Haemostasis Flashcards
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 the aim of haemostasis?
A
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
3
Q
What are the four stages of Haemostasis?
A
- vessel constriction
- formation of an unstable platelet plug (primary haemostasis)
- stabilisation of the plug with fibrin (secondary haemostasis)
- vessel repair and dissolution of clot
4
Q
What happens when vessel constriction occurs?
A
- vascular smooth muscle cells contract locally
- limits blood flow to injured vessel
5
Q
What happens during primary haemostasis?
A
formation of an unstable platelet plug
- platelet adhesion
- platelet aggregation
- limits blood loss and provides surface for coagulation
6
Q
What happens during secondary haemostasis?
A
stabilisation of the plug with fibrin
- blood coagulation
- stops blood loss
7
Q
What happens during fibrinolysis?
A
vessel repair and dissolution of the clot
- cell migration/proliferation and fibrinolysis
- restores vessel integrity
8
Q
Why is understanding of haemostatic mechanisms important?
A
- diagnose and treat bleeding disorders
- control bleeding
- identify thrombosis risk factors
- treat thrombotic disorders
- monitor drugs used to treat bleeding/thrombotic disorders
9
Q
What is balanced in normal haemostasis?
A
- fibrinolytic factors and anticoagulant proteins
AND - coagulant factors
- platelets
10
Q
What can cause the lack of a specific factor?
A
- failure of production (congenital and acquired)
- increased consumption and clearance
11
Q
What can cause defective function of a specific factor?
A
- genetic
- drugs and other chemicals
12
Q
What are the 3 main components of primary haemostasis?
A
- platelets
- Von Willebrand factor
- Vessel wall
13
Q
What do platelets adhere to in direct platelet adhesion?
A
Collagen revealed in wall damage via the GPIa receptor
14
Q
What do platelets adhere to in indirect platelet adhesion?
A
Collagen revealed in wall damage via VWF which binds to GPIb receptor
15
Q
What is involved in platelet aggregation?
A
- adhesion
- ADP and thromboxane A2
- platelet activation
- formation of platelet plug
16
Q
What happens in adhesion?
A
ADP, fibrinogen and VWF released from storage granules in platelets
17
Q
What activates platelets in a positive feedback mechanism?
A
ADP and thromboxane A2
18
Q
What happens when platelets are activated?
A
- binding sites change from GPIa/GPIb to GPIIa/GPIIb
- binding sites can now bind fibrinogen
- fibrionogen links platelets together to form an unstable platelet plug
19
Q
What does Thrombocytopenia mean?
A
platelet insufficiency
20
Q
What are the 3 causes of Thrombocytopenia?
A
- decreased production caused by bone marrow failure
- Accelerated clearance
- Pooling and destruction in an enlarged spleen
21
Q
What can cause bone marrow failure?
A
- leukaemia
- B12 deficiency
22
Q
What causes accelerated platelet clearance?
A
- immune thrombocytopenia purpura (ITP)
- Disseminated Intravascular Coagulation (DIC)
(cleared in the peripheral system)
23
Q
What happens in Immune Thrombocytopenic Purpura (ITP)?
A
- anti-platlet antibodies
- attach to sensitised platlets
- cleared by macrophages of the reticula endothelial system of the spleen
(COMMON)
24
Q
What causes the impaired function of platelets?
A
- Hereditary absence of glycoproteins or storage granules (rare)
- Acquired due to drugs
25
What causes storage pool disease?
Reduction in the granular contents of platlets
26
What drugs are associated with causing impaired platelet function?
- aspirin
- NSAIDs
- clopidogrel (common)
27
When are anti-platelet drugs used?
in the prevention and treatment of cardiovascular and cerebrovascular disease
28
How does aspirin have an anti-platelet effect?
aspirin prevents the production of Thromboxane A2 by irreversibly blocking COX enzyme causing reduced platelet aggregation
29
How does aspirin have an anticoagulant effect?
irreversibly blocks the ADP receptor on platelets (P2Y12), preventing platelet activation
30
What can cause Von Willebrand disease?
- Hereditary: decrease of quantity +/ function (COMMON)
- Acquired: antibody (rare)
31
What are the roles of Von Willebrand factor in Haemostasis?
