Anticoagulation Safety

Etiology

Vitamin K Antagonists

Warfarin, acenocoumarol, phenprocoumon, and fluindione are VKAs with a narrow therapeutic window influenced by genetic variation, drug interactions, and diet. Monitoring patients on warfarin can be quite challenging, as variations in dietary vitamin K intake, multiple medications, tobacco and alcohol use, and kidney, liver, thyroid, and heart disease can all affect international normalized ratio (INR) stabilization.

Genetic diversity also affects a patient's sensitivity to warfarin. The 2 genes that primarily determine a patient's warfarin sensitivity are vitamin K epoxide reductase, subunit 1 (VKORC1), which is the drug target, and hepatic cytochrome P450 2C9 isoform (CYP2C9), which metabolizes the drug to an inactive form. VKORC1 polymorphisms affect the required doses of warfarin.[5] Likewise, CYP2C9 gene differences affect the metabolism of warfarin and acenocoumarol.[6] Indications for VKAs include the following: 

• Atrial fibrillation
• Acute coronary syndrome 
• Heart failure 
• Prosthetic heart valve 
• Stroke 
• Venous thromboembolism (VTE) 
• Pulmonary embolism 
• Antiphospholipid syndrome 

Direct Oral Anticoagulants

The direct factor Xa inhibitors include apixaban, edoxaban, and rivaroxaban. Dabigatran is the only oral direct thrombin inhibitor. The indications for DOACs are VTE prophylaxis and treatment, atrial fibrillation, and acute coronary syndromes.

Adverse Effects of Oral Anticoagulants

Both VKAs and DOACs can produce allergic reactions, increase the risk of bleeding, and lead to thromboembolic events if dosed subtherapeutically or discontinued too soon. Larger studies do not support the existence of acute liver injury associated with DOACs despite case reports.[7][8] Warfarin may also cause additional adverse effects like skin necrosis, teratogenicity during pregnancy, cholesterol embolization, vascular calcification, nephropathy, and interference with hypercoagulability testing.

Patients on oral anticoagulants can experience subcutaneous, intramuscular, retroperitoneal, intracranial, gastrointestinal, and intraarticular bleeding. Patients receiving neuraxial anesthesia are at risk of developing a spinal epidural hematoma. Subclinical bleeding that would not typically cause a problem can present as clinically severe bleeding in a patient on anticoagulation. The risk of ICH increases with a history of stroke, hypertension, and cerebral amyloid angiopathy. Additional factors that increase the risk of bleeding include the following:

• Active peptic ulcer disease
• Thrombocytopenia with a platelet count lower than 50,000/µL
• Patients admitted to the intensive care unit
• Active cancer
• Rheumatologic disease
• Chronic kidney disease
• Liver disease
• An episode of bleeding in the last 3 months
• Presence of a central venous catheter
• Male sex
• Increasing age
• Concurrent antiplatelet medications
• Obesity
• Diabetes [9]

Epidemiology

Given their efficacy and better safety profile, DOACs have become the preferred choice over VKAs in treating nonvalvular atrial fibrillation and VTE, 2 of the most common reasons for long-term anticoagulation. The risk of bleeding-related complications is highest within the first 3 months.[10][11][12] The risk of bleeding associated with DOACs is generally less than that of warfarin. The overall risk of ICH is approximately 50% less with DOACs than with VKAs.[13]

In a study of adults 66 and older receiving warfarin for nonvalvular atrial fibrillation, the overall bleeding rate is approximately 4% per person-year. The annual risk of ICH in patients with atrial fibrillation treated with a DOAC is approximately 0.3%. Overall, the rate of spontaneous ICH related to anticoagulant therapy occurs in 0.5% to 1.0% of patients each year and carries a 30-day disability or mortality risk of 50%. The rate of bleeding associated with an oral anticoagulant in patients with VTE is higher at 7.22 per 100 patient-years.

Risk factors for spontaneous ICH are Asian, Latin American, or Black ethnicity, increasing age, hypertension, concurrent antiplatelet medication use, thrombocytopenia, cerebral amyloid angiopathy, having a prior stroke or transient ischemic attack, and a history of bleeding. Studies comparing the incidence of gastrointestinal bleeding between DOACs and VKAs provide mixed results. The risk of major gastrointestinal bleeding may be higher with dabigatran 150 mg, rivaroxaban, and edoxaban 60 mg. Gastrointestinal bleeding may be lower with edoxaban 30 mg and comparable to warfarin with dabigatran 110 mg and apixaban.[14][15][16]

Studies reveal that rivaroxaban has a slightly higher rate of gastrointestinal bleeding. However, the results are not statistically significant.[17][18] Apixaban has the best safety profile for gastrointestinal hemorrhage compared to VKAs and other DOACs in patients with nonvalvular atrial fibrillation. 

