Cardiovascular systems 12 - Haemostasis Flashcards
Describe the composition of the blood and surrounding tissue when haemostasis is at rest.
- Factors and cofactors are all separated
- The endothelium is intact
- Collagen and tissue factor contained in the subendothelial tissue.
Describe the structure of Von Willeband factor.
- Usually in a rolled up form
- When bound to collagen, the force of blood flow unwinds it to become a long thin molecule
- It has multiple binding sites
Describe the key features of platelet structure.
- ADP receptor
- Thromboxane receptor
- GP1b-alpha complex binds to von willeband factor
- GP1a and GPV1 bind to collagen
Describe the process that occurs in the formation of a platelet plug in primary haemostasis.
- Von Willeband factor binds to collagen exposed by vessel damage, and unwinds due to blood flow
- Platelets are captured as they go past, as receptors for them are exposed when Von Willeband factor is unwound
- Platelets are activated to release granules by calcium influx, which contain more Von Willeband factor.
- Platelets are linked by fibrinogen.
Describe what changes occur in activated platelets.
- They change shape
- Expose phospholipid
- Present new activated proteins on their surface, such as GpIIb/IIa.
What do the granules released from platelets contain?
- Dense granules release ADP, which binds to receptors on platelets
- Alpha granules released von willeband factor
Apart from granule release, what else is released by activated platelets?
The platelet uses lipids from the membrane to produce thromboxane, to which they have receptors for. This causes positive feedback.
What vessels is primary haemostasis sufficient for?
Small vessels - larger vessels require stabillisation with fibrin
Describe what occurs in coagulation up to thrombin formation.
- There is formation of a fibrin mesh, also known as secondary haemostasis
- Tissue factor binds to Factor VII
- This activates conversion of factor ix to its active form, as well as conversion of factor x to its active form.
- Activated fxa converts factor II to thrombin
What are the sites of synthesis for clotting factors, fibrolytic factors and inhibitors?
- The liver (main site)
- Endothelial cells
- Megakaryocytes
Describe the regulatory reactions that occur in coagulation.
- Factor x is converted to inactive forms by TFPI, tissue factor pathway inhibitor
Following initial thrombin production, what are the next stages of coagulation?
- Activates factors V and VIII
- Factor VIII forms a complex with factor ixa (an enzyme), calcium on the surface phospholipids released from platelets
- The same occurs with activated factor V, though the enzyme is factor x
- There is also conversion of fxi to its active form, which makes some more ix
- This makes more thrombin, which converts soluble fibrinogen to insoluble fibrin which forms a mesh
Describe the pattern of thrombin production following activation
There is a lag while factor Va and VIIIa are activated, which causes a rush of thrombin production.
Describe the function of the thrombin burst
- Generates a stronger, denser clot more resistant to fibrinolysis
- Factor xiii is activated by thrombin, which cross links fibrin to inhibit fibrinolysis
- Activates TAFI which inhibits fibrinolysis
What are the direct inhibitory mechanisms in anticoagulation?
- Antithrombin is an inhibitor of thrombin and other clotting proteinases
- TFPI in the initiation phase
What is the indirect inhibitory mechanism of coagulation?
- Inhibition of thrombin generation by the protein C anticoagulant pathway
Describe the function of antithrombin.
- It directly binds to thrombin (factor IIa) and neutralises it
- Heparin makes the antithrombin more active, and helps binding to thrombin
- In hibits xa, ixa and xia
Describe the protein C pathway
- Thrombin binds to thrombomodulin and is redirected. It is no longer a procoagulant molecule, instead it activates protein C
- Activated protein C breaks down factor Va and factor VIIIa, using protein S as a cofactor
Describe the process of fibrolysis
- TIssue plasminogen activator and plasminogen bind together on the fibrin
- Plasminogen is converted to active plasmin, an enzyme which breaks down fibrin to fibrin degredation product
- Plasmin is regulated by antiplasmin
List the characteristics of abnormal bleeding
Bleeding that is:
- Spontaneous
- Put of proportion with the injury
- Unduly prolonged
- Restarts after appearing to stop
What is the deficiency in the defects of primary haemostasis?
- Collagen
- Von willeband factor
- Platelets
What are the common examples of causes of deficient primary haemostasis?
- Steriod therapy/age (collagen)
- Von willeband disease
- Aspirin/thrombocytopenia (platelet)
Describe the pattern of bleeding in defects of haemostasis.
