Case 20- Clotting Flashcards
Clotting process
- Vasoconstriction- vascular spasm
- Primary haemostasis- adhesions of platelets to the injury site forming a weak platelet plug
- Secondary haemostasis- coagulation cascade to produce a fibrin network stabilising platelets and trapping red and white cells to make a stable clot
- Clot retraction and repair of endothelial linning
- Fibrinolysis
Vasoconstriction
The endothelium releases NO so the platelets are not prematurely activated and don’t adhere to the endothelium or each other. NO retains vasodilation, damage to the endothelium disrupts NO release, causing activation of the smooth muscle and vasoconstriction.
Primary haemostasis
Damage exposes the subendothelial collagen activating platelets. Platelets are shed from Megakaryocytes. Platelets have no nuclei and when activated they form pseudopodia finger like projections. Normally 2/3 of platelets are in the circulation and 1/3 are in the spleen. The activated platelets bind to each other and the damaged area to form a platelet plug.
Steps of primary haemostasis
- ADP is released from damaged endothelial cells and binds to P2Y 12 receptors on platelets activating them.
- Granules are released from platelets which attract more platelets to the area (can be ADP)
- Exposed collagen has vWF which binds to the GP1b receptor on the platelet, attaching the platelet to the damaged collagen and activating them
- Collagen binds directly to the GPVI receptor on the platelet promoting activation
- Activated platelets use the enzyme COX-1 to convert arachidonic acid to Thromboxane A2 (TXA2) which attracts more platelets to the area
- The GP IIb/IIa receptor on platelets binds platelets to each other and they are anchored together by the molecule Fibrinogen between the two receptors
- A platelet plug is formed to stop bleeding. Receptor activation attracts more platelets
- In small injuries the primary platelet plug is enough to stop bleeding. In bigger cuts it needs to be stabilised by Fibrin which makes it stronger and long lasting
Molecules involved in clot formation
Other molecules involved in clot formation= Thrombin, Epinephrine, Prostaglandin E2, Serotonin • ADP – P2Y12 • vWF – GP1b • TXA2 – TXA2 receptor • Fibrinogen – GP IIb/IIIa
Drugs which inhibit blood clotting
ClopidoGREL, PrasuGREL, TicaGRELor inhibit the P2Y12 receptor
Aspirin binds to COX-1 to stop the formation of TXA2
Tirofiban binds to GP IIb/IIIa receptors stopping a myocardial infarction
Common pathway in secondary haemostasis
Based on the coagulation cascade. Fibrinogen converts to Fibrin
• Factor 1 (Fibrinogen) is activated to Factor 1a (Fibrin) by the enzyme Factor IIA (Thrombin) which is the activated form of Factor II (Prothrombin)
Secondary haemostasis
1) The intrinsic and extrinsic sides of the coagulation cascade converge to form factor Xa and Va which converts Prothrombin to Thrombin, they are assisted by Ca+2 and Phospholipids.
2) The intrinsic pathway is triggered by endothelial damage and is also known as the contact activation pathway.
3) The Tissue Factor Pathway (Extrinsic pathway) is triggered when Tissue Factor enters the blood system.
4) The Prothrombinase complex is made up of phospholipids, Ca+2, activated Va and Xa.
5) The common system is from factor Xa and Va downwards.
6) The coagulation cascade amplifies the signal so enough fibrin is made to form a clot
Extrinsic pathway
When the tissue is damaged tissue factor is in contact with the blood, indicating damage has occurred. Tissue factor causes the conversion of VII to VIIa. VIIa converts factor X to factor Xa in the common pathway.
Intrinsic pathway
1) Triggered by Endothelial damage/collagen which is negatively changed and converts factor XII to factor XIIa (twelve)
2) Factor XIIa converts to XI to factor XIa (eleven)
3) Factor XIa and Ca+2 convert factor IX to factor IXa (nine)
4) With phospholipid and Ca+2 factor IXa converts factor X to active factor Xa, (ten) it is also helped with activated VIIIa from factor VIII which is normally bound to vWF. Thrombin helps to release VIII from vWF (eight)
Trick for remembering intrinsic pathway
In the intrinsic pathway the last letter of the previous factor is the first letter of the next factor.
