Flashcards in Cardiology - Atherosclerosis and haemodynamic disorders Deck (58):
What is arteriosclerosis?
The walls of arterial vessels are made of smooth muscle, elastin, and collagen which help maintain vascular tone. Alterations in the relative amounts of these specialised elements leads to hardening, thickening and loss of elasticity of the vessel walls leading to disease. The term arteriosclerosis is often used as a general descriptive term for such diseases.
What is atherosclerosis?
The commonest type of arteriosclerosis is that affecting large and medium sized arteries. The underlying pathological lesion is called an atheroma, so this form of arteriosclerosis is known as atherosclerosis. Other forms of arteriosclerosis do occur, such as thickening of the walls of arterioles in association with hypertension but atherosclerosis is the most important clinical condition.
Name some risk factors associated with atherosclerosis?
These risk factors predispose to severe atherosclerotic lesions and have a high incidence of complications. They are:
1) Constitutional - age, sex, genetic
2) Modifiable - hyperlipidaemia*, hypertension, smoking, diabetes, alcohol
* atherosclerosis is associated with raised total cholesterol and higher LDL:HDL ratio. Hypertriglyceridaemia appears to be more associated with myocardial infarction than coronary artery disease, possibly because it affects coagulation.
What is the structure of a normal artery?
The artery is lined internally by smooth flat endothelium which lies on a thin tunica intima. This is fibroelastic loose connective tissue that contains occasional multifunctional myointimal cells. Underneath the intima is a strong internal elastic lamina underneath which is the tunica media. This is a layer of smooth muscle containing some elastic fibres. On the outer surface is the lose tunica adventitia.
What causes the development of atheroma?
Initial events in plaque formation are likely to be due to:
1) Endothelial cell damage allowing reaction of platelets with the intima
2) Release of platelet mitogen factors causing smooth muscle proliferation
3) The damaged endothelial cells allow lipid from the plasma to pass through to the intima where they accumulate - called insudation
What is a fatty streak?
These are the earliest microscopic evidence of atherosclerosis. Lipid (mainly cholesterol) enters the intima, probably from the blood across a damaged endothelium. Much of the lipid is phagocytosed by foam cells (probably blood derived macrophages and myointimal cells) but some eventually becomes free and more free lipid accumulates when bloated foam cells undergo cell death.
What happens during the fibro-lipid plaque stage?
Lipid in the intima initiates the formation of fibrocollagenous tissue. Cytokines secreted by macrohages stimulate the proliferation of myotintimal cells and switch the function of some of them towards active collagen synthesis to form a thick cartilagenous cap.
As the intimal deposit of atheroma enlarges, the underling muscular media begins to atrophy and thin as smooth muscle cells are lost.
What is a complicated atheroma?
This happens when the atheromatous intimal plaque is extensive, and there is marked atrophy of the associated tunica media, with contractible muscle being replaced by collagen. The lipid deposits in the intima frequently acquire deposits of calcium salts, and the fibro-lipid plaque becomes progressively calcified. Ulceration of the overlying endothelium predisposes to the deposition of thrombus on the exposed atheromatous plaque.
Surface ulceration happens because the enlarging atheromatous plaque becomes very thick relative to the normal thickness of the vessel wall. The blood supply to the intima may become insufficient and the lesion may undergo necrosis and surface ulceration.
What vessels are most commonly affected by atherosclerosis?
Atherosclerosis can affect all arterial vessels, but the aorta, coronary, cerebral, carotid, renal and ilio-femoral arteries tend to be most severely affected.
What are the most important consequences of atheroma?
1) Occlusions - narrowing of the arterial lumen produces partial or complete obstruction to blood flow and may result in ischaemia and infarction of the tissue supplied
2) Thrombosis - endothelial ulceration stimulates formation of an overlying thrombus. This may occlude the vessel at the site of thrombosis, or fragments of the thrombus may become detached to form emboli which block one or more smaller vessels distally
3) Aneurysm - loss of muscle and elastin from the media causes weakening of the vessel wall, pre disposing to localised areas of dilatation. This dilatation is known as an aneurysm. Rupture of the weakened and dilated artery wall, leading to a fatal haemorrhage. Aneurysm may also lead to thrombus formation because of venous stasis in some areas of the aneurysm cavity
What are non staining angular clefts?
