Platelets and Thrombolytics Flashcards
Platelets (thrombocytes)
Platelets have no cell nucleus: they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow, and then enter the circulation. 10 day life cycle. Due to their small size, they get pushed to the sides of vessels and are often the first on scene.
They have glycoprotein receptors on their membranes that are important for binding to collagen, fibrinogen, and Von Willibrand Factor. GPIIb/IIIa,
What do intact endothelial cells do prevent platelet activation?
- Secret prostacyclin (PGI2)
- Secret nitric oxide (NO)
- Expression of heparin sulfate
- Expression of thrombomodulin
- Expression of Tissue Factor Pathway inhibitor (TFPI), which inhibits TF/VIIa/Xa
Prostacyclin (PGI2)
Inhibits platelet activation and aggregation. It is within the arachidonic acid family and COX inhibition reduces its synthesis.
Secret nitric oxide (NO)
Vasodilates and inhibits platelet activation. .
Plasminogen (PLG) and Plasmin
Plasminogen is an inactive plasma protein secreted by intact endothelial cells. Plasminogen binds to booth fibrin and fibrinogen and becomes incorporated into clots as they form.
Platelet activation
Triggers:
- exposed collagen
- ADP secreted from activated platelets
- Thromboxane, diffuses out from activated platelets.
- Thrombin, formed by activation of coagulation cascade.
Steps:
- Exposed collagen binds to platelet GP receptors. Binding activates the platelets, which begin secreting fibrinogen, Factor V, ADP, Thromboxane, which induce aggregation and recruit more platelets.
- Other GP receptors (GPIIb,IIIa) function as bridges, linking neighboring platelets together, with fibrinogens in-between.
- More recruited platelets continue to aggregate, forming platelet plug.
- Platelet activation triggers the extrinsic cascade which essentially is the fibrous weaving of fibrin around the aggregated platelets.
Fibrinolysis (thrombolysis)
The process by which clots are degraded.
Plasminogen, a circulating proenzyme is activated by tissue-type plasminogen (t-PA) activator secreted from endothelial cells. Plasmin cleaves fibrin within the clot, breaking it into fibrin degradation products (one of which is the D-Dimer).
How do healthy endothelial cells regulate platelet aggregation?
Healthy endothelial cell release Nitric Oxide (a vasodilator) and Prostacyclin (PGI2, another prostaglandin) which inhibit platelet aggregation outside of injury. They have short half lives so that they cannot travel far.
t-PA
Tissue plasminogen activator is released by healthy endothelial cells. Goes on to activate plasminogen that is bound within clots, inducing fibrinolysis.
Inhibited by Plasminogen Activator Inhibitor (PAI-1) and alpha2 Anti-plasmin.
D-Dimer assay
D-Dimer is a clot degradation fragment that can be measured in the plasma after fibrinolysis. A positive D-dimer test indicates recent fibrinolytic activity. However, this can be the result of a injury and does not indicate thrombosis. A negative result, though, is useful in ruling out a throtmbolism as a diagnosis.
tPA as medication
tPA can be giving intravenously to patients who experienced Deep vein thrombosis, PE, MI, or ischemic stroke. Half life can be tweaked to last longer.
It is often given with heparin.
tPA inhibitors
Plasminogen activator inhibitor (PAI)
alpha2 anti-plasmin.
Streptokinase
Streptokinase is a medications that mimics tPA and is used for fibrinolysis. It is administered intravenously after a heart attack to dissolve clots. It is used for treatment of DVT, PE, MI, ischemic stroke. It is not available in the North America.
It is only used after the first heart attack, as the body will build antibodies against it.
Atherosclerosis
Atherosclerosis is when an artery-wall thickens as a result of invasion and accumulation of white blood cells creating a fibrofatty plaque. When an artery is narrowed, platelet aggregation is more likely. Can cause angina, MI, stroke, or peripheral arterial disease.
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure. When an artery is narrowed, platelet aggregation is more likely.
