1B haemostasis Flashcards
(86 cards)
1
Q
What is haemostasis?
A
The cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult
2
Q
What is haemostasis for?
A
- Prevention of blood loss from intact vessels
- Arrest bleeding from injured vessels
- Enable tissue repair
3
Q
Describe the overall mechanism of haemostasis
A
1) Injury to endothelial cell lining
2) Vessel constriction and vascular smooth muscle cells contract locally to limit blood flow to injured vessel
3) Primary Haemostasis: Formation of unstable platelet plug. Platelet adhesion and aggregation to vessel wall (via VWF) and each other. This limits blood loss and provides surface for coagulation.
4) Secondary haemostasis: Stabilisation of plug with fibrin. Causes blood coagulation to stop blood loss.
5) Fibrinolysis: Vessel repair and dissolution of clot. Cell migration/proliferation and fibrinolysis. Restores vessel integrity.
4
Q
Why do we need to understand homeostatic mechanisms?
A
- Diagnose and treat bleeding disorders
- Control bleeding in individuals who don’t have an underlying bleeding disorder
- Identify risk factors for thrombosis
- Treat thrombotic disorders
- Monitor drugs used to treat bleeding and thrombotic disorders
5
Q
What is haemostasis a balance between?
A
- Bleeding (fibrinolytic factors, anticoagulant proteins)
- Thrombosis (coagulant factors, platelets)
6
Q
When can the balance in homeostasis be tipped towards bleeding?
A
When there’s either:
- Too many fibrinolytic factors or anticoagulant proteins
- Not enough coagulant factors or platelets
7
Q
What are the types of causes for a lack of coagulant factors?
A
- Lack of specific factor
- failure of production: congenital and acquired
- increased consumption/clearance
- Defective function of a specific factor
- genetic
- acquired: drugs, synthetic defect, inhibition
8
Q
Describe what is happening in this diagram
A
- Platelets can adhere directly to vessel wall through GP1a receptor or via VWF via GP1b receptor
- Platelets need to release granular contents and they become activated along with thromboxane release
- Leads to flip flopping and activation of GP2b/3a receptors on platelets
9
Q
Causes of disorders of primary haemostasis
A
-
Platelets
- Low numbers, i.e. thrombocytopenia
- Impaired function of platelets
-
VWF
- Von Willebrand disease
-
Vessel wall
- Inherited diseases (rare)
- Acquired (common)
10
Q
What can low numbers of platelets be due to?
A
- Bone marrow failure e.g. leukaemia, B12 deficiency
- Accelerated clearance, e.g. disseminated intramuscular coagulation (DIC), immune thrombocytopenic purpura (ITP)
- Pooling and destruction in an enlarged spleen
11
Q
Describe how ITP works
A
- Antiplatelet antibodies bind to sensitised platelets
- Macrophages of reticular endothelial system in spleen clear these platelets
- ITP is v common cause of thrombocytopenia
12
Q
What can impaired function of platelets be due to?
A
- Inherited causes due to hereditary absence of glycoproteins or storage granules (rare)
- Glanzmann’s thrombasthenia
- Bernard Soulier syndrome
- Storage pool disease
- Acquired due to drugs: aspirin, NSAIDS, clopidogrel (common)
13
Q
What is Glanzmann’s thrombasthenia?
A
Absence of GP2b/3a receptor
14
Q
What is Bernard Soulier syndrome?
A
Absence of GP1b receptor
15
Q
What is storage pool disease?
A
Reduction in contents of dense granules of platelets
16
Q
What is antiplatelet therapy used for?
A
Prevention and treatment of cardiovascular and cerebrovascular disease
17
Q
How does clopidogrel work?
A
Blocks ADP receptor P2Y12 on platelets
18
Q
What are some causes of Von Willebrand disease?
A
- Hereditary decrease of quantity (and sometimes function)- common
- Acquired due to antibody- rare
19
Q
What are the two main functions of VWF in haemostasis?