- binding to collagen and capturing platelets
- stabilising factor VIII
32
What is the relationship between Von Willebrand Factor and Factor VIII?
VWF is needed for Factor VIII, so if VWF is low, so is Factor VIII
33
What are the 3 different types of Von Willebrand factor problems?
- Type 1/3: deficiency of VWF
- Type 2: VWF with abnormal function
34
What can cause inherited problems with the vessel wall?
RARE
- Haemorrhagic telangiectasia
- Ehlers-Danlos syndrome
(other connective tissue disorders)
35
What can cause acquired problems with the vessel wall?
COMMON
- steroid therapy
- Ageing (senile purpura)
- Vasculitis
- Scurvy
36
What causes VWF to unfold/uncoil?
shear force
37
What does VWD impact in haemostasis?
primary haemostasis
38
What are the clinical features of primary haemostasis disorders?
- immediate bleeding
- prolonged bleeding from cuts/trauma/surgery
- nose bleeds (epistaxis) >20mins
- prolonged gum bleeding
- heavy menstrual bleeding (menorrhagia)
- bruising (ecchymosis), spontaneous/easy
39
What are the visible signs seen in primary haemostasis disorders?
Petechiae and Purpura
40
What is the difference between petechiae and purpura?
- petechiae are smaller (< 3mm)
- purpura are larger (3-10mm) and do not blanch under pressure
41
What is a key clinic feature of severe VWD?
haemophilia-like bleeding (due to low FVIII)
42
What are tests are done for primary haemostasis disorders?
- platelet count/morphology (electron)
- FBC
- bleeding time (PFA100)
- VWF assays
- clinical observation
- coagulation screen (PT, APTT)
43
What should be the expected results from the coagulation screen?
normal (PT, APTT)
UNLESS
severe VWD cases where factor VIII
44
How would you treat the failure of production/function in haemostasis disorders?
replace missing factor/platelets
- prophylactic
- therapeutic
STOP drugs (aspirin, NSAIDs)
45
How would you treat the immune destruction in primary haemostasis disorders?
- immunosuppression via corticosteroids (prednisolone)
- splenectomy for ITP as second line
46
How would you treat the increased consumption/clearance in haemostasis disorders?
- treat cause
- replace as necessary
47
What additional treatments can be used to support haemostasis?
- Desmopressin
- Tranexamic acid (antifibrinolytic)
- Fibrin glue/spray post surgery
48
What is Desmopressin?
Vasopressin analogue
49
What does Desmopressin do?
- 2-5 fold increase in VWF (+ Factor VIII)
- releases endogenous stores (only used in mild disorders)
50
What is another name for secondary haemostasis?
coagulation
51
What is the role of coagulation?
- generate thrombin (Factor IIa) - which converts fibrinogen to fibrin
52
What is the result of a coagulation factor deficiency?
failure of thrombin generation and therefore fibrin formation
53
What are the 3 phases of coagulation?
- initiation
- amplification
- propagation
54
Which factors are part of the extrinsic pathway?
- Tissue factor (factor VIII)
- Factor VII (binds to TF)
- Factor IX and factor
55
Which factors are part of the intrinsic pathway?
- Thrombin (factor II)
- Factor XI
- Factor VIII
56
What can cause disorders of coagulation?
- deficiency of coagulation factor production
- dilution
- increased consumption
57
What hereditary causes are there for the deficiency of coagulation factor production?
- haemophillia A (facotr VIII deficiency)
- haemophillia B (factor IX deficiency)
58
What acquired causes are there for the deficiency of coagulation factor production?
- liver disease
- anticoagulant drugs
(warfarin, DOACs)
59
What are the acquired causes of dilution?
blood transfusion (with inadequate plasma replacement)
60
What are the acquired causes of increased consumption/clearance?
COMMON: Disseminated intravascular coagulation (DIC)
RARE: immune (autoantibodies)
61
What are the 2 common hereditary coagulation disorders?
Haemophilia A (FVIII) + B (FIX)
62
What happens in haemophilia?
failure to generate fibrin to stabilise the platelet plug
63
What is the hallmark of haemophilia?
haemarthrosis
64
What is Haemarthrosis?
spontanteous joint bleeding (very low FVIII and FIX)
65
What happens in chronic haemarthrosis?
