Anticoagulants

Pharmacology

Anticoagulants

Pre-anticoagulation patient evaluation

What to know about every anticoagulant:
- Mechanism of action, metabolism/elimination, monitoring.
- Indications and dosing.
- Adverse effects: all cause bleeding, so know the non-hemorrhagic toxicities.
- Select populations: obesity, pregnancy, kidney disease, liver disease.
- Reversal.

Before anticoagulation: what to review

Domain	Key items
Past medical history	Prior bleeding, CNS lesions at risk for bleeding, bleeding diathesis, peptic ulcer disease; APLS, cancer, atrial fibrillation; chronic kidney disease, liver disease.
Past surgical history	Recent major surgery; bariatric surgery, bowel resection (affects absorption); cardiac surgery (valve replacement).
Obstetric history	Pregnancy or breastfeeding.
Social history	Alcohol use; supplements (St. John's wort interacts with DOACs); occupation (trauma risk).
Medications	Estrogen, carbamazepine, antifungals, antiplatelets; GI prophylaxis with PPI or H2 blocker.
Allergies	History of HIT.
Exam	Obesity, extreme weight.
Labs	CBC; creatinine to CrCl by Cockcroft-Gault; LFTs to Child-Pugh score; baseline PT/aPTT; baseline INR for warfarin.
Patient preferences	Once vs twice daily dosing; lab monitoring; reversibility; administration route; diet; drug access; cost.

Anticoagulant targets (mechanistic classification)

Schematic of factor Xa, thrombin and fibrin showing that heparins act through antithrombin, apixaban, rivaroxaban and edoxaban block Xa directly, dabigatran, argatroban and bivalirudin block thrombin directly, and warfarin blocks VKORC1, with the reversal agent for each class. — Anticoagulant targets with the matching reversal agent for each class. Tap to enlarge.

Anticoagulants by targetBold letters: name clues

Target	Agents
Factor Xa	Apixaban, edoxaban, rivaroxaban, fondaparinux.
Factor IIa (thrombin), direct thrombin inhibitors	Argatroban, bivalirudin, dabigatran.
Both Xa and IIa (thrombin)	Heparin (UFH); enoxaparin (Xa > thrombin); dalteparin.
Vitamin K dependent factors (VKA)	Warfarin: FII, FVII, FIX, FX plus protein C and S.

Renal and hepatic dose adjustment overview

Renal and hepatic dose adjustmentCrCl in mL/min; swipe sideways on phone

Agent	ESRD / dialysis	CrCl 10 to 30	CrCl 30 to 50	Severe hepatic impairment	Reversal
Heparin					Protamine sulfate
Enoxaparin	Avoid	Dose adjust
Fondaparinux	Avoid	Avoid (contraindicated CrCl < 30)
Argatroban				Dose adjust (HIT: start 0.5 mcg/kg/min; avoid for PCI in significant hepatic disease)
Bivalirudin	Dose adjust	Dose adjust	Dose adjust	Ok
Danaparoid		Dose adjust	Dose adjust	Dose adjust
Apixaban	Ok per US label (limited data)	?	Ok	Avoid
Rivaroxaban	AF: 15 mg daily per US label; VTE: avoid	?	AF: 15 mg daily (reduce from 20 mg when CrCl ≤ 50)	Avoid
Dabigatran	Avoid	Dose adjust	Ok	Avoid

Heparins (parenteral)

Unfractionated heparin (UFH)

Parameter	Detail
Mechanism	Enhances antithrombin (AT), which inactivates thrombin (FIIa) and factor Xa (also IXa, XIa, XIIa).
Half-life	1 h for a 100 U/kg bolus; ~1 to 1.5 h for a therapeutic heparin drip (dose-dependent, rises with higher doses); rapid offset.
Prophylactic dose	5,000 U SQ BID or TID.
Therapeutic dose	5,000 to 10,000 IV units bolus, then 1,000 to 2,000 units/hour IV titrated to range.
Monitoring	Anti-Xa heparin level 0.3 to 0.7 U/mL, or aPTT 1.5 to 2.5 times mean normal. Anti-IIa level in some hospitals if patient was recently on a Xa inhibitor.
Clearance	Mainly reticuloendothelial system, less by kidney (preferred in renal failure and when rapid reversibility needed: CABG, ECMO, CRRT, severe instability).
Reversal	Protamine sulfate 1% solution, 1 mg neutralizes ~100 units heparin, give slowly over 10 min; may repeat 0.5 mg per 100 units if aPTT stays elevated. Protamine itself can decrease platelet function and coagulation factors (bleeding risk).
Toxicity	Bleeding, osteoporosis, HIT.