The incidence rate of all major bleeding events combined gradually increases with age, rising from 1.5 per 100 patient-years in individuals younger than 60 to 4.2 per 100 patient-years in patients older than 80. Fatal hemorrhage, often due to ICH, occurs at a rate of 0.3 per 100 patient-years across all age groups, except in individuals younger than 60 who have a lower rate at 0.1 per 100 patient-years. No gender-based or anticoagulation indication-based difference in hemorrhage rates exists. Overall, hemorrhage risk rises by 2% per year of age. The risk of thromboembolic events, mainly myocardial infarction, is double in patients older than 80 compared to people younger than 60, increasing by 2% per year of age.[19]

DOACs are safer and more effective than warfarin for treating nonvalvular atrial fibrillation in frail older patients. Experts recommend apixaban and edoxaban for safety and efficacy in this demographic.[20] However, a recent study suggests that frail older patients with atrial fibrillation may not benefit from switching to DOACs from VKAs, as bleeding complications may increase without reducing thromboembolic complications.[21]

Pathophysiology

Bleeding complications from anticoagulant therapy stem from disruptions in the normal hemostatic process, which can arise from factors like mechanical trauma, tumor infiltration, thrombosis, and hypertension, compromising vascular integrity. The breakdown of endothelial barrier function due to sepsis, ischemia, or other effects of medication may further contribute to hemostatic dysfunction. Microscopic bleeding can also progress to clinically significant hemorrhage in patients receiving anticoagulants.

Vitamin K Antagonists

VKAs block the vitamin K epoxide reductase complex in the liver, causing a dysfunction of the vitamin K-dependent factors II (prothrombin), VII, IX, and X. VKAs also inhibit vitamin K-dependent γ-carboxylation of protein S and protein C, which inhibit activated factors VIII and V. This mechanism gives warfarin a transient procoagulant effect during the first 1 to 2 days of use.

Clinicians monitor VKA therapy using prothrombin time (PT) and INR, with the latter providing a standardized measure due to variability in PT across laboratories. Effective anticoagulation with VKAs is delayed until previously synthesized coagulation factors are depleted, which typically occurs within 1 week. The PT rises within 1 to 3 days as factor VII, with a half-life of 4 to 6 hours, depletes, while factor II, with a 3-day half-life, remains active. A supratherapeutic INR increases bleeding risk, whereas a subtherapeutic INR heightens thromboembolic risk.

Medications interact with VKAs in various ways to increase the risk of complications. The following list outlines common interactions between VKAs and other medications.

Increase bleeding risk 

• Medication interactions: Antimicrobials like metronidazole, macrolides, and fluoroquinolones can alter the intestinal microflora and decrease vitamin K absorption and synthesis. Fluconazole, amiodarone, and sulfamethoxazole inhibit hepatic CYP2C9 and warfarin metabolism. Warfarin circulates bound to albumin, and only the non-protein-bound fraction is active. Some medications can displace warfarin from albumin. Note that acetaminophen is a safer alternative than nonsteroidal anti-inflammatory drugs (NSAIDs) for patients on VKAs. Acetaminophen can interrupt vitamin K recycling. Patients using acetaminophen in doses of 2 or more grams a day for 3 or more consecutive days should have their INR checked 3 to 5 days after the first dose of acetaminophen.[22][23] 
• Damage to the gastrointestinal mucosa: Aspirin and NSAIDs are the usual culprits.
• Interference with platelet function: Aspirin, NSAIDs, clopidogrel, ticagrelor, and dipyridamole are common agents.
• Other mechanisms: Smoking marijuana or ingesting cannabidiol oil and other tetrahydrocannabinol-containing products can inhibit CYP29.[24] Excess alcohol consumption can interfere with warfarin metabolism. Patients with severe liver disease may also have concurrent coagulopathy, thrombocytopenia, or gastrointestinal varices, all of which increase a patient's bleeding risk. Cigarette smoking increases warfarin dosage requirements through induction of hepatic cytochrome P-450 activity. Nicotine replacement products do not have the same effects.

Increase thromboembolic risk

• Induction of hepatic hepatic cytochrome P450 2C9 isoform and warfarin metabolism: Commonly used agents include rifampin, carbamazepine, phenytoin, and primidone.
• Variations in vitamin K intake: With increased intake or vitamin supplements containing vitamin K, vitamin K can bypass vitamin K epoxide reductase, causing a subtherapeutic INR. Patients should maintain a consistent level of vitamin K in their diet to avoid frequent INR fluctuations and dose adjustments. 

Comorbid conditions such as thyroid disease, liver disease, and heart failure can impact INR stabilization. Warfarin is primarily metabolized in the liver, while thyroid disease influences clotting factor clearance. Hyperthyroidism accelerates clearance, enhancing warfarin’s effect, while hypothyroidism slows clearance, diminishing its effect.