- recurrent spontaneous bleeds
- significant joint deformity
- muscle wasting
66
What should be avoided in patients with haemophilia?
avoid IM injections
67
What is the impact of the absence of Factor VII and Factor IX?
- severe but compatible with life
- spontaneous joint and muscle bleeding
68
What is the impact of the absence of Factor II (Prothrombin)?
Lethal
69
What is the impact of the absence of Factor XI?
bleed after trauma, but not spontaneously
70
What is the impact of the absence of Factor XII?
no bleeding at all
71
What is the impact of liver failure on coagulation?
decreased, as most clotting factors are synthesised in the liver.
72
What is the impact of dilution on coagulation?
- red cell transfusions don't consider plasma
- major haemorrhage requires transfusion of plasma as well as RC and platelets to prevent.
73
What is Disseminated intravascular coagulation?
generalised (and unregulated) activation of coagulation - Tissue factor
74
What can trigger Disseminated Intravascular Coagulation?
- sepsis
- major tissue damage (cancer)
- inflammation
75
Wjhat happens in Disseminated Intravascular Coagulation?
- consumption and depletion of coagulation factors
- consumed platelets (thrombocytopenia)
- activation of fibrinolysis depletes fibrinogen (raised D-dimer)
- fibrin deposit in vessels can cause organ failure
76
Why is D-dimer raised in Disseminated Intravascular Coagulation?
D-dimer is a product of fibrin breakdown
77
How do you manage Disseminated Intravascular Coagulation?
Replacemnet of missing coagulation factors
78
What characterises Disseminated Intravascular Coagulation?
combined clotting and bleeding pattern
79
What are the clinical features of coagulation disorders?
- superficial cuts do not bleed
- common: bruising, rare: nosebleeds
- spontaneous bleeding is deep (muscles or joints)
- bleeding after trauma is delayed/prolonged
- bleeding may restart after stopping
80
Why do superficial cuts not bleed?
small, therefore platelets can form a plug
81
How can you clinically distinguish between platelet and coagulation defects?
- where the bleeding occurs
- time for bleeding after trauma/injury
82
What is the difference in bleeding in platelet and coagulation defects?
Platelet:
- superficial bleeding into skin and mucosal membranes
Coagulation:
- bleeding into deep tissues, muscles and joints
83
What is the difference in time for bleeding after injury in platelet and coagulation defects?
```
Platelet:
- bleeding immediate after surgery
Coagulation
- delayed, but severe after injury
- often prolonged
```
84
What tests are available for coagulation disorders?
```
Screening
- Prothrombin time (PT)
- Activated partial thromboplastin time (APTT)
- FBC (platelets)
Coagulation factor assays
Tests for inhibitors
```
85
What does prothrombin time measure?
the extrinsic pathway
86
What does the Activated Partial Thromboplastin Time (APTT) measure?
the intrinsic pathway
87
What do we use to trigger the Prothrombin Time (PT)?
Tissue factor (recombinant)
88
What do we use to trigger the Activated Partial Thromboplastin Time (PT)?
by contact activation with NO
89
What would cause a normal PT time but an prolonged APTT?
- haemophilia A/B
- Factor XI deficiency
- Factor XII deficiency
90
Why is APTT elongated in haemophilia A/B?
many of the factors in the intrinsic pathway are affected by a deficiency
91
What would cause a prolonged PT time but a normal Activated Partial Thromboplastin time?
- Factor VII deficiency
92
What would cause a prolonged PT time and a prolonged APTT?
- Liver disease
- anti-coagulant drugs
- DIC
- Dilution
(deficiency of the factors of the common pathway)
93
What factors are part of the common pathway?
- FX
- FV
- FII
94
What are the principles of abnormal secondary haemostasis?
- failure of production
- immune destruction
- increased consumption
95
What are the 4 different types of factor replacement therapy?
- Plasma (Fresh Forzen Plasma)
- Cryoprecipitate
- Factor concentrates
- Recombinant forms of FVIII and FIX
96
What is in Fresh Frozen Plasma (FFP) and what is it used for?
- contains all coagulation factors
- DIC
97
What is in cryoprecipitate and what is it used for?
