A thrombus is defined as a solid mass formed in the circulation from the constituents of the blood during life. Fragments of thrombi (emboli) may break off and block vessels downstream. Thromboembolic disease is much more common than abnormal bleeding; nearly half of adult deaths in England and Wales are due to coronary artery thrombosis, cerebral artery thrombosis or pulmonary embolism.
A thrombus results from a complex series of events involving coagulation factors, platelets, red blood cells and the vessel wall.
This usually occurs in association with atheroma, which tends to form at areas of turbulent blood flow such as the bifurcation of arteries. Platelets adhere to the damaged vascular endothelium and aggregate in response to ADP and TXA2 to form a ‘white thrombus’. The growth of the platelet thrombus is limited at its margins by PGIz. Eventually blood coagulation may be activated at the site of the thrombus, resulting either in complete occlusion of the vessel or embolization that produces distal obstruction. The risk factors for arterial thrombosis are related to the development of atherosclerosis.
Arterial thrombi may form in the heart, as mural thrombi in the left ventricle after myocardial infarction, in the left atrium in mitral valve disease or on the surfaces of prosthetic valves.
Unlike arterial thrombosis, venous thrombosis often occurs in normal vessels. Important causes are stasis and hypercoagulability. The majority of venous thrombi occur in the deep veins of the leg, originating around the valves as ‘red thrombi’ consisting mainly of red cells and fibrin. The propagating thrombus is formed of fibrin and platelets and is particularly liable to embolize. Chronic venous obstruction in the deep veins of the leg results in a permanently swollen limb and may lead to ulceration (postphlebitic syndrome). Risk factors for venous thrombosis are shown. Both arterial and venous thrombosis may occur with changes in blood cells such as polycythaemia, thrombocythaemia and sickle cell anaemia. The clinical features and diagnosis of venous thrombosis are discussed.
Thrombophilia is a term describing inherited or acquired defects of haemostasis leading to a predisposition to venous or arterial thrombosis. It should be considered in patients with:
• Recurrent venous thrombosis
• Venous thrombosis for the first time under 40
• A family history of venous thrombosis
• An unusual venous thrombosis such as mesenteric vein thrombosis
• eonatal thrombosis
• Recurrent abortions
• Arterial thrombosis in the absence of arterial disease Laboratory investigation of such patients includes:
• Full blood count including platelet count
• Coagulation screen including a fibrinogen level
• Screen for a coagulation factor inhibitor including a lupus anticoagulant
• Assays for naturally occurring anticoagulants such as AT-III, protein C and protein S
• Tests of the fibrinolytic pathway
Prevention and treatment of arterial thrombosis
Attempts to prevent or reduce arterial thrombosis are mainly directed at minimizing factors predisposing to atherosclerosis. Treatment of established arterial thrombosis includes the use of antiplatelet drugs and thrombolytic therapy.
Platelet activation at the site of vascular damage is crucial to the development of arterial thrombosis, and this can be altered by the following drugs:
ASPIRIN inhibits the enzyme cyclo-oxygenase and this results in reduced platelet production of TXA2•.
DIPYRIDAMOLE, which inhibits platelet phosphodiesterase causing an increase in cyclic AMP with potentiation of the action of PGI2, has been widely used as an anti thrombotic agent but there is little evidence that it is effective.
The indications for and results of antiplatelet therapy are discussed in the appropriate sections.
STREPTOKINASE is a purified fraction of the filtrate obtained from cultures of haemolytic streptococci. It forms a 1:1 complex with plasminogen, resulting in a conformational change in plasminogen, revealing an active site which activates other plasminogen molecules to form plasmin. Streptokinase is given as an infusion of 1 500000 units over 1 hour in acute myocardial infarction.
Laboratory monitoring of such short-term thrombolytic therapy is not necessary.
The main problem with streptokinase is its indiscriminate activation of plasminogen so that both fibrin in clots and free fibrinogen are lysed, leading to low fibrinogen levels and the risk of haemorrhage.
ANISOYLATED PLASMINOGEN STREPTOKINASE ACTIVATOR COMPLEX (APSAC) is a complex of plasminogen and an anisoylated form of streptokinase. The complex binds to any fibrin within intravascular clots where the anisoyl group is hydrolysed and the streptokinaseplasminogen complex produces fibrinolysis. The advantage of APSAC over streptokinase is its more sustained duration of action and it is given as a single bolus dose. UROKINASE is produced naturally by the kidney. It cleaves plasminogen directly to produce plasmin.
TISSUE-TYPE PLASMINOGEN ACTIVATOR (t-PA) and single-chain urokinase-type plasminogen activator (scu- PA) are produced using recombinant gene technology. They were claimed to be relatively ‘clot-specific’, i.e. to have a greater affinity for fibrin-bound plasminogen than circulating plasminogen, and therefore to cause less systemic fibrinolysis and bleeding than streptokinase. However, the use of these newer thrombolytic agents has not yet been shown to produce fewer bleeding episodes than streptokinase. An accelerated dosage schedule of t- PA seems to produce a more rapid restoration of coronary flow.
THROMBOLYTIC THERAPY. The indications for and results of the use of thrombolytic therapy in myocardial infarction are discussed . The combination of aspirin with thrombolytic therapy produces better results than thrombolytic therapy alone.
The main risk of thrombolytic therapy is bleeding and treatment should not be given to patients who have had recent bleeding, uncontrolled hypertension or a stroke, or surgery or other invasive procedures within the previous 10 days.