Coagulation & Anticoagulants

👩‍⚕️ First of all, you need to be able to draw the clotting cascade. Start practicing.

✨ The intrinsic pathway 

• “TENET”: 12 → 11 → 9 → 8 → 10 
• Assessed using aPTT

💫 The extrinsic pathway 

• Tissue Factor → 7 → 10
• Assessed using PT

🌟 The common pathway

• Both intrinsic and extrinsic pathways converge on the activation of factor 10 to 10a, leading to the common pathway

⏱️ Clotting inhibitors

• Plasmin is the main fibrinolytic enzyme that degrades fibrin clots and limits thrombus propagation
  • Tissue plasminogen activator is released in large amounts from endothelium during trauma and shock, and activates plasminogen to plasmin, causing excessive fibrinolysis: Trauma → endothelial tPA surge → plasmin activation → hyperfibrinolysis
• Antithrombin III inhibits activated factors 2, 10 and less so 9, 11 and 12.
• Factors VIIIa and Va are inactivated by activated protein C and S, not ATIII

A pregnant woman develops a hot swollen leg. An Iliofemoral DVT is confirmed. Which of these clotting factors belongs to the (i) intrinsic, (ii) extrinsic and (iii) common pathway?

• ((Factor IXa::Intrinsic pathway))
• ((Factor VIIa::Extrinsic pathway))
• ((Factor X::Common pathway))
• ((Factor IIa::Common pathway))

In the coagulation cascade, which factor is the end result of intrinsic pathway activation?

• ((Factor IX::Intermediate intrinsic factor))
• ((Factor XI::Upstream intrinsic factor))
• ((Factor Xa::☑️ Final product of intrinsic pathway before entering common pathway))
• ((Factor XIII::Stabilises fibrin clot in the common pathway))

Antithrombin III does not inactivate which of the following factors?

• ((Factor VIII::☑️ Factor VIIIa and Va are inactivated by activated protein C and S, not ATIII))
• ((Factor IX::Antithrombin III inhibits activated factors 2, 10 and to a lesser extent 9, 11 and 12))
• ((Factor X::Antithrombin III inhibits activated factors 2, 10 and to a lesser extent 9, 11 and 12))
• ((Factor II::Antithrombin III inhibits activated factors 2, 10 and to a lesser extent 9, 11 and 12))

A patient presents with deep vein thrombosis. Which physiological mechanism helps control thrombosis formation in the body?

• ((Plasmin::☑️ Plasmin is the main fibrinolytic enzyme that degrades fibrin clots and limits thrombus propagation))
• ((Protein C::Natural anticoagulant that inactivates factors Va and VIIIa but does not directly lyse formed fibrin clots))
• ((TNF::Pro-inflammatory cytokine; promotes coagulation rather than limiting thrombosis))
• ((Antithrombin III::Inhibits thrombin and factor Xa but does not directly break down established fibrin clots))

During major trauma, which factor increases and contributes significantly to coagulopathy and hyperfibrinolysis?

• ((TNF::Pro-inflammatory cytokine; does not drive trauma-related hyperfibrinolysis))
• ((Plasmin activator inhibitor::Inhibits fibrinolysis; increase would reduce, not cause, hyperfibrinolysis))
• ((Activated protein C::Has anticoagulant effects but is not the main driver of trauma-induced hyperfibrinolysis))
• ((Tissue plasminogen activator::☑️ Tissue plasminogen activator is released in large amounts from endothelium during trauma and shock, and activates plasminogen to plasmin, causing excessive fibrinolysis))

👩‍⚕️ Make sure you know the mechanism of action of these drugs...

Heparin

Heparin activates antithrombin III, which inhibits IIa, Xa, IXa, XIa, XIIa. Remember that you can get heparin-induced thrombocytopenia!

Fondaparinux

Fondaparinux is a selective Xa inhibitor via antithrombin III

Warfarin

Warfarin inhibits vitamin K epoxide reductase, reducing the synthesis of II, VII, IX, X, protein C, and protein S 

Warfarin is reversed urgently by administering prothrombin complex concentrate which contains factors 1972 (X, IX, VII, II) and acts faster than vitamin K (6-8h onset) for longer-term reversal.

DOAC

DOAC is a direct factor Xa inhibitor

Dabigatran

Dabigatran is a direct factor IIa inhibitor

Aspirin

Aspirin irreversibly inhibits both COX1 and COX2;

• ↓ COX1 → ↓ Thromboxane A₂ → Impairs platelet aggregation
• ↓ COX2 → ↓ Renal PGE2/PGI2 → Afferent arteriole vasoconstriction → ↓ GFR

Clopidogrel

Clopidogrel blocks P2Y12 ADP receptors → Impair platelet aggregation

Tranexamic acid

A synthetic lysine analogue, inhibits tissue plasminogen activator, plus prevents plasmin from binding to fibrin, protecting clots from degradation.

