How do Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) affect bleeding?

How NSAIDs Affect Bleeding

NSAIDs increase bleeding risk through two primary mechanisms: irreversible (aspirin) or reversible (other NSAIDs) inhibition of platelet cyclooxygenase, which blocks thromboxane A2 formation and impairs platelet aggregation, plus direct gastric mucosal injury that increases gastrointestinal bleeding risk. 1

Primary Mechanisms of Bleeding

Antiplatelet Effects

• All NSAIDs inhibit cyclooxygenase (COX) enzymes, preventing thromboxane A2 synthesis and impairing platelet aggregation. 1, 2
• Aspirin acetylates and permanently inactivates COX, causing effects that persist for the entire 7-10 day circulating lifetime of the platelet. 1, 2
• Non-aspirin NSAIDs reversibly block COX, with duration of action depending on the specific drug's half-life and serum levels. 2, 3
• This produces a systemic bleeding tendency by impairing thromboxane-dependent platelet aggregation and prolonging bleeding time. 3

Gastrointestinal Mucosal Injury

• NSAIDs cause direct injury to the GI tract mucosa, creating a second independent mechanism for bleeding beyond the antiplatelet effects. 1
• The FDA label for aspirin explicitly warns that NSAIDs may cause severe stomach bleeding, with risk increasing in patients over age 60, those with prior ulcers or bleeding problems, and those taking anticoagulants or steroids. 4

High-Risk Populations Requiring NSAID Avoidance

Absolute Contraindications

• NSAIDs must be avoided in persons with preexisting platelet defects or thrombocytopenia due to dangerous synergistic effects on bleeding risk. 1
• Patients with cirrhosis should avoid NSAIDs to prevent acute renal failure and worsening coagulopathy. 5
• Patients with dengue or other conditions causing thrombocytopenia and coagulopathy should never receive NSAIDs, as the bleeding risk becomes multiplicative rather than additive. 6

Relative Contraindications

• Advanced age (≥60 years) significantly increases bleeding risk. 4, 3
• Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy. 1
• Concurrent use of anticoagulants, steroids, or multiple NSAIDs dramatically amplifies risk. 1, 4
• Heavy alcohol consumption (≥3 drinks daily) increases bleeding complications. 4, 3

Magnitude of Bleeding Risk with Anticoagulants

When NSAIDs are combined with anticoagulants, there is a 3-6 fold increased risk of GI bleeding due to pharmacokinetic interactions that can increase INR by up to 15%, in addition to the direct antiplatelet effects. 1

• Recent research confirms this risk, showing adjusted odds ratios of 3.59 for GI bleeding in anticoagulated patients exposed to NSAIDs, and 2.72 for non-GI bleeding. 7
• The combination of any NSAID (except aspirin in specific cardiovascular circumstances) with warfarin should be discouraged. 1
• If NSAIDs must be co-administered with anticoagulants, anticipate INR increases, monitor closely, adjust warfarin dosing, and initiate GI prophylaxis with a proton pump inhibitor. 1

Perioperative Management Algorithm

Preoperative NSAID Discontinuation

• Aspirin should be stopped 7-10 days before surgery in patients without high cardiovascular risk. 1
• Other NSAIDs should be withheld for 5 elimination half-lives: 1
  • Ibuprofen: stop 2 days preoperatively
  • Naproxen: stop 2-3 days preoperatively
  • Piroxicam: stop 10 days preoperatively

High-Risk Cardiovascular Patients

• For patients with recent myocardial infarction or recent cardiac stent placement, aspirin should be continued before and after surgery despite bleeding risk. 1
• For other patients at increased cardiovascular risk, continuation of aspirin should be considered and used perioperatively if possible. 1

Clinical Bleeding Manifestations

Hemorrhagic Stroke Risk

• Aspirin is associated with a slightly increased rate of hemorrhagic stroke and small increase in overall mortality. 1
• The survival benefits in high-risk cardiovascular patients outweigh these risks, but aspirin should be avoided in low-risk individuals. 1

Spontaneous Bleeding

• Spontaneous bleeding complications outside the GI tract very rarely result from NSAID use in otherwise hemostatically normal individuals. 2
• Most surgery types are not associated with clinically significant bleeding in patients taking NSAIDs, making routine discontinuation unnecessary except for operations where optimal hemostasis is critical (neurosurgery, ophthalmologic surgery), genitourinary tract manipulation, oral cavity surgery, and possibly cardiac surgery. 2

Safer Alternatives

Acetaminophen is the preferred analgesic for patients with thrombocytopenia or bleeding risk, limiting chronic administration to ≤3g/day due to hepatotoxicity concerns. 6

• Among NSAIDs studied, sulindac and celecoxib demonstrated no significant antiplatelet effect and did not reduce aspirin's antiplatelet activity, potentially making them safer choices when NSAIDs are required in patients needing aspirin. 8
• Ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block aspirin's antiplatelet effect and should be avoided in patients requiring aspirin for cardiovascular protection. 8

Key Clinical Pitfalls

• Do not assume all NSAIDs have equivalent bleeding risk profiles—aspirin's irreversible COX inhibition creates longer-lasting effects than reversible NSAIDs. 2, 3
• Bleeding time is prolonged in only approximately 25% of aspirin-treated and 10% of NSAID-treated patients, so normal bleeding time does not guarantee absence of risk. 9
• The risk of GI bleeding increases as the number of risk factors accumulates—single risk factors may be manageable, but multiple concurrent risks require aggressive prophylaxis or NSAID avoidance. 1
• When GI prophylaxis is needed, PPIs reduce upper GI bleeding to a greater degree than H2 receptor antagonists. 1