Week 2 & 7 - Cardiovascular System (Blood) and Drugs Affecting Blood Coagulation, Aggregation and Thrombosis Flashcards
What are the main components of blood
- RBC (40-45% of total blood vol.)
- are small, have no nucleus, bi-concave shape, have Hb which binds to O2 / CO2
- have enzymatic activity - Plasma (≤ 50% inc. serum + clotting proteins)
- spin plasma in centrifuge again causes separation (proteins sink) - Other cells (1% inc WBC + platelets)
- form thin layer between RBC + plasma when blood is spin
- platelets (thrombocytes) are smaller than RBC + important for stopping flow of blood (haemostats) - Water (extra cellular water)
What can cross capillary membrane
- small molecules, ions and water
- proteins and cells can NOT (too large)
Membrane is mono layer of epithelial cells
Membrane is semi-permeable (acts as barrier)
List the types of blood tests + what they measure
- Haematocrit (HCT) - ratio of red cell to blood volume
- Erythrocyte count - no. of RBC per mm3 of blood
Measures:
- no. of RBC per micro litre of blood
- average vol. of RBC - Leukocyte count - no. of WBC in blood
- high amount when infection is present
- e.g. basophils, esosinophills, neutrophils
Proteins found in plasma
- Haemoglobin - found in small amounts (usually trapped in RBC)
- Albumin - most abundant protein in plasma
- helped buff pH, binds to molecules/drugs (transport)
- carry lipophilic molecules with low solubility
- helped buff pH, binds to molecules/drugs (transport)
- Fibrinogen (clot precursor)
- Globulin (inc. transferrin, immunoglobulin, clotting enzymes, hormone, lipoproteins)
- lipoproteins = HDL and LDL
- hormones = EPO (erythropoietin)
- enzymes = thrombin
- immunoglobulins = antibodies
Describe the processes of haematopoiesis
Is the formation / synthesis of ALL blood cells
- erythrocyte (RBC)last 120 days
- leukocyte (WBC) last a few hours
- platelets last 10 days
- All blood cells are formed from pluripotent stem cells in bone marrow
- Hematopoietic growth factors (HGF) stimulate stem cells to differentiate
- pluripotent stem cell differentiates into myeloid OR lymphoid progenitor (a precursor)
2a. Myeloid progenitor has 3 routes
- can become megakaryocyte, erythrocytes or myleoblast
- megakaryocyte precursor for platelets
- myleoblast can divide to form 4 types of WBC
2b. Lymphoid progenitor becomes lymphoblasts
- lymphoblasts form lymphocytes (WBC) ~ a type of leukocyte
Describe the processes of erythropoiesis (RBC formation)
- Begins when kidney cells detect hypoxia (low O2 in blood)
- Kidneys release erythropoietin (EPO ~ hormone)
- Stimulates bone marrow to produce erythrocytes = ↑ rate of production of RBC
↑ production rate can cause ↑ in viscosity of blood due to more blood cells present
Explain erythrocyte (RBC) destruction
RBC can be damaged by plasma, chemical force etc. causing changes in shape + size = need to be replaced quickly
RBC have no nucleus = can’t make proteins to repair damage + over time cytoplasmic enzyme activity decreases
Loss in enzyme activity + cell damage causes RBC to be recycled and removed from circulation
1. RBC passes through spleen
2. Spleen filters out old / damaged cells as they get jammed in splenic capillaries
- altered shape (from damage) allows them to be filtered
3. Cell fragment gets taken up + recycled by macrophage
What is the definition of anaemia + its causes
Reduced O2 carrying capacity in blood due to low haemoglobin conc.
