Lecture 10 - Thrombosis 1 Flashcards
What is thrombosis? And what is found within a thrombus
Its the formation of a solid mass (thrombus) in a blood vessel or heart
It’s a pathological process that’s closely linked to haemostasis, as it’s just a pathological extension of normal processes
Thombi contain variable amounts of
- Platelets
- Fibrin
- Trapped red cells
What are the three key factors for thrombosis to occur?
(Virchow’s triad)
Abnormal blood flow: If the blood flow is too turbulent e.g. if going around a corner too fast, this produces too much shearing stress/turbulence. It’s the high shearing stress which activates the platelets and vWF. Or it’s due to the blood being too static, as this permits the accumulation of activated coagulation factors and activated platelets (stasis is more of a problem in veins than arteries).
There is also a loss of axial flow, which means that the centre is no longer a red cell rich zone and the peripheries are not a plasma rich zone. Loss of axial flow means that vWF can attach to endothelium, contributing to thrombi development.
Endothelial damage: Can contribute due to damage of endotehlium, from things like shearing stress, trauma, atherosclerosis. They can be damaged acutely (trauma), or chronically (athersclerosis). The endothelial damage exposes vWF (provides surface for platelet activation), collagen and tissue factor, and this permits platelet adhesion.
Hypercoagulability: Can contribute by raised levels of blood clotting fators and/or reduced levels of anti-clotting proteins (coagulation inhibitors). This results in bigger thrombin bursts, increasing that persons risk. Can also be caused by some antibodies.
THOMBOSIS FORMATION IS MULTIFACTORIAL
What can endocardial injury cause?
MI - an important initiating factor for thrombus development leading to MI is endothelium damge.
Damage to the endothelium of heart valves can also produce thrombi.
What are some common causes of arterial injury (which can lead to thombi formation)
Ulcerated or ruptured athersclerotic plaque
- Smoking, bacterial endotoxins, hypercholesterolaemia, raid homocysteine
- Hypertension, turbulent blood flow
Endothelium in blood vessels can also be damaged by vasculitis (inflammation of blood vessel), or through trauma (vascular cannula, irritant drug infusion, direct trauma
What happens to the endothelium in an MI?
And what is necrotic tissue in MI replaced with?
It survives since it is in contact with the blood, but it’s injured from hte products from ischaemic and necrotic underlying muscle.
Necrotic heart tissue is replaced by fibrotic tissue (seen as pale areas)
Also, in MI stasis of blood occurs between the inactive (infarcted) trabecule, which can cause emoblisms due to thrombi formaion
When laminar flow is lost in abnormal blood flow, how does this increase the risk of thrombi formation?
Turbulence causes endothelial injury and activation of adhesion receptors (Gplla, Gpllb). This causes platelet activation, and leads to thrombi formation.
Also, when vWF is exposed to shearing stress (when endothelium is damaged it exposed vWF beneath) it forms long strings to bind platelets, allowing for more platelet activation (the string formation is irreversible)
Where is there an increased risk for thrombi formation?
At sites of turbulence (e.g. in arota and branches)
In the aorta atherosclerosis can become so severe it starts to buldge out and there isn’t much elastin to hold it in place. In this aneurysm sac you get blood stasis, and thombus formation, this grows inside it. As it grows it buldges further out. (doesn’t occlude vessel since blood flow is too fast). The thrombus buids up as a layering of platelets, fibrin and red cells.
Corneres where blood has to turn also have more atherosclerotic plaques
What problems can occur from stasis due to altered blood flow?
In stasis endothelial cell activation is promoted, since there is more contact betweent the platelets and vessel wall.
Stasis can occur wherever there’s pressure on veins, e.g. on calf or buttock during surgery - so during and after surgery we give anti-clotting agents to help prevent thrombi formation. Or it can occur due to surgery, trauma in the veins in the lower limb.
There is an increased risk of thrombi formation in surgery since when tissues are handled coagulation factors may become activated (not inactivated if conc. rises rapidly), and then move further down the circulation. If they move through an area of stasis that can cause thrombosis.
Stasis of blood flow can also cause aneurysms (when thrombi form in the sacs)
Describe how venous thrombosis develops
Thrombosis is a dynamic process over time
At the start of thrombosis theres a few RBCs trapped, but mostly platelets and fibrin - it slowly builds up. Obstructed flow and stasis can cause it to extend more rapidly.
Blood flows past the developing thombus, this causes platelets and fibrin to be activated and allows them to stick to and adhere the thrombus. The clot may not propagate much, since it’s not well adherent to the vessel wall, part of it will break off. This is because the parts further away from the wall are not held on as strongly, and may break away to form a thrombotic embolus
What defines hypercoagulability?
