Syed (Clotting mechanisms - thrombolytic agents) Flashcards
Homeostasis
The process that stops bleeding in a blood vessel. Normal homeostasis involves a complex process of extrinsic and intrinsic factors.
It is the cessation of blood loss from a damaged vessel.
Platelets first adhere to macromolecules in the sub-endothelial regions of the injured blood vessel. They then aggregate to form the primary haemostatic plug.
Platelets stimulate local activation of plasma coagulation factors leading to the generation of a fibrin clot that reinforces the platelet aggregate.
Later, as wound healing occurs, the platelet aggregate and fibrin clot are degraded.
Intrinsic and extrinsic pathway
In intrinsic pathway all factors are present within the circulating blood.
In extrinsic pathway the factors are not found in the circulating blood but on the outside of the blood vessel.
Both pathways result in activation of factor 10 leading into common pathway.
Thrombosis
The formation of a clot.
May form in any vessel, artery or vein when blood flow is impeded.
May begin small, but fibrin, platelets, and RBCs attach to the thrombus, increasing its size and shape.
When intravascular thrombi do occur, a system of fibrinolysis is activated to restore fluidity. Normally a delicate balance prevents both thrombosis and haemorrhage allowing physiological fibrinolysis without pathological fibrinogenolysis.
Caused by
- abnormality in blood flow
- abnormality in surface in contact with blood
- abnormality of clotting components
Thrombolytic drugs dissolve fibrin clot. Safety of these drugs increases when drug is more fibrin specific
Selection of therapeutic agents for thromboembolism
UFH, LMWH, Warfarin, and other NOACs are used in the treatment and prevention of both arterial and venous thrombi.
Platelet aggregation inhibitors (e.g. aspirin, clopidogrel) are used alone or in combination with anticoagulants for the prevention of arterial thrombi.
Fibrinolytic agents are used in the rapid dissolution of thromboembolism (notably during MI)
Fibrinolytic system
The fibrinolytic system is involved in restricting clot propagation in the blood and in the removal of fibrin as wounds heal.
Treatment of patients with fibrinolytic drugs that activate the fibrinolytic system is not a substitute for the anticoagulant drugs.
Plasminogen converts to plasmin by tissue plasminogen activator (t-PA). The endothelium also releases a plasminogen activator inhibitor which complexes with and inactivated t-PA in the plasma.
Activation of the fibrinolytic system with thrombolytic drugs can disturb the balance of these regulatory mechanisms and elevate circulating plasmin activity.
Plasmin has low substrate specificity and degrades fibrinogen, plasminogen, and coagulation factors.
The systemic un-physiological activation of the fibrinolytic system with thrombolytic drugs causes consumption of the coagulation factors, a lytic state, and bleeding.
Thrombolytic drugs
Thrombolytic drugs cause lysis of formed clots in both arteries and veins and reestablish tissue perfusion. they are plasminogen activators.
The older (first gen) agents are not clot selective (huge risk of bleeding) whereas newer (third gen) agents have more improved fibrin specificity.
An ideal fibrinolytic is one which can provide clot-selective effects. (We don’t currently have this but there are meds close to this).
Actions and clinical use
They are indicated for the management of life threatening conditions (severe pulmonary embolism, DVT, arterial thromboembolism) and are an especially important therapy after MI and acute ischaemic stroke. (Don’t need thrombolytic therapy as the risk factors present means first choice would be fibrinolytic therapies- dissolve clot first then add anti clotting medication).
Thrombolysis must be accomplished quickly after myocardial or cerebral infarction, since clots become more difficult to lyse as they age. (If you try to dissolve clot through these drugs the body will work against it and form new clots at a much higher rate. Must be given an anticoagulant within 12-24 hours).
The incidence of re-thrombosis and re-infarction is greater when thrombolytic drugs with shorter plasma half lives are used.
First generation
First generation drugs are thrombolytic as they are not fibrinospecific.
Streptokinase is an indirectly acting plasminogen activator derived from beta-haemolytic streptococci. Systemic administration results in significant lysis of thrombus.
Early sage appeared to be greater in terms go benefits.
Side effects include haemorrhage, pyrexial, anaphylactic reaction (allergy as it is from a natural source).
Urokinase can activate both circulating and fibrinogen bound plasminogen. It is derived from human cell hence it is not antigenic (has no ability to produce an immune response).
Second and third generations
The principal physiological activator of plasminogen in the blood, tissue-type plasminogen activator (t-PA), has a high binding affinity for fibrin and produces a fibrin selective activation of plasminogen (after IV administration).
Alteplase is more effacions than streptokinase in establishing coronary reperfusion.
The rate of re-thrombosis after t-PA is greater than after streptokinase because alteplase is rapidly cleared from the blood (short half-life).
Different medications differ in pharmacokinetic and fibrinospecificity.
Adverse effects
Risk of bleeding due to fibrinogenolysis or fibrinolysis at the site of vascular injury.
Hypo-fibrinogenemia may occur and should be monitored with laboratory tests.
Life-threatening intercranial bleeding may be necessitate stoppage of therapy, administration of whole blood, platelets or fresh frozen plasma and an anti-fibrinolytic.
Contraindications
Similar to those for anticoagulant drugs.
Absolute contraindications (life-threatening, do not use medication) include active bleeding, cardiopulmonary resuscitation, intercranial trauma, vascular trauma, and cancer.
Relative contraindications (could use medication but not ideal) include uncontrolled hypertension, earlier central nervous system surgery, and any known bleeding risk.
Relative contraindications can become absolute but absolute cannot become relative.