In early atherosclerotic disease, foam cells filled with lipid break down and liberate free lipid into the intima where it is represented by non staining angular clefts. The presence of free lipid appears to induce a fibrous reaction in the surrounding tissues, which appear eosinophilic.
How does haemorrhage into an atherosclerotic plaque occur?
There are 2 mechanisms by which haemorrhage can occur into a plaque:
1) the rigid fibrotic plaque may split under the constant trauma of pulsatile movements and allow blood from the vessel lumen to greatly expand the plaque lesion - this is called plaque fissuring
2) small capillary vessels that develop in established plaques may rupture and lead to haemorrhage
The haemorrhage can reduce the diameter of the arterial lumen (which has already been reduced by the atheromatous plaque) which can lead to an abrupt reduction in arterial flow causing acute ischaemia.
What is the difference between haemostasis and thrombosis?
Haemostasis is the consequence of tightly regulated processes that maintain blood in a fluid, clot free state in NORMAL VESSELS while rapidly forming a localized haemostatic plug at the site of vascular injury.
Thrombosis is a pathological form of haemostasis. It involves blood clot (thrombus) formation in uninjured vessels or thrombotic occlusion of a vessel after relatively minor injury.
Both haemostasis and thrombosis involve 3 components - the vascular wall, platelets and the coagulation cascade.
Outline the process of normal haemostasis
After vascular injury, a period of arteriolar vasoconstriction occurs mostly as a result of reflex neurogenic mechanisms mediated by endothelin (potent vasoconstrictor produced by endothelium). The effect is transient, and bleeding would resume were it not for activation of the platelet and coagulation systems.
Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix, allowing platelets to adhere and be activated. Activation of platelets results in dramatic shape change and release of secretory granules. These recruit additional platelets (aggregation) to form a haemostatic plug; this is the process of primary haemostasis.
Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, tissue factor is a membrane bound procoagulant glycoprotein synthesised by endothelium. It works with factor VII as the major in vivo pathway to activate the coagulation cascade, eventually leading to thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork. Thrombin also induces further platelet recruitment and granule release. This secondary haemostasis sequence lasts longer than the initial platelet plug and helps to stabilise it. At this stage counter regulatory mechanisms (e.g. t-PA) are set into motion to limit the haemostatic plug to the site of injury.
What is the pathogenesis of thrombosis?
Three major factors predispose to thrombosis, they are Virchow's triad:
1) Endothelial injury
- turbulent blood flow at arterial bifurcations
- homocysteine, oxidised LDL, cigarette smoking, cytokines
- atherosclerosis (arterial), endocardial damage (heart)
2) Stasis of blood flow
- sluggish blood flow due to prolonged bed rest or sitting (e.g. long flight or immobilisation)
- left atrial dilatation due to mitral valve disease (e.g. mitral stenosis)
- activation of the coagulation cascade - e.g. DIC
- hereditary or acquired factor deficienes - e.g. hereditary anti-thrombin III deficiency, oral contraceptives
- antiphospholipid syndrome
- thrombocytosis (increased number of platelets)
How do arterial thrombi form?
These form in areas of active blood flow, and damage to the intimal layers is the most common predisposing factor. Thrombosis in the arterial system is mostly due to atherosclerosis.
Less commonly, arterial thrombi occur in other disorders such as arteritis, trauma and blood diseases.
They form by successive deposition of a number of layers of platelets and fibrin. This layering results in the lines of Zahn, a lamination of alternate dark and pale areas.
What are the consequences of arterial thrombi?
Arterial thrombosis secondary to atherosclerosis is the most common cause of death in the western world. Because most arterial thrombi occlude vessels, they often lead to ischaemic necrosis of tissue supplied by that artery (i.e. an infarct). Thrombosis in a coronary vessel will cause myocardial infarction, or thrombosis in a cerebral artery will lead to cerebral infarction.
