What are the 3 general principles of haemostasis?
- Clot production
- Clot control
- Clot breakdown
What are the essentials for haemostasis?
- blood needs to keep moving
- platelets
- coagulation factors
- anticoagulant factors
Describe the steps in clot initiation, clot formation and fibrinolysis.
- Vessel wall is damaged (extrinsic)
- Platelets aggregate
- Coagulation is activate d
- Thrombin converts fibrinogen into fibrin
- Fibrin polymerises
- Fibrin is broken down into fragments
How are platelets produced?
Produced by megakaryocytes in the bone marrow - platelets bud off from the cytoplasm of megakaryocytes
What is the normal platelet count and oral life span?
150-400x10(9)/L
7-10 days
How do platelets adhere to the damaged vessel wall?
They adhere to collagen (exposed in the damaged vessel wall) via platelet receptors binding to vWF
How are platelets activated?
Platelets secrete ADP, thromboxane and others substances to activate themselves and to activate other platelets
This is part of activating the clotting cascade
- They also release some coagulation factors buy secretion from internal stored
How do platelets aggregate?
They cross-link with other platelets to form a platelet plug
What are some mediating factors of platelet plug formation?
- platelet receptors
- Von willebrands factor (vWF)
- fibrinogen
- collagen
- ADP
- thromboxane/arachidonic acid
- thrombin
What is the clotting cascade?
An amplification system that activates precursor proteins to generate thrombin (IIa). Thrombin then converts soluble fibrinogen into insoluble fibrin which entangles with the platelet plug to make a stable clot.
This is a controlled process
What controls the clotting cascade?
- natural anticoagulants inhibit activation
* clot destroying proceedings that are activated by the clotting cascade
Where are coagulation factors made?
In the liver
What are the coagulation factors?
- fibrinogen (I)
- prothrombin (II)
- factor V
- factor VII
- factor VIII
- factor IX
- factor X
- factor XI
- factor XIII
- tissue factor
What are the natural anticoagulants?
- protein C
- protein S
- antithrombin
- tissue factor pathway inhibitor
Where does tissue factor pathway inhibitor (TFPI) act to inhibit coagulation?
Inhibits activation of factor VII
Where does antithrombin act to inhibit coagulation?
Acts to inhibit activation of factor X and action of thrombin (activation of fibrin)
Where does protein C act to inhibit coagulation?
Acts to inhibit activation of factor VIII and activation of factor V
How does protein S act to inhibit coagulation?
Protein S activates protein C (protein C + thrombomodulin —> activated protein C)
The clotting cascade is an example of positive feedback, how do products of the cascade activate further action of the cascade?
Thrombin (IIa) stimulates factor XI and factor VIII, factor V and factor XIII activation but also stimulates protein C + thrombomodulin
What are the three pathways in the clotting cascade? What does each activate?
- extrinsic (endothelial cell injury/trauma) - tissue factor activation
- intrinsic (damaged surface) - contact activation
- common
What factors are involved in the extrinsic pathway?
- factor VII
What factors are involved in the intrinsic pathway?
- factor XII
- factor XI
- factor IX
- factor VIII
What factors are involved in the common pathway?
- factor X
- thrombin (II)
- fibrin (I)
How can coagulation be measured?
- Using PT, APTT and TT
- fibrinogen count
- D dimers
What does prothrombin time (PT) measure?
Measures the extrinsic and common pathway (factors VII, V, X, prothrombin and fibrinogen)
What is INR?
International normalised ratio
Calculated from PT and is used to measure warfarin
What does activated partial thromboplastin time (APTT) measure?
Measures the intrinsic and common pathway (factors VIII, IX, XI, XII, V, X, prothrombin and fibrinogen)
What does fibrinogen count measure?
Measures the amount of fibrinogen
What does D dimers count measure?
Measures the fibrin degradation product
What is TT?
Thrombin time or thrombin clotting time (TCT)
Time taken to produce thrombin from prothrombin (time taken to form a clot)
What is Von Willebrand Factor (vWF)?
A factor involved in platelet adhesion to the vessel wall, platelet aggregation and it also carries factor VIII
What happens to the vessel wall when it is damaged?
- vasoconstriction
- production of vWF - platelet adhesion and carrier of factor VIII
- exposure of collagen and tissue factor - initiates the activation of clotting factors (proteins)
What do natural anticoagulants do?
Stop further coagulation
What are the 3 natural anticoagulants?
- protein C
- protein S
- anti-thrombin
What is fibrinolysis?
Break down of the fibrin clot
How does fibrinolysis occur?
- A plasminogen activator catalyses plasminogen to convert to plasmin
- Plasmin catalyses the break down of the fibrin clot into D-Dimers
How do bleeding disorders arise?
Due to abnormalities in the vessel wall, platelets or coagulation factors
Can be inherited or acquired
What are some congenital coagulation factor disorders?
- haemophilia A (factor VIII)
* haemophilia B (factor IX)
What are some acquired coagulation factor disorders?
- liver disease
- vitamin K deficiency
- anticoagulants inc. warfarin which inhibits vitamin K
What signs and symptoms can coagulation factor disorders lead to?