Cause:
- Dietary or metabolic deficiency (e.g. Fe anemia, poor vitamin B12 absorption)
- Destruction of / damage to bone marrow
- Blood loss
- Kidney disease (kidneys fail to EPO)
How is anaemia diagnosed
- Size + appearance of RBC (macrolytic or microcytic RBC)
- Reduced haematocrit (< 40%)
Explain haemostasis (prevention of blood loss)
Haemostasis is a process to prevent blood loss after blood vessel damage
- involves coagulation + platelet aggregation (clot formation)
- Vascular spasm
- blood vessels contract (develop spasm) to slow down blood flow into injured area
- spams occurs as damaged vessel + activated platelets release vasoconstrictors (e.g. thromboxane A2) = smooth muscle contraction - Platelet plug formation
- Activated platelets move to site of injury + stick to (adhesion) expose tissues and other platelets forming a plug
- Plug is fragile / easily disrupted - Blood coagulation
- Blood coagulates (liquid into solid / semi-solid state)
- Fibrinogen is polymerised into fibrin = fibrin network / mesh formed
- Fibrin holds platelets + other blood cells together = more effective plug (= a fibrin clot) - Formation of Fibrous Tissue
- cells at site of injury synthesise more collagen fibres
- produce connective tissue around injured area = promotes healing
What is the difference between platelet activation and coagulation
Platelets circulate within blood + are mediators which trigger pathway for coagulation cascade
- when encounter damaged blood vessel
Coagulation = blood is solidified (semi-solid / gel state)
- involves clotting factors (factor 10a, factor 5)
- factors usually inactivate, activated by enzymatic cleave
- factors increase thrombosis risk (clotting of blood)
- platelets have no nucleus, also called thrombocytes
What is the role of platelet aggregation in haemostasis
Platelets are strictly controlled by prostacyclin ~ PGI2 (a prostaglandin) which suppresses their activation / aggregation
- platelets have receptors for PGI2 (which is produced by vessel wall)
- damage to vessel wall = PGI2 production is disrupted = ↑ platelet activation
Platelet Activation
1. Circulating platelets (disc shaped)
2. Platelets become activated when come in contact with damaged vessel
3. Platelets release chemical mediators e.g. thromboxane A2
= more platelets are activated
4.-Platelets begins to change shape (spreads until it flattens)
5. Fully spread platelet can then aggregation with other platelets (holds clot together)
- fibrinogen binding with fibrinogen receptor
6. Acidic phospholipids on membrane of platelets become exposed = coagulation prompted
What is the role of platelet aggregation in thrombosis (clot formation)
- Can cause blockage in a intact vessel = ↓ tissue perfusion
- ↑ risk of embolism (clot detaches from vessel + blocks a smaller vessel)
- ↑ risk of myocardial infarction, stroke, disrupted blood oxygenation
Explain the coagulation cascade
Have intrinsic and extrinsic pathway
- extrinsic is main pathway, very fast, get a burst of thrombin at wound site
- intrinsic is slow
- F = factor (i.e. factor 12 = F12)
Intrinsic Pathway (sustains clotting):
1. Injury to vessel wall activates F12 which is activated to 12a
- 12a promotes conversion of inactivate factor 11 to activated F11
2. 11 promotes conversion of F9 from inactivated to activated + factor 8 is activated which stimulates activation of F10
Extrinsic Pathway (initiates clotting):
HAVE tissue damage
1. Trauma / damage to blood vessel activates F7
2. Factor 7 stimulates production of factor 10 which is converted into 10a
SAME PATHWAY IN BOTH
3. Activated factor 10a is under influence of factor 5
4. Activated factor 5 and Ca2+ promotes conversion of prothrombin (F2) to thrombin (F2a)
5. Active thrombin converts fibrinogen (F1) into fibrin (F1a)
- thrombin also amplifies cross linking of fibrin (=mesh)
- thrombin promotes prothrombin conversion
- thrombin causes platelet aggregation + platelet GP to occur
How does clotting factors affect disease (thrombosis) / What are coagulation problems
- Inappropriate activation of factor 10
- Insufficiency in intrinsic pathway (loss of factor 8 = no factor 10 stimulated AND loss of factor 9)
- Vitamin K deficiency results in coagulation being compromised
Explain the 3 general steps for blood coagulation
- Vessel damage which generates prothrombin activators
- activated via extrinsic / intrinsic pathway - Prothrombin converted into thrombin (by factor 5 & Ca2+)
- Thrombin has 3 effects
- converts fibrinogen into fibrin
- promotes cross linking of fibrin = stronger clot formed
- increased conversion of prothrombin into thrombin (as it stimulates prothrombin activation)
Very controlled process as it is not needed everywhere in body
How is harmful clotting prevented
- Constant blood flow dilutes clotting factors = if they become activated they won’t cause clot formation
- Macrophage system removes activated factors
- Anti-platlet drugs (prevent platelet activation + plug formation)
