Overview
This lecture covers thrombosis outside the venous system: atrial fibrillation (AF) as a cause of left atrial appendage thrombus and stroke, and arterial thrombosis arising from atherosclerotic plaque rupture or erosion. It then works through the pharmacology used to prevent and treat these clots (antiplatelet drugs, heparins, fibrinolytics), contrasts drug efficacy in venous versus arterial thrombosis, and finishes with three other clot types: heparin-induced thrombocytopenia (HIT), microthrombi, and mural thrombosis.
Atrial fibrillation and left atrial appendage thrombosis
- In AF the atrial appendage fails to contract and empty properly, causing stasis of blood within it.
- This stasis sequence progresses: stasis → thrombus → embolus → stroke, with the clot forming specifically in the left atrial appendage.
- About 25% of all people will develop AF during their life.
- Because the mechanism is stasis-driven (as in DVT), anticoagulants are effective in AF whereas antiplatelet drugs are not.
- Stroke risk reduction by drug class in AF: DOACs (direct oral anticoagulants) ~70%; warfarin ~64%; aspirin only ~22%.
- DOACs are safer than warfarin.
Arterial thrombosis: atherosclerosis and plaque rupture/erosion
- Arterial thrombosis is responsible for ~25% of deaths, mostly attributable to atherosclerotic vascular disease.
- Normal vessel breach vs atherosclerotic vessel: in a normal vessel a wall breach is sealed proportionately by a small haemostatic platelet plug, blood flow otherwise unobstructed. In an atherosclerotic vessel, plaque rupture triggers thrombosis that occludes the lumen.
- Endothelial injury overlying an atherosclerotic plaque is often associated with plaque rupture (a bleed into the plaque, i.e. plaque fissure) or plaque erosion.
- Rupture vs erosion distinguished on histology: rupture is a breach releasing necrotic core (NC) content into the lumen with thrombus (Th) breaking through at the rupture site; erosion is thrombus forming on a denuded but structurally intact (non-ruptured) endothelial surface.
- Progressive plaque-associated thrombus growth: (1) plaque fissure with platelet adhesion and fibrin forming over the necrotic core → (2) increasing luminal stenosis from platelet debris and fibrin, at the subtotal stage (70–90% stenosis) causing unstable angina → (3) layering of older thrombi causing total occlusion, i.e. acute myocardial infarction (AMI).
Platelet-mediated arterial thrombus formation
Platelets are key players in arterial thrombus formation: they bind von Willebrand factor (vWF) and collagen, and platelets activate the coagulation pathway. The sequence under flow:
- Translocation: platelets roll along the vessel wall via GPIbV-IX binding vWF.
- Adhesion: platelets adhere via α2β1, α5β1 and GPVI binding collagen.
- Aggregation: platelets cross-link via αIIbβ3 and fibrinogen.
- Thrombus formation: a dense platelet mass forms with fibrin.
Risk factors for arterial thrombosis
- Atherosclerosis is the dominant risk factor, driven by: hyperlipidaemia, hypertension, diabetes, cigarette smoking, male sex, family history.
- Polycythaemia (raised haemoglobin).
- Elevated fibrinogen.
- Other acquired factors: raised coagulation factor levels; diabetes (increased platelet aggregation, among other effects); inflammation associated with the acute phase response; oestrogens (pregnancy is a moderate risk, oral contraceptives a weak risk).
- Antibodies that enhance platelet activation are uncommon causes: antiphospholipid syndrome; heparin-induced thrombocytopenia (HIT).
Consequences of arterial thrombosis: infarction
- Ischaemia and infarction occur where no collateral (alternative arterial) circulation exists.
- Arterial thrombosis can cause infarction in any organ (heart, brain, kidney, gut, legs, spleen, etc).
- Example: a myocardial infarct at 3 weeks shows necrotic muscle that has become pale yellow and is being invaded and replaced by granulation tissue.
Drug management of arterial thrombosis
Main drug classes for managing risk of arterial thrombosis and recurrence:
- Antiplatelet drugs: aspirin (low dose); clopidogrel and others.
- Heparin: unfractionated heparin (UFH), given intravenously; low molecular weight heparin (LMWH), given subcutaneously.
- Fibrinolytic activators: alteplase (tissue plasminogen activator).