Low molecular weight heparin (enoxaparin, dalteparin, tinzaparin)

Low molecular weight heparinDetails for enoxaparin

Parameter	Detail (enoxaparin)
Mechanism	Enhances AT, inactivates Xa > thrombin (IIa); more anti-Xa than anti-IIa activity.
Half-life	4 to 7 hours.
Prophylaxis	40 mg daily or 30 mg BID SQ; use 30 mg daily if CrCl < 30 mL/min, avoid in dialysis.
Treatment	1 mg/kg BID or 1.5 mg/kg daily (low-risk patient) SQ; 1 mg/kg daily if CrCl < 30 mL/min.
Monitoring	Anti-Xa level 3 to 4 h after last dose; therapeutic 1.0 to 2.0 U/mL for once-daily, 0.6 to 1.0 U/mL for BID. Check in obesity, pregnancy, renal failure, peds, very low body weight (levels affected by obesity and low CrCl).
Elimination	Renal; caution when CrCl < 30 mL/min; avoid in hemodialysis (enoxaparin is nondialyzable).
Transitions	From therapeutic enoxaparin: start heparin drip 1 to 2 h before the next enoxaparin dose. From heparin drip: start enoxaparin within 1 h after stopping the drip.
Reversal	Protamine sulfate, partial effect (maximum ~60% to 75%); andexanet (previously used off-label) withdrawn from US market Dec 2025.
Toxicity	Lower risk of HIT, osteoporosis, and injection-site skin necrosis than UFH.

Fondaparinux

Parameter	Detail
Mechanism	Potentiates AT against factor Xa only (pure anti-Xa pentasaccharide).
Half-life	17 to 21 h; do not use if a procedure or surgery is anticipated.
Prophylaxis	2.5 mg daily SQ.
Treatment	5.0 mg daily if < 50 kg; 7.5 mg daily if 50 to 100 kg; 10 mg daily if > 100 kg; SQ.
Monitoring	Generally not required; anti-factor Xa activity calibrated to fondaparinux (rarely used).
Elimination	Renal; dose-adjust or use caution at CrCl 30 to 50 mL/min; do not use if CrCl < 30 mL/min.
Reversal	Protamine will not work; use 4F-PCC 50 U/kg (andexanet withdrawn from US market Dec 2025).
Toxicity	Very low HIT risk (can even be used to treat VTE in HIT); osteoporosis, injection-site skin necrosis.

Heparin-induced thrombocytopenia (HIT)

Flow for suspected heparin-induced thrombocytopenia: type I versus immune type II HIT, the 4Ts score bands (low score: HIT unlikely), and for intermediate or high scores confirmation by ELISA then SRA or HIPA, treatment by stopping all heparin and starting a non-heparin anticoagulant, warfarin only after platelets exceed 150K, and duration of 30 days or 3 months. — Heparin-induced thrombocytopenia: type I vs type II, 4Ts score, confirmation and management. Tap to enlarge.

Pathophysiology: IgG antibodies to PF4 (platelet factor 4), heparin complexes activate platelets via the FcγRIIa receptor, causing a thrombosis paradox.
Type I HIT (non-immune, mild, transient): direct heparin-platelet effect; not significant; heparin can be continued.
Type II HIT (immune, dangerous): typically days 5 to 10 after heparin exposure; earlier (within hours) if recent prior exposure (within 3 months); platelet drop ≥ 50% from baseline; thrombosis (venous > arterial) in ~50%.
4Ts score (pretest probability: Thrombocytopenia, Timing, Thrombosis, oTher causes excluded; max 8 points): 0 to 3 low, 4 to 5 intermediate, 6 to 8 high.
Confirmation: anti-PF4/heparin ELISA (sensitive, less specific), then if positive serotonin release assay (SRA) or HIPA (gold standards).
Treatment:
- STOP all heparin (including flushes, LMWH, heparin-coated catheters).
- Start a non-heparin anticoagulant: argatroban (preferred in renal failure, hepatic clearance), bivalirudin, fondaparinux (off-label, no cross-reactivity).
- Avoid platelet transfusion unless bleeding (theoretical risk of fueling thrombosis).
- Bridge to warfarin only after platelets recover (> 150K), otherwise risk of warfarin-induced skin necrosis or venous limb gangrene from imbalanced protein C decline.
- DOACs (rivaroxaban, apixaban) increasingly used, including before platelet recovery in stable low-bleeding-risk patients; only warfarin must wait for platelet recovery, supported by case series and emerging evidence.
- Duration: minimum 30 days if HIT alone (no thrombosis); 3 months if HIT with thrombosis.
- Document heparin allergy; avoid re-exposure long term.