A 51-year-old patient had surgery while continuing aspirin and clopidogrel until the day before. Now he has a wound oozing. What is the most likely cause?

• ((Deranged platelet aggregation due to aspirin and clopidogrel::☑️ Aspirin inhibits COX → ↓ TXA₂. Clopidogrel blocks P2Y12 ADP receptors. Both impair platelet aggregation.))
• ((Decreased extrinsic pathway of clotting factors::Would prolong PT, not typical for antiplatelets))
• ((Decreased intrinsic pathway of clotting factors::Would prolong APTT, not caused by these drugs))
• ((Increased capillary fragility::Not the mechanism of action of antiplatelet agents))

How does aspirin cause bleeding?

• ((COX2 inhibition and decreased prostaglandins::COX2 inhibition is not the main mechanism for platelet effects))
• ((COX1 inhibition and decreased thromboxane A₂::☑️ Irreversible COX1 inhibition → ↓ TXA₂ → impaired platelet aggregation))
• ((Inhibition of clotting factors::Aspirin does not affect coagulation factors))
• ((Inhibition of clotting factor synthesis in the liver::That is the mechanism of warfarin))

A 75-year-old man with hypertension develops confusion 24 hours after a femur fracture. He was on aspirin, codeine, and flurothiazide. Postoperatively, he is given an NSAID. Bloods show ↓Na⁺, ↑K⁺, ↑urea, ↑creatinine, and ↓GFR. Which enzyme is most likely affected?

• ((Catechol-O-methyltransferase::Involved in catecholamine metabolism, not renal haemodynamics))
• ((Carbonic anhydrase::Target of acetazolamide, not NSAIDs))
• ((Cyclooxygenase::☑️ Reduction in COX2 → ↓ renal prostaglandins → Vasoconstriction of the afferent arteriole → ↓ GFR → AKI))
• ((Monoamine oxidase::Involved in neurotransmitter metabolism))

Which describes the mechanism of action of tranexamic acid?

• ((Direct thrombin inhibitor::Acts on coagulation cascade, not fibrinolysis))
• ((Factor Xa inhibitor::This is the mechanism of rivaroxaban))
• ((Plasmin inhibitor::☑️ Tranexamic acid inhibits conversion of plasminogen to plasmin, reducing fibrin degradation))
• ((Vitamin K antagonist::Warfarin mechanism))
• ((Antithrombin III activator::Heparin mechanism))

Which describes the mechanism of action of warfarin?

• ((Inhibits antithrombin III::Antithrombin is a natural anticoagulant; warfarin does not inhibit it))
• ((Inhibits factor X::Warfarin reduces synthesis of factor X but does not directly inhibit it))
• ((Inhibits synthesis of factors IX, X, VII and prothrombin::☑️ Warfarin inhibits vitamin K epoxide reductase, reducing synthesis of vitamin K–dependent clotting factors II, VII, IX and X))
• ((Kills bacterial flora::Not its primary anticoagulant mechanism))
• ((Inhibits protein C and S::Warfarin reduces synthesis of protein C and S, but this is not its primary intended mechanism))

A patient on warfarin presents with bleeding. Which test is used to measure the effect of warfarin?

• ((Activated partial thromboplastin time::Used to monitor heparin, not warfarin))
• ((Bleeding time::Assesses platelet function, not warfarin effect))
• ((Prothrombin time standardised as INR::☑️ Warfarin prolongs PT by reducing factor VII; INR standardises PT))
• ((Thrombin time::Measures fibrinogen to fibrin conversion))
• ((Platelet count::Warfarin does not affect platelet number))

A woman with a past myocardial infarction, now in atrial fibrillation, is found to have a dilated left ventricle on echocardiogram. She is on warfarin and her INR is 6.1. Which of the following does warfarin inhibit?

• ((Antithrombin::Natural anticoagulant that inhibits thrombin and factor Xa; not inhibited by warfarin))
• ((Plasminogen::Precursor of plasmin involved in fibrinolysis; not affected by warfarin))
• ((Prothrombin::☑️ Warfarin inhibits vitamin K epoxide reductase → ↓ II, VII, IX, X, Protein C & S.))
• ((Von Willebrand factor::Mediates platelet adhesion; not vitamin K dependent))

A 65-year-old man with a strangulated femoral hernia requires urgent surgery. He is on warfarin for atrial fibrillation and his INR is 5. What is the most appropriate IV therapy to urgently reverse anticoagulation before surgery?