Genetic variations in CYP2C9 and vitamin K epoxide reductase (VKORC1) enzymes significantly influence warfarin sensitivity. Missense mutations in VKORC1 are thought to contribute to resistance to warfarin and other VKAs, with VKORC1 variants accounting for nearly 25% of warfarin dosing variability. High-dose and low-dose haplotypes were identified.[25] The CYP2C9*3 variant allele reduces CYP2C9 activity by 80%, necessitating lower warfarin doses. Although testing for VKORC1 polymorphisms is available, studies show pharmacogenetic-based dosing does not outperform clinically guided dosing.[26]

Additional complications associated with vitamin K antagonists

The rapid reduction of protein C levels and the transient hypercoagulable state during the initiation of VKA therapy can cause skin necrosis, typically in areas with subcutaneous fat such as the extremities, breasts, trunk, and penis. Skin necrosis is a rare complication. Approximately one-third of affected patients have an underlying protein C deficiency.[27]

Long-term warfarin use can also lead to calcification of the aortic valve, coronary arteries, and femoral arteries due to the inhibition of vitamin K-dependent matrix Gla protein, which usually inhibits calcification in its active state. Researchers have not established a link between warfarin use and clinical events like myocardial infarction or stroke despite these findings. However, cholesterol crystal embolization is a potential complication of anticoagulant therapy in general, believed to be caused by plaque hemorrhage.

Excessive anticoagulation can induce nephropathy by triggering glomerular hemorrhage, thereby obstructing renal tubules by red blood cell (RBC) cast formation and damaging tubular epithelial cells. Intraluminal RBC casts are the hallmark histologic feature of ARN. 

Direct Oral Anticoagulants

The DOACs prevent thrombin from cleaving fibrinogen to yield fibrin and factor Xa from cleaving prothrombin to form thrombin. Thrombin is the final enzyme of the clotting cascade. Besides cleaving fibrinogen into fibrin, thrombin activates other procoagulant factors, including factors V, VIII, XI, and XIII, and activates platelets. 

Supratherapeutic response

• Chronic kidney disease: The kidney excretes dabigatran. Experts recommend dose reductions for patients with a creatinine clearance (CrCl) of 15 to 30 mL/min.[28] The dosing guidelines concerning renal impairment vary somewhat for each DOAC. In the United States, product labeling recommends avoidance of dabigatran in individuals with CrCl below 15 mL/min or in those who are hemodialysis-dependent. The Canadian, United Kingdom, and European Medicines Agency labeling recommends avoiding use in patients with a CrCl below 30 mL/min. Apixaban has the most negligible dependence on clearance by the kidney. Canadian product information does not recommend apixaban in individuals with CrCl less than 15 mL/min, while the United States recommends dose adjustments based on CrCl, body weight, and age. The kidney excretes edoxaban, which is a substrate for P-glycoprotein. Product labeling has a boxed warning regarding reduced efficacy in nonvalvular atrial fibrillation in patients with a high CrCl greater than 95 mL/min and advises a dose reduction for people with CrCl of 15 to 50 mL/min.
• Body weight: The International Society on Thrombosis and Haemostasis states that any DOAC is appropriate for individuals with a body mass index (BMI) of up to 40 kg/m2 or a weight of up to 120 kg. 
• P-glycoprotein inhibitors: Medications like ketoconazole and verapamil in patients with kidney failure can potentiate the effects of dabigatran.
• Patients receiving dual inhibitors of cytochrome P450 3A4 and P-glycoprotein: Patients receiving strong dual inhibitors of cytochrome P450 3A4 (CYP-3A4) and P-glycoprotein, like apixaban, in combination with fluconazole should receive a dose reduction.[29] 

Subtherapeutic response

P-glycoprotein inducers can reduce the effects of dabigatran. Rifampin is a P-glycoprotein inducer.

Factors that increase bleeding with the use of both vitamin K antagonists and direct oral anticoagulants

• Malignancy: Patients with cancer, especially if undergoing cancer treatment, may have an increased risk of bleeding due to thrombocytopenia, increasing inflammatory cytokines, and disruption of vascular integrity at the primary tumor site or metastases. Blood vessels in tumors are also more structurally immature.
• Cerebral amyloid angiopathy: Amyloid β-peptide deposition in the walls of small- to medium-sized blood vessels weakens their structure and makes them prone to bleeding.
• Drug abuse: Cocaine and other sympathomimetic drugs heighten the risk of intracranial bleeding and ischemia by causing tachycardia and elevated blood pressure through sympathetic activation. These agents also induce vasoconstriction, vasospasm, and intravascular thrombosis due to increased platelet aggregation.
• Hypertension: The most modifiable risk factor, hypertension, leads to vasculopathy in small penetrating arteries, promoting the formation of microscopic pseudoaneurysms and resulting in microhemorrhages.

History and Physical

Medical experts categorize major bleeding events as instances that result in death, involve critical organs such as the brain or large joints, cause hemodynamic instability, lead to a hemoglobin drop of 2 g/dL or more, or require the transfusion of at least 2 units of RBCs. Clinically significant bleeding, while requiring intervention, is less severe and does not meet the criteria for major bleeding.