A
- Binding to collagen and capturing platelets
- Stabilising factor VIII (factor VIII may be low if VWF is very low)
20
Q
Describe the inheritance of VWD
A
- Autosomal inheritance pattern
- Deficiency of VWF is type 1 or 3
- VWF with abnormal function is type 2
21
Q
What are some inherited diseases that affect the vessel wall that can cause a problem in primary haemostasis?
A
- Hereditary haemorrhagic telangiectasia (connections between arteries and veins prone to bleeding)
- Ehlers-Danlos syndrome and other connective tissue disorders
22
Q
What are some acquired diseases that affect the vessel wall that can cause a problem in primary haemostasis?
A
- Steroid therapy
- People on long term steroids can develop atrophy of collagen fibres supporting blood vessels in skin
- Ageing (senile purpura)
- Dark purple, well defined margins that don’t undergo same colour changes as a bruise and can take up to 3 weeks to resolve
- Most commonly on extensor surfaces and dorsal aspects of hands
- Scurvy (vit C deficiency)
- Defects in collagen synthesis leading to weakening of capillary walls
- Vasculitis
23
Q
What are the clinical features of disorders of primary haemostasis?
A
- Immediate bleeding
- Prolonged bleeding from cuts
- Nose bleeds (epistaxis)- are prolonged if >20 mins
- Gum bleeding- prolonged
- Heavy menstrual bleeding (menorrhagia)
- Bruising (ecchymosis), may be spontaneous/easy
- Prolonged bleeding after trauma/surgery
24
Q
What is a particular feature of thrombocytopenia?
A
Petechiae- small spots under skin caused by bleeding under skin
25
In what types of disorders do we see purpura?
- Platelet disorders (thrombocytopenic purpura)
- Vascular disorders (sometimes called wet purpura when its over mucosal surfaces like gums)
26
How to tell the difference between petechiae and purpura?
- Both caused by bleeding under skin
- Purpura don’t blanch when pressure is applied
- Petechiae are <3mm in size and purpura is 3-10mm → it’s called bruising when >10mm
27
What is the bleeding pattern like in severe VWD?
Haemophilia-like bleeding (due to low FVIII)
28
What are the tests for disorders of primary haemostasis?
- Platelet count, platelet morphology (often not seen under light microscopy and electron microscope needed)
- Bleeding time (PFA100 in lab)- we used to make an incision in skin and measure time it took for bleeding to stop- brutal and not sensitive/specific so replaced with PFA1000
- Assays of VWF
- Clinical observation
Note: coagulation screen (PT, APTT) are usually normal in primary haemostasis disorders (except more severe VWD cases where FVIII is low)
29
What do we give for failure of production or function?
- Replace missing factor/platelets e.g. VWF containing concentrates
- Can be prophylactic e.g. before surgery or therapeutic e.g. after bleeding
- Stop drugs e.g. aspirin/NSAIDs
- Stop drugs e.g. aspirin/NSAIDs
30
What do we give for immune destruction?
- Immunosuppression e.g. prednisolone
- Splenectomy for ITP
31
What do we give for increase in consumption e.g. in DIC?
- Treat underlying cause
- Replacement therapy as necessary
32
What additional haemostatic treatments for primary homeostasis disorders are there?
- Desmopressin (ddAVP)- vasopressin analogue which causes 2-5x increase in VWF (and FVIII)- releases endogenous stores so only useful in mild disorders
- Tranexamic acid- it’s antifibrinolytic
- Fibrin glue/spray
- Other approaches e.g. hormonal (oral contraceptive pill for menorrhagia)
33
What is the role of coagulation?
To generate thrombin (factor IIa) which converts fibrinogen into fibrin
34
What would a deficiency of any coagulation factor cause?
A failure of thrombin generation and hence fibrin formation
35
What are the main causes of disorders of coagulation?
- Deficiency of coagulation factor production
- Dilution
- Increased consumption
36
What are the two types of coagulation factor production deficiency?
- Hereditary
- Acquired
37
What is an example of hereditary coagulation factor production deficiency?