Direct thrombin inhibitors and danaparoid (parenteral)

Direct thrombin inhibitors and danaparoidParenteral

Agent	Parameter	Detail
Argatroban	Mechanism	Direct thrombin inhibitor
	Half-life	40 to 50 min (~180 min in hepatic impairment)
	Use	HIT, PCI; IV drip
	Monitoring	aPTT 1.5 to 3.0 times baseline but < 100 sec; prolongs PT/INR (complicates warfarin bridging)
	Elimination	Hepatic; adjust in hepatic impairment, HF anasarca, post-cardiac surgery; usable in renal failure/dialysis
	Reversal	No agent, short acting; high cost
Bivalirudin	Mechanism	Direct thrombin inhibitor
	Half-life	25 min
	Use	UA with PCI, PCI with or without GPIIb/IIIa inhibitor, HIT (off-label); IV drip
	Monitoring	aPTT 1.5 to 2.5 times baseline; prolongs PT/INR (less than argatroban)
	Elimination	Proteolytic cleavage (~80%), ~20% renal; adjust in severe renal failure; usable in hepatic failure without adjustment
	Reversal	No agent, short acting; high cost
Danaparoid	Mechanism	Indirect Xa via AT (weakly increases AT and heparin cofactor II to inactivate FIIa)
	Half-life	24 h
	Use	VTE ppx, HIT (off-label); IV; not available in US (drug substance shortage)
	Monitoring	Danaparoid-specific anti-Xa
	Elimination	Renal; adjust for renal and hepatic function

Lepirudin: direct thrombin inhibitor, discontinued in many markets.
Dabigatran is an oral direct thrombin inhibitor, covered under DOACs below.

Vitamin K antagonist (warfarin)

Mechanism: FII, FVII, IX, X and proteins C and S are activated by carboxylation of glutamic acid residues by γ-glutamyl carboxylase; reduced (active) vitamin K is the cofactor. During carboxylation vitamin K becomes oxidized (inactive) and is regenerated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin inhibits VKORC1. (WARF = Wisconsin Alumni Research Foundation, plus -arin for its coumarin link.)
Half-life: 20 to 60 h (~40 h). Onset delayed (days), so bridge if rapid anticoagulation is needed.
Elimination: hepatic; can be used in severe renal impairment; use with caution in hepatic impairment (potentiated effect: reduced warfarin metabolism and clotting factor synthesis, elevated baseline INR). In ESRD on HD, dose daily as usual (no renal adjustment); use a lower starting dose and monitor closely if CrCl < 60.
Monitoring: PT/INR (INR = (patient PT / mean normal PT)^ISI). Target 2 to 3 for most indications; 2.5 to 3.5 for mechanical mitral valves; for APLS with arterial events or recurrent VTE, target INR 3 to 4 or INR 2 to 3 plus low-dose aspirin. Microdose oral vitamin K (100 to 300 mcg/day) reduces INR fluctuation. Pharmacogenomics: CYP2C9 and VKORC1 polymorphisms affect dose (not routinely tested).
Indications: atrial fibrillation, mechanical AV/MV (warfarin preferred), VTE, APLS, HIT (off-label), cardioembolic sources (e.g. LV thrombus); stable CAD and noncardioembolic CVA use antiplatelets.
Teratogen: avoid in first trimester unless benefit outweighs risk (for example mechanical heart valve); warfarin embryopathy includes nasal hypoplasia and stippled epiphyses.

Prothrombotic window: factor and protein half-lives

Once warfarin starts, new factor activation falls per each factor's half-life. FVII and protein C fall first, creating a transient prothrombotic state; the true antithrombotic effect (FII, FX decline) is delayed. Bridge high-risk patients with a parenteral anticoagulant for at least 5 days until INR is therapeutic on 2 values 24 h apart. Warfarin started for acute thrombosis without bridging risks warfarin-induced skin necrosis (protein C deficiency predisposes). Treatment: stop warfarin, give vitamin K and a therapeutic heparin drip, consider protein C concentrate or FFP.

