Coronary Artery Thrombosis

Coronary artery thrombosis is thrombus that partly or fully obstructs an epicardial coronary artery. It is the immediate cause of most acute coronary syndromes and of acute stent failure.

Atherothrombosis is the commonest mechanism. Plaque rupture accounts for about 55 to 65% of fatal coronary thrombi and plaque erosion for about 30 to 35%. A calcified nodule makes up the rest. Erosion is more frequent in women, younger patients and smokers.

Stent thrombosis occurs in about 0.5 to 1% of patients in the first year after PCI with current drug eluting stents. It is classed as acute (under 24 hours), subacute (24 hours to 30 days), late (30 days to 1 year) or very late (over 1 year).

Thrombosis in an angiographically normal or minimally diseased artery arises in prothrombotic states: antiphospholipid syndrome, essential thrombocythaemia, polycythaemia vera, paroxysmal nocturnal haemoglobinuria, heparin induced thrombocytopenia and nephrotic syndrome.

Other settings are malignancy, inflammatory bowel disease, severe infection (including COVID-19), cocaine use, vasculitis, coronary aneurysm and spontaneous coronary artery dissection.

Pathophysiology. Rupture exposes tissue factor and collagen and produces a platelet rich thrombus. Erosion produces thrombus on denuded endothelium over a proteoglycan rich plaque. Stasis adds fibrin and red cells, and the thrombus propagates.

Distal embolisation of thrombus and plaque material obstructs the microcirculation and causes no reflow, so epicardial patency does not always restore myocardial perfusion.

• Chest pressure or pain for over 20 minutes, radiating to the arm, jaw or back, with sweating, nausea and dyspnoea. Presentation is often atypical in women, older adults and diabetes.
• ECG: ST elevation, ST depression, T wave change, or a normal early tracing.
• Complications: heart failure, cardiogenic shock, ventricular arrhythmia, atrioventricular block, and mechanical complications (papillary muscle rupture, septal rupture, free wall rupture) at 2 to 7 days.
• Stent thrombosis usually presents abruptly as a large ST elevation infarct, after stopping antiplatelet therapy in many cases.
• Features of a prothrombotic cause: previous venous or arterial thrombosis, pregnancy losses and livedo (antiphospholipid syndrome), plethora or erythromelalgia (myeloproliferative disease), haemolysis (paroxysmal nocturnal haemoglobinuria), oedema with proteinuria, cocaine use.

Red flags.

• Cardiogenic shock, ventricular arrhythmia or high grade block
• Stent thrombosis or recent interruption of antiplatelet therapy
• Thrombosis in a young patient with few risk factors, or with thrombosis in other vascular beds
• Falling platelet count 5 to 10 days after starting heparin
• New murmur or pericardial effusion

• ECG within 10 minutes of first contact, repeated every 15 to 30 minutes while non-diagnostic, with posterior and right sided leads when indicated.
• High sensitivity troponin at presentation and at 1 to 3 hours. Reperfusion for ST elevation is never delayed for the result.
• Echocardiography. Regional wall motion, ejection fraction, mechanical complications, ventricular thrombus.
• Coronary angiography. Thrombus grade (0 none to 5 total thrombotic occlusion; 4 or more is a large burden) and antegrade flow grade (0 no flow to 3 normal flow). Optical coherence tomography shows rupture, erosion or calcified nodule, and in stent thrombosis shows underexpansion, malapposition, edge dissection or uncovered struts.
• Cause workup when no atherosclerotic cause is evident, in young patients and in recurrent events: full blood count with film, JAK2 testing, lupus anticoagulant, anticardiolipin and anti-beta-2 glycoprotein I antibodies (repeated at 12 weeks to confirm persistence), platelet count trend with a heparin induced thrombocytopenia assay after heparin exposure, flow cytometry for paroxysmal nocturnal haemoglobinuria, urine protein, homocysteine, urine toxicology, HIV, CRP and ANCA. Protein C, protein S and antithrombin are not measured during acute thrombosis or on warfarin or heparin.
• Lipids, HbA1c, creatinine.

Differential diagnosis.

• Coronary vasospasm
• Spontaneous coronary artery dissection
• Coronary embolism
• Takotsubo syndrome
• Myocarditis and pericarditis
• Aortic dissection involving a coronary ostium
• Pulmonary embolism
• Type 2 myocardial infarction
• ST elevation mimics (early repolarisation, left bundle branch block, hyperkalaemia, Brugada pattern, ventricular aneurysm)

ST elevation: immediate reperfusion. Emergency.