Haemophilia
38
What is haemophilia A?
- Factor VIII deficiency
- Sex linked
39
What is haemophilia B?
- Factor IX deficiency
- Sex linked
40
What do both haemophilia A and B do mainly?
- Cause a failure to generate fibrin to stabilise platelet plug
- Platelet plug breaks away leading to bleeding
41
What is the hallmark of haemophilia?
**Haemarthrosis**
- Spontaneous bleeding of joints when factors are low
- Usually seen in more developing countries because factor replacement therapy is more accessible in developed countries
42
What happens long term with haemarthrosis?
- Causes chronic haemarthrosis with target joints having recurrent bleeds and damaging the synovial lining leading to joint deformity
- Muscle wasting occurs
43
What happens if an intramuscular injection is given to a haemophilia patient?
There is extensive haematoma that occurs
44
Is haemophilia compatible with life?
Yes
45
Is factor II (prothrombin) deficiency compatible with life?
No, it is lethal
46
What does factor XI deficiency lead to?
Bleed after trauma but not spontaneously (so not as severe as haemophilia)
47
What does factor XII deficiency lead to?
No bleeding at all
48
What are examples of acquired coagulation factor production deficiency?
- Liver disease: liver produces most coagulation factors (apart from VWF made by endothelial cells and FV made by platelets) so liver failure will mean decreased production
- Anticoagulant drugs like warfarin and Direct Oral Anticoagulants (DOACs)
49
What is dilution causing coagulation disorder caused by?
- Can be acquired through red cell transfusions that don't have plasma
- A major haemorrhage requires a transfusion of plasma as well as red cells and platelets to avoid dilutional effect with reduction in coagulation factors
50
What is a common cause of increased consumption of coagulation factors and platelets?
Disseminated intravascular coagulation (DIC)
51
What happens in DIC?
- **Generalised activation of coagulation due to tissue factor** (which usually doesn’t come into contact with FVIIa)
- Consumes and depletes coagulation factors and platelets consumed leading to **thrombocytopenia**
- Activation of fibrinolysis depletes fibrinogen: **raises D-dimer** (a breakdown product of fibrin)
- Deposition of fibrin in vessels occurs: causes **organ failure**, shearing of RBCs causing **red cell fragmentation**
52
What can DIC be triggered by?
- Sepsis
- Inflammation
- Major tissue damage
- Pre-eclampsia
53
How do we treat DIC?
- Treat underlying cause
- Meanwhile we give supportive treatment with replacement of missing coagulation factors i.e. giving FFP and platelets
54
What is a rare cause of increased consumption of coagulation factors and platelets?
Immune- autoantibodies
55
What are the clinical features of coagulation disorders?
- Superficial cuts don’t bleed (because platelets are working fine and platelet plug is sufficient)
- Bruising is common, nosebleeds are rare
- Spontaneous bleeding is deep, into muscles and joints
- Bleeding after trauma may be delayed and is prolonged
- Bleeding frequently restarts after stopping
56
What are key differences between platelet/vascular deficiencies and coagulation deficiencies?
- **Platelet/vascular**
- Superficial bleeding into skin, mucosal membranes
- Bleeding immediate after injury
- **Coagulation**
- Bleeding into deep tissues, muscles and joints
- Delayed, but severe bleeding after injury and bleeding often prolonged
57
What tests are there for coagulation disorders?
- Screening tests ('clotting screen')
- Coagulation factors assays (for Factor VIII, etc)
- Tests for inhibitors
58
What are examples of screening tests for coagulation disorders?
- Prothrombin time (PT)
- Activated partial thromboplastin time (APTT)
- Full blood count (platelets)
59
What could cause a PT of 10.6s (9.6-11.6) and APTT of 85s (26-32)?
Deficiencies in intrinsic pathway factors
- Haemophilia A (factor VII deficiency)
- Haemophilia B (factor IX deficiency)
- Factor XI deficiency
- Factors XII deficiency
60
What could cause a PT of 26s (9.6-11.6) and APTT of 29s (26-32)?