Example acute management of a heart attack: aspirin immediately; a second antiplatelet agent (clopidogrel or ticagrelor); an anticoagulant (heparin); a fibrinolytic (e.g. alteplase, within 12 hours) or percutaneous coronary intervention (e.g. stents).
Antiplatelet drugs
- Aspirin, low dose (~100 mg/day): permanently blocks cyclooxygenase, so platelet function is affected for several days. Used for prophylaxis of arterial thrombosis and arterial emboli, and protects the brain especially.
- Clopidogrel: used for medium-term prophylaxis after MI or stenting of atherosclerotic plaques in coronary and other arteries, usually combined with aspirin.
Unfractionated heparin (UFH)
- Binds antithrombin and increases its anticoagulant activity by >300-fold; antithrombin then neutralises factor IIa (thrombin), factor Xa, factor IXa and factor XIa.
- Immediate anticoagulant effect; injected, short half-life of approximately 50-60 minutes.
- Effect is monitored with the APTT; when used to treat thrombosis the aim is to increase the APTT to about 2x the reference range (e.g. reference 22-32s → target APTT 44-64s).
Low molecular weight heparin (LMWH)
- Used more frequently than UFH, has slightly less bleeding risk, and does not normally require lab monitoring.
- Given by subcutaneous or intravenous injection.
- Bleeding is the main risk of all heparins.
Fibrinolytic agents
- Must be used within a few hours of thrombosis; example is recombinant tissue plasminogen activator (alteplase and others).
- Indicated in: early acute myocardial infarction (<12 hours); some cases of acute stroke (<4.5 hours); major pulmonary embolism.
Principles of treating thrombosis: venous vs arterial
- Antiplatelet agents (aspirin, clopidogrel): minimal benefit in venous thromboembolism (30-40% effective); major benefit and easy to use in arterial thrombosis.
- Anticoagulants (dabigatran, rivaroxaban, warfarin): major benefit in venous thromboembolism, the standard treatment unless bleeding risk is high (80-90% effective); in arterial thrombosis, may be considered if antiplatelet agents do not control recurrent arterial thromboses.
- Fibrinolytic agents: in venous thromboembolism, used only for massive pulmonary embolism; in arterial thrombosis, often effective if the thrombosis is fresh (coronary thrombosis <12 hours, or cerebral thrombosis <4.5 hours).
Other clots
- Heparin-induced thrombocytopenia (HIT).
- Microthrombi in capillaries (e.g. in DIC, COVID-19): generalised activation of the coagulation system, with platelet consumption.
- Mural thrombosis.
Heparin-induced thrombocytopenia (HIT)
- Immune-mediated, causing progressive thrombocytopenia.
- Affects ~1% of patients after 5-7 days of IV UFH therapy.
- Mechanism: an antibody binds to heparin bound to platelet factor 4 (PF4) on platelets, and the antibody then activates the platelets, driving antibody-mediated platelet aggregation.
- Platelet counts should be monitored in patients receiving heparin for more than 4-5 days.
Mural thrombosis
- A mural thrombus is an outcome of myocardial infarction: thrombus adherent to the endocardial wall lining part of the ventricular cavity.
- The endocardium (endothelium lining the heart chamber) is injured by products released from the underlying ischaemic and necrotic muscle.
Self-test
- Describe the stasis-to-stroke sequence that occurs in the left atrial appendage during atrial fibrillation.
- Explain why anticoagulants, rather than antiplatelet drugs, are the effective treatment for stroke prevention in atrial fibrillation.
- Compare the stroke risk reduction achieved by DOACs, warfarin and aspirin in atrial fibrillation.
- Distinguish plaque rupture from plaque erosion as causes of arterial thrombosis.
- Describe the progressive stages of plaque-associated thrombus growth from plaque fissure to total occlusion, including the clinical correlate of each stage.
- Describe, in order, the steps by which platelets form an arterial thrombus under flow, naming the receptor involved at each step.
- List the main risk factors for arterial thrombosis grouped as atherosclerosis-related versus other acquired factors.
- Why does infarction occur after arterial thrombosis in some tissues but not others?
- A patient has a coronary thrombosis 6 hours after symptom onset. Describe the drugs used in the immediate management sequence and the mechanism of each.
- Describe the mechanism of action of unfractionated heparin and how its anticoagulant effect is monitored, including a worked example of a target APTT.
- Distinguish unfractionated heparin from low molecular weight heparin in terms of route, monitoring and bleeding risk.