Symptoms of significant bleeding vary by site, and early symptoms include epistaxis, gum bleeding, heavy menstrual bleeding, or excessive bruising. Airway-related hematomas may cause sore throat, painful or difficult swallowing, nosebleeds, shortness of breath, or hemoptysis. Extremity involvement may manifest as pain, swelling, weakness, or limited motion. Intraabdominal bleeding can lead to pain and distension, while intracranial bleeds may cause severe headaches, vomiting, dizziness, or seizures. Ocular bleeding may result in vision changes. Gastrointestinal bleeding may present as melena, hematochezia, or hematemesis.

Physical examination findings in various body locations include the following:

• Upper airway findings: Spontaneous hematoma may arise. Dysphonia, neck swelling, and dyspnea are common findings.
• Intracranial manifestations: Spontaneous ICH usually occurs during normal activities. Neurological symptoms progress over minutes to hours. Some develop headaches, vomiting, and decreased levels of consciousness. The exact location of the hemorrhage determines the specific neurological symptoms. Some patients may develop seizures and catecholamine-induced prolonged QT interval and ST-T wave changes on the electrocardiogram (ECG). Mild serum myocardial enzyme elevations may accompany the ECG changes.
• Cardiovascular indicators: Cardiac tamponade may occur due to hemopericardium and cause hypotension, jugular venous distention, tachycardia, pulsus paradoxus, and muffled heart sounds.
• Gastrointestinal signs: Patients may have evidence of hypovolemia manifesting as tachycardia and hypotension, visible or occult blood in the stool, and pain on abdominal examination.
• Findings in the extremities: A hemorrhage or hematoma located beneath the fascia can cause compartment syndrome, which presents with pain with passive muscle stretching in the affected compartment, a tense compartment with a firm "wood-like" feeling, pallor from vascular insufficiency, diminished sensation, muscle weakness, and paralysis.
• Retroperitoneal signs: Patients may present with a palpable abdominal mass and ecchymosis of the flank, periumbilical area, scrotum, upper thigh, pubis, and groin. 
• Thoracic manifestations: Tachypnea with shallow breaths is common. Patients will also have diminished ipsilateral breath sounds and dullness to percussion. Hypotension and tachycardia indicate significant blood loss.

Skin necrosis associated with VKAs appears as petechiae progressing to ecchymoses and hemorrhagic bullae with eventual necrosis and slow-healing eschar formation. Patients with anticoagulant-related nephropathy (ARN) may present with hypertension, hematuria, signs of volume overload, and reduced urine output. Livedo reticularis, gangrene, cyanosis, skin ulcers, purpura or petechiae, and firm, painful erythematous nodules are the most common clinical findings associated with cholesterol crystal emboli. Acute kidney injury (AKI) is an additional common finding. Emboli in the gastrointestinal system cause abdominal pain, diarrhea, and occasionally bleeding. Emboli to the central nervous system may cause amaurosis fugax, transient ischemic attack, stroke, confusional state, headache, and dizziness.

Evaluation

Healthcare professionals must swiftly determine the severity and location when assessing bleeding complications in patients taking oral anticoagulants. A comprehensive history and medication review are crucial, documenting the anticoagulant regimen, last dose timing, and potential overdose risk. In addition, exploring the history of renal or hepatic disease, bleeding disorders, thrombocytopenia, and medications affecting hemostasis is necessary. Understanding the anticoagulation indication and thrombosis risk aids treatment decisions.

Monitoring serial vital signs is essential to track blood loss rates, with serial hemoglobin levels helpful in suspected significant blood loss, considering the potential delay in initial hemoglobin decline with massive blood loss. Symptom-based imaging studies include brain and abdominal computed tomography (CT) for intracranial and retroperitoneal bleeds, chest radiograph or ultrasound for hemothorax, and echocardiogram for cardiac tamponade. Patients with upper and lower gastrointestinal bleeding may need endoscopy or CT angiography. A CT angiogram-tagged RBC scan may be useful in patients with intermittent lower gastrointestinal bleeding, where the bleeding stops before the source can be identified but then resumes. Compartment syndrome is a clinical diagnosis. 

Required laboratory and imaging tests include the following:

• PT and INR
• Activated partial thromboplastin time (aPTT)
• Thrombin clotting time for suspected dabigatran use
• Antifactor Xa heparin level for direct factor Xa inhibitor presence
• Quantitative factor Xa inhibitor and dabigatran levels for specific DOACs
• Complete blood count for serum hemoglobin and platelet count
• Serum creatinine
• Serum aminotransferases to assess direct factor Xa inhibitor clearance or coagulation factor synthesis impairment
• Fibrinogen and D-dimer for suspected disseminated intravascular coagulation
• Organ-specific labs to indicate end-organ involvement in cholesterol crystal embolization

Clinicians may recognize warfarin-induced skin necrosis clinically, but a skin biopsy can identify the cause of necrosis if the diagnosis is uncertain. Elevated creatinine or eosinophiluria in cases of kidney involvement may signal end-organ damage and dysfunction in patients with cholesterol crystal embolization. Clinicians may visualize plaques in the aorta with transesophageal echocardiography, but identifying the specific plaque that caused the embolization does not often occur. CT and magnetic resonance imaging are less invasive and can provide more complete evaluations of the extent of atherosclerosis in the aorta.