Factor VII deficiency (extrinsic pathway factor deficiency)
61
What could cause a PT of 26s (9.6-11.6) and APTT of 49s (26-32)?
- Liver disease
- Anticoagulants like warfarin
- DIC (platelets and D dimer)
- Dilution following red cell transfusion
- Deficiency of factors II, V, X (the common factors in both pathways)
62
What are the treatments for coagulation disorders?
Factor replacement therapy
63
What does plasma (FFP) include?
Contains all coagulation factors
64
What does cryoprecipitate include?
Rich in fibrinogen, VWF, FVIII, FXIII
65
What do factor concentrates include?
- Concentrates available for all factors except Factor V (have to use platelets or FFP for it)
- Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
66
What are recombinant forms of FVIII and FIX used to treat?
- ‘On demand’ to treat bleeds
- Prophylaxis to prevent bleeds
67
What novel treatments for haemophilia are emerging?
- Gene therapy (for both haem A and B)
- RNA silencing (for both haem A and B)
- Targets natural anticoagulant - antithrombin
- Bispecific antibodies for haem A e.g. emicizumab
- Binds to FIXa and FX
- Mimics procoagulant function of FVIII
68
What other treatments can be used alongside factor replacement?
- Desmopressin
- Tranexamic acid
- These 2 can be used on their own with milder bleeding disorders
69
When can fibrinolytic factors and anticoagulant proteins be increased? (it’s very rare)
When induced by drugs e.g.
- tPA (stroke)
- Heparin
70
What are 2 examples of venous thrombosis?
- Pulmonary embolism (PE)
- Deep vein thrombosis (DVT)
71
What are the symptoms of pulmonary embolism?
- Tachycardia
- Hypoxia
- Shortness of breath
- Chest pain (may be worse when taking a breath)
- Haemoptysis
- Sudden death
72
What are the symptoms of DVT?
- Painful leg
- Swelling
- Red
- Warm
- May embolise to lungs resulting in PE
- **Post thrombotic syndrome**- damage to valves causing long term damage
73
What do most people with thrombosis die of?
At the haemostatic endpoint
74
What is thrombosis?
- An intravascular, inappropriate coagulation
- Venous (or arterial)
- Obstructs blood flow
- May embolise to lungs
75
What is Virchow’s triad?
- Blood- dominant in venous thrombosis
- Vessel wall- dominant in arterial thrombosis
- Blood flow- contributes to both venous and arterial thrombosis
76
How does blood flow contribute to both venous and arterial thrombosis?
- Reduced flow (stasis) increases risk of thrombosis
- Surgery
- Long haul flight (prolonged sitting --> DVT)
- Pregnancy
77
What is thrombophilia?
Increased risk of venous thrombosis
78
How may thrombophilia present/what is indicative that someone has thrombophilia?
- If someone develops thrombosis at a young age
- A spontaneous unprovoked thrombosis
- Multiple thromboses
- Thrombosis while anticoagulated
79
What anticoagulant proteins would decrease to cause thrombosis?
- Antithrombin
- Protein C
- Protein S
80
What coagulant factors would increase to cause thrombosis?
- Factor VIII
- Factor II
- Factor V Leiden (increase activity due to activated protein C resistance)
81
What would cause an increase in platelets?
Myeloproliferative disorders
82
Out of all deficiencies which is the most powerful?
Antithrombin deficiency
83
What proteins are active in coagulation that are expressed on endothelial cell surfaces?
- endothelial protein C receptor
- Thrombomodulin receptor
- Tissue factor
Expression is altered in inflammation
84
How do we treat venous thrombosis?
- Prevention
- Reduce risk of recurrence/extension
85
How is prevention done?
- Assess and prevent risks
- Prophylactic anticoagulant therapy
86
How is risk of recurrence/extension reduced?
- Lower procoagulant factors e.g. warfarin/DOACs
- Increase anticoagulant activity e.g. heparin
