concern, until recently.
Physiology/Pathophysiology
- 1.
Overview of hemostasis: This overview is purposefully simplified! Non-hematologists only need to have a functional knowledge of this topic as it pertains to management of anticoagulants and their reversal.
Hemostasis occurs as part of a tightly regulated balance between clot formation and clot breakdown, which develops through an interaction of two independent processes – primary and secondary hemostases.
Primary hemostasis. When damaged vascular endothelium is exposed, platelets bind via von Willebrand’s factor to the endothelium. Bound and activated platelets release various substances, which attract, activate, and facilitate aggregation of other platelets [4]. The efficacy of primary hemostasis depends on both the number of platelets available (platelet count) and the platelet’s ability to correctly function during the process. Many medications (aspirin, nonsteroidal anti-inflammatory drugs, and other antiplatelet drugs) can “poison” the ability of platelets to aggregate.
Secondary hemostasis [5]. The goal of secondary hemostasis (coagulation) is the formation of fibrin. Activation of the clotting cascade can be initiated by two separate pathways – the tissue factor (TF) pathway (a.k.a. the extrinsic pathway) and the contact activation pathway (a.k.a. the intrinsic pathway) (See Fig. 1.1). When an injury to the blood vessel allows factor VII (FVII) to come in contact with tissue factor (found on stromal fibroblasts and leukocytes), the FVII–TF complex activates the common pathway, leading to a large thrombin burst. This pathway generates the most fibrin in the shortest time. When collagen in the basement membrane of a blood vessel is exposed, a complex of high-molecular-weight kininogen (HMWK), prekallikrein, and FXII is formed, activating the contact activation pathway. This causes the sequential activation of factors, culminating in the activation of the common pathway. The common pathway leads to the formation of fibrin, which cross-links platelets, strengthening the primary platelet plug. For coagulation to work properly, there has to be an adequate amount of functional clotting factors.
- 2.
Effects of anticoagulants: Using Fig. 1.1 , one can explain where all anticoagulants work within the system, making this figure very crucial to know about the otherwise incredibly complicated coagulation system. A more detailed “bigger picture” illustration can be seen in Fig. 1.2.
Apixaban (Eliquis®), rivaroxaban (Xarelto®), edoxaban (Savaysa®), and betrixaban (Bevyxxa®) reversibly and competitively inhibit free and clot-bound factor Xa [6].
Dabigatran exelate is a reversible competitive direct factor II inhibitor prodrug, which assumes its active form while in the intestines. Dabigatran prevents the downstream cleavage of fibrinogen to fibrin [7].
Warfarin inhibits hepatic synthesis of active forms of vitamin K-dependent coagulation factors, II, VII, IX, and X [8].
Unfractionated heparin binds to antithrombin through a high-affinity pentasaccharide. This complex then binds to factors II and X irreversibly [9].
Low-molecular-weight heparins (LMWHs) are prepared by depolymerizing heparin. LMWH indirectly inhibits factor Xa activity by activating the antithrombin III complex, similar to heparin. This complex then inactivates factor Xa with some minimal anti-II effect [10].
Fondaparinux is a synthetic pentasaccharide that serves as a highly selective factor Xa inhibitor. It selectively binds to antithrombin III to inhibit factor Xa. Unlike heparin or LMWH, it does not inhibit factor II. There is rapid and complete bioavailability, and elimination half-life is 17–21 hours [11].
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