Generally, a presumptive diagnosis of ARN is made in the setting of AKI and severe warfarin or DOAC coagulopathy if clinicians exclude other AKI causes. Kidney biopsy makes the definitive diagnosis but is generally not performed due to the level of anticoagulation. Patients with AKI should undergo a renal ultrasound to exclude obstruction as a potential cause. Subsequent laboratory evaluation depends on systemic symptoms like hypertension and edema and the amount of protein and blood on the patient's urinalysis.

Treatment / Management

When prescribing oral anticoagulants, healthcare professionals must carefully weigh the risks of adverse effects against the clinical benefits. Although current guidelines recommend anticoagulation for most patients with atrial fibrillation, 30% to 60% of patients do not receive this therapy due to concerns about intracranial and gastrointestinal bleeding. While oral anticoagulants pose a risk of severe adverse effects, the incidence of serious or fatal bleeding in older patients is low, and individuals with appropriate indications should receive anticoagulation.

Tools like the Hypertension, Abnormal liver/renal function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol (HAS-BLED) score can help assess bleeding risk. However, these tools do not outperform clinical judgment and are most useful for identifying modifiable bleeding risk factors.[30][31] The CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category) score estimates thromboembolic risk in patients with atrial fibrillation to guide the use of anticoagulants.[32] (A1)

When patients on oral anticoagulants present with bleeding, the first step is to stop all anticoagulant and antiplatelet therapy, documenting the incident in the patient's chart and hospital orders. Monitoring their hemodynamic stability, securing their airway, and obtaining intravenous access are crucial. Clinicians should consider transfusions of RBCs and platelets as necessary and administer plasma for trauma-induced coagulopathy.

Vitamin K Antagonists

Management of serious life-threatening bleeding from VKAs differs from that associated with DOACs. The recommendations are explained below.

Serious life-threatening bleeding

To manage patients with severe life-threatening bleeding, start by giving 10 mg of vitamin K intravenously, infused over 20 to 60 minutes, to prevent anaphylactic and anaphylactoid reactions. Vitamin K requires 12 to 24 hours to become effective. Clinicians can administer another dose if the INR remains high after 12 hours. Awaiting laboratory and imaging results is unnecessary before administering vitamin K if severe bleeding is evident. If anticoagulation needs to resume, clinicians can administer heparin while the patient remains resistant to warfarin.

Patients with an INR greater than 2 should also receive 4-factor prothrombin complex concentrate (PCC) containing factors II, VII, IX, X, protein C, and protein S, using a standardized dose or a dose based on the patient's INR and weight on presentation. The benefit of 4-factor PCC is that it does not require thawing or blood group typing. Additionally, 4-factor PCC lowers the risk of volume overload, transfusion-related acute lung injury, transfusion reactions, and transmission of infectious diseases. Clinicians may obtain a second INR 30 minutes after administration. Patients may receive a second dose of 4-factor PCC if the INR is still above 1.5. Clinicians may base subsequent INR measurements on the severity of bleeding.

Antifibrinolytic agents like tranexamic acid and ε-aminocaproic acid may be useful, and desmopressin may be helpful in the presence of platelet dysfunction. The tranexamic acid dose is 1 to 1.5 grams orally every 8 to 12 hours or 10 to 20 mg/kg as an intravenous bolus followed by 10 mg/kg intravenously every 6 to 8 hours for the duration of bleeding.

Alternate approaches

If 4-factor PCC is unavailable, in addition to vitamin K, the following regimens are viable alternatives:

• Give 3-factor PCC, containing factors II, IX, and X, 1500 to 2000 units intravenously over 10 minutes. Clinicians can obtain the INR 15 minutes following the infusion and repeat the dose if the INR remains above 1.5.
• Give factor VIIa 20 µcg/kg intravenously or fresh frozen plasma (FFP) 2 units intravenously by rapid infusion. Factor VIIa may be a better option if volume overload is a concern.

