Haemostasis - Bleeding and Thrombosis Flashcards
What is the key job of the endothelium lining the blood vessel wall?
To prevent cells from sticking to the surface and therefore encourages flow
What lines an intact blood vessel wall?
Endothelium
What does endothelium produce to make it non-stick?
Heparins
Anticoagulants e.g. TFPI, thrombomodulin
Prostacyclin
Nitric oxide
What does prostacyclin prevent?
White cells and platelets from sticking to vessel walls
What do you need to form a clot?
Platelets
vWF - a big sticky factor
Coagulation factors
What do coagulation factors do?
They become activated in a coagulation cascade to produce a fibrin clot
What do natural anticoagulants do?
Once an adequate clot is formed, these substances switch off the clot
So they tell the clot that it has done its job and to stop.
Therefore the clot stops forming and is remained confined to the site of the injury
What removes the clot once it has done its job?
The fibrinolytic system
How is a clot localised?
Signals
Abnormal surface
Localised physiological activator
What happens when there is vessel damage?
Platelet adhesion
- platelets see the subendothelial collagen and stick to it - becoming sticky and active
Von Willebrand factor also has binding sites for collagen and platelets so it sticks to these to start to make the clot
Physiological activators are very localised
Platelets have a series of receptors
ADP receptors
Epinephrine receptors
Thrombin receptors
Glycoprotein receptors
What is inside a platelet?
Granules containing important chemicals involved in coagulation
Glycoprotein receptors of platelets and what they bind to
GP ia/iia binds to collagen in a damaged wall
GP iib/iiia binds to fibrinogen
GP Ib binds to von Willebrand factor
Platelets function in homeostasis
Adhere
- glycoproteins binding to factors
- holding the platelet in place where there is tissue damage
Activation
- ADP pathway (P2Y12)
- Cyclooxygenase pathway producing thromboxane
Aggregation (stick)
- thromboxane allows platelets to stick
- phospholipid membrane produced by scramblase enzyme
Provides phospholipid surface for coagulation proteins to be activated upon
Features of von Willebrand factor
Big protein around areas of damage
Contains binding sites
Capable of sticking to all the things you want it to - things that are exposed during tissue damage
Also can bring factor VIII into area of tissue damage
What is a primary haemostatic (platelet) plug?
After damaged blood vessel, platelets adhere and become activated, and bind fibrinogen
This plug on its own is not enough - it is weak and will fall apart unless stabilised by a fibrin clot
What is definitive haemostasis?
Fibrin formation
Formation of fibrin clot on top of the platelet clot
Clotting agents (cascade effect)
Factor XII Factor XI Factor IX Factor VIII Factor X Prothrombin Fibrinogen
Normal clotting sequence
Fibrin net and platelets plugs at hole in vessel wall in an injury or surgery
Fibrin clot = prevents bleeding from area of damage
What do anticoagulants to?
Resist and stop clotting factors, affecting the whole process/cascade
What would happen in the clotting if a factor was missing?
The process would become not complete, the fibrin clot does not form and the blood continues to come from the damaged vessel
In haemophilia A, what factor is deficient?
Factor VIII
In haemophilia B, what factor is deficient?
Factor IX
What binds with factor VII to activate it?
Tissue factor
What does the conversion of prothrombin to thrombin lead to?
The conversion of fibrinogen to fibrin
What happens to fibrinogen ontop of platelets?
It is cleaved to form a fibrin clot
Types of natural anticoagulants
TFPI (tissue factor pathway inhibitor)
- binds to and inactivates forms of coagulation factors
- when switches off one or two - then reduces the amount of fibrin which stops the clot forming
Protein C and S
- switching off clotting factors
- reducing the amount of thrombin and therefore reducing the clot
Antithrombin
- Inactivates factor 10 and THROMBIN
Most important natural anticoagulant
Antithrombin
What is fibrinolysis?
Breaking down the clot - the first stage to tissue repair
What happens in fibrinolysis?
Once the clot is formed, this becomes the dominant feature
Endothelium produces activators of plasminogen
- t-PA main one
- u-PA
Plasminogen is cleaved by t-PA to produce active plasmin which breaks down the fibrin clot to reorganise the vessel
Regulation of fibrinolysis
Inhibitors - PA1-1 - PA2-2 Inhibitors of plasmin (not that significant) - A2 - antiplasmin - A2 - macroglobulin
What is a D dimer?
A bit of fibrin broken down by plasmin
Antithrombotic/anticoagulant drugs
Warfarin
Heparins
Dalbigatran
Antiplatelet drugs
Aspirin
Clopidogrel/prasugrel/ticagrelor
Tirofiban/eptifibatide/abciximab
What does aspirin do?
Prevents platelets from being sticky
It can inhibit thromboxane - less likely to form clots in vessels
What does tirofiban/epitifibatide/abciximab do?
prevents activated glycoproteins from binding to fibrinogen
What does warfarin do?