- Distinguish the effectiveness of antiplatelet agents, anticoagulants and fibrinolytic agents in venous thromboembolism versus arterial thrombosis.
- Describe the mechanism by which heparin-induced thrombocytopenia develops and how it is detected clinically.
- Explain how a mural thrombus forms after myocardial infarction.
Answers
Reveal answers
- The atrial appendage fails to contract and empty properly during AF, causing stasis of blood within it; this leads to thrombus formation, which can embolise, causing stroke (stasis → thrombus → embolus → stroke).
- Because the atrial appendage clot forms through blood stasis rather than platelet-driven arterial injury (the same mechanism as DVT), and in the setting of stasis anticoagulants are effective while antiplatelet drugs are not.
- DOACs reduce stroke risk by about 70%, warfarin by about 64%, and aspirin by only about 22%; DOACs are also safer than warfarin.
- Plaque rupture is a bleed into the plaque (plaque fissure) that breaches into the vessel lumen, releasing necrotic core content and triggering thrombus formation at the rupture site. Plaque erosion is thrombus forming on a denuded but structurally intact endothelial surface overlying the plaque, without a breach into the necrotic core.
- (1) Plaque fissure, with platelet adhesion and fibrin forming over the necrotic core; (2) increasing stenosis from platelet debris and fibrin reaching a subtotal 70-90% stenosis, which causes unstable angina; (3) layering of older thrombi leading to total occlusion, which causes acute myocardial infarction.
- Translocation: platelets roll via GPIbV-IX binding vWF. Adhesion: platelets adhere via α2β1, α5β1 and GPVI binding collagen. Aggregation: platelets cross-link via αIIbβ3 binding fibrinogen. This produces a dense platelet mass with fibrin (thrombus formation).
- Atherosclerosis-related: hyperlipidaemia, hypertension, diabetes, cigarette smoking, male sex, family history (plus polycythaemia and elevated fibrinogen). Other acquired factors: raised coagulation factor levels, diabetes (increased platelet aggregation), inflammation/acute phase response, oestrogens (pregnancy moderate risk, oral contraceptives weak risk), and uncommon antibody-mediated platelet activation (antiphospholipid syndrome, HIT).
- Ischaemia and infarction occur only where no collateral (alternative arterial) circulation exists to compensate for the occluded vessel; where collateral circulation is present, infarction can be avoided.
- Aspirin immediately, a second antiplatelet agent (clopidogrel or ticagrelor) for additional platelet inhibition, an anticoagulant (heparin), and since the thrombosis is under 12 hours old, a fibrinolytic (e.g. alteplase) to dissolve the clot, or alternatively percutaneous coronary intervention (e.g. stenting).
- UFH binds antithrombin and increases its anticoagulant activity by more than 300-fold, so that antithrombin neutralises thrombin (FIIa), FXa, FIXa and FXIa; the effect is immediate. It is monitored with the APTT, aiming to increase it to about twice the reference range, e.g. if the reference range is 22-32s, the target APTT is 44-64s.
- UFH is given intravenously, has an immediate effect with a short half-life (~50-60 minutes), and requires APTT monitoring. LMWH is given subcutaneously (or IV), does not normally require lab monitoring, is used more frequently than UFH, and carries slightly less bleeding risk; bleeding remains the main risk of all heparins.
- Antiplatelet agents give minimal benefit in venous thromboembolism (30-40% effective) but major, easy-to-use benefit in arterial thrombosis. Anticoagulants (dabigatran, rivaroxaban, warfarin) give major benefit in venous thromboembolism and are standard treatment unless bleeding risk is high (80-90% effective), but in arterial thrombosis are only considered if antiplatelets fail to control recurrence. Fibrinolytics are used in venous thromboembolism only for massive pulmonary embolism, but are often effective in fresh arterial thrombosis (coronary <12h, cerebral <4.5h).
- An antibody binds to heparin complexed with platelet factor 4 (PF4) on the platelet surface, and this antibody then activates the platelets, causing antibody-mediated platelet aggregation and progressive thrombocytopenia; it affects about 1% of patients after 5-7 days of IV UFH therapy, so platelet counts should be monitored in patients on heparin for more than 4-5 days.
- After myocardial infarction, the endocardium overlying the infarcted area is injured by products released from the underlying ischaemic and necrotic muscle, and thrombus then forms adherent to this injured endocardial wall lining the ventricular cavity.