Cardiovascular systems 12 - Haemostasis Flashcards
1
Q
Describe the composition of the blood and surrounding tissue when haemostasis is at rest.
A
- Factors and cofactors are all separated
- The endothelium is intact
- Collagen and tissue factor contained in the subendothelial tissue.
2
Q
Describe the structure of Von Willeband factor.
A
- 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
3
Q
Describe the key features of platelet structure.
A
- ADP receptor
- Thromboxane receptor
- GP1b-alpha complex binds to von willeband factor
- GP1a and GPV1 bind to collagen
4
Q
Describe the process that occurs in the formation of a platelet plug in primary haemostasis.
A
- 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.
5
Q
Describe what changes occur in activated platelets.
A
- They change shape
- Expose phospholipid
- Present new activated proteins on their surface, such as GpIIb/IIa.
6
Q
What do the granules released from platelets contain?
A
- Dense granules release ADP, which binds to receptors on platelets
- Alpha granules released von willeband factor
7
Q
Apart from granule release, what else is released by activated platelets?
A
The platelet uses lipids from the membrane to produce thromboxane, to which they have receptors for. This causes positive feedback.
8
Q
What vessels is primary haemostasis sufficient for?
A
Small vessels - larger vessels require stabillisation with fibrin
9
Q
Describe what occurs in coagulation up to thrombin formation.
A
- 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
10
Q
What are the sites of synthesis for clotting factors, fibrolytic factors and inhibitors?
A
- The liver (main site)
- Endothelial cells
- Megakaryocytes
11
Q
Describe the regulatory reactions that occur in coagulation.
A
- Factor x is converted to inactive forms by TFPI, tissue factor pathway inhibitor
12
Q
Following initial thrombin production, what are the next stages of coagulation?
A
- 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
13
Q
Describe the pattern of thrombin production following activation
A
There is a lag while factor Va and VIIIa are activated, which causes a rush of thrombin production.
14
Q
Describe the function of the thrombin burst
A
- 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
15
Q
What are the direct inhibitory mechanisms in anticoagulation?
A
- Antithrombin is an inhibitor of thrombin and other clotting proteinases
- TFPI in the initiation phase
16
Q
What is the indirect inhibitory mechanism of coagulation?
A
- Inhibition of thrombin generation by the protein C anticoagulant pathway
17
Q
Describe the function of antithrombin.
A
- 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
18
Q
Describe the protein C pathway
A
- 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
19
Q
Describe the process of fibrolysis
A
- 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
20
Q
List the characteristics of abnormal bleeding
A
Bleeding that is:
- Spontaneous
- Put of proportion with the injury
- Unduly prolonged
- Restarts after appearing to stop
21
Q
What is the deficiency in the defects of primary haemostasis?
A
- Collagen
- Von willeband factor
- Platelets
22
Q
What are the common examples of causes of deficient primary haemostasis?
A
- Steriod therapy/age (collagen)
- Von willeband disease
- Aspirin/thrombocytopenia (platelet)
23
Q
Describe the pattern of bleeding in defects of haemostasis.
A
- Immediate
- Easy bruising
- Frequent nosebleeds over 20 mins
- Gum bleeding
- Menorrhagia (anaemia- heavy menstral bleeding)
- Bleeding after trauma
- Petechiae
24
Q
What are petechiae?
A
- Red spots on the skin typical of thrombocytopenia (low levels of platelets)
- Due to damage to capillaries that is unrepaired
25
What is deficient if a patient has a defect of secondary haemostasis?
- Lack of coaglation factors, poor thrombin burst, and poor fibrin mesh
26
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)
27
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
28
What is the consequence of disseminated intravascular coagulation?
- Widespread bleeding from IV lines (bruising/internal)
| - Deposition of fibrin in vessels causes organ failure
29
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
30
What is ecchymosis?
Easy bruising
31
What is haemarthrosis?
Bleeding into joint spaces, a common feature of haemophilia. It results in swelling of the joint and pain.
32
What causes excess fibrinolysis?
- Excess fibrinolytic (plasmin/tPA)
| - Deficient antifibrinolytic (antiplasmin)
33
List causes of excess fibrinolysis
- Therapeutic administration/tumours cause excess fibrinolytic
- Antiplasmin defiency is genetic
34
What causes anticoagulant excess?
Usually therapeutic administration - heparin/thrombin and factor xa inhibitors
35
What is thrombosis?
- Innappropriate coagulation inside a blood vessel
- Not preceded by bleeding
- May be venous or arterial
36
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
37
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
38
List the consequences of thromboembolism?
- Death
- Recurrance (20% in first 2 years and 4% per year after)
- Thrombophlebitic syndrome (chronic leg pain)
- Pulmonary hypertension
39
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
40
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)
41
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
42
What can cause turbulent flow?
- Surgery
- Fracture
- Long haul flight
- Bed rest
43
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
44
What conditions alter blood coagulation, vessel wall/flow to increase likelihood of thrombosis?
- Pregnancy
- Malignancy
- Surgery
- Inflammatory response
45
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)
