1. Haemostasis and thrombosis Flashcards
(165 cards)
1
Q
The body achieve haemostasis by balancing pro-coagulant and anti-coagulant factors. What are the PRO-coagulant factors?
A
Primary haemostasis: platelets, endothelium, vWF. Coagulation cascade.
2
Q
The body achieve haemostasis by balancing pro-coagulant and anti-coagulant factors. What are the ANTI-coagulant factors?
A
Fibrinolysis. Natural inhibitors of thrombosis: anti-thrombins, protein C/S, tissue factor pathway inhibitor (TFPI)
3
Q
What three responses does vessel injury stimulate?
A
- Vasoconstriction - in order to minimise blood loss.
- Platelet activation - forms the primary haemostatic plug.
- Activation of the coagulation cascade
4
Q
Coordinated haemostasis - what are the components of blood clot formation?
A
Vascular endothelium; platelets; coagulation proteins; white blood cells
5
Q
What is the endothelium composed of?***
A
Endothelial cells, basement membrane, smooth muscles, collagen, elastin, glycosaminoglycans???
6
Q
What are the functions of the endothelium?
A
Synthesis of PGI2, vWF, plasminogen activators, thrombomodulin. Maintains a barrier between blood and procoagulant subendothelial structures.
7
Q
What happens as a result of endothelial damage?
A
Endothelial damage will expose those pro-coagulant substances which then triggers a haemostatic response.
8
Q
What do endothelial cells also produce?
A
Prostaglandins, vWD, plasminogen activators (important for activating fibrinolysis), thrombomodulin
9
Q
What does the exposure of subendothelial pro-coagulant factors lead to?
A
Platelet aggregation at the site of damage
10
Q
Explain how platelets are produced?
A
Produced in the bone marrow and originate from megakaryocytes.
- Stem cell precursors (2n) undergo nuclear replication to form megakaryocytes and become multinucleate.
- Maturation with granulation occurs.
- The megakaryocytes enter circulation.
- Each megakaryocyte produces ~4000 platelets.
- Lifespan ~10 days, 1/3 stored in spleen.
11
Q
What is the relevance of the lifespan of platelets?
A
NOTE: this is significant because once anti-platelet drugs halt platelet activity, its effect will last for 10 days.
Clinical relevance: if someone on aspirin needs to have surgery, they need to stop aspirin 7-10 days before surgery.
12
Q
How is the production of platelets regulated?
A
By a range of thrombopoietic factors (e.g. thrombopoietin, IL-6, IL-12). These can be given therapeutically to stimulate platelet production.
13
Q
What are glycoproteins on platelets?
A
Glycoproteins are cell surface proteins via which platelets can interact with the endothelium, vWF and other platelets
14
Q
Why do platelets have dense granules?
A
Dense granules contain energy stores (in the form of ATP and ADP)
15
Q
What is in the dense granules of platelets?
A
ADP, ATP, serotonin, Ca 2+
16
Q
What does the presence of open cannalicular system, microtubules and actomyosin mean?
A
Platelets are capable of massively expanding their surface area
17
Q
How do platelets adhere to the exposed sub-endothelial structures, directly and indirectly?
A
DIRECTLY - through GlpIa. INDIRECTLY - by binding to vWF via GlpIb (this is the MORE IMPORTANT route).
18
Q
What is the adhesion of platelets to the exposed subendothelial structures followed by?
A
It is followed by release of various mediators such as ADP and thromboxane A2
19
Q
What do ADP and thromboxane A2 promote?
A
Platelet aggregation
20
Q
How do platelets attach to each other? And what attaches to it?
A
Platelets attach to each other via GlpIIb/IIIa (aka fibrinogen receptor). Fibrinogen also binds to this receptor.
21
Q
Aspirin reversibly inhibits COX, true or false?
A
False, aspirin irreversibly inhibits COX
22
Q
NSAIDs are different from aspirin because they reversibly block COX, true or false?