How is it caused?
Hypercoagulability is any alteration of coagulation pathways that predisposes to thrombosis.
- It can be increased concentration of coagulation proteins
- OR
- Decreased concentration of coagulation inhibitors
It’s often multifactorial (Genetic or acquired)
Is it arterial or venous in which endothelial injury plays a larger role in thrombi formation?
Arterial
How does altered blood flow form thrombi in arteries and veins?
Turbulence in arteries, stasis in veins
Where are thrombi most likely to cause ischaemia and infarcation?
In the arterial supply in places where no collateral circulation exists.
E.g. the brain, heart
What is the most common cause of arterial thrombosis which leads to infarction?
Usual predisposing factor is rupture of an atherosclerotic plaque, this triggers platelet aggregation, fibrin formation and then extension of the thrombis occlude the vessel.
The fibrous tissue can tear on a pulse walve , and allow blood to leak into the plaque leading to clot formation. This leads to thrombus formation back out into the lumen.
When mural thombi form, the embolisation of platelet thrombi can occur, which increases the risk for small strokes or transient ischaemic events (the person recovers fully but loses a small area of brain).
What are the acute and chronic concequences of venous thrombosis?
Acute
- Local pain and oedema (pain due to swelling of blood vessels)
- The organisation of the thrombus occurs over months, with granulation tissue growing into it and eventually replacing it
- this often results in loss of valves in veins
- Pulmonary embolism
Chronic
- Post-phlebitic syndrome can occur (period of chronic pain and swelling) - legs keep swelling over time since the venous aren’t draining properly
- Varicose veins
- Chronic ulcers at ankles after minimal trauma (they aren’t getting adequate arterial supply since the venous pressure is too high)
- Pain in leg
- Oedema
- *
What can cause recurrent thrombosis?
- Acquired prothrombotic conditions present
- Abnormal venous blood flow: loss of valves in veins
- Trauma or inflammation near vein
- Antiphospholipid syndome
- Autoantibody reacting with phospholipids on partially activated platelets, it triggers then to have complete activation. This can activate too many platelets, leading to increased risk of venous thrombi.
What is thrombophilia?
It’s just an increased risk for thrombosis
- May be acquired or genetic
- Arterila or venous
- Multifactorial
What are some common thrombophilia risk factors for arterial thrombosis?
- Hyperlipidaemia
- Hypertension
- Diabetes
- Cigarette smoking
- Male
- Family history
- Polycythaemia (raised Hb)
- Elevated fibrinogen
- Homocysteine
What are some causes of acquired thrombophilias?
- Raised coagulation or reduced inhibitors (oestrogens, pregnancy, contraceptives, diabetes, inflammation)
- Antibodies
- antiphospholipid syndrome
- heparin induced thrombocytopenia
- Rasied homocysteine - produced too much when Vit B6 or folic acid intake too low
- Loss of antithrombin in urine - risking nephrotic syndrome
How does inflammation cause acquired thrombophilia?
In inflammation there is reduced thrombomodulin on endothelial cells - needed to permit activation of protein C by thrombin.
so inflammed endothelium find it harder to turn off clotting pretty much.
And inflammed endothelium also cause acquired thrombophilia because there are elevated clotting factors in the blood during the acute phase response
What is antiphospholipid syndrome?
Autoantibodies that bind to phospholipids on partially activated platelets.
The platelets are first activated by: turbulent blood flow, small amounts of thrombin etc. making the platelet phospholipid exposed. So autoantibodies enhance platelet activation, which results in thombeses and thrombocytopenia.
These can cause
- Venous and, or arterial thrombosis
- Recurrent second trimester miscarriage
- placental thrombosis
- Thrombocytopenia
- Some autoimmune disorders (SLE)
Who two test features can be used in the diagnosis of antiphospholipid syndrome
- APTT prolonged
- Immunological test
What is heparin-induced thrombocytopenia?
It’s severe thrombocytopenia, caused by the formation of an immune complex made of antibody + heparin + PF4. This complex activates platelets, neutrophils and macrophages through Fc receptors.
PF4 is found in platelet alpha granules, and has an anti-heparin effect and is released when platelets are activated or partially activated
How does unfractionated heparin work?
It’s present in mast cells, and when in the blood it binds to and increases the activity of antithrombin (x300), having immediate anti-coagulant effects.
Anit-thrombin neutralises Flla, FXa, FlXa and FXla , so essentially inhibiting the whole pathway
We monitor the heparins effect with APTT e.g. if reference range is 22-32 sec, we aim for 44-64sec
