MoD 5 + 6 (Haemostasis, Thrombosis & Atherosclerosis) Flashcards
Define haemostasis:
The process of stopping bloodflow
Haemostasis depends on what 4 factors?
- Vessel wall (changes in tone and secretion)
- Coagulation cascade
- Platelets
- Fibrinolytic system
What changes occur to endothelial cells to stop bleeding?
- Vasoconstriction
- Stop secreting coagulation/aggregation inhibitors
- Secrete von Willebrand factor, ADP, Factor III and Endothelins
What substances are secreted by damaged endothelial cells to promote haemostasis?
- von Willebrand factor
- Factor III
- ADP
- Endothelins
What cell are platelets derived from?
Megakaryocytes
What do platelets contain?
alpha granules - von Willebrand factor, thrombin
dense granules - ADP
What do platelet alpha granules contain?
von Willebrand factor
Thrombin
Fibrinogen
What do platelet dense granules contain?
ADP
Serotonin (5HT)
Ca2+
What 4 substances can activate platelets?
- Collagen
- Thromboxane
- Thrombin
- ADP
What causes platelets to change shape, allowing them to adhere to each other to form a platelet plug?
Activation = exocytosis of alpha and dense granules
Activated platelets express receptors for what substances?
- von Willebrand factor
- Fibrinogen
What protein cleaves fibrinogen into fibrin?
Thrombin
What test could be done to obtain a platelet count?
Complete blood count
What co factor is required for prothrombin to be cleaved into thrombin?
Activated factor V
What conditions may a low Factor V assay indicate?
- Factor V deficiency
- Disseminated Intravascular Coagulation
- Liver disease
- Primary fibrinolysis
What is an ideal prothrombin time?
25-30 secs
What is Prothrombin time?
Time it takes for blood to clot
What may an abnormally long prothrombin time indicate?
- Blood thinning drugs
- Haemophilia
- Malabsorption
- Liver disease
Name 5 (endogenous) Thrombin inhibitors:
1) Anti thrombin III
2) alpha-1-antitrypsin macroglobulin
3) Protein C
4) Protein S
What is the role of anti-thrombin III in the fibrinolytic system?
Degrades thrombin and factor Xa
Which enzyme is required for the degradation of fibrin?
Plasmin
List some anti-thrombotic factors released from healthy endothelial cells:
- Plasminogen activators
- Prostacyclin
- Nitric oxide
- Thrombomodulin
What are the anti-thrombotic roles of prostacyclin?
- Vasodilation
- Inhibits platelet activation
What are the anti-thrombotic roles of nitric oxide?
- Vasodilation
- Inhibits platelet aggregation
What is the anti-thrombotic role of thrombomodulin?
Converts thrombin into an anticoagulant
What class of drug is Streptokinase?
Fibrinolytic
How does Streptokinase and tPA cause the lysis of fibrin?
Increase plasmin formation
Define Thrombosis:
The formation of a solid mass of blood within the circulatory system, during life
What is Virchow’s Triad?
1) Abnormalities of vessel wall
2) Abnormalities of blood composition
3) Abnormalities of blood flow
Give some examples of causes of abnormalities of the vessel wall which may lead to thrombosis:
- Atheroma
- Trauma
- Inflammation
Give some examples of causes of abnormalities of blood composition, which may lead to thrombosis:
- Pre/Post-partum
- Post-surgery
- Smoking
- Oral contraceptive pill
- Cancer and/or Chemotherapy
- Central obesity
Give some examples of abnormalities of blood flow, which may lead to thrombosis:
- Stagnation
- Turbulence
Why do smokers have an increased risk of thrombosis?
More coagulable blood
Describe the appearance of an arterial thrombus:
Pale
Lines of Zahn
What makes arterial thrombi pale?
Low cell content, high levels of fibrin
What are Lines of Zahn, and where are they seen?
Layers of fibrin and platelets, alternating with layers of red blood cells.
Seen in arterial thrombi, formed in areas of rapid blood flow
Describe the appearance of a venous thrombus:
Deep red
Gelatinous
Soft
Name the possible outcomes of thrombosis:
1) Lysis/Resolution
2) Propagation
3) Organisation
4) Recanalisation
5) Embolism
What is the most likely outcome of small thrombi?