A
True
23
Q
ADP receptors also important for platelet aggregation. What are some examples of inhibitors?
A
Clopidogrel, ticagrelor
24
Q
Which pathway mainly occurs in vitro during clotting studies?
A
intrinsic pathway
25
Is the intrinsic or extrinsic pathway more important in the body?
Extrinsic
26
What is the rate limiting step for fibrin formtion?
Factor Xa
27
What is the coagulation cascade triggered by?
The pathway is triggered by trace amounts of thrombin (which is formed following the activation of the platelet plug)
28
What are the effects of thrombin?
Activates fibrinogen, activates platelets, activates pro-cofactors (Factor 5 and Factor 8), activates zymogens (Factor 7, 11 and 13).
These will all link together to form a prothrombinase complex which results in the activation of prothrombin to thrombin.
29
What is the most important step of the coagulation cascade?
Generation of THROMBIN
30
What does thrombin catalyse in the final step of the coagulation cascade?
Thrombin will catalyse the breakdown of fibrinogen to FIBRIN which is the final step in the coagulation cascade
31
Describe the initiation phase of the coagulation cascade:
- Damage to the endothelial results in the exposure of Tissue Factor which binds to Factor 7, thereby activating it to Factor 7a
- The tissue factor/factor 7a complex will result in activation of Factor 9 and Factor 10
- Factor 10a binds to Factor 5a which results in the FIRST STEP OF THE COAGULATION CASCADE
32
What can people with Factor V Leiden not do?
NOTE: people with Factor V Leiden will not be able to bind their Factor 5a to Factor 10a
33
Describe the amplification phase of the clotting cascade:
- The activated factors 10 + 5 will result in the formation of a small amount of thrombin.
- Once the thrombin has been generated, it will activate platelets.
- The thrombin will also activate Factor 11 which will activate Factor 9
- Thrombin will also activate Factor 8 and recruit more Factor 5a
- Factors 5a, 8a and 9a will bind to the activated platelet which then goes on to perform the last phase of the clotting cascade
34
Describe the propagation phase of the clotting cascade:
- The activate platelet with factors 5, 8 and 9 will recruit Factor 10a
- This will then result in the generation of large amounts of thrombin (THROMBIN BURST)
- The high levels of thrombin will convert fibrinogen to FIBRIN
- This enables the formation of a stable fibrin clot
35
Why is the prothrombinase complex important?
The formation of thrombin is influenced by the presence or absence of the above component. If all the components are present, you will be able to activate prothrombin at 300,000 times the rate of Factor 10a alone
36
Which factors are vitamin K dependent?
2, 7, 9, 10
37
Where are vitamin K dependent factors produced?
In the liver
38
How can we activate factors 2, 7, 9 and 10?
To biologically activate these factors, vitamin K is required as a co-enzyme for the gamma-carboxylation of the clotting factors
39
What can reduce your vitamin K absorption?
Bacteria are important for the production of vitamin K, so taking antibiotics and harming your gut flora can reduce your vitamin K absorption.
Similarly, vitamin K is fat soluble so you need bile to be able to absorb vitamin K (if you have an obstruction of the biliary tree, it can cause vitamin K deficiency)
40
What is the most common cause of vitamin K deficiency?
Warfarin
41
What process causes blood clot removal?
Fibrinolysis
42
What is tissue plasminogen activator (tPA) produced by and what does it do?
Tissue plasminogen activator (tPA) is produced by the endothelium and it converts plasminogen to plasmin
43
What is the clinical relevance of tPA?
tPA is sometimes given in stroke, MI and peripheral vascular disease
44
Apart from tPA what else activates plasminogen to plasmin?
Urokinase
45
What does plasmin break down fibrin into?
Fibrin degradation products (FDP)
46
What are tPA and urokinase inhibited by?
Plasminogen activator inhibitor 1 & 2.
47
What is plasmin inhibited by?