Warfarin: half-lives of vitamin K dependent proteinsWhy early INR rise is not true anticoagulation

Factor / protein	Half-life	Note
FVII	4 to 6 h	Falls first; drives early INR rise (not true anticoagulation)
Protein C (anticoagulant)	8 h	Early fall creates transient prothrombotic state
FIX	24 h
Protein S (anticoagulant)	30 h
FX	48 to 72 h
FII (prothrombin)	60 h	Slow to fall; true antithrombotic effect delayed

Warfarin drug and diet interactions

Increase INR (potentiate): amiodarone, fluconazole, metronidazole, sulfa, macrolides, fluoroquinolones, statins, omeprazole. NSAIDs and SSRIs raise bleeding risk via platelet effects, often without increasing INR.
Decrease INR (antagonize): rifampin, carbamazepine (phenytoin is variable: may raise INR early then lower it; monitor closely), St. John's wort, phenobarbital, dietary vitamin K (green leafy vegetables; counsel consistent intake, not avoidance).

Supratherapeutic INR management

Hold warfarin and reduce the next dose. No bleeding means no PCC and no FFP unless a procedure is needed.

Supratherapeutic INR: management

Scenario	INR	Management
No bleeding	4.5 to 10	Hold warfarin, reduce next dose; consider vitamin K 1.25 to 2.5 mg PO x1 daily if high bleeding risk.
No bleeding	> 10	Hold warfarin; vitamin K 2.5 to 5.0 mg PO x1.
Bleeding	Nonmajor (any INR)	Hold warfarin; consider vitamin K 1 to 2.5 mg PO.
	Major (any INR)	4F-PCC (INR-based dose) plus vitamin K 5 to 10 mg IV.
	Any INR	FFP only if 4F-PCC unavailable.
CNS or life-threatening bleed	any	4F-PCC (superior to FFP), factors II, VII, IX, X, plus IV vitamin K.

FFP has a near-normal INR (~1.1); it changes INR little when the INR is only mildly elevated, but imposes no fixed floor of 1.5.
FFP dose 15 mL/kg (1 U of FFP is 200 to 250 mL; a 70 kg patient needs ~1,050 mL, about 5 units).

PCC products available in the United States

PCC products available in the US

Product	Type	Factors and contents
Kcentra	Unactivated 4-factor PCC	Inactive factors II, VII, IX, X; also contains heparin.
Profilnine	Unactivated 3-factor PCC	Inactive factors II, IX, X; little or no factor VII; no heparin.
FEIBA	Activated 4-factor PCC (aPCC)	Factors II, VIIa, IX, X (only VII activated); no heparin.

Perioperative warfarin: stop 5 days before the procedure; give therapeutic enoxaparin or heparin drip if high thrombotic risk (annual risk > 10%, mechanical mitral valve, AF with CHADS2 5 to 6, CVA or VTE within 3 months, antithrombin deficiency or APLS). Restart warfarin 12 to 24 h postop.

Direct oral anticoagulants (DOACs)

Creatinine clearance rulers showing DOAC doses in atrial fibrillation and VTE treatment: apixaban needs no renal adjustment, edoxaban 30 mg at CrCl 15 to 50 and not used in AF above 95, rivaroxaban 15 mg daily in AF at CrCl 50 or less and avoided below 15 for VTE, dabigatran 75 mg BID at CrCl 15 to 30 in AF and avoided at 30 or less for VTE. — DOAC dosing across CrCl bands for atrial fibrillation and VTE treatment (US labels). Tap to enlarge.

DOACs: pharmacology and reversalSwipe sideways on phone

Agent (brand)	Target	Half-life	Renal elimination	Metabolism	Reversal
Apixaban (Eliquis)	Direct FXa	8 to 15 h (~12 h)	~25% (lowest of marketed DOACs)	CYP3A4/5, P-gp	4F-PCC (andexanet withdrawn in US, Dec 2025)
Rivaroxaban (Xarelto)	Direct FXa	9 to 13 h	~65% (2nd highest)	CYP3A4/5, CYP2J2, P-gp	4F-PCC (andexanet withdrawn in US, Dec 2025)
Edoxaban (Savaysa)	Direct FXa	10 to 14 h	~50%	Weak CYP3A4, P-gp	4F-PCC (andexanet never labeled for edoxaban; withdrawn in US Dec 2025)
Dabigatran (Pradaxa)	Direct thrombin (IIa)	12 to 14 h	~80% (highest)	P-gp; prodrug activated by esterase hydrolysis; tartaric-acid core lowers local pH to aid absorption, not activation	Idarucizumab
Betrixaban (discontinued in US)	Direct FXa	19 to 27 h	10 to 20%

Avoid potent CYP3A4/P-gp inhibitors; apixaban has the fewest interactions.