• ((Factor VIII::Used in haemophilia A; does not reverse warfarin))
• ((Platelet concentrate::Used for thrombocytopenia or platelet dysfunction; warfarin affects clotting factors))
• ((Protamine sulphate::Reverses heparin, not warfarin))
• ((Vitamin K::Reverses warfarin but takes several hours which is not rapid enough for urgent surgery))
• ((Prothrombin complex concentrate::☑️ Contains factors II, VII, IX and X for rapid reversal of warfarin))

Which is the mechanism of action of heparin?

• ((Inhibits factors V, VIII and X::Heparin does not directly inhibit these factors; it acts via antithrombin III))
• ((Inhibits factor X::Heparin enhances factor Xa inhibition but via antithrombin III, not direct inhibition))
• ((Inhibits antithrombin III::Heparin accelerates antithrombin III; it does not inhibit it))
• ((Accelerates antithrombin III leading to inhibition of thrombin and factor Xa::☑️ Heparin potentiates antithrombin III, which inactivates IIa and Xa))

A patient on heparin develops bleeding. What is the most likely cause?

• ((Thrombocytopenia::☑️ Heparin-induced thrombocytopenia leads to reduced platelet count and bleeding))
• ((Factor X deficiency::Heparin inhibits factor Xa activity via antithrombin III but does not cause a true deficiency))
• ((Vitamin K deficiency::Causes prolonged PT; unrelated to heparin therapy))
• ((Von Willebrand disease::Inherited platelet adhesion disorder, not caused by heparin))

What is the mechanism of action of rivaroxaban?

• ((Direct factor Xa inhibitor::☑️ Rivaroxaban directly inhibits factor Xa, preventing conversion of prothrombin to thrombin))
• ((Thrombin inhibitor::Dabigatran is the direct thrombin (IIa) inhibitor))
• ((Plasmin::Involved in fibrinolysis, not anticoagulation mechanism))
• ((Prekallikrein::Part of the contact activation pathway, not the target of rivaroxaban))

👩‍⚕️ So now we've covered the clotting cascades and the drugs that affect it: now let's look at the prophylaxis and management of thromboembolic pathologies! There are x4 main themes they like to quiz about -

Prophylaxis of VTE in elective colorectal surgery

Includes LMWH from pre/peri-op, for 7-10 days, or 28 days in high-risk cancer cases plus compression stockings or intermittent pneumatic compression devices.

Treatment of VTE

Usually is LMWH, unless this patient has had recurrent VTE events despite LMWH prophylaxis in which case they need an IVC filter. They also need an IVC filter if already on IV heparin but the heparin needs to be stopped for surgery.

Peripheral vascular disease

In peripheral vascular disease compression stockings are contraindicated

Antithrombin III deficiency

Deficiency in antithrombin III causes a 10x increase in risk of thrombotic events. Note that patients with Antithrombin III deficiency will not respond to heparin as heparin acts on antithrombin III. These patients need lifelong warfarin.

👩‍⚕️ So here are practice MCQs...

A 75-year-old man with ischaemic heart disease and bilateral peripheral vascular disease undergoes a mid-thigh amputation. What is the most appropriate anti-thromboembolic prophylaxis?

• ((Aspirin therapy::Antiplatelet therapy prevents arterial events, not postoperative VTE))
• ((LMWH::☑️ Pharmacological VTE prophylaxis of choice post major lower limb surgery))
• ((LMWH and stockings::Compression stockings often unsuitable/contraindicated in severe peripheral vascular disease))
• ((TED stockings::Mechanical only; insufficient alone and may be contraindicated in PVD))

A 52-year-old heavy smoker is due to undergo an elective colon resection. What is the most appropriate method of thromboprophylaxis?

• ((Aspirin therapy::Aspirin alone is insufficient for VTE prophylaxis in major abdominal surgery))
• ((LMWH::LMWH alone is effective, but mechanical prophylaxis should also be used in high-risk surgical patients))
• ((LMWH and stockings::☑️ Major colorectal surgery carries high VTE risk; combined pharmacological (LMWH) and mechanical (graduated compression stockings or IPC) prophylaxis is recommended))
• ((IVC filter::Reserved for patients with contraindications to anticoagulation or recurrent VTE despite adequate anticoagulation))

A patient continues to develop venous emboli despite therapeutic heparin. What is the next step in management?