- Immediate
- Easy bruising
- Frequent nosebleeds over 20 mins
- Gum bleeding
- Menorrhagia (anaemia- heavy menstral bleeding)
- Bleeding after trauma
- Petechiae
What are petechiae?
- Red spots on the skin typical of thrombocytopenia (low levels of platelets)
- Due to damage to capillaries that is unrepaired
What is deficient if a patient has a defect of secondary haemostasis?
- Lack of coaglation factors, poor thrombin burst, and poor fibrin mesh
List some examples of defects of secondary haemostasis.
- Haemophilia (factor VIII or factor Ix deficiency)
- Liver disease
- Drugs, such as warfarin which inhibits synthesis
- Dilution due to volume replacement
- Consumption (DIsseminated intravasculr coagulation)
What is disseminated intravascular coagulation?
- Generalised activation of coagulation (tissue factor is inside the vasculature)
- Associated with sepsis, major tissue damage, inflammation
- Consumes and depletes coagulation factors and platelets.
- The activation of fibrinolysis depretes fibrinogen
What is the consequence of disseminated intravascular coagulation?
- Widespread bleeding from IV lines (bruising/internal)
- Deposition of fibrin in vessels causes organ failure
What is the pattern of bleeding in defects of secondary haemostasis?
- It is delayed due to successful primary haemostasis
- Deep, in the joints and muscles
- Not from small cuts
- Nosebleeds are rare
- Bleeding after trauma/intramuscular injections
What is ecchymosis?
Easy bruising
What is haemarthrosis?
Bleeding into joint spaces, a common feature of haemophilia. It results in swelling of the joint and pain.
What causes excess fibrinolysis?
- Excess fibrinolytic (plasmin/tPA)
- Deficient antifibrinolytic (antiplasmin)
List causes of excess fibrinolysis
- Therapeutic administration/tumours cause excess fibrinolytic
- Antiplasmin defiency is genetic
What causes anticoagulant excess?
Usually therapeutic administration - heparin/thrombin and factor xa inhibitors
What is thrombosis?
- Innappropriate coagulation inside a blood vessel
- Not preceded by bleeding
- May be venous or arterial
What are the effects of thrombosis?
Obstructed blood flow
- Artery - myocardial infarction, stroke, limb ischaemia
- Vein - pain and swelling
Embolism (migration of thrombus)
- Venous emboli to the lungs (pulmonary)
- Arterial emboli from the heart, causing stroke/limb ischaemia
What is the prevalence of venous thromboembolism?
- Overall 1 in 1000/1-10000 per annum (age dependent)
- Indicence doubles each decade
- Causes 10% of hospital deaths
- 25k preventable deaths a year
List the consequences of thromboembolism?
- Death
- Recurrance (20% in first 2 years and 4% per year after)
- Thrombophlebitic syndrome (chronic leg pain)
- Pulmonary hypertension
What risk factors are there for thrombosis?
- Genes
- Effects of age, illness, previous events/medication
- Acute stimulus
- This is a cumulative risk from interaction of these risk factors
What is virchows triad?
There are three factors contributing to thrombosis, which may be genetic or aquired.
- Blood (hypercoaguability - dominant in venous thrombosis)
- Vessel wall (injury - dominant in arterial thrombosis)
- Flow (stasis/turbulent - contributes to both)
What deficiencies/excesses can contribute to increased thrombosis risk?
- Deficiency of anticoagulant proteins (antithrombin, protein C/protein S)
- Excess of coagulant proteins (factor VIII, factor II, factor V leiden, Thrombocytosis)
- Factor V leiden is increased activity due to protein C resistance
- Thrombocyteosis is increased platelets
What can cause turbulent flow?
- Surgery
- Fracture
- Long haul flight
- Bed rest
What is thrombophilia?
- Increased risk of thrombosis
- Thrombosis occurs at a young age
- There are multiple thromboses
- Thrombosis occurs while anticoagulated
- There is an identifiable cause of increased risk
What conditions alter blood coagulation, vessel wall/flow to increase likelihood of thrombosis?
- Pregnancy
- Malignancy
- Surgery
- Inflammatory response
What is the treatment for venous thrombosis?
- Treatment to lyse clot (eg. tissue plsaminogen activator)
- Increase anticoagulant activity (heparin)
- Lower procoagulant factors (warfarin)
- Inhibit procoagulant factors (direct inhibitors)