DOAC dosing by indication

DOAC dosing by indicationCrCl in mL/min

Agent	Indication	Dosing
Apixaban	Atrial fibrillation	5 mg BID (2.5 mg BID if 2 of 3: age ≥ 80, weight ≤ 60 kg, Cr ≥ 1.5 mg/dL)
	VTE treatment	10 mg BID x 7 d then 5 mg BID (no reduction as in AF)
	VTE prophylaxis	2.5 mg BID 12 to 24 h postop
	Renal cutoffs / notes	US label: no renal adjustment beyond AF criteria, including ESRD on HD (limited data; ARISTOTLE excluded CrCl < 25 or Cr > 2.5); avoid in severe hepatic impairment
Rivaroxaban	Atrial fibrillation	20 mg daily (15 mg/d if CrCl ≤ 50, including CrCl < 30)
	VTE treatment	15 mg BID x 21 d then 20 mg daily (avoid if CrCl < 15)
	VTE prophylaxis	10 mg daily > 6 to 10 h postop
	Renal cutoffs / notes	Avoid if CrCl < 15 for VTE indications (AF: 15 mg daily per US label, including ESRD on HD); avoid in Child-Pugh B or C; also used in PAD, CAD, superficial VTE
Edoxaban	Atrial fibrillation	60 mg daily (30 mg if CrCl 15 to 50); do not use if CrCl > 95 (boxed warning: reduced efficacy)
	VTE treatment	60 mg daily, or 30 mg daily if ≤ 60 kg, CrCl 15 to 50, or on certain P-gp inhibitors; after 5 to 10 days of parenteral therapy
	VTE prophylaxis	Not FDA-approved for VTE prophylaxis
Dabigatran	Atrial fibrillation	150 mg BID (75 mg BID if CrCl 15 to 30; avoid if CrCl < 15)
	VTE treatment	150 mg BID; acute VTE needs ≥ 5 day parenteral overlap; avoid if CrCl ≤ 30
	Renal cutoffs / notes	RE-COVER: non-inferior to warfarin for recurrent DVT/PE. No hepatic dose adjustment (not CYP-metabolized), but avoid in severe hepatic impairment
Betrixaban	VTE prophylaxis	160 mg loading dose x1 then 80 mg daily
Betrixaban	Renal cutoffs / notes	Discontinued in US; monitor with anti-Xa or specific levels

DOAC absorption, food, and obesity

Agent	Topic	Detail
Apixaban	Absorption site	Mainly distal small bowel, some ascending colon
	Surgery / food	Bioavailability reduced with distal small bowel / ascending colon resection; not much affected by Roux-en-Y. Take with or without food
	Obesity	Good for VTE tx regardless of BMI, no adjustment for BMI ≥ 30; do not use for acute VTE after bariatric surgery
Rivaroxaban	Absorption site	Stomach
	Surgery / food	Reduced with gastric bypass; not much affected by colectomy. 15 and 20 mg tablets must be taken with food
	Obesity	Same as apixaban; do not use for acute VTE after bariatric surgery
Dabigatran	Absorption site	Lower stomach and duodenum; acidic pH aids absorption (prodrug activated by esterases)
	Surgery / food	With or without food (food delays absorption without lowering exposure; may ease dyspepsia); PPI/H2 blockers lower drug level but clinically insignificant
	Obesity	Insufficient data if > 120 kg or BMI > 40
Edoxaban	Obesity	Insufficient data if > 120 kg or BMI > 40

Monitoring: anti-Xa activity calibrated to the specific agent (apixaban, rivaroxaban); rivaroxaban can prolong PT. Dabigatran: dilute thrombin time or ecarin-based assay is ideal; aPTT may be prolonged (not always).
ANNEXA-4 trial (final, NEJM 2019): median anti-FXa activity fell 92% for both rivaroxaban and apixaban; thrombotic events ~10% at 30 days.
Obesity dosing is expert opinion (ISTH, Martin 2021); some guidelines advise caution if ≥ 150 kg.
Cancer: DOACs preferred except gastric/gastroesophageal or upper GI malignancy, where enoxaparin is preferred.

DOAC contraindications and special populations

Pregnancy: avoid all DOACs; use LMWH throughout pregnancy plus 6 weeks postpartum.
Severe renal (CrCl < 30): dabigatran is most renally cleared (VTE: no dosing if CrCl ≤ 30; AF: 75 mg BID if CrCl 15 to 30; avoid if CrCl < 15 or dialysis); edoxaban: not recommended if CrCl < 15; rivaroxaban: avoid if CrCl < 15 for VTE indications (AF label permits 15 mg daily including ESRD on HD); apixaban least renally cleared (US label permits use in ESRD on HD, limited data).
Mechanical valve: avoid all DOACs; warfarin only.
Antiphospholipid syndrome (triple-positive): avoid DOACs; warfarin INR 2 to 3 or LMWH.
GI/GU malignancy with luminal disease: LMWH preferred (excess GI bleeding with edoxaban in Hokusai-VTE-Cancer and rivaroxaban in SELECT-D); if a DOAC is used, apixaban (no excess GI bleeding in CARAVAGGIO).