- Anti-coagulant drugs (interfere with cascade + prevent fibrin formation)
- e.g. Heparin inhibits clotting cascade
What is the difference between red + white thrombus (clot) and explain the drugs used
White thrombus:
- clot is formed in arteries
- use anti-platelet drugs
- condition is predominately platelet activation
Red thrombus:
- clot is formed in veins
- use anti-coagulant drugs
- condition is predominantly coagulation + RBC trapped
List the 4 drugs types which may affect coagulation and platelet aggregation
- Anti-coagulants
- Anti-platelets
- Fibrinolytics
- Anti-fibrinolytics
AIM: inhibit thrombus formation without preventing normal haemostats
Give some examples of anti-coagulants
- Heparin (parenteral)
- Warfarin (oral)
- Hirudin (parenteral)
- e.g. Bivalirudin used in UA and MI - Thrombin inhibitors (e.g. Dabigatran)
- Factor 10a inhibitors (e.g. Apixaban; Edoxaban; Rivaroxaban)
Common risk: haemorrhage (blood loss form ruptured / damaged vessel)
Describe the effects of anti-coagulants
Clot prevention drug (targets coagulation)
More effective against red thrombi
MECHANISM: Inhibits thrombin, inhibits factor 10a
Oral or parenteral (non-oral) administration
- Heparin (parenteral)
- occur naturally in body (from endothelium, mast cells and basophils)
- bind to anti-thrombin III (AT III) forming AT III heparin complex
- complex inhibits thrombin, factor 10a + other clotting factors
Have 2 SIZES; unfractionated (longer) and low molecular weight (shorter)
- unfractionated: acts on factor 10a + thrombin
- low molecular weigh (LMW): acts on factor 10 ONLY
- LMW is most commonly used, has longer duration + better bioavailability
- binds to factor 10 / AT III complex
ISSUES: risk of haemorrhage, heparin-induced thrombocytopenia (HIT) - Warfarin (oral)
- most commonly used oral anti-coagulant
- prevents gamma-carboxylation (maturation) of clotting factors 7, 9, 10 and prothrombin
- carboxylation oxidises vitamin K which is then reduced by vita K reductase
- drug inhibits vitamin K reductase
- has slow onset (days) as pre-existing factors need to be removed to see effects
- given for 3-6 months after 1st deep vein thrombosis
ISSUES: risk of haemorrhage, skin necrosis, metabolised by CYP450 some drugs inhibit this enzyme, taking vitamin K supplements
DDIs: e.g. antibiotics (can inhibit its breakdown OR enhance its activity as it kills microbiota which produces vitamin K)
can be displaced form plasma albumin by other drugs
Give some examples of anti-platelets
- Aspirin
- irreversibly blocks COX = TXA2 production is inhibited (until new platelets are formed = new COX synthesised)
- endothelial cells synthesise COX which is used to produce prostacyclin
- need to use LOW dose to only inhibit COX in platelets not endothelial cells
- high doses can cause GI bleeding, bronchospasm - Drugs that ↑ cAMP in platelets = ↓ activation
- e.g. Epoprostenol (a prostacyclin agonist, potent vasodilator = good in hypertension)
- e.g. Dipyridamole prevents breakdown of cAMP by blocking PDE enzyme = TXA2 synthesis is inhibited - P2Y Receptor antagonist
- e.g. clopidogrel, Prasugrel
- activated platelets release ADP which binds to P2Y receptors to activate more platelets = aggregation ↑ - Block fibrinogen from binding to GP receptors on platelets
- GP crosslinks platelets
- e.g. biologics, only used in hospitals, have risk of bleeding
Describe the effects of anti-platelets
Clot prevention drug (targets platelet activation)
- platelet aggregation is controlled by prostacyclin
- platelets produce TXA2 = ↑ platelet aggregation by ↓ cAMP
(need to balance the 2)
More effective in white thrombi
MECHANISM:
- inhibit thromboxane A2 (TXA2) production = ↑ cAMP = platelet activation is prevented
- high cAMP in platelets = ↓ platelet activation
- Inhibit / block P2Y receptors (prevents ADP binding + activating platelets)
- blocks fibrinogen form binding to GP receptor on platelets
- Get AA from membrane phospholipids
- COX (enzyme) converts AA into cyclic endoperoxides (a precursor for TXA2 and prostacyclin)
- Aspirin inhibits COX = not enough substrate to produce TXA2 or prostacyclin
3a. if endoperoxide goes through thromboxane synthase = TXA2 formed
3b. if endoperoxide goes through prostacyclin synthase = prostacyclin formed
- Aspirin inhibits COX = not enough substrate to produce TXA2 or prostacyclin
Describe the effects of fibrinolytics
Used if thrombus (clot) ALREADY FORMED
- given after MI or for thromboembolic disease
- Breaks clot apart by converting plasminogen (in fibrin mesh) to plasmin
- plasmin (= potent enzyme) digests fibrin mesh = clot breakdown
ISSUES: his risk of haemorrhage / embolism
Describe the effects of anti-fibrinolytics
Stabilise clots + promote haemostats to prevent bleeding
- Block tranexamic acid (a plasminogen activator) = plasminogen is converted into plasmin
- = bleeding is reduced
- Counteracts life threatening bleeding after fibrinolytic administration