- muscle haematomas
- recurrent haemarthroses (bleeding into joints)
- joint pain and deformity
- prolonged bleeding post dental extraction
- life threatening post op and post traumatic bleeding
- intracerebral haemorrhage
What is the inheritance of haemophilia A? What is it? What can it cause? How is it treated?
- x-linked recessive
- a congenital lack of factor VIII (can be mild/moderate/severe dependent on the amount of factor present)
- bleeding into muscles and joints
- treated with recombinant factor VIII (or DDAVP)
When is haemophilia A diagnosed? What abnormalities would you expect to see in the blood results?
- diagnosed pre-natally/soon after birth if theres a family history or in infancy if a new spontaneous mutation
- prolonged APTT
What is haemophilia B?
- has a similar presentation to haemophilia A
* due to a congenital reduction in factor IX
What is Von Willebrand’s Disease?
- a common autosomal dominant disease
- abnormal platelet adhesion to vessel wall
- reduced amount/reduced activity of factor VIII
- main defect is due to a reduction in vWF production
How does vWD present clinically?
- skin and mucous membrane bleeding (epistaxis - nose bleeding, gum bleeding, bruising)
- prolonged bleeding after trauma (heavy periods, post surgery, post dental extraction)
How can vessel wall abnormalities present clinically?
- easy bruising
- spontaneous bleeding from small vessels
- affects skin and mucous membranes
What problems can you have with blood vessels?
- congenital - hereditary haemorrhagic telangiectasia (HHT) - autosomal dominant, dilated micro vascular swellings that increase with time and GI haemorrhage leading to iron deficiency anaemia
- acquired - senile purpura, steroids, infections, scurvy/vit C deficiency causing defective collagen production
What is disseminated intravascular coagulopathy (DIC)?
- type of microangiopathic haemolytic anaemia
- pathological activation of coagulation
- many microthrombi form in circulation
- leads to consumption of clotting factors and platelets and haemolytic anaemia develops
What will clotting tests show for someone with DIC?
- raised PT/INR
- raised APTT
- low fibrinogen
- raised D dimers/fibrin degradation products
What will a blood film for DIC show?
Schistocytes due to haemolysis
How does DIC occur?
There must be a trigger:
- malignancy
- massive tissue injury e.g. burns
- infections - gram -ve sepsis (bacteria release endotoxins which activate coagulation)
- massive haemorrhage and transfusion
- ABO transfusion reaction
- obstetric cause - placental abruption, pre-eclampsia (high BP and protein in urine), amniotic fluid embolism
How do you treat DIC?
- treat the underlying cause
* transfusion of plasma which contains clotting factors (fresh frozen plasma (FFP) or cryoprecipitate)
What are thrombophilias?
- acquired or congenital defects of haemostasis that increase patients risk of thrombosis
- congenital - deficiency of natural anticoagulants or abnormal factor V (factor V Leiden)
- acquired - antiphospholipid syndrome (immune system disorder)
What are four types of plasminogen activator?
- tissue plasminogen activator - circulates in the blood
- urokinase - found in urine
- streptokinase - usually not present in the body
- alteplase - recombinant tissue plasminogen activator
Why are plasminogen activators used therapeutically?
They dissolve fibrin and so thrombi and thrombolemboli
Why should streptokinase only be given once?
As it is antigenic
What is a side effect of plasminogen activators?
Bleeding (of gums and nose and more seriously the brain)
What is thrombocytopenia? When does spontaneous bleeding occur?
A platelet count of less than 100x10(9)/L
When platelet count is less than 20x10(9)/L
How will PT, APTT and bleeding time present for someone with thrombocytopenia?
Bleeding time - prolonged
PT - normal
APTT - normal
Where can spontaneous bleeding due to thrombocytopenia occur? What can this present as on the skin?
Bleeding from small vessels in: * skin * GI tract * genitourinary trac (* intracerebral)
Petechiae
What are the 4 possible causes of thrombocytopenia?
- decreased platelet function - due to bone marrow malignancy, drugs, infections, B12/folate deficiency
- decreased platelet survival - immunological destruction (immune thrombocytopenic purpura) or non-immunological destruction (DIC)
- sequestration - hypersplenism
- dilutional - massive blood transfusions
When is warfarin used?
- prophylaxis and treatment for thrombosis
- atrial fibrillation - risk of clot formation in heart
- heart surgery - artificial heart valves tend to form clots on surface
How does warfarin work?
Prevents formation of vitamin k dependent clotting factors e.g. factors II, VII, IX and X
If patient is taking warfarin, what can a high INR suggest?
The dose of warfarin is too high or if a patient is also on antibiotics, the antibiotics are interfering with the warfarin metabolism
What treatments can reverse the action fo warfarin?
- give vitamin K (but takes a few days to work)
* give prothrombin complex concentrate (prothrombin and factor VIII) - quicker acting
What do rivaroxaban and apixiban inhibit?
Inhibit factor Xa
What does dabigatran inhibit?
Inhibits thrombin
What are the advantages and disadvantages of these newer anticoagulant drugs?
Advantage - don’t need to measure INR and can give once a day
Disadvantage - not sure how to reverse the effects