- rich in: fibrinogen, FVIII, VWF and FXIII
- hypofibrinogenemia, VWD, haemophillia A
98
What is in factor concentrates and what are they used for?
- available for all factors apart from FV
- specific factor deficiencies
99
What are recombinant forms of FVIII and FIX used for?
Haemophillia A and B
100
What are the future possible treatments of haemophilia?
- prolonged half life
- gene therapy
- novel agents
101
What are the risks of haemophilia treatment?
- safety
- potential of transfer of blood borne pathogens
102
What are the novel treatments available?
- gene therapy (haemophilia A/B)
- bispecific antibodies (haemophilia A)
- RNA silencing (haemophilia A and B)
103
What additional haemostatic treatments are available for anti-coagulant blood disorders?
- desmopressin
- tranexamic acid
- fibrin glue/spray
- other indirect (treat symptoms, like: OCP)
104
What can cause an increase in fibrinolytic factors and anti-coagulant proteins?
induced by drugs:
- tPA - tissue plasminogen activator (stroke)
- Heparin
105
What is thrombosis?
- intravascular coagulation
- inappropriate coagulation
- venous or arterial
- obstructs flow
- may embolise to the lungs
106
What is Virchow's triad?
the 3 factors that contribute to thrombosis
107
What is in Virchow's triad?
- reduced blood flow
- vascular injury
- hypercoagulability
108
What is the impact on risk when there are changes in blood hypercoagulability in Virchow's triad?
dominant in venous thrombosis
109
What is the impact on risk when there is vascular injury in Virchow's triad?
dominant in arterial thrombosis
110
What is the impact on risk when there is decreased blood flow in Virchow's triad?
contributes to both arterial and venous thrombosis
111
What are the presentations of a pulmonary embolism?
- tachycardia
- hypoxia
- shortness of breath
- chest pain
- haemoptysis
- sudden death
112
What is the presentation of deep vein thrombosis?
- painful leg
- oedema
- erythema
- warm
- embolise to lung
- post thrombotic syndrome
113
What is thrombophilia?
increased risk of venous thrombosis
114
How does thrombophilia present?
- thrombosis at a young age
- spontaneous thrombosis
- multiple thromboses
- thrombosis while anti-coagulated
115
What factors can increase the risk of venous thrombosis?
- Reduced anticoagulant proteins
- Increased coagulant factors
(increased activity due to activated protein C resistance)
116
What can cause an increased platelet count?
myeloproliferative disorders
117
What can cause reduced anticoagulant proteins ?
nephrotic disease
118
What do protein C and S inactivate?
- FVa
- FVIIIa
119
What are the anticoagulant proteins?
- antithrombin
- protein C
- protein S
120
What are the coagulant factors?
- FVIII
- FII
- FV
121
What does antithrombin inactivate?
- FVIIa
- FXa
122
What deficiency puts you most at risk of a venous thrombosis?
antithrombin deficiency (25-50 odds ratio)
123
What is the effect of abnormal FVa Lieden?
increased thrombotic activity
124
Why is the vessel wall thought to have an effect on venous thrombosis?
many proteins are expressed on the endothelial surface and their expression changes in inflammation
125
What is the change in blood flow that increases the risk of thrombosis?
```
reduced flow (stasis)
EG: surgery, long haul flight, and pregnancy
```
126
What is the nature of the cause of venous thrombosis?
multi-causal - interacting genetic and acquired factors
127
How do you prevent venous thrombosis?
- assess and prevent risks
- prophylactic anticoagulant therapy
128
How do you reduce the risk of recurrence/extension of venous thrombosis?
- lower procoagulant factors (warfarin, DOACs)
- increase anti-coagulant activity (heparin)
129
What are the risk factors for thrombosis?
- age
- obesity
- thrombosis at a young age
- multiple thromboses
- thrombosis while anticoagulated
130
What is heparin?
- inactivates thrombin and factor X
- via activating antithrombin III
- IV administration
131
What is low molecular weight heparin
- same as heparin but only inhibits factor X
- SC administration
132
What is warfarin?
- inhibits factor II, VII, IX and X
- via inhibiting vitamin K reductase
- oral
133
What are direct oral anticoagulants?
- directly inhibits thrombin or Xa
- oral