Alpha-2 antiplasmin and alpha-2 microglobulin
48
What does Thrombin-activatable fibrinolysis inhibit?
Fibrin breakdown
49
What are three physiological anticoagulants?
Antithrombins, protein C and protein S, tissue factor pathway inhibitor
50
How do antithrombins work?
Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine. There are FIVE types of antithrombin but the most active is antithrombin-III
51
What is the most thrombogenic condition?
The lack or deficiency of antithrombin is the MOST THROMBOGENIC condition
52
What is the clinical relevance of antithrombin?
Clinical Relevance: heparin augments the effect of antithrombin-III
53
What do protein C and protein S do?
In order to stop thrombin generation, activated Factors 5 and 8 need to be in. These factors are inactivated through the protein C and protein S pathway
54
What activates thrombomodulin (transmembrane receptor)?
The trace amounts of thrombin generated at the start of the cascade will activate thrombomodulin (transmembrane receptor)
55
What does activation of thrombomodulin do?
Activation of thrombomodulin will open up the receptor for thrombomodulin to bind to Protein C through endothelial protein C receptor (EPCR)
56
What do you call protein C which is bound to thrombomodulin through the endothelial protein C receptor (EPCR)?
Activated protein C (APC)
57
In the presence of what does protein C fully activate?*
Protein S (acting as a non-enzymatic co-factor)
58
What does the fully activated protein C do?
It will inactivate factor 5a and factor 8a
59
In which condition do you have activated protein C resistance?
Factor V Leiden
60
What does activated protein C resistance in factor V Leiden mean?
This means that the factor 5a in people with Factor V Leiden, will be resistant to breakdown by activated protein C. This results in a prothrombotic state
61
What are the two causes of activated protein C resistance?
Mutated Factor 5 (e.g. factor V leiden), or high levels of Factors 8
62
What step of the coagulation cascade does tissue factor pathway inhibitor target?
The first step of the coagulation cascade (initiation phase)
63
What factor is released in the first step of the coagulation cascade?
Tissue factor
64
As soon as the coagulation cascade is initiated and tissue factor is released, tissue factor pathway inhibitor is activated to neutralise what?
TF-factor 7a complex
65
The TF-factor 7a complex is NOT needed for very long - what is it only needed to activate?
Factor 10 and factor 9
66
The TF-factor 7a complex is NOT needed for very long, what is it neutralised by?
Tissue factor pathway inhibitor (TFPI)
67
What are examples of genetic defects that cause excessive bleeding?
Platelet abnormalities, vessel wall abnormalities, clotting factor deficiencies and excess clot breakdown
68
What are acquired defects that cause excessive bleeding?
Liver disease, vitamin K deficiency, autoimmune disease (platelet destruction), trauma and anticoagulants/antiplatelets
69
What are examples of genetic defects that cause excessive thrombosis?
Clotting factor inhibitor deficiencies, decreased fibrinolysis
70
What is an example of an acquired defect that cause excessive thrombosis?
Atherosclerosis
71
What are the types of disorders of haemostasis?
Vascular disorders (e.g. scurvy), platelet disorders, (e.g. low number or abnormal function), coagulation disorders (e.g. factor deficiency), mixed/ consumption (e.g. DIC)
72
What is an example of a vascular disorder causing haemostasis
Scurvy
73
What is an example of a mixed/consumption disorder causing haemostasis?
E.g. DIC
74
What are clinical features of bleeding disorders?
Local vs general (spontaneous), haematoma or bleeding joint, skin/mucous petechiae and purpura, wound/surgical bleeding
75
What is haematoma or joint bleed associated with?
Haemophilia
76
What is skin/mucous petechiae and purpura associated with?
Suggestive of platelet deficiency or von Willebrand disease
77
What does the timing of bleeding indicate?
Immediate - issue with the primary haemostatic plug (platelet, endothelium, vWF). Delayed - issue with coagulation cascade
78
What is the difference in the site of bleeding between platelet disorders and coagulation disorders?