DOAC perioperative management

Timeline around a procedure: continue DOACs for minimal bleeding risk procedures; hold apixaban or rivaroxaban 24 h (low to moderate risk) or 48 h (high risk) and resume at 24 h or 48 to 72 h; hold dabigatran 48 h if CrCl 50 or above or 96 h if CrCl 30 to below 50; stop warfarin 5 days before and restart 12 to 24 h after, bridging only high thrombotic risk patients. — Perioperative interruption of DOACs (PAUSE) and warfarin. Tap to enlarge.

Minimal bleeding risk (minor dental, cataract, minor skin procedures): continue DOAC; no interruption.
Low to moderate or high bleeding risk (PAUSE): apixaban/rivaroxaban hold 24 h (low to moderate risk) or 48 h (high risk), resume 24 h (low to moderate risk) or 48 to 72 h (high risk) postop. Dabigatran (high risk) hold 48 h if CrCl ≥ 50, hold 96 h if CrCl 30 to < 50; resume as above.
Bridge: not recommended during DOAC interruption (short half-life; CHEST 2022, PAUSE). Mechanical valve or high-risk APS patients belong on warfarin, not a DOAC.

Anticoagulant reversal (quick reference)

Anticoagulant reversal: quick reference

Anticoagulant	Reversal agent	Dose and notes
Heparin (UFH)	Protamine sulfate	1 mg per 100 units UFH (max 50 mg), give slowly (≤ 5 mg/min); onset < 5 min; repeat q30 min prn.
LMWH	Protamine sulfate (partial)	1 mg per 100 units anti-Xa; ~60% to 75% reversal; full dose if within 8 h of LMWH (0.5 mg per 100 units if > 8 h).
Fondaparinux	4F-PCC	50 U/kg; protamine ineffective (andexanet withdrawn from US market Dec 2025).
Warfarin	4F-PCC plus vitamin K	4F-PCC 25 to 50 U/kg (preferred over FFP) plus IV vitamin K 5 to 10 mg; INR corrects within ~30 min with 4F-PCC; IV vitamin K sustains reversal (12 to 24 h).
Dabigatran	Idarucizumab (Praxbind, FDA 2015)	5 g IV total (two consecutive 2.5 g vials, as infusions or bolus injections); ~100% reversal; most specific agent.
Apixaban / rivaroxaban	4F-PCC (andexanet alfa withdrawn from US market Dec 22, 2025)	4F-PCC 25 to 50 U/kg (off-label). Andexanet alfa (Andexxa, FDA 2018) was withdrawn in the US after FDA concluded risks outweigh benefits (ANNEXA-I thrombotic signal). Charcoal if last dose < 2 to 4 h and bleeding; FFP and dialysis do not work.
Edoxaban	4F-PCC	Andexanet never labeled for edoxaban and withdrawn from US market (Dec 2025).
Antiplatelets (aspirin, P2Y12, dipyridamole)	Platelet transfusion, desmopressin	Desmopressin 0.3 mcg/kg IV may be considered; platelet transfusion only for emergency surgery or life-threatening non-ICH bleeding; avoid in spontaneous ICH without surgery (PATCH: harm).
GPIIb/IIIa inhibitors	Platelet transfusion plus cryoprecipitate	If bleeding: stop infusion and give supportive care; platelets help reverse abciximab, but circulating eptifibatide/tirofiban inhibit transfused platelets until cleared; cryoprecipitate only for documented hypofibrinogenemia.

Antiplatelet drugs

COX inhibitors

Agent	Mechanism	Use	Reversal
Aspirin	Irreversible COX-1 inhibition, decreased thromboxane, decreased platelet aggregation	Primary or secondary CAD prevention, secondary CVA prevention, PAD	Desmopressin, platelet transfusion
NSAIDs	Reversible COX-1 inhibition

