Anticoagulants
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)
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)
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 |
|
| Clearance | Mainly reticuloendothelial system, less by kidney (preferred in renal failure and when rapid reversibility needed: CABG, ECMO, CRRT, severe instability). |
| Reversal |
|
| 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 |
|
| Elimination | Renal; caution when CrCl < 30 mL/min; avoid in hemodialysis (enoxaparin is nondialyzable). |
| Transitions |
|
| 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
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)
- 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 or hepatic impairment. 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. |
| > 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, event within 3 months, CVA, VTE, antithrombin deficiency or APLS). Restart warfarin 12 to 24 h postop.
Direct oral anticoagulants (DOACs)
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 |
| Renal cutoffs / notes | Discontinued in US; monitor with anti-Xa or specific levels |
DOAC absorption, food, and obesity
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 | Give with food; 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 (CARAVAGGIO, Hokusai-VTE-Cancer); if a DOAC is used, apixaban.
DOAC perioperative management
- 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 72 to 96 h if CrCl < 50.
- 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) |
|
| 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
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 excluded routine use for most iliofemoral DVTs.
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