Lysis/Resolution
What is meant by propagation of a thrombus?
Progressive spread of a thrombus
- distally in arteries
- proximally in veins
What is meant by organisation of a thrombus?
Invasion of fibroblasts and endothelial cells into the thrombus, which form granulation tissue, and convert the thrombus into fibrous scar-like tissue, may contain tiny capillaries
What is meant by recanalization of a thrombus?
Organised thrombus with small blood vessels running through the fibrous tissue, incompletely restoring flow
Why may a venous thrombus cause congestion and oedema?
- Thrombus blocks vein, preventing venous drainage of tissue
- Tissue fluid pressure increases, until equal to arterial pressure
Define embolism:
The blockage of a blood vessel by a solid, liquid or gas at a site distant from its origin
Define Deep Vein Thrombosis:
Thrombus in a deep vein, composed mainly of fibrin
Why is central obesity a risk factor for hypercoagulable blood?
Central obesity causes an increase in adipocytokines in the blood, which increases the coagulability of blood
Give 2 risk factors of endothelial damage:
- Trauma
- Hypertension
- Cigarette smoking
Why does immobilisation increase the risk of DVT formation?
- Deep veins of the legs are dependent on the muscle-pump action to return blood to the heart
- If no muscle pump action, blood pools in the veins = change in blood flow = increased risk of thrombosis
What is the classical presentation of a patient with a DVT?
- Limb oedema
- Pain
- Warm or red skin
- History of immobilisation or long-haul flight
What is the most dangerous complication of a DVT?
Pulmonary embolism
What can be used for DVT prophylaxis?
- Subcutaneous heparin
- Leg compression
How does heparin prevent the formation/growth of a thrombus?
- Binds to and activates Anti-thrombin III
- This inactivates Thrombin and Factor Xa
What is the treatment of a DVT?
- IV Heparin
- Oral Warfarin
How does Warfarin prevent the formation/growth of a thrombus?
- Inhibits vitamin K Reductase
- Prevents formation of vitamin K dependent clotting factors: II, VII, IX, X
The formation of which clotting factors is vitamin K dependent?
Factors II, VII, IX, X
What is Trousseau syndrome?
Medical sign of a rare form of thrombo-embolism, associated with pancreatic, gastric and lung cancer. Multiple migratory thrombi form in superficial veins, chest wall and arms, and present as tender palpable nodules.
What medical sign is associated with the thrombo-emboli which may form due to pancreatic, lung or gastric cancer?
Trousseau syndrome
Define pulmonary embolism:
Occlusion of a pulmonary artery caused by a fragment of a thrombus carried by the blood stream.
Why does a pulmonary embolism cause changes in a patients ECG?
- PE causes pressure in pulmonary arteries to increase
- This increases the afterload of the right ventricle
- Right ventricle must work harder to eject blood = right ventricle hypertrophy, detectable on ECG
What is a saddle embolism?
A pulmonary embolism which lodges in the pulmonary artery, and bridges and extends into the left and right pulmonary arteries
What are the symptoms of a significant pulmonary embolism?
- Pleuritic chest pain (sharb stabbing pain in lateral chest and upper back)
- Breathlessness
- Hypoxia
Describe pleuritic chest pain:
Sharp, stabbing pain in lateral chest and/or upper back
What is a paradoxical embolism?
An arterial embolism of venous origin
Why is a paradoxical embolism rare, even when an atrial/ventricular septal defect is present?
The pressure difference between the RH and the LH prevents blood entering the LH from the RH
List some substances which may form an embolism:
- Air
- Thrombus (blood)
- Amniotic fluid
- Nitrogen
- Bone marrow
- Fat
- Medical equipment
- Tumour cells
What are the 2 types of Haemophilia?
1) Haemophilia A
2) Haemophilia B
What is the inheritance pattern of Haemophilia A?
X-linked
Is Haemophilia A more common in males or females?
Males - as follows X-linked inheritance pattern
What is Haemophilia A?
Deficiency of clotting Factor VIII, therefore unable to clot normally
Why are people with Haemophilia A unable to clot normally?