• Aspirin 300 mg orally chewed once, then 75 to 100 mg once daily.
• P2Y12 inhibitor loading:
  • Ticagrelor 180 mg orally once, then 90 mg twice daily. Contraindicated with previous intracranial haemorrhage, active bleeding and severe liver impairment, and with strong CYP3A4 inhibitors or inducers (ritonavir, cobicistat, ketoconazole, rifampicin). Dyspnoea and bradyarrhythmia are common. Keep the aspirin dose at 100 mg daily or less.
  • Prasugrel 60 mg orally once, then 10 mg once daily (5 mg daily at under 60 kg). Avoid at age 75 years or over where possible. Contraindicated with previous stroke or transient ischaemic attack.
  • Clopidogrel 600 mg orally once, then 75 mg once daily, when the others are unavailable or contraindicated. With fibrinolysis use 300 mg (75 mg at age 75 years or over), then 75 mg daily. Avoid omeprazole and esomeprazole, and use pantoprazole 40 mg once daily for gastric protection.
• Primary PCI when it can be done within 120 minutes of diagnosis, by radial access. Give unfractionated heparin 70 to 100 units/kg intravenously (activated clotting time 250 to 350 seconds, 200 to 250 seconds with a glycoprotein IIb/IIIa inhibitor), or enoxaparin 0.5 mg/kg intravenously. Routine thrombus aspiration is not used because of stroke risk. For a large thrombus burden or no reflow, give tirofiban 25 microgram/kg intravenously over 3 minutes, then 0.15 microgram/kg/min for up to 18 hours (halve the infusion at creatinine clearance 60 mL/min or less), checking platelets at 2 to 6 hours and daily. Deferred stenting is an option with a large thrombus burden. For no reflow: intracoronary adenosine 100 to 200 microgram boluses (total up to 1 mg), or sodium nitroprusside 50 to 200 microgram boluses, with blood pressure and rhythm monitoring. Avoid adenosine in high grade block.
• Fibrinolysis when PCI cannot be done within 120 minutes, started within 10 minutes of diagnosis and within 12 hours of symptom onset, followed by angiography at 2 to 24 hours. Rescue PCI for failed lysis (under 50% ST resolution at 60 to 90 minutes), shock or ongoing pain.
  • Tenecteplase single intravenous bolus over 5 to 10 seconds by weight: under 60 kg 30 mg; 60 to under 70 kg 35 mg; 70 to under 80 kg 40 mg; 80 to under 90 kg 45 mg; 90 kg or over 50 mg. Give half the dose at age 75 years or over.
  • Alteplase 15 mg intravenous bolus, then 0.75 mg/kg over 30 minutes (maximum 50 mg), then 0.5 mg/kg over 60 minutes (maximum 35 mg). Maximum total 100 mg.
  • Streptokinase 1.5 million units intravenously over 30 to 60 minutes where fibrin specific agents are unavailable. Avoid if given in the previous 12 months or after a recent streptococcal infection. Monitor for hypotension.
  • Anticoagulant: enoxaparin 30 mg intravenous bolus then 1 mg/kg subcutaneously 15 minutes later and every 12 hours (maximum 100 mg for each of the first two doses) at age under 75 years; at age 75 years or over no bolus and 0.75 mg/kg every 12 hours (maximum 75 mg for each of the first two doses); 1 mg/kg once daily at creatinine clearance under 30 mL/min. Continue until revascularisation or discharge, up to 8 days. Alternatively unfractionated heparin 60 units/kg intravenous bolus (maximum 4,000 units), then 12 units/kg/h (maximum 1,000 units/h) for 24 to 48 hours, aPTT 1.5 to 2.0 times control.
  • Contraindications: previous intracranial haemorrhage, ischaemic stroke within 3 months, intracranial neoplasm or vascular lesion, active bleeding, suspected aortic dissection, significant head or facial trauma within 3 months, recent intracranial or spinal surgery. Relative: blood pressure over 180/110 mm Hg, anticoagulant use, major surgery within 3 weeks, pregnancy, prolonged CPR.
• Glyceryl trinitrate 400 microgram sublingually every 5 minutes up to 3 doses, or 10 to 20 microgram/min intravenously, increased by 5 to 10 microgram/min every 5 to 10 minutes, usual maximum 200 microgram/min, for ongoing pain, hypertension or heart failure. Contraindicated with systolic pressure under 90 mm Hg, right ventricular infarction and phosphodiesterase type 5 inhibitors.
• Morphine 2.5 to 5 mg intravenously, titrated, only for severe pain. It delays absorption of oral antiplatelet drugs. Give an antiemetic. Oxygen only when saturation is under 90%.
• Cardiogenic shock: culprit vessel PCI at once, noradrenaline 0.05 microgram/kg/min intravenously titrated to a mean pressure of 65 mm Hg (usual maximum 0.5 microgram/kg/min), and mechanical support chosen by the heart team.