Reduces the amount of 4 of the coagulation factors
- 2, 7, 9 and 10
- Vitamin K dependents
- prevents these levels by inhibiting vitamin K
- can reverse it by giving them vitamin K e.g. in bleeding
How do dabigatran etc work?
Oral inhibitor of thrombin
How do DOACs (direct oral anticoagulants) work?
Bind to active site of factor Xa and stop it from working
Two ways to initiate a clot
- Damaged surface - intrinsic pathway
2. Tissue factor - extrinsic pathway
What does thrombin convert?
Fibrinogen to fibrin
What is haemophilia?
The tendency to bleed
Why is cancer a hypercoagulable state?
Inflammatory cytokines
Less mobile
Chemo
Hypercoagulable states
Nephrotic syndrome Malignancy OCP / oestrogen therapy Pregnancy Trauma IBD Sepsis Thrombophilia
What causes circulatory stasis?
AF LV systolic dysfunction Immobility Venous insufficiency e.g. varicose veins Venous obstruction e.g. pelvic tumour, obesity, pregnancy
Symptoms of PE
Pleurisy
Chest pain
SOB
What does Wells score tell us?
The probability of PE / DVT
What scores of the wells score are PE unlikely and likely?
Likely > 4
Unlikely < 4
What scores of the wells score are DVT unlikely and likely?
Likely > 2
Unlikely < 1
What is used to investigate a DVT?
D-dimer
Doppler
When is a doppler used to investigate a suspected DVT?
If wells score > 2
What is rivoroxaban?
An anticoagulant
What does rivoroxaban block?
Factor Xa
What does heparin promote?
Antithrombin
How does warfarin work?
Affects protein C and S first
Blocks vitamin K (need this to make factors active)
What is used with warfarin? When?
LMWH
Not active before INR becomes therapeutic
What do protein C and S do?
Accelerate destruction of VIII and V
When is there a high rate of relapse of DVT / PE? Therefore how long would you carry on treatment for?
First 3 - 6 months
Carry on Tx for 6 months
What involves thromboprophylaxis?
LMWH
Stockings
Mobilisation
Causes of thrombophilia
Acquired (5 most common) - malignancy - nephrotic syndrome - antiphospholipid syndrome - heparin induced thrombocytopenia Hereditary - protein C or S deficiency - Prothrombin mutation - Factor V leidein mutation - Antithrombin III deficiency
What type of inheritance is factor V Leiden deficiency?
Autosomal dominant
How does factor V leiden work?
Resists destruction from protein C
What factors does protein C destroy?
5 and 8
What type of inheritance is Protein C and S deficiency?
Autosomal dominant
What type of inheritance is antithrombin III deficiency?
Autosomal dominanttt
Acquired causes of antithrombin III deficiency
nephrotic syndrome
Liver disease
DIC
pregnancy
Does liver disease make you bleed or clot?
Both
Due to not making either of the factors
Diagnosis of thrombophilia
Test for genes
Test for factors
Check for antiphospholipid syndrome
What can be the first sign of cancer in some people?
Clot
Who gets purpura fulminans?
Children
Why is thrombophilia testing in pregnancy less reliable?
As you are already protein S deficient
Pathology of heparin induced thrombocytopenia
Antibodies against heparin as body sees it as foreign
How long after heparin does HIT take to develop?
5 - 10 days after as antibodies take time to make
Tx of HIT
Take off
Give alternative
What stops you bleeding?
Vascular constriction
Collagen and von Willebrand factor exposed
Platelet activation, adherence and aggregation
Platelet plug formed
How many platelets are needed for surgery?
100
How many platelets are needed for minor surgery?
50
What level of platelets do purpura appear?
< 30
What level of platelets do spontaneous bleeding occur?
< 10
Causes of thrombocytopenia
Liver disease - reduced thrombopoietin production
Bone marrow failure
Platelets pooled in enlargened spleen
Major haemorrhage
DIC
Autoimmune platelet destruction (immune thrombocytopenic purpura)
HIT
Causes of reduced marrow production
Cancer
Chemo
Aplastic anaemia
Vitamin deficiency (B12 or folate)
Who does ITP occur in?
Children and teenagers often after a viral illness e.g. glandular fever
Autoimmune in adults
When should ITP be treated?
If platelets < 30
Pathology of DIC
Tissue factor can be activated by endotoxin, snake bites, TNF etvc
Activated factor VII, and also IX, XI, and XII
Excess thrombin binds to fibrinogen, thus creating fibrin clots which trap platlets
This causes clot using up platelets and clotting factors
Tx of DIC
Remove underlying cause
FFP
Platelets
Tx of ITP
Steriods / immunosuppressants
IV immunoglobulins
Spleenectomy
Dapsone / anti D
What is the reversal agent for dabigatran?
Idarucizumab