Deficiency of clotting Factor VIII
What is the inheritance pattern of Haemophilia B?
X linked
What is Haemophilia B?
Deficiency of clotting Factor IX
What is the name of the disease in which the person has a deficiency of the clotting Factor IX?
Haemophilia B
What is the name of the disease in which the person has a deficiency of the clotting Factor VIII?
Haemophilia A
What is the inheritance pattern of von Willebrand disease?
Autosomal recessive
What is von Willebrand disease?
Deficiency of von Willebrand factor (required for normal blood clotting)
Name some risk factors of Disseminated Intravascular Coagulation:
- Cancer
- Inflammation ie liver disease, pancreatitis
- Infection ie recent surgery, septicaemia, tissue injury
How does Disseminated Intravascular Coagulation lead to multiple thrombi and serious bleeding?
- Systemic activation of clotting cascade = microvascular thrombi in various organs
- Over time clotting factors are ‘used up’ = high risk of serious bleeding (cannot clot)
What does DIC stand for?
Disseminated Intravascular Coagulation
What is Thrombocytopenia?
Low platelet count (below lower limit)
What may cause Thrombocytopenia?
- Inherited mutation (congenital)
- Viral infection
- Drugs
- Neoplasm malignancy to bone marrow
- Autoimmune disease
- DIC
- (Miliary) TB
What is the name given to the disorder characterised by a platelet count lower than the lower limit?
Thrombocytopenia
What is Thrombophilia?
Predisposition to form thrombus, which may lead to thromboembolism
Define Atherosclerosis:
The thickening and hardening of arterial walls as a consequence of atheroma
Define Atheroma:
The accumulation of intra- and extracellular lipid in the tunica media and intima of large and medium arteries
What is the name given to the thickening and hardening of arterial walls as a consequence of atheroma?
Atherosclerosis
What is the name given to the accumulation of intra- and extracellular lipid in the tunica media and intima of large and medium arteries?
Atheroma
Define arteriosclerosis:
The thickening of the walls of arteries/arterioles usually as a result of hypertension or diabetes mellitus
What conditions cause arteriosclerosis?
Diabetes mellitus
Hypertension
What name is given to the thickening of the walls of arteries/arterioles as a result of hypertension or diabetes mellitus?
Arteriosclerosis
What name is given to the thickening or arteries or arterioles, NOT due to atheroma?
Arteriosclerosis
What are the 4 stages of atherosclerosis formation?
1) Chronic endothelial injury
2) Accumulation of LDLs in the tunica intima
3) Recruitment of macrophages and smooth muscle cells
4) Smooth muscle proliferation, collagen, matrix and extracellular lipid deposition, and neovascularisation
How does lipid get into the tunica media during atherosclerosis formation?
Macrophages and smooth muscle cells engulf the lipid in the tunica intima, and migrate into the tunica media
What are the 3 types of atherosclerosis, characterised by macroscopic appearance?
1) Fatty streak
2) Simple (stable) plaque
3) Complicated (unstable) plaque
What are the macroscopic features of a stable/simple plaque?
- Small necrotic core
- Thick fibrous cap
- Yellow/white
- Raised
- Irregular outline
What are the macroscopic features of a fatty streak?
- Yellow
- Slightly raised
- Lipid deposition in tunica intima
What are the macroscopic features of an unstable/complicated plaque?
- Large necrotic core
- Thin fibrous cap
- Thrombosis
- Calcification
- Haemorrhage
- Aneurysm formation
Define aneurysm:
Abnormal blood-filled bulged blood vessel (usually artery), due to a weakening of the vessel wall
What are the microscopic changes of early atherosclerosis?
- Smooth muscle cell proliferation
- Extracellular lipid deposition
- Accumulation of foam cells
What are the microscopic changes of later atherosclerosis?
- Fibrosis
- Necrosis
- Cholesterol clefts
- Disruption of internal elastic lamina (extends into media)
- Ingrowth of blood vessels
- Plaque fissuring/rupture
What are cholesterol clefts, seen in later atherosclerosis microscopically?
Areas of cholesterol crystals in later atherosclerosis, which are removed by the staining process, leaving clefts
Name some common sites of atherosclerosis:
- Thoracic/Abdominal aorta
- Coronary arteries
- Carotid and cerebral arteries
- Iliac, femoral and popliteal arteries
Atherosclerosis in the coronary arteries causes what disease?