TwelvE -> EleveN -> NinE -> EighT-> Ten
A thrombin burst
Lots of Thrombin is produced and helps activate the Prothrombinase complex, release vWF from VIII and activates XLa and converts XIII to XIIIa which stabilises Ia Fibrin by cross-linking the fibres.
The factors in the extrinsic and intrinsic pathway
The factor(s) in the extrinsic pathway are: Factor VII (7) (plus calcium) -> common pathway (10…) The factor(s) in the intrinsic pathway are: Twelve, eleven, nine, eight (plus calcium for some steps) -> common pathway (10…) Factor IV is just the name for Ca+2
The factors in the common pathway are
- Ten and five plus calcium and phospholipid (prothrombinase complex)
- Prothrombin (II) -> Thrombin (IIa)
- Fibrinogen (I) -> Fibrin (1a)
- XIII
Clot retraction
The contraction and twisting of the fibrin mesh in order to shrink the blood clot bringing the edges of the blood vessel wall together allowing repair of the damage. Fibroblasts and epithelium help repair the new vessel lining.
Fibrinolysis
1) Helps break down the cross linked fibrin mesh
2) The Tissue Plasminogen Activator (tPA) and Urokinase converts Plasminogen into Plasmin. Plasmin cuts up the Fibrin into FDP’s i.e. D dimer
3) Clots are in equilibrium between being made and being broken down
4) Drugs which activate Plasmin can be used to break down clots
Natural anti and pro-coagulation factors
Natural anti-coagulation= Natural anticoagulants (Protein C and S, antithrombin, Thrombolysis
Natural pro-coagulation= Platelets, Von Willebrand factors, Coagulation factors
Virchow’s triad
3 factors which contribute to the formation of a venous thrombosis:
• Venous stasis- people who are immobilised increases this
• Hypercoagulability- increased by inflammation, cancer, oestrogen, pregnancy, smoking and inherited thrombophilia
• Endothelial injury- cellulitis/phlebitis, injury, indwelling catheter
Steps in the formation of an arterial thrombosis
- Formation of an atheromatous plaque
- Plaque breakdown reveals collagen and a lipid core
- This triggers platelet aggregation and the coagulation cascade
- A platelet-rich thrombus forms
Blood tests for clotting are
Full blood count (platelet count)- contains EDTA
Coagulation screen- contains sodium citrate (reversible anti-coagulant) which removes calcium
1. PT (measures extrinsic pathway), APTT (measures intrinsic pathway) and fibrinogen are done as standard
2. D-dimer can be requested if a blood clot is suspected
3. INR can be requested for monitoring warfarin
FBC- Platelet count
- High platelets >400 x 10^9/L (thrombocytosis)- occurs due to an infection/inflammation, essential thrombocytosis or Splenectomy
- Low platelets <150 x 10^9/L (Thrombocytopenia)- due to Immune thrombocytopenic purpura (ITP), Thrombotic microangiopathy and Sepsis/infection. Tend to get utriculi, bruising, nose bleeds, bleeding gums, heavy periods
Coagulation screen- PT
Measures the extrinsic and common pathway
• Sample in sodium citrate blue top tube to prevent coagulation
• Centrifuged to separate blood cells from the plasma, tests plasma
• You add calcium to reverse anticoagulation
• Add phospholipid and tissue factor to trigger the extrinsic pathway
• No trigger for intrinsic pathway
• Measures time for clot formation
Coagulation screen- APPT
Measures the intrinsic and common pathway
• Sample in sodium citrate blue top tube to prevent coagulation
• Centrifuged to separate blood cells from the plasma, tests plasma
• You add calcium to reverse anticoagulation
• Add phospholipid and contact activating substance i.e. silica to trigger the intrinsic pathway
• No trigger for extrinsic pathway
• Measure time for fibrin clot to form
Coagulation screen- Fibrinogen
Can be measured from the PT. Can be increased due to inflammation (infection, cancer). Often low in DIC
Disseminated intravascular coagulation (DIC)
- Life threatening
- A disease i.e. sepsis, trauma, burns, cancer and eclampsia leads to excess tissue factor
- There is excessive thrombin generation
- Microvascular thrombi occur, damaging organs
- There is consumption of clotting factors causing bleeding
- Platelets and Fibrinogen decrease. APTT, PT and d-dimer increase