Stent thrombosis. Emergency PCI with intravascular imaging to find the mechanism. Correct underexpansion, malapposition or edge dissection with post-dilatation, an additional stent or a drug coated balloon. Check adherence, switch clopidogrel to ticagrelor or prasugrel, and prolong dual antiplatelet therapy.

Non-atherosclerotic thrombosis. Treat the cause with haematology.

• Antiphospholipid syndrome: warfarin to an INR of 2.0 to 3.0 (a target of 3.0 to 4.0, or added low dose aspirin, is used in some practice for recurrent arterial events, with limited evidence). Avoid direct oral anticoagulants, particularly in triple positive disease.
• Myeloproliferative neoplasm: aspirin 75 to 100 mg daily, with cytoreduction and venesection (haematocrit under 45% in polycythaemia vera) directed by haematology.
• Heparin induced thrombocytopenia: stop all heparin including flushes and coated lines, and use a non-heparin anticoagulant under haematology. Avoid platelet transfusion.
• Cocaine: diazepam 5 to 10 mg intravenously or lorazepam 1 to 2 mg intravenously, aspirin and glyceryl trinitrate. Avoid beta blockers in acute intoxication.

Secondary prevention.

• Aspirin 75 to 100 mg once daily with ticagrelor 90 mg twice daily, prasugrel 10 mg once daily or clopidogrel 75 mg once daily for 12 months, then single antiplatelet therapy long term. Shorten to 1 to 6 months, then P2Y12 monotherapy, with high bleeding risk.
• Atorvastatin 40 to 80 mg once daily (liver enzymes at baseline and 3 months; LDL cholesterol under 1.4 mmol/L and a fall of at least 50%). Ramipril 2.5 mg orally once daily, increased every 2 to 4 weeks to 10 mg once daily (maximum 10 mg daily, 5 mg daily at creatinine clearance under 30 mL/min; potassium and creatinine 1 to 2 weeks after each change; contraindicated in pregnancy and bilateral renal artery stenosis).
• Bisoprolol 2.5 mg orally once daily, increased to 5 to 10 mg once daily, maximum 20 mg daily (do not exceed 10 mg daily at creatinine clearance under 20 mL/min or in severe liver impairment). Contraindicated in cardiogenic shock, high grade atrioventricular block without a pacemaker and severe asthma.
• Ejection fraction 40% or less with heart failure or diabetes: eplerenone 25 mg orally once daily, increased to 50 mg once daily within 4 weeks, with potassium and creatinine at 1 week and 4 weeks. Do not start at potassium over 5.0 mmol/L. Contraindicated with strong CYP3A4 inhibitors.
• Cardiac rehabilitation, smoking cessation, blood pressure and glucose control.

Special groups.

• Pregnancy: primary PCI is preferred and fibrinolysis is reserved for when PCI is unavailable. Use low dose aspirin and clopidogrel, avoid ticagrelor, prasugrel, statins and ACE inhibitors, and look for spontaneous coronary artery dissection.
• Kidney impairment: give enoxaparin 1 mg/kg subcutaneously once daily at creatinine clearance under 30 mL/min and limit contrast volume.
• Region: where PCI is not accessible, early fibrinolysis followed by transfer is the usual route. In patients on ritonavir or cobicistat, ticagrelor is contraindicated, so use prasugrel.

Monitoring. Telemetry for 24 to 48 hours. Echocardiography before discharge and at 6 weeks to 3 months, with an implantable defibrillator considered when ejection fraction stays 35% or less after at least 40 days post infarct and 3 months of therapy. Platelet count daily on glycoprotein IIb/IIIa inhibitors. Potassium and creatinine 1 to 2 weeks after each change of ramipril and at 1 week and 4 weeks after starting eplerenone. Lipids at 4 to 6 weeks. Repeat antiphospholipid testing at 12 weeks.

Referral and escalation. Refer to cardiology, and to haematology for non-atherosclerotic thrombosis. Urgent for shock, stent thrombosis, failed lysis or mechanical complications.