Ischaemic Heart Disease (or coronary heart disease)
What are the modifiable risk factors for ischaemic heart disease?
Smoking Diabetes Hypercholesterolaemia Hypertension Stress Obesity Fruit + Veg intake
What are the complications of Ischaemic Heart Disease?
Angina
Myocardial Infarction
Heart failure
Arrhythmia
Describe the pain associated with Ischaemic Heart Disease:
Central tightening chest pain, which may radiate to arms and/or neck
What are the non-modifiable risk factors for Ischaemic Heart Disease?
- Male gender
- Increasing age
- Family history
- Ethnicity
Which ethnic groups are at higher risk of developing Ischaemic Heart Disease?
- South Asians
- African-Caribbeans
What are the risk factors for Cerebral Ischaemia?
Hypertension Diabetes Cardiac disease Hypercholesterolaemia Carotid stenosis
What is Cerebral Ischaemia?
Lack of blood to the brain, leading to ischaemic stroke
What is Peripheral Vascular Disease?
Slow progressive narrowing of blood/lymph vessels outside of the heart and brain, usually caused by atherosclerosis.
What is the common presenting symptom of peripheral vascular disease affecting the legs?
Intermittent claudication
If a patient presents with bilateral intermittent claudication, what is the problem?
Occlusion of the abdominal aorta just above the bifurcation into common iliac arteries, due to an atherosclerosis
Define claudication:
Pain and/or cramping in the leg due to inadequate blood flow to the muscles
What is Leriche syndrome?
Aortoiliac occlusion due to atherosclerosis, causing bilateral claudication
What is an abdominal aortic aneurysm?
Focal dilation of the abdominal aorta to 3cm or more (>50%)
How does atherosclerosis sometimes lead to an abdominal aortic aneurysm?
Atherosclerosis mechanically weakens the aortic wall, causing loss of the elastic recoil, allowing focal dilation
What is Rokitansky’s Thrombogenic hypothesis?
- Atheromas form due to repeated thrombi composed of fibrin, platelets and leukocytes
- Lipid is derived from the thrombi
How could you externally localise the site of occlusion in the lower limb, due to peripheral vascular disease?
Compare lower limb pulses from distal to proximal
What is Virchow’s Insudation theory?
- Atheromas form in response to endothelial injury and subsequent inflammation, which increases the permeability of the endothelial cells to lipid (from plasma)
What is Ross & Glomset’s Reaction-to-Injury hypothesis?
- Atheromatous plaques form in response to endothelial injury, due to an increase in oxidised LDLs.
- The injury increases endothelium permeability, and allows platelet adhesion, followed by monocyte and smooth muscle migration.
What is Benditt & Benditt’s Monoclonal hypothesis?
- Atheromas develop from the proliferation of smooth muscle cells, from a single progenitor cell (each plaque is a monoclonal benign tumour)
Whose hypothesis for atheroma formation is currently accepted - ‘unifying hypothesis’?
Ross & Glomset’s Reaction-to-Injury hypothesis
What cells are involved in atherogenesis?
- Endothelial cells
- Macrophages
- Smooth muscle cells
- Neutrophils
- Platelets
- Lymphocytes
Define atherogenesis:
The formation of abnormal fatty or lipid masses in arterial walls
Which cells form foam cells during atherogenesis?
Macrophages
Smooth muscle cells
What cell type involved in atherogenesis can oxdise LDLs?
Macrophages
Infection of which microbes increase the risk of atherosclerosis formation?
- Chlamydia pneumonia
- Helicobacter pylori
- Cytomegalovirus
How can you prevent atherosclerosis?
- No smoking
- Reduce fat intake
- Treat hypertension
- Regular exercise
- Weight control (maintain healthy BMI)
- Alcohol control (moderate intake)
What are the interventions available for atherosclerosis?
- Modify diet
- Treat hypertension/diabetes
- Lipid-lowering drugs ie Statins
- Blood thinners ie Aspirin
- Percutaneous coronary intervention
- Coronary artery bypass grafting