End arteries can be affected by atherosclerosis and also suffer thrombosis. These include the mesenteric arteries, renal arteries and arteries of the leg (gangrene).
What can happen to a thrombus once it has been formed?
1) Lysis - thrombolytic activity of the blood
2) Propagation (i.e. an increase in size) - thrombus serves as a focus for other thrombus formation
3) Organisation - invasion of connective tissue elements involved in repair causes the thrombus to appear firm and greyish white
4) Canalisation - new lumen lined by endothelial cells forms WITHIN an organised thrombus
5) Embolisation - when part or all of the thrombus becomes detached, travels through the circulation and lodges in a blood vessel some distance from the site of formation
What causes thrombosis in the heart?
Endocardial injury and changes in blood flow within the heart may lead to MURAL thrombosis (i.e. a thrombus adhering to the underlying wall of the heart).
Myocardial infarction is often associated with mural thrombi adherent to the left ventricle. Damaged myocardium does not pump effectively and ischaemia disrupts the endocardium. This creates a surface on which blood can clot.
Mural thrombi are also associated with AF, cardiomyopathies, and endocarditis - the last is characterised by small thrombi (vegetations) on cardiac valves.
What is the main complication of mural thrombi?
The major complication of thrombi in the heart is detachment of fragments and lodging in blood vessels at distant sites (e.g. cerebral arteries) - EMBOLISATION.
What causes venous thrombi?
DVT (deep vein thrombosis) is the most common manifestation of thrombosis in the venous system.
Venous thrombosis is multifactorial. DVT are caused by the same factors that favour arterial and cardiac thrombi (i.e. altered blood flow, endothelial damage, hypercoagulability). Certain conditions may predispose to venous thrombosis:
- Stasis: heart failure, chronic venous insufficiency and postoperative immobilization and prolonged bed rest
- Injury: trauma, surgery and childbirth
- Hypercoagulability: oral contraceptives, late pregnancy, cancer and inherited thrombophilic disorders
- Advanced age: venous varicosities and phlebosclerosis
- Sickle cell disease
Where do venous thrombi commonly form?
Most (>90%) of venous thrombi occur in the deep veins of the legs, the rest usually involve the pelvic veins. Most start in the large calf veins, frequently in the sinuses above the venous valves. The fate of thrombi in this location are the same as those in the arterial system. A thrombus may lyse and cause no further problems, or it may propagate to involve the iliofemoral vessels. The thrombus may then dislodge (embolise) and be carried to the lung (most commonly) as a pulmonary embolus.
What are the clinical features of venous thrombi?
Small thrombi in the calf veins or even larger ones in the iliofemoral vessels may cause no symptoms. Occlusive thrombosis of femoral and iliac veins result in severe congestion, oedema and cyanosis of the lower extremity.
Venous valves are always impaired in a vein with thrombosis and oragnisation. As a result, chronic deep vein insufficiency (i.e. impaired venous drainage) occurs. If a lesion is restricted to a small segment of the venous system then the condition may be asymptomatic. More extensive involvement leads to pigmentation, oedema and induration of the skin. Ulceration above the medial malleolus can also occur.
Venous thrombi elsewhere may also be dangerous: thrombosis in the mesenteric veins can cause haemorrhagic small bowel infarction; thrombosis in cerebral veins may be fatal and hepatic vein thrombosis (Budd-Chiari syndrome) may destroy the liver.
How are thrombotic disorders classified?
Thrombotic disorders can be either antithrombotic (haemorrhagic) leading to pathologic bleeding states such as haemophilia and von Willebrand disease. Haemorrhagic disorders can be further subdivided into those associated with primary haemostasis, secondary haemostasis or both.
Disorders can also be prothrombotic, leading to hypercoagulability with pathologic thrombosis. These are subdivided into inherited thrombophilia syndromes and acquired thrombosis syndromes.