Patients with massive hemorrhage undergoing massive blood transfusion should receive FFP rather than 4-factor PCC, which does not significantly reduce 24-hour blood product usage and has a higher incidence of thromboembolic events.[33](A1)

Supratherapeutic international normalized ratio without bleeding

For patients with this manifestation, the recommended therapeutic strategies are as follows:

• For patients with INR greater than 10 without bleeding: Hold the patient's warfarin until their INR returns to the desired therapeutic range. Additionally, administer 2.5 to 5 mg of vitamin K and monitor the INR every 24 to 48 hours. The INR typically begins to correct within 1 to 2 days after taking vitamin K, but an additional dose may be necessary. Once the INR is back in the desired range, restart warfarin at a lower dose. In the absence of significant bleeding, avoid using 4-factor PCC and FFP due to their increased risk of thromboembolic events and transfusion reactions.
• For patients with INR 4.5 to 10 without bleeding: Hold 1 to 2 doses of warfarin and recheck the INR in 1 to 3 days. Clinicians may contemplate administering 1.25 to 2.5 mg of oral vitamin K. Nevertheless, research shows no reduction in bleeding or mortality risk.[34] Vitamin K could be particularly beneficial for bleeding-prone individuals, such as patients of advanced age or with active cancer or exacerbated heart failure. Resume warfarin at a reduced maintenance dose.
• For patients with INR below 4.5 without bleeding: Hold the next warfarin dose and reduce the maintenance dose, with INR taken 1 to 2 times weekly during the adjustment period.
(A1)

Direct Oral Anticoagulants

Coagulation testing is generally not useful for patients on DOACs who present with bleeding. Prolonged coagulation tests may indicate residual effects of DOACs, but normal results do not confirm the absence of these effects. Patients with ongoing bleeding despite normal coagulation studies require treatment, except for individuals on dabigatran who have a normal thrombin time.

For patients who had their last prescribed dose within 2 hours, or 6 hours in cases of intentional overdose, oral activated charcoal may be administered to absorb any residual medication from the gastrointestinal tract. Specialized testing, if quickly available, can provide valuable information. Antifactor Xa levels may indicate the presence of a direct factor Xa inhibitor. In contrast, quantitative factor Xa inhibitor levels and quantitative dabigatran levels can be measured using a dilute thrombin time. Clinicians should evaluate the degree of anticoagulation by considering the timing of the last dose, the specific agent used, and the patient's renal and hepatic function.

Direct reversal agents

Clinicians may opt for reversal agents or PCCs in the presence of life-threatening bleeding, weighing the potential risk of thrombosis from underlying conditions and the prothrombotic effects of reversal agents.[35] Practitioners typically administer these agents when confident that the anticoagulant is still active. The anticoagulant effects of DOACs fully resolve after 5 half-lives have elapsed since the last dose.

• Dabigatran: Idarucizumab 5 grams, an anti-dabigatran monoclonal antibody fragment, reverses the effects of dabigatran. Patients with a normal thrombin time should not receive idarucizumab. If idarucizumab is unavailable, some authors recommend activated PCC (aPCC) or factor 8 inhibitor bypassing activity (FEIBA) at a fixed dose or a weight-based dose of 50 to 80 U/kg.[36] Using aPCC carries a significant risk of thrombosis. Additional studies are necessary to establish their safety, and clinicians should avoid using aPCC except in extreme circumstances. If aPCC is unavailable, clinicians may choose unactivated 4-factor PCC or 3-factor PCC at a fixed dose or weight-based dose of 25 to 50 U/kg. FFP may be necessary, in combination with 3-PCC, to supplement factor VII. Hemodialysis will result in the removal of nearly 50% of dabigatran from the circulation in patients with renal impairment. Hemodialysis is ineffective against direct factor Xa inhibitors, which circulate bound to protein. Experts recommend adding an antifibrinolytic agent like tranexamic acid or ε-aminocaproic acid with direct thrombin and Xa inhibitors.
• Oral factor Xa inhibitors: Two possible first-line options are andexanet and 4-factor PCC. Andexanet is an inactive form of factor Xa that binds and sequesters the anticoagulant. Studies are currently lacking to support recommending andexanet over 4-factor PCC.[37][38]
  • Patients receiving rivaroxaban greater than 10 mg, apixaban greater than 5 mg, or an unknown dose within the previous 8 hours should receive an 800 mg bolus of andexanet at 30 mg/min, followed by a 960 mg infusion at 8 mg/min for up to 120 minutes.
  • If the patient takes rivaroxaban 10 mg or less or apixaban 5 mg or less, or if 8 hours or more have elapsed since the last dose of a factor Xa inhibitor, give a 400 mg bolus of andexanet at 30 mg/min, followed by 480 mg infusion at 4 mg/min for up to 120 minutes.
• The dosing for 4-factor PCC is a fixed dose of 2000 U or 25 to 50 U/kg.
• Clinicians can use 3-factor PCC with FFP to supplement factor VII if both are unavailable. 
(A1)

Minor bleeding, like epistaxis or excessive bruising, should be managed conservatively with local measures like pressure or cauterization. 