• ((Increase heparin dose::The patient is already therapeutically anticoagulated; dose escalation is not appropriate if emboli continue))
• ((Switch to warfarin::Warfarin is used for long-term anticoagulation but does not address failure of adequate anticoagulation))
• ((Thrombolysis::Reserved for massive PE with haemodynamic instability, not recurrent emboli despite anticoagulation))
• ((IVC filter::☑️ If venous thromboembolism recurs despite adequate anticoagulation, insertion of an inferior vena cava filter is indicated to prevent further pulmonary emboli))

A 55-year-old woman on IV heparin for recurrent PE is scheduled for elective hysterectomy. What is the most appropriate thromboprophylaxis?

• ((LMWH and stockings::Standard prophylaxis, but insufficient in very high-risk patients requiring interruption of therapeutic anticoagulation))
• ((LMWH::Anticoagulation alone will need to be stopped peri-operatively, leaving high embolic risk))
• ((IVC filter::☑️ In patients with very high thromboembolic risk where anticoagulation must be interrupted for surgery, a temporary inferior vena cava filter is indicated))
• ((Oral anticoagulant::Must be discontinued peri-operatively and does not provide immediate protection))

A patient presents with a newly diagnosed deep vein thrombosis. What is the most appropriate initial management?

• ((LMWH::☑️ First-line treatment for uncomplicated newly diagnosed DVT))
• ((Unfractionated heparin::Used in renal failure, very high bleeding risk, or when rapid reversal may be required))
• ((Thrombolysis::Reserved for massive limb-threatening DVT or haemodynamically unstable PE))
• ((Embolectomy::Indicated in surgical emergencies or failed thrombolysis in massive PE/DVT))

A patient is diagnosed with an extensive mobile femoral DVT. What is the most appropriate immediate treatment?

• ((LMWH::☑️ First-line immediate anticoagulation for extensive DVT, including femoral involvement))
• ((Streptokinase::Systemic thrombolysis is reserved for massive PE with haemodynamic instability or limb-threatening DVT, not routine femoral DVT))
• ((Thrombolysis::Considered only in selected cases such as phlegmasia or severe limb compromise))
• ((Embolectomy::Reserved for surgical emergencies or failed thrombolysis in massive PE/DVT))

What is the best long-term management to prevent post-thrombotic (post-phlebitic) syndrome after DVT?

• ((Anticoagulation indefinitely::Prevents recurrence of DVT but does not directly prevent post-thrombotic syndrome))
• ((NSAIDs::Help pain but do not prevent chronic venous hypertension))
• ((Graduated compression stockings::☑️ Improve venous return, reduce venous hypertension, and decrease oedema and pain))
• ((Early mobilisation alone::Important but insufficient to prevent post-thrombotic syndrome on its own))

A patient is diagnosed with antithrombin III deficiency. Which of the following is the most appropriate treatment?

• ((LMWH::Heparin acts on antithrombin III - which this patient is deficient in, so heparin won't work))
• ((Unfractionated heparin::Heparin acts on antithrombin III - which this patient is deficient in, so heparin won't work))
• ((Warfarin for life::☑️ Inherited antithrombin III deficiency carries high risk of recurrent VTE; lifelong anticoagulation is indicated))
• ((Warfarin for 6 months::Insufficient - needs lifelong treatment))

A 35-year-old woman with antithrombin III deficiency develops a DVT 10 days after abdominal surgery. What is the most appropriate management?

• ((Heparin::Initial treatment of DVT, but does not address long-term high recurrence risk in hereditary thrombophilia))
• ((Warfarin for life::☑️ Inherited antithrombin III deficiency carries high risk of recurrent VTE; lifelong anticoagulation is indicated))
• ((Warfarin for six months::Insufficient duration given underlying high-risk inherited thrombophilia))
• ((Stockings alone::Adjunctive therapy; does not prevent recurrence))

👩‍⚕️ Peri-operative management: Let's briefly cover how to adjust anticoagulation for surgery!

• Unfractionated heparin is stopped 4-6h pre-op
• pLMWH is stopped 12h pre-op
• tLMWH and fondaparinux are stopped 24h pre-op
• DOACs are stopped 24h before low bleeding risk procedures and 48–72h before high bleeding risk procedures
• High VTE risk e.g. mechanical heart valves → Bridging with LMWH/UFH
• Impaired renal function → Earlier discontinuation, as slower clearance

How long before surgery should apixaban be stopped?

• ((6 hours before surgery::This applies to unfractionated heparin, not DOACs))
• ((12 hours before surgery::This applies to prophylactic LMWH, not DOACs))
• ((24 hours before all surgeries::Low bleeding risk procedures only; insufficient for high-risk surgery))
• ((2–3 days before surgery::☑️ DOACs are stopped 24h before low bleeding risk procedures and 48–72h before high bleeding risk procedures))

👩‍⚕️ Okay - finished! Draw the clotting cascade one last time before moving on to the next lesson.