D-dimer
Measures the presence of clots like a pulmonary embolism of DIC. High levels suggest a clot is present but can also be raised in an infection
How does Warfarin affect vitamin K dependent clotting factors
Affects the pro-coagulant factors X, IX, VII, II and the Anticoagulant factors Protein C and S. Has mainly anticoagulant effect. Effects both the intrinsic, extrinsic and common pathway. Measured using an equation with PT to form the INR. Because the extrinsic pathway only has factor VII its particularly susceptible to Warfarin, also has the shortest half life so is most accurate
The INR
The INR is standard across all labs and can be compared accurately
In patients with AF, DVT or PE the INR should be between 2-3
If a patient has a mechanical heart valve it should be between 2.5-3.5
Heparin
Anticoagulant drug. Activates anti-thrombin III which activates factor Xa and Thrombin. Mostly measured with APTT
Direct oral anticoagulant
Works directly to inhibit factor Xa and Thrombin. Don’t need monitoring. The ones that work on factor Xa have Xban in the name like Apixaban.
MoA of different anticoagulant drugs
Heparin- activates antithrombin III
Warfarin- affects synthesis of factors 2,7,9,10 (and protein C and S)
Dabigatran= Direct thrombin inhibitor
Apixaban, Rivaroxaban= Anti-xa
Causes of isolated prolonged PT
1) Anticoagulant (warfarin)
2) Vitamin K deficiency
3) Liver disease
Can prolong both PT and APTT
Causes of isolated prolonged APTT
1) Lupus anticoagulant
2) Haemophilia A (VIII), B (IX) and other factor deficiencies
3) Anticoagulantion (heparin, DOAC)- can prolong both APTT and PT
Causes of Isolated prolonged PT, Isolated prolonged APTT and both being prolonged
Bad/contaminated sample
Massive haemorrhage
Disseminated intravascular coagulation
Clotting and bleeding conditions
Clotting conditions= Atrial fibrillation, Deep vein thrombosis, Pulmonary embolism, Myocardial infarction
Bleeding conditions= Anticoagulants, Antiplatelet agents, Thrombolytic/Fibrinolytic agents
The two types of thrombus= Arterial thrombus, Venous thrombus
Arterial thrombus
Arterial thrombus has a large head formed from platelets. Its mainly treated and prevented with antiplatelet drugs. The primary trigger is rupture of an atherosclerotic plaque. Fibrin rich arterial thrombus form in atrial fibrillation and myocardial infarction. Anticoagulant drugs helps to prevent arterial embolism related to AF and prevention of CAD.
Venous thrombus
Consists of a fibrin web enmeshed with red blood cells and platelets, the tail can break off giving rise to embolisms, mainly treated with anticoagulants. Antiplatelet agents help to prevent venous thromboembolic disorders.
The role of community based services
Visit patients in their own home
This enables the patient to retain as much independence as possible whilst getting their health/medications etc managed
The diversity of community based services
Community pharmacy Community nurse Ambulance service Community psychiatric teams Community midwife Health visitors Community physiotherapists
The value of community based services
Gives the patient social interaction
Reduces the burden on the patient to travel in to hospital e.g. mobility, travel costs
Improves quality of life for the patient
Promotes independence
Benefits of MDT working on patient outcomes
Improved satisfaction
Increased patient centred care - each part of their health can be focused on
A more thorough and detailed treatment plan can be given
Patient has access to an entire team of experts
Patients can have a greater say in their own care
Social care agencies that support a patient
Social services Carers Meals on wheels Care homes/sheltered housing Support
Voluntary agencies that support a patient
Charities Day care centres Social groups Community exercise groups Befriending groups
Community agencies that support a patient
Community nursing Community mental health team Ambulance service Community physiotherapists Community midwife Health visitor
Complementary medicine that support a patient
Acupuncture therapy Meditation Biofeedback Exercise/yoga Herbal remedies