Resuming Anticoagulation After a Bleeding Episode 

The decision to restart anticoagulation should be individualized, taking into account overall risks and patient preferences. Clinicians must carefully evaluate the risks and benefits. For instance, patients using anticoagulants for primary prevention during high-risk periods or for treatment after a provoked VTE may not need to resume anticoagulation. Conversely, patients with atrial fibrillation, prosthetic heart valves, or a history of arterial thrombotic events are likely to benefit from resuming therapy. Factors that increase the risk of rebleeding include ICH with central nervous system microbleeds on imaging, persistent sources of bleeding such as gastrointestinal telangiectasia, and concurrent bleeding disorders. Most studies support the resumption of anticoagulants following a bleeding episode.[39][40]

Patients who restart their anticoagulants face an increased risk of rebleeding, but they also experience a reduced risk of thrombosis and death.[41] For instance, patients with atrial fibrillation who resume an oral anticoagulant after achieving hemostasis have lower rates of all-cause mortality and thromboembolism compared to those who do not resume treatment.[42] In this population, the incidence of recurrent ICH is 2.5 per 100 patient-years with warfarin and 1.3 per 100 patient-years with a DOAC.

Management of Other Complications Associated with Oral Anticoagulants

Bleeding in various sites is approached separately. The recommended measures are discussed below.

Gastrointestinal bleeding

Patients experiencing severe upper or lower gastrointestinal bleeding with a prolonged PTT or INR exceeding 1.5 should have their warfarin or DOACs held. Individuals with an INR surpassing 2.5 should receive 4-factor PCC or FFP if PCC is unavailable. Clinicians tranfuse platelets to maintain a count above 30,000/µL, increasing to over 50,000/µL if endoscopy is imminent.

Reversal agents are imperative in cases of unresponsiveness to anticoagulant cessation and resuscitation. Endoscopy can proceed concurrently with reversal agent administration for patients with an INR between 1.5 and 2.5, while those with higher INR levels require coagulopathy therapy before endoscopy. Experts do not recommend antifibrinolytic agents for treating acute gastrointestinal bleeding. Endoscopy is the preferred diagnostic and therapeutic approach, with local therapy often sufficient, though surgical intervention may be necessary.

Continuation of aspirin is generally recommended for secondary cardiovascular prevention, along with dual antiplatelet therapy, for patients with an episode of acute coronary syndrome within the past 90 days, recipients of a bare-metal stent within the last 6 weeks, or individuals with a drug-eluting stent placed within the last 6 months.[43] Studies indicate that patients with cardiovascular disease who develop bleeding peptic ulcers and discontinue aspirin face increased all-cause mortality.[44] Patients who achieve hemostasis and require ongoing oral anticoagulant treatment, with a low risk of rebleeding, can resume warfarin on the day of an endoscopic procedure and DOACs within 48 to 72 hours. In individuals at high risk of rebleeding, resumption of anticoagulants is delayed until the bleeding risk is minimized.(A1)

Warfarin-induced skin necrosis

Discontinuation of warfarin is crucial in cases of warfarin-induced skin necrosis. Intravenous vitamin K and unfractionated heparin administration are recommended. Patients with confirmed or familial protein C deficiency should additionally receive protein C concentrate or FFP. For patients with protein C deficiency requiring warfarin, initial dosing should commence at 2 mg daily for 3 days, gradually increasing by 2 to 3 mg until therapeutic levels are achieved. However, DOAC use may circumvent this complication when suitable. Warfarin may be resumed in patients with necrosis with protein C concentrate support until they achieve therapeutic levels. Protein C concentrate should not be confused with recombinant activated protein C. Small necrotic areas may heal with local care, while larger areas may necessitate surgical intervention and skin grafts.

Cholesterol crystal embolism

Despite conflicting evidence on the causal relationship between cholesterol embolization syndrome and anticoagulation, the prescribing information for Coumadin (Bristol-Myers Squibb, Princeton, NJ), a brand-name version of warfarin, states that therapy may increase the risk of atheromatous plaque emboli and complications from systemic cholesterol microembolization. Thus, experts recommend discontinuing warfarin therapy when cholesterol embolization is present.[45] See StatPearls' companion reference, "Cholesterol Emboli," for additional information regarding managing cholesterol emboli.

Anticoagulant-related nephropathy

Management of ARN begins with reversing coagulopathy, followed by rendering supportive care for AKI. Most patients show normalization of serum creatinine within a few weeks of normalizing coagulopathy. Refer to "Vitamin K Antagonists" and "Direct Oral Anticoagulants" for additional information on the appropriate steps in reversing coagulopathy from VKAs and DOACs. Additionally, see StatPearls' companion reference, "Acute Kidney Injury," for a complete discussion regarding managing AKI.

Intracranial hemorrhage

As with most other complications associated with oral anticoagulants, discontinuing the anticoagulant and all antiplatelet medications and reversing the anticoagulant effects are imperative in patients with ICH. Appropriate blood pressure management is also central to patient management.

