Disorders of coagulation or thrombosis - use of anticoagulants and antiplatelet agents

Classes and targets

Anticoagulants act on the fibrin-rich venous thrombus; antiplatelets on the platelet-rich arterial thrombus
- Using the wrong class for the territory is a common exam trap - aspirin is not treatment for VTE, and a DOAC is not treatment for a coronary stent

Class	Agents	Target
Vitamin K antagonist	Warfarin	II, VII, IX, X (+ protein C, S)
Direct thrombin inhibitor	Dabigatran; argatroban, bivalirudin (IV)	IIa
Direct Xa inhibitor	Apixaban, rivaroxaban, edoxaban	Xa
Antithrombin-dependent	UFH, enoxaparin, fondaparinux, danaparoid	Xa +/- IIa
COX-1	Aspirin	TXA2
P2Y12	Clopidogrel, prasugrel, ticagrelor	ADP receptor
GPIIb-IIIa	Tirofiban, abciximab, eptifibatide	Final common aggregation step

Bleeding and procedural burden

Anticoagulant-related bleeding is among the commonest causes of medication-related hospital admission in Australia
Major bleeding on a DOAC ~2-3%/yr; intracranial haemorrhage ~50% lower than warfarin, GI bleeding higher with rivaroxaban and dabigatran 150
~10-15% of anticoagulated patients need a procedure each year - periprocedural management is a routine, high-volume decision
Clopidogrel: ~25-30% of the population carry a reduced-function CYP2C19 allele (higher in East Asian populations)

Onset and offset - the numbers that drive periprocedural planning

Agent	Peak	Half-life	Offset
UFH	Immediate (bolus); ~4 h to steady state on infusion	1-2 h	4-6 h
Enoxaparin	~3 h	2-4 h	16-24 h
Dabigatran	1-2 h	12-17 h	1-4 days (renal)
Rivaroxaban	2.5-4 h	5-13 h	1-3 days
Apixaban	~3 h	~12 h	1-3 days
Warfarin	4-5 days to full effect	36-42 h	3-5 days

*Offset is prolonged disproportionately by renal impairment for dabigatran* (~80% renal), less so for apixaban (~27%)

Handling and interactions

Handling

Dabigatran - P-glycoprotein substrate, renally cleared, not CYP-metabolised
- Interactions: amiodarone, verapamil, dronedarone (inc); rifampicin (dec)
Rivaroxaban and apixaban - CYP3A4 + P-gp
- *Contraindicated with strong dual inhibitors (azoles, HIV protease inhibitors) and strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort)*
Rivaroxaban 15/20 mg must be taken with food for absorption

Antiplatelet pharmacology

Antiplatelets

Aspirin - irreversible COX-1 acetylation; effect lasts the platelet lifespan (7-10 days)
Clopidogrel, prasugrel - irreversible P2Y12; prodrugs (clopidogrel needs CYP2C19 - reduced-function alleles and omeprazole blunt it)
Ticagrelor - reversible, not a prodrug, twice daily; dyspnoea, bradyarrhythmia
Prasugrel: *contraindicated after stroke/TIA*, avoid age >75 or weight <60 kg

Measuring effect

Warfarin - INR (only validated for VKA)
UFH - APTT or anti-Xa; LMWH - anti-Xa (renal impairment, extremes of weight, pregnancy)
DOACs need no monitoring - but:
- *Thrombin time is the best routine test for dabigatran - a normal TT excludes clinically significant levels*
- Apixaban/rivaroxaban: drug-calibrated anti-Xa; a normal PT/APTT does not exclude drug effect

Heparin-induced thrombocytopenia - 4Ts score

Heparin-induced thrombocytopenia - 4Ts score (0-2 points each)

	2 points
Thrombocytopenia	Fall >50% to nadir >=20
Timing	Day 5-10 (or day 1 with heparin in the last 30 days)
Thrombosis	New confirmed thrombosis, skin necrosis, or anaphylactoid reaction after IV heparin bolus
oTher cause	None apparent

<=3 = low probability -> HIT effectively excluded, no further testing
4-5 intermediate, 6-8 high -> stop heparin now and test (anti-PF4/heparin ELISA -> confirm with functional assay: serotonin release or heparin-induced platelet activation)
ELISA is sensitive but poorly specific - a positive immunoassay alone does not make the diagnosis
HIT is a prothrombotic disorder - thrombosis, not bleeding, is the risk

Choosing the agent

A. Choosing the agent

DOAC first-line for non-valvular AF and for VTE
*Use warfarin instead* for:
- Mechanical heart valve; moderate-severe rheumatic mitral stenosis
- Triple-positive antiphospholipid syndrome (TRAPS: rivaroxaban arm stopped early for excess arterial thrombosis)
- Severe renal impairment (CrCl <15-30), significant hepatic impairment (Child-Pugh B/C for rivaroxaban)
- Unusual-site thrombosis - cerebral venous sinus, splanchnic/portal (evidence base is with warfarin/LMWH)
Enoxaparin in pregnancy (warfarin teratogenic, DOACs contraindicated); warfarin or enoxaparin in breastfeeding
Caution/relative contraindication: extremes of body weight, significant thrombocytopenia, luminal GI or GU malignancy, active high bleeding risk

