Block C - stroke

Question 1

what is thrombosis and what does it lead to ?

Answer 1

This is a pathological condition that results in clot formation in a blood vessel. If the clot (thrombus) is large enough it can restrict blood flow leading to ischaemia and could lead to necrosis in this area.`

Question 2

commenest cause of death in pregnancy ?

Answer 2

lood clots in veins are the commonest cause of death in pregnant women (linked to being overweight or obese).

Question 3

stroke ?

Answer 3

A major blood vessel is blocked, for example by a thrombus at a bifurcation of a blood vessel or an emboli more distant that breaks off and travels into more narrow blood vessels such as the brain as shown here and blood carrying oxygen and glucose can not reach the tissue. The brain is particularly vulnerable to emboli as the vessels in the brain are usually narrower.

Question 4

where do DVT occur ?

Answer 4

Occurs in a vein that is situated deep within the body (e.g. femoral vein in leg). Can result in pulmonary embolism which, if left untreated, can be fatal. This is because the thrombus can break off into emboli and travel throughout the body and lodge in areas that are distant from the original thrombus.

Question 5

normal blood physiology hinge on ?

Answer 5

Normal blood physiology hinges on a delicate balance between pro- and anti-coagulant factors.

Question 6

3 key processes for DVT?

Answer 6

Decreased blood flow (venous stasis)

Increased tendency to clot (hypercoagulability)

Changes to the endothelium (lining) of the blood vessel e.g. physical damage or endothelial activation.

Question 7

is venis stasis alone enough to cause thrombis

Answer 7

Venous stasis alone appears to be insufficient to cause thrombus formation. The concurrent presence of venous stasis and vascular injury or hypercoagulability greatly increases the risk for clot formation. As blood flow slows, oxygen tension declines with a coincident increase in hematocrit. The hypercoagulable micro-environment that ensues may downregulate certain antithrombotic proteins that are preferentially expressed on venous valves including thrombomodulin and endothelial protein C receptor. In addition to reducing important anticoagulant proteins, hypoxia drives the expression of certain procoagulants. Among these is P-selectin, an adhesion molecule which attracts immunologic cells containing tissue factor to the endothelium.

Question 8

treatment for DVT ?

Answer 8

DVT is a major preventable cause of global morbidity and mortality. Injectable anticoagulant is essential for example heparin or thrombin inhibitor. The goal is to prevent progression to pulmonary embolism and recurrence of thrombosis. Oral anticoagulant like warfarin (vit K antagonist) or thrombin inhibitor such as dabigatran etexilate or rivaroxaban are given.

It is important to remember that there is a wide variation in response to warfarin and the dose needs to be individualised and effects monitored.

Question 9

critical role of thrombin in clot formation ?

Answer 9

Thrombin is the link between vascular injury, coagulation and platelet activation. Thrombin converts fibrinogen into fibrin, which is a major component of blood clots.

Question 10

what happens if thrombin is inhibited ?

Answer 10

If we inhibit thrombin then this will inhibit the ability for the clot to form as fibrin is blocked

Question 11

heparin ?

Answer 11

Heparin binds to the enzyme inhibitor antithrombin III (ATIII) causing a conformational change that results in its activation. Once activated, ATIII then indirectly inactivates thrombin, factor Xa and other proteases acting as an anticoagulant

Question 12

role of platelets in clot ?

Answer 12

Platelets play an important central role in the formation for a clot by thrombus initiation, ).

Question 13

platelet inhibitor ?

Answer 13

hence antiplatelets are used in secondary stroke prevention (e.g., aspirin, clopidogrel

Question 14

why do ischeamic strokes occur ?

Answer 14

Ischaemic strokes usually occur due to thrombosis (blockage of a small blood vessels) of a major cerebral artery

In ischaemic stroke, a major blood vessel is blocked, for example by a thrombus at a bifurcation of a blood vessel or an emboli more distant that breaks off and travels into more narrow cerebral blood vessels as shown here and blood carrying oxygen and glucose can not reach the tissue. The brain relies heavily on its blood supply for its glucose and tissue that is deprived of oxygen and glucose becomes damaged.

Question 15

haemorrhagic strokes ?

Answer 15

Haemorrhagic strokes (~15% of strokes) are due to rupture of a cerebral artery, bleed in the brain. In haemorrhagic stroke, there are two type intracerebral and subarachnoid

Question 16

whats more sever , hemoraggic or ischemic stroke ?

Answer 16

haemorrhagic strokes are more severe than ischemic strokes.

Question 17

tranient ichaemic attack?

Answer 17

Immediately after a stroke the brain becomes infarcted, loss of blood flow, (in the specific area of damage) and cannot be recovered. The area of the brain immediately adjacent to this (the penumbra) is subject to reduced blood flow and can also become damaged. Rapid treatment is needed. A TIA is a short episode of focal ischaemia without permanent infarction, or damage. This can highlight potential risk of stroke.

Question 18

Risk factors for thrombosis ?

Answer 18

Age

Major surgery

Inactivity

Trauma to area

Pregnancy

Inflammatory disease

Obesity

Question 19

what is key for treatment of stroke

Answer 19

Time window is key.

Question 20

mediators of cellular damage in ischemia /

Answer 20

hese are the four hallmarks of ischaemic damage after stroke:

Glutamate - excitatory neurotransmitter

Calcium - second messenger

Neuroinflammation

Free radicals

When these levels are altered and not in balance this can lead to cellular damage

Question 21

Glutamate ?

Answer 21

Glutamate is involved in intermediary metabolism and is a major Excitatory Neurotransmitter, it is essential for healthy brain function, it is only toxic if levels are elevated such as following stroke (experimental MCA – see below). It has a role in neuronal degeneration associated with ischaemia.

Question 22

microdialysis ?

Answer 22

extracellular glutamate was extracted using a technique called microdialysis and then measured by HPLC

Question 23

glutamate activation ?

Answer 23

Glutamate activates AMPA/KA receptors which allow influx of sodium ions. This results in depolarisation of the cell membrane which results in relief of the magnesium block from the NMDA receptor allowing influx of both sodium and calcium into the cell. This is important for cell excitability and normal neuronal function.

Question 24

how is excess glutamate released in ischaemic stroke ?

Answer 24

During ischaemia or hypoxia, there is an increase in intracellular calcium levels which lead to increased calcium dependent release of glutamate. In addition there is a loss of the sodium gradient which results in a reduction in glutamate uptake by the sodium dependent reuptake. Failure of reuptake results in increased extracellular glutamate resulting in excessive activation of glutamate receptors.

Question 25

glutamate mediated cell death ?

Answer 25

Glutamate mediated cell death results from excessive activation of glutamate receptors. Excessive activation of AMPA and NMDA receptors leads to increased intracellular sodium and calcium. Excess intracellular sodium leads to loss of ionic homeostasis, cell swelling and lysis as well as excessive depolarisation. Elevated intracellular calcium levels lead to cell death by mechanisms described later.

Question 26

neuroprotection NMDA receptor antagonist ?

Answer 26

The theory behind blocking the NMDA receptors is that by blocking the receptors, it would prevent the excessive levels of sodium, excessive depolarisation and neuronal damage

Question 27

are there any NDMA RA available ?

Answer 27

However, all NMDA receptor antagonists have failed in clinical trials. D-CCPene Competitive glutamate antagonist No efficacy in phase 3 (head injury) MK-801 Non-competitive antagonist Discontinued in phase 2 (hypotension) Aptiganel Non-competitive antagonist Discontinued in phase 3 (stroke) No efficacy in phase 3 (head injury) Eliprodil No efficacy in phase 3 (stroke)

Question 28

calcium IS ?

Answer 28

Free intracellular calcium levels are physiologically normally low. Intracellular calcium levels are increased after cerebral ischaemia by increased activation of influx (see previous schema on glutamate receptor overactivation); failure of efflux and reduced intracellular buffering which leads to cell damage.

Question 29

role of calcium ?

Answer 29

Calcium has many cellular functions important as a second messenger. It’s when the intracellular levels of calcium are increased that calcium can cause damage due to overactivation of calcium-dependent enzymes. This rise in calcium will increase kinase activity, which can lead to cell damage and the DNA and proteins of a cell. Furthermore, it can increase the inflammatory signals ( prostaglandin and leukotrienes) inside the cell as well as increase proteases activity causing cytoskeletal disruption.

Question 30

neuroinflammation ?

Answer 30

Neuroinflammation is increased after cerebral ischaemia and have detrimental effects. For example, the increased release of cytokine TNFa can increase infarct size after stroke as shown in this slide where inhibition of TNFa is shown to decrease infarct size after experimental stroke.

Question 31

oxygen derived free radicals ?

Answer 31

Other mechanisms of cellular injury after ischaemia is by free radicals, they cause lipid peroxidation which is self-perpetuating (the brain is particularly vulnerable to lipid peroxidation due to its high lipid content). In addition to this, they cause damage to proteins such as glycosaminoglycans and nucleic acids. Mitochondrial destruction, once you get destruction of mitochondria you get decrease in energy production and impaired Ca2+ buffering so an increase in calcium levels in a cell. Also, cytoskeletal disruption occurs via proteases.

Question 32

what is the only drug available for stroke ?

Answer 32

Only drug currently licenced for stroke is thrombolytic (tPA) , tissue plasminogen activator.

Question 33

tPA ?

Answer 33

(tPA) is released by any damage to the endothelium, which causes activation of plasminogen into the active form plasmin. Plasmin can then trigger fibrinolysis – breakdown of the clot by the activating factor (tPA). Plasmin cuts the fibrin mesh at various places leading to the production of circulating fragments that are cleared by other proteases.

Question 34

fibronlysis ?

Answer 34

Fibrinolysis is the endogenous plasmin-mediated process of dissolving a formed thrombus – the enzymatic breakdown of fibrin in blood clots.

Question 35

streptokinase ?

Answer 35

Streptokinase is a bacterial product which combines with and activates plasminogen. It is antigenic/immunogenic – problems. Activates all circulating plasminogen so undesirable systemic anticoagulant effect. Streptokinase works by activating plasminogen to form plasmin which degrades fibrin and so breaks up the thrombi. However please note undesirable effects as it activates all the plasminogen.

Question 36

Alteplase ?

Answer 36

It is a recombinant, single chain, tissue plasminogen activator. It is administered through an i.v. and binds to fibrin in clots. It only activates plasminogen that is bound to fibrin, thus described as clot-selective and better than streptokinase. Commonly it is administered with heparin and aspirin to reduce re-occlusion. It is similar to reteplase, tenecteplase.

Question 37

when is thrombolytic therapy used ?

Answer 37

Used during an acute phase of MI or ischaemic stroke, when there is a life-threatening venous thrombosis or pulmonary embolism. EARLY rapid administration of fibrinolytics is very effective in acute MI BUT……Endogenous plasminogen activator can inactivate the fibrinolytic drug. Generation of free thrombin can occur from the lysed clot. There can be release of spasmogens (TxA2 - thromboxane, 5-HT) from platelets. The inflammatory response can block small arterioles. Only less than 2% of patients receive licenced therapy.