Individuals with a systolic blood pressure between 150 and 220 mm Hg should undergo rapid lowering to reach a target blood pressure of 140 mm Hg. Patients with a systolic blood pressure exceeding 220 mm Hg should have their blood pressure rapidly reduced to below this threshold, followed by gradual lowering to a target range of 140 to 160 mm Hg. Clinicians manage intracranial pressure using osmotic therapies, ventricular drainage of cerebrospinal fluid, or surgical evacuation, depending on the patient's condition and imaging results. See StatPerals' companion topic, "Intracranial Hemorrhage," for an in-depth discussion on ICH management. 

Hematoma

Managing a hematoma in patients on anticoagulation can be challenging, particularly when the anticoagulant is essential for their care. A retroperitoneal hematoma may be managed with volume resuscitation and blood transfusion, along with possible embolization to control the bleeding source or drainage guided by interventional radiology. Clinicians evaluate each case individually to determine the need for anticoagulant reversal. Hemodynamically unstable patients may require open surgical intervention.[45] Patients with a spinal epidural hematoma and minor stable neurological symptoms may be observed. Others require prompt surgical intervention and evacuation of the blood to avoid permanent loss of neurologic function.

Hemothorax

Reversal of the anticoagulant followed by tube thoracostomy drainage is the primary mode of treatment for hemothorax. See StatPearls' reference companion, "Hemothorax," for a detailed discussion on hemothorax management.

Cardiac tamponade

Cardiac tamponade requires an emergent pericardiocentesis. The decision to continue anticoagulation should be made with cardiology, hematology, and, possibly, nephrology specialists in patients with renal disease. 

Compartment syndrome

Fasciotomy is the treatment of choice for patients with compartment syndrome. See StatPearls' companion reference, "Compartment Syndrome," for a more in-depth discussion of the management of compartment syndrome.

Differential Diagnosis

The differential diagnoses for bleeding complications associated with oral anticoagulants include the following:

• Peptic ulcer disease
• Subdural hematoma
• Subarachnoid hemorrhage
• Retroperitoneal hemorrhage
• Vitamin K deficiency
• Hemophilia A
• Hemophilia B
• Factor X deficiency
• Factor V deficiency
• Epistaxis
• Gastrointestinal bleeding
• Ectopic pregnancy
• Postpartum hemorrhage
• Hypovolemic shock
• Hemorrhagic stroke
• Vitreous hemorrhage
• Liver failure
• Afibrinogenemia
• Dysfibrinogenemia
• Malabsorptive states
• Domestic violence
• Child abuse

Differential diagnoses for warfarin-induced skin necrosis include the following conditions:

• Necrotizing fasciitis
• Venous gangrene
• Heparin-induced thrombocytopenia and thrombosis
• Disseminated intravascular coagulation
• Purpura fulminans
• Calciphylaxis
• Cholesterol microemboli
• Cryoglobulinemia

Given its nonspecific symptoms, the differential diagnoses for cholesterol microembolization are extensive, and the following list includes some of the potential considerations:

• Aortic dissection
• Left atrial myxoma
• Lymphoma
• Renal cell carcinoma 
• Cyanotic congenital heart disease
• Secondary syphilis
• Pheochromocytoma
• Raynaud phenomenon
• Vasculitis like polyarteritis nodosa, systemic lupus, dermatomyositis, leukocytoclastic angiitis, rheumatoid vasculitis, and thromboangiitis obliterans
• Tuberculosis
• Antiphospholipid syndrome
• Polycythemia vera [46][47] 

Prognosis

Patients with ICH associated with warfarin use have a 6-month mortality rate ranging from 23% to 58%. Stupor or coma and large-volume ICHs are associated with poor outcomes. INR or time to correct INR does not correlate with outcomes. ICH expansion is associated with the most significant risk of fatal outcomes.[48] The 30-day mortality after a nonvariceal major gastrointestinal bleed on DOACs is 9%.[49] A previous history of peptic ulcer, upper gastrointestinal bleeding, and a higher Charlson comorbidity index score—indicative of 10-year survival in patients with multiple comorbidities—are all associated with increased all-cause mortality. Duodenal bleeding and an elevated Charlson comorbidity index score are significant risk factors for rebleeding.[50] 

Complications

As mentioned, oral anticoagulant use carries several potential complications, including hemorrhage, skin necrosis, cholesterol embolism, and hematoma formation. Additional adverse effects include allergic reactions and thromboembolic events, which can occur due to transient hypercoagulability during warfarin initiation, premature discontinuation, use of reversal agents, and improper dosing. Active malignant disease is also a risk factor for thromboembolic complications.

Studies reveal that DOACs are often underdosed in about 15% of patients, particularly older women and individuals with reduced creatinine clearance, diabetes, anemia, or liver disease. This inappropriate dosing is associated with a trend toward adverse events, including stroke, transient ischemic attack, and embolism, with some investigations reporting statistically significant associations while others only indicate a trend.[51][52] Additional complications from thromboembolic events may include myocardial infarction, blindness, mesenteric ischemia, AKI, limb ischemia, pulmonary infarction, and death.