Platelet disorders: skin, mucous membranes (epistaxis, gum, vaginal, GI tract).
Coagulation factor disorders: soft tissues, joints, muscles
79
How do petechiae present as a platelet disorder or a coagulation factor disorder?
Platelet disorder
80
How do ecchymoses ("bruises") present as a platelet disorder or a coagulation factor disorder?
As a platelet disorder they are small and superficial and as a coagulation factor disorder they are large and deep
81
How do haemarthrosis / muscle bleeding present as a platelet disorder or coagulation disorder?
As a platelet disorder - extremely rare. As a coagulation factor disorder - common
82
How does bleeding after cuts and scratches present as a platelet disorder or coagulation disorder?
Platelet disorder only
83
How does bleeding after surgery or trauma present as a platelet disorder or coagulation disorder?
Platelet disorder - Immediate, usually mild. Coagulation factor disorder - delayed (1-2 often severe)
84
When the platelet drops below what level is treatment required?
Treatment is required when platelet count drops below 30 x 109/L. This is associated with spontaneous haemorrhage
85
Why is it important to look at platelets under the microscope?
Because you could get pseudothrombocytopaenia where the platelets clump together creating an erroneously low platelet count. Microscopy also allows you to see other abnormalities such as Grey Platelet Syndrome (you see large platelets)
86
What are reasons for disorders of platelets due to decreased number?
Decreased production, decreased survival (ITP), increased consumption (DIC) and dilution
87
What are reasons for disorders of platelets due to decreased platelet function?
Acquired (e.g. aspirin, end-stage renal failure), congenital (e.g. thrombasthenia), cardiopulmonary bypass
88
What is the mode of action of antiplatelet drugs?
The main aim of platelet activation if GlpIIb/IIIa activation.
Clopidogrel prevents blood clots by irreversibly binding to the P2Y12 receptor on platelets, preventing adenosine diphosphate (ADP) from activating platelets.
89
What are the causes immune-mediated thrombocytopaenia?
Idiopathic, drug-induced (e.g. quinine, rifampicin, vancomycin), connective tissue disease (e.g. rheumatoid arthritis, SLE), lymphoproliferative disease, sarcoidosis
90
What are the causes of non-immune mediated thrombocytopenia?
DIC and MAHA
91
What happens in idiopathic immune thrombocytopaenic purpura (ITP)?
- ITP is a very common cause of thrombocytopenia.
- Autoantibodies are generated against platelets
- Platelets are tagged by antibodies and are then destroyed in the reticuloendothelial system (liver, spleen, bone marrow - anywhere where you find macrophages)
92
What is the peak age of acute ITP and chronic ITP?
Acute: children (2-6 years). Chronic: adults (Peak age 20-40 years)
93
What is the female:male ratio of acute and chronic ITP?
Acute: 1:1, chronic: 3:1
94
Is there a preceding infection in acute ITP and chronic ITP?
Acute: common. Chronic: rare
95
What is the onset of symptoms like in acute and chronic ITP?
Acute: abrupt. Chronic: abrupt-indolent
96
What is the platelet count at presentation in acute and chronic ITP?
Acute: <20,000. Chronic: <50,000
97
What is the duration of acute ITP and chronic ITP?
Acute: 2-6 weeks and chronic: long-term
98
Does spontaneous remission occur in acute or chronic ITP?
Acute ITP: common, chronic ITP: uncommon
99
What is ITP like in adults and in childhood?
Childhood ITP is usually acute, SEVERE but it is self-limiting and resolves without any treatment. In adults, ITP is usually chronic and indolent.
100
What does treatment of ITP depend on?
Platelet count and symptoms
101
How does IVIG work in ITP?
Works by competing with the anti-platelet antibodies
102
How is ITP with platelet count > 50,000 and no symptoms treated?
No treatment
103
How is ITP with platelet count 20-50,000 and not bleeding treated?