P2Y12 inhibitors

P2Y12 inhibitorsSwipe sideways on phone

Agent	Reversibility	Half-life	Prodrug / CYP	Dosing and use	Reversal / notes
Clopidogrel	Irreversible	6 h	Prodrug, hepatic activation, CYP2C19	Load 300 mg then 75 mg daily; with ASA for secondary CAD prevention, CAD with or without stents	Platelet transfusion
Prasugrel	Irreversible	7 h	Prodrug, hepatic activation, no CYP interaction	Load 60 mg then 10 mg daily (5 mg if < 60 kg or > 75 y); with ASA in CAD plus PCI	Desmopressin, platelet transfusion
Ticlopidine	Irreversible			Rarely used in US	Causes neutropenia and TTP
Ticagrelor	Reversible	8 to 12 h	CYP3A interaction	Load 180 mg then 90 mg BID; with ASA in CAD	Desmopressin, platelet transfusion
Cangrelor	Reversible			IV

PDE inhibitors, PAR1 inhibitor, and GPIIb/IIIa inhibitors

PDE, PAR1 and GPIIb/IIIa inhibitors

Class / agent	Mechanism	Use	Reversal / notes
Dipyridamole (PDE inhibitor)	Phosphodiesterase inhibition	With ASA (Aggrenox) for secondary stroke prevention	Desmopressin, platelet transfusion
Cilostazol (PDE inhibitor)	Inhibits PDE III, increases cyclic AMP, decreases platelet aggregation	Intermittent claudication, PCI, secondary stroke or TIA prevention
Vorapaxar (PAR1 inhibitor)	Thrombin receptor (PAR1) inhibitor	History of MI or PAD, 2.08 mg once daily
Abciximab (GPIIb/IIIa)	Monoclonal antibody	CAD requiring PCI (discontinued in US, 2019); thrombocytopenia ~1% (0.5% severe < 20K), drop 1 to 2 h after dose	Platelets; if bleeding, platelet transfusion plus cryoprecipitate
Eptifibatide (GPIIb/IIIa)	Small molecule resembling fibrinogen, blocks binding site	CAD requiring PCI
Tirofiban (GPIIb/IIIa)	Small-molecule inhibitor	CAD requiring PCI

Factor XI inhibitors (investigational)

Abelacimab: anti-FXI monoclonal antibody (monthly SC); phase 3 ASTER (vs apixaban) halted Feb 2026 after a data review indicated it would not meet its objective, and MAGNOLIA (vs dalteparin) then terminated Apr 2026, with no reported results; phase 2 AZALEA-TIMI 71 (vs rivaroxaban in AF) stopped early in 2023 for a large reduction in bleeding (Ruff NEJM 2025); LILAC-TIMI 76 (vs placebo, AF unsuitable for anticoagulation) ongoing, filing planned around 2028. Not FDA-approved.
Asundexian: oral FXIa inhibitor; OCEANIC-AF stopped early Nov 2023, inferior to apixaban for stroke prevention in AF. OCEANIC-STROKE (NEJM 2026) positive: reduced recurrent ischemic stroke after noncardioembolic stroke without more major bleeding.
Milvexian: oral FXIa inhibitor; LIBREXIA program, phase 3 in AF, post-ACS, post-stroke. LIBREXIA-ACS stopped for futility (Nov 2025; results 2026, HR 1.05); AF and STROKE ongoing.
Class promise: separate hemostasis from thrombosis (FXI predominantly drives pathologic thrombus, not bleeding).

Cancer-associated thrombosis (CAT)

Preferred DOACs: apixaban (CARAVAGGIO) and edoxaban (Hokusai-VTE-Cancer) first-line for most cancer VTE, equivalent to LMWH; rivaroxaban also used.
LMWH preferred if GI/GU luminal primary (higher bleeding risk), intracranial metastases, platelets < 50K (dose-adjusted LMWH; usually hold if < 25K), high-dose chemo, or DOAC drug interactions.
Duration: minimum 6 months; often indefinite while cancer is active or on cancer therapy. Reassess q3 to 6 months; stop if remission and off treatment > 6 months.
Pivotal trials: CARAVAGGIO (apixaban vs LMWH, NEJM 2020); Hokusai-VTE-Cancer (edoxaban vs LMWH, NEJM 2018).
Khorana score for primary VTE prophylaxis in ambulatory cancer patients: BMI ≥ 35, Hb < 10, leukocytes > 11K, platelets ≥ 350K, very high-risk primary site (pancreas, stomach). Score ≥ 2, consider prophylactic apixaban or rivaroxaban (CASSINI, AVERT).