Periprocedural management

B. Periprocedural management

Assess procedural bleeding risk and thrombotic risk separately

Procedure	DOAC interruption
Minimal (dental extraction, cataract, skin lesion, endoscopy without biopsy)	Do not interrupt - or omit a single dose
Low/moderate bleeding risk	Stop 24 h before (48 h if CrCl <50 on dabigatran)
High bleeding risk (neuraxial, neurosurgery, major cancer surgery)	Stop 48 h before (72-96 h for dabigatran with renal impairment)

Restart 24 h after low-risk, 48-72 h after high-risk procedures once haemostasis is secure
*Bridging with LMWH is essentially never indicated for a DOAC* (PAUSE) - it increases bleeding without reducing thrombosis
- Bridge only for mechanical valves, recent (<3 months) VTE or stroke, or very high-risk AF on warfarin
No preoperative DOAC level is required if the interval is respected

Reversal and bleeding

C. Reversal and bleeding

Drug	Reversal
Warfarin, major bleeding	Prothrombinex-VF 25-50 IU/kg + vitamin K 5-10 mg IV
Warfarin, INR high, no bleeding	Withhold; oral vitamin K 1-2 mg if INR >4.5-10
UFH	Protamine (1 mg per 100 units)
Enoxaparin	Protamine - only ~60% reversal
Dabigatran	Idarucizumab - Fab fragment binding dabigatran with ~350x the affinity dabigatran has for thrombin
Apixaban / rivaroxaban	Andexanet alfa where available; otherwise Prothrombinex-VF

*Do not give idarucizumab on suspicion alone - a normal thrombin time argues strongly against significant dabigatran level*. Reserve it for major bleeding or urgent surgery
Adjuncts: tranexamic acid, mechanical haemostasis, activated charcoal if ingestion <2-4 h, dialysis removes dabigatran (not the Xa inhibitors - highly protein bound)

HIT - management

D. HIT

*Stop all heparin, including flushes and heparin-bonded catheters, and start a non-heparin anticoagulant at therapeutic dose* - even without thrombosis

Situation	Agent
Critically ill, high bleeding risk, likely procedure	Argatroban or bivalirudin (short-acting, IV)
Clinically stable	Fondaparinux or a DOAC
Life- or limb-threatening thrombosis	Argatroban, bivalirudin, danaparoid or fondaparinux
Moderate-severe hepatic dysfunction	Avoid or dose-reduce argatroban; avoid DOACs

*Never start warfarin while the platelet count is low - protein C falls first -> venous limb gangrene and skin necrosis*. Wait until platelets >150 and overlap for >=5 days
*Never give platelet transfusions* unless there is life-threatening bleeding
Anticoagulate for 4 weeks if isolated HIT, 3 months if thrombosis
Defer elective surgery >=1 month; if unavoidable, bridge with argatroban/bivalirudin
Document the allergy; re-exposure is possible after >100 days if antibodies have cleared, but avoid

Antiplatelet therapy

E. Antiplatelet therapy

DAPT after ACS/PCI: aspirin + a P2Y12 inhibitor, usually 12 months (shorter with high bleeding risk, longer with high ischaemic risk)
- Ticagrelor or prasugrel preferred over clopidogrel after ACS
Triple therapy (DAPT + anticoagulant): shortest possible - aspirin usually stopped at discharge or 1 week, then DOAC + clopidogrel to 6-12 months, then DOAC alone
Add a PPI to any patient on DAPT or on an anticoagulant plus antiplatelet
Aspirin need not be stopped for most minor surgery and dental work; stop 7 days before neurosurgery or intraocular surgery
*Do not interrupt DAPT within 1 month of a coronary stent* - discuss with cardiology; stent thrombosis is often fatal

Agent-specific adverse effects

Warfarin skin necrosis - protein C/S deficiency, first days without heparin cover
Purple toe syndrome - cholesterol embolisation on warfarin
Heparin: HIT, osteoporosis with prolonged use, hyperkalaemia (aldosterone suppression), transaminitis
Vaccine-induced immune thrombotic thrombocytopenia (VITT) - anti-PF4 antibodies without heparin exposure; treated as HIT plus IVIG; also spontaneous HIT after infection or orthopaedic surgery
Warfarin interactions: antibiotics (metronidazole, macrolides, cotrimoxazole), amiodarone, azoles, NSAIDs, alcohol, dietary vitamin K, CYP2C9 and VKORC1 polymorphisms
Anticoagulant-associated nephropathy - glomerular haemorrhage with over-anticoagulation
Aspirin: peptic ulceration, exacerbated respiratory disease, Reye syndrome

Bleeding risk over time

Bleeding risk is highest in the first 90 days of anticoagulation, then plateaus
HAS-BLED / ORBIT identify modifiable risk (hypertension, alcohol, NSAIDs, labile INR, concurrent antiplatelet)
- *A high bleeding score is a prompt to modify risk, not to withhold anticoagulation*
Time in therapeutic range <65% on warfarin -> outcomes no better than no anticoagulation; switch to a DOAC
HIT antibodies are transient - usually undetectable by 100 days; the disorder does not recur without re-exposure
Anticoagulation decisions require annual reassessment of renal function, weight, falls, cognition and bleeding history - the dose that was right at 68 may be wrong at 82

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