No treatment
104
How is ITP with platelet count 20-50,000 with bleeding treated?
Steroids and IVIG
105
How is ITP with platelet count <20,000 and bleeding treated?
Steroids, IVIG, and hospitalisation
106
Are petechiae in thrombocytopaenia blanching or non-blanching?
They do not blanch
107
What are features to look for in thrombocytopenia?
Haematomas and subconjunctival haemorrhages
108
Why is it important to look at the blood film in patients with thrombocytopenia?
There are various causes of thrombocytopaenia that can be diagnosed from the blood film: Vitamin B12 deficiency, acute leukaemia
109
What are examples of coagulation factor disorders that are inherited?
Haemophilia A and B, Von Willebrand disease, and other factor deficiencies
110
What are examples of coagulation factor disorders that are acquired?
Liver disease, vitamin K deficiency/warfarin, DIC
111
What is haemophilia a deficiency of?
Congenital deficiency of factor 8 or 9
112
What is haemophilia characterised by?
Deep bleeding into joints and muscles
113
What is the inheritance pattern of haemophilia?
X-linked disease
114
What pathway is haemophilia a disorder of?
It is caused by an isolated abnormality in the INTRINSIC pathway
115
What is APTT and PT like in haemophilia?
Prolonged APTT, normal PT
116
In haemophilia, clotting factor replacement is required temporarily - true or false?
False, required for life
117
What are clinical features of haemophilia?
Haemarthroses (MOST COMMON), soft tissue haematomas (e.g. muscle atrophy, shortened tendons), other sites of bleeding (e.g. urinary tract, CNS, neck), prolonged bleeding after surgery or dental extractions
118
What is the factor deficiency in haemophilia A and B?
A: factor VIII. B: factor IX
119
What is the inheritance pattern in haemophilia A and B?
A and B: X-linked recessive
120
What is the incidence of haemophilia A and B?
A: 1/10,000 males. B: 1/50,000 males
121
What is the severity of haemophilia A and B?
In both, related to factor level.
```
<1% = severe - spontaneous bleeding
1-5% = moderate - bleeding with mild injury
5-25% = mild - bleeding with surgery or trauma
```
122
What are the complications of haemophilia A and B?
Soft tissue bleeding. Ecchymoses are typical of coagulation disorders
123
What is the most common coagulation disorder?
Von Willebrand disease
124
What is the incidence of VWd?
1/10,000
125
What is the inheritance pattern of vWD?
Autosomal dominant
126
What are the clinical features of Von Willebrand disease?
Mucocutaneous bleeding
127
What is the classification for vWD?
Type 1 - PARTIAL quantitative deficiency
Type 2 - QUALITATIVE deficiency
Type 3 - TOTAL quantitative deficiency
128
Why is the classification of vWD similar to haemophilia A?
Because there is a strong relationship between vWF and factor 8. Binding of factor 8 to vWF protects factor 8 from being destroyed in the circulation
129
In Type 1 vWD, what are the results of the diagnostic laboratory tests?
PARTIAL quantitative deficiency. So vWF is low, vWF activity is low, and multimer is normal.
130
In Type 2 vWD, what are the results of the diagnostic laboratory tests?
Qualitative deficiency. So vWF antigen is normal, vWF activity is low, multimer is normal
131
In Type 3 vWD, what are the results of the diagnostic laboratory tests?
TOTAL quantitative deficiency. So, vWF antigen is very low, vWF activity is very low and multimer is absent
132
What are sources of vitamin K?
Green vegetables. Synthesised by intestinal flora
133
What is vitamin K required for the synthesis of?
Factors 2, 7, 9 and 10 and Protein C, S and Z
134
What are the causes of vitamin K deficiency?
Malnutrition; biliary obstruction (reduces absorption of vitamin K); malabsorption; and antibiotic therapy (kills gut flora)
135
What is the treatment for vitamin K deficiency?
Vitamin K, FFP
136
DIC is an EMERGENCY. What is activation of