Special clinical situations

Heparin resistance (cannot reach therapeutic aPTT despite escalating doses): suspect antithrombin deficiency; check AT level; supplement with AT concentrate or FFP.
Mechanical heart valves: warfarin (target INR 2.5 to 3.5 for mitral, 2 to 3 for aortic). DOACs contraindicated.
Catheter-related thrombosis: anticoagulate while catheter remains; remove if no longer needed.
Splanchnic vein thrombosis (mesenteric, portal, splenic): evaluate for myeloproliferative neoplasm (JAK2), PNH, malignancy, cirrhosis. Anticoagulate unless severe bleeding risk.
Cerebral venous thrombosis (CVT): anticoagulate (LMWH then warfarin or DOAC) even with hemorrhagic infarct. Workup includes OCP, pregnancy, infection (mastoiditis), thrombophilia.
Catheter-directed thrombolysis for selected cases: phlegmasia cerulea dolens, massive PE with shock, IVC thrombosis with severe symptoms, May-Thurner; ATTRACT (NEJM 2017) does not support routine pharmacomechanical thrombolysis, even for iliofemoral DVT (no reduction in post-thrombotic syndrome, more major bleeding).

High yield

HIT cardinal rule: stop heparin, start argatroban or fondaparinux; do not start warfarin until platelet recovery; do not use platelet transfusion unless bleeding.
Cancer-associated VTE: DOACs (apixaban or edoxaban) preferred over LMWH; LMWH for GI cancer with bleeding risk.
Mechanical valves: warfarin only.
APS triple-positive: warfarin (target INR 2 to 3); DOACs inferior (TRAPS).
Pregnancy: LMWH preferred; warfarin teratogenic in first trimester (embryopathy: nasal hypoplasia, stippled epiphyses); DOACs contraindicated throughout.
Heparin resistance means consider antithrombin deficiency.
Warfarin-induced skin necrosis means protein C deficiency until proven otherwise (also seen with protein S deficiency).
4F-PCC is superior to FFP for warfarin reversal in major bleeding.
Idarucizumab specifically reverses dabigatran only; 4F-PCC for Xa inhibitors (andexanet withdrawn from US market Dec 2025).
Khorana score ≥ 2, consider primary VTE prophylaxis (apixaban or rivaroxaban) in ambulatory cancer patients (CASSINI, AVERT).

2026 update: factor XI landscape maturing

Abelacimab (anti-FXI mAb)

ASTER (vs apixaban) and MAGNOLIA (vs dalteparin in GI/GU cancer-associated VTE): phase 3 trials terminated by sponsor decision in 2026; no efficacy results reported.
AZALEA-TIMI 71 (Ruff NEJM 2025): phase 2 abelacimab vs rivaroxaban in AF; stopped early (announced Sep 2023) for a large reduction in major or clinically relevant nonmajor bleeding (HR 0.38 for 150 mg). LILAC-TIMI 76 (vs placebo in AF patients unsuitable for anticoagulation) still recruiting.
No NDA; not FDA-approved.

Milvexian (oral FXIa inhibitor)

LIBREXIA program: LIBREXIA-AF (stroke prevention in AF vs apixaban), LIBREXIA-STROKE (secondary stroke prevention), LIBREXIA-ACS (post-ACS on antiplatelet therapy). LIBREXIA-ACS stopped for futility Nov 2025 (Gibson NEJM 2026: HR 1.05); AF and STROKE trials ongoing.

Asundexian (oral FXIa inhibitor): failed in AF

OCEANIC-AF (Piccini NEJM 2024): asundexian vs apixaban in AF stroke prevention, stopped early Nov 2023 for inferiority (stroke/SE 1.3% vs 0.4%). Bleeding lower with asundexian.
OCEANIC-STROKE (Sharma NEJM 2026; add-on to antiplatelet after non-cardioembolic stroke or high-risk TIA): positive, ischemic stroke 6.2% vs 8.4% (HR 0.74); major bleeding not increased (1.9% vs 1.7%). NDA under FDA priority review (accepted May 2026).

Andexanet alfa: ANNEXA-I

ANNEXA-I (Connolly NEJM 2024): andexanet vs usual care (mostly PCC) for acute ICH on a FXa inhibitor; superior hemostatic efficacy at 12 h (67% vs 53%) but higher thrombotic events (10.3% vs 5.6%). Stopped early. Andexxa withdrawn from the US market Dec 22, 2025 (FDA: risks outweigh benefits); 4F-PCC is the US option.

Cancer-associated thrombosis: API-CAT reduced-dose extended

API-CAT (Mahe NEJM 2025): after 6 months of anticoagulation for cancer-VTE, apixaban 2.5 mg BID (reduced dose) vs 5 mg BID extended. Non-inferior for recurrent VTE and reduced bleeding, supporting reduced-dose extended anticoagulation in cancer-VTE.

Veli Bakalov MD, Board Review Notes 2026