What are the important features of hereditary thrombophilia?
Hereditary thrombophilia is a prothrombotic familial syndrome occurring most often in adolescents or young women.
Characteristic features include recurrent venous thrombosis and thromboembolism. The syndrome is autosomal dominant and can be caused by deficiency of a number of antithrombotic proteins, including antithrombin III, protein C and protein S.
What is factor V Leiden deficiency?
A point mutation in the factor V gene renders it resistant to proteolysis by activated protein C (APC). Resistance to activated protein C is the most common genetic disorder associated with hypercoagulability and hereditary thrombophilia. The mutation prevents cleave of factor Va by APC.
What is the prothrombin 20210A transition?
This is the second most common cause of hereditary thrombophilia. This G-A mutation in the 3" untranslated region of the prothrombin gene is associated with elevated plasma levels and an increase in venous thrombosis.
What is the methylene tetrahydrofolate reductase mutation?
This results in a moderate increase in serum homocysteine, which is associated with both arterial and venous thrombosis. The increased homocysteine can be reduced by dietary supplementation with folic acid and vitamin B 6 (pyridoxine) and B12 (cobalamin). This is also associated with an increased risk of neural tube defects and possibly a number of diverse neoplasms.
Increased levels of these coagulation factors can also cause increased venous thrombosis?
Factors VIII, IX, XI or fibrinogen.
What is protein C and protein S deficiency?
Homozygous protein C deficiency causes life threatening neonatal thrombosis with purpura fulminans. Up to 0.5% of the general population are heterozygous for protein C deficiency, but many of these persons are symptom free. The clinical presentations of protein C and S deficiencies are similar to that for ATIII deficiency.
What are the acquired causes of thrombosis?
1) Post operative state with stasis of blood flow
- increased synthesis of coagulation factors
- release of procoagulants from tumours, especially pancreatic tumours
3) Folic acid or vitamin B 12 deficiency
- increased plasma homocysteine levels increase risk of thrombosis
4) Oral contraceptive pill
- oestrogen increases the synthesis of coagulation factors and decreases the concentration of antithrombin III
5) Hyperviscosity syndromes
- Waldenstrom macoglobulinaemia
6) Antiphospholipid syndrome
Patients who are heterozygous for protein C deficiency develop this condition when placed on warfarin?
Haemorrhagic skin necrosis.
There is potential for patients who are heterozygous for protein C to develop this when placed on warfarin. Heterozygote carriers have 50% of protein C compared with normal. Protein C has a short half life (approx. 6 hours). When these patients are placed on warfarin, protein C activity falls to zero in 6 hours, causing a hypercoagulable state due to increased activity of factors V and VIII. This causes cutaneous vessel thrombosis and concomitant skin necrosis.
What is antiphospholipid syndrome?
APLS is an acquired cause of thrombosis most often associated with SLE. Other diseases associated with it are RA, Sjogren syndrome, ITP and HIV infection.
Most patients are young to middle aged adults. Both venous (most common) and arterial thrombi may occur.
What is the pathogenesis of APLS?
Presence of antiphospholipid antibodies (APAs) directed against phospholipids on plasma membranes.
- anticardiolipin antibodies (ACA)
- lupus anticoagulant
- anti beta 2 glycoprotein 1 antibody
This produces arterial and venous thrombosis syndromes. Venous thrombi are more common than arterial thrombi. Mechanism by which APAs produce thrombosis is not fully understood. Possible mechanisms include resistance to protein C, impaired fibrinolysis and endothelial cell injury with activation of platelets.
What are the clinical findings in APLS?
Venous thrombosis. Vessels commonly involved include:
- deep veins in the calf
- renal, hepatic, axillary, subclavian, and retinal veins, vena cavae and the placental bed (recurrent miscarriages)
Arterial thrombus sites include
- cerebral vessels (most common site, produces stroke)
- coronary, renal, mesenteric and bypass arteries
What laboratory findings are present in APLs?
1) False positive syphilis serology test
- occurs if ACAs are present
- ACAs react with beef cardiolipin in the test system for RPR and VLDL however the FTA-ABS test is negative
- Increased PTT that does NOT correct with mixing studies
- most sensitive and specific test (positive in >80% of cases)
4) Anti beta 2 glycoprotein 1 antibodies
Why is the PTT time increased in APLS?
This syndrome is most often diagnosed because of an incidental finding of a prolonged PTT. This is paradoxical, because a prolonged PTT is usually considered to be an indicator of antithrombotic or haemorrhagic syndromes. The reverse of the prothrombotic tendencies of APLS. The prolonged PTT is thought to be an in vitro artifact caused by interaction of the phospholipid antibodies with phospholipid reagant used in the PTT test.
What is heparin induced thrombocytopaenia (HIT) syndrome?
This syndrome is characterised by heparin induced thrombocytopaenia (AND thrombosis) and is a consequence of therapy with low molecular weight heparin.
What are the 2 types of HIT syndrome?
Type I HIT = results in a mild to moderate drop in platelets. It occurs in about 5% of heparinized platelets and can appear within a day of therapy. It is not immune mediated and is not a contraindication to future heparin use.
Type II HIT = leads to a severe drop in platelets (often <50% of baseline) and imparts a high risk of thrombosis. It usually manifests 5 to 10 days after heparin therapy and occurs in approximately 1% of patients. It is thought to be caused by antibodies to the complex of heparin and platelet factor 4 (PF4). The gold standard for diagnosis is the serotonin release assay, although this test is rarely used in practice and a diagnosis is made on clinical factors and the presence of raised PF4 antibodies. Once type II HIT has been diagnosed, it is a contraindication to future heparin therapy.
What mediates platelet adhesion following vessel injury?
Vessel injury exposes subendothelial collagen, leading to platelet adhesion (adherence to the sub endothelial surface). Interaction of specific platelet surface glycoprotein receptors and subendothelial collagen is mediated by von Willebrand factor (vWF).
What is von Willebrand factor (vWF)?
vWF is a platelet adhesion molecule that is synthesised in the Weibel-Palade bodies in endothelial cells or megakaryocytes. Binds to platelet Gp Ib receptor.
vWF also complexes with factor VIII coagulant (factor VIII:c) in the circulation to prevent degradation. Decreased vWF (as in von Willebrand disease) causes a decrease in VIIIc. Factor VIIIc is synthesised in reticuloendothelial cells and the liver. When activated by thrombin it dissociates from vWF and activates the intrinsic pathway.
When does the platelet release reaction?
Platelet adhesion is responsible for forming the primary haemostatic plug. Soon after adhesion, platelets release ADP, histamine, serotonin and PDGF and other platelet granule constituents. These factors help platelet recruitment and aggregation.
How do platelets activate the coagulation cascade?
Conformation changes in the platelet membrane make the platelet phospholipid complex available, thus contributing to the activation of the coagulation cascade, leading to the formation of thrombin.
How are eicosinoid mediators produced by platelets?
Eicosinoid mediators include derivatives of arachidonic acid metabolism. Arachidonic acid is provided by the activation of the platelet membrane phospholipase. It proceeds through the cyclooxygenase pathway to produce thromboxane A2. Platelet TXA2 is a potent vasoconstrictor and platelet aggregant.
Is platelet aggregation different to platelet adhesion?
Yes. Platelet aggregation is the next step in formation of the primary haeomstatic plug. Platelets stick together (as opposed to adhesion, adherence to the subendothelium). Additional platelets are recruited from the circulation to produce the initial haemostatic plug. This process is mediated by glycoprotein IIb-IIIa complex on the surface of platelets that is required for the linking of platelets by fibrinogen bridges.
Agonists that promote aggregation include ADP, thrombin, and TXA2 as well as collagen, adrenaline, and platelet activating factor (derived from the granules of basophils and mast cells).
How is the platelet plug stabilised?
Fibrinogen bridges bind the aggregated platelets together. The platelet mass is stabilised by the insoluble fibrin.
How is the platelet plug limited?
Prostacyclin (PGI2), another produce of the cyclo-oxygenase pathway, is synthesised by endothelial cells. Endothelial PGI2 is antagonistic to platelet TXA2 and limits further platelet aggregation. Fibrin degradation products are also inhibitors of platelet aggregation.
What is the extrinsic pathway of coagulation?
There are 2 coagulation pathways. The extrinsic pathway involves activation of factor VII by tissue thromboplastin (tissue factor) released from damaged tissue.
Factor VII activates factor IX and X (intrinsic system and the final common pathway, respectively). Factor Xa converts prothrombin (factor II) to thrombin (factor IIa). Factor Va is a cofactor required for the conversion of prothrombin to thrombin. Thrombin converts fibrinogen to fibrin.
What is the intrinsic pathway?
The intrinsic pathway involves the activation of ALL clotting factors with the exception of factors VII and XIII.
Factor XII (Hageman factor) is activated by:
- exposed subendothelial collagen
- high molecular weight kininogen (HMWK)
- activates factor XI, plasminogen (produces plasmin) and the kinin system (produces kallikrein and bradykinin)
Factors XI and VIIa activate factor IX to form factor IXa:
- four component complex is formed (factors VIII and IXa, PF3 and calcium)
- the complex is far more potent than factor VIIa alone in activating factor X
What is the final common pathway in the coagulation cascade?
The final common pathway involves factors I, II, V and X. Prothrombin is factor II and fibrinogen is factor I.
Fibrinogen is converted into fibrin monomers. Fibrin monomers aggregate to form soluble fibrin which is then cross linked (with the help of factor XIIIa) to form insoluble fibrin.
What are the functions of thrombin in the coagulation cascade?
Thrombin converts fibrinogen to fibrin. It also activates factor XIII (fibrin stabilising factor). Factor XIIIa cross links insoluble fibrin to strengthen the fibrin clot. Thrombin also activates factor VIII:c (intrinsic pathway).
Thrombin has some anticoagulant effects: complexes with thrombomodulin to activate protein C, which inactivates factors Va and VIIIa.
What are the vitamin K dependent clotting factors?
X, IX, VII and II
Plus the anticoagulants protein C and S.
What is the function of vitamin K?
Majority of vitamin K is synthesised by colonic bacteria and is activated in the liver by epoxide reductase. Activated vitamin K gamma carboxylates each of the vitamin K dependent clotting factors which are then able to bind calcium and PF3 in the cascade sequence.
What laboratory test examines the extrinsic pathway?
Prothrombin time (PT). Evaluates the extrinsic system down to the formation of the fibrin clot so involves factors VII, X, V, I and II.
The normal reference is 11 to 15 seconds - the time is only prolonged when a factor is level is 30-50% of normal; hence it is not a very sensitive test.
PT is used for:
- monitoring warfarin Rx
- evaluate liver synthetic function (e.g. cirrhosis, chronic hepatitis); increased PT indicates severe liver dysfuction
- used to detect factor VII deficiency if the PTT is normal
What is the INR?
The international normalised ratio (INR) standardises PT for warfarin therapy. Usual range is 2-3.
What coagulation test examines the intrinsic pathway?
Partial thromboplastin time (PTT). Evaluates the intrinsic pathway down to the formation of the fibrin clot, so includes factors XII, XI, IX, VII, X, V, II and I (separate test). Normal reference range is 20-40 seconds.
PTT is used for:
- monitoring heparin Rx (heparin enhances antithrombin III activity)
- used to detect deficiencies in the intrinsic coagulation system if PT is NORMAL
What is fibrinolysis?
This is thrombus dissolution. It occurs alongside thrombogenesis and modulates coagulation. It restores blood flow in vessels occluded by thrombus and facilitates healing after inflammation.
The proenzyme plasminogen is converted by proteolysis to plasmin. Plasmin splits fibrin. Plasminogen is produced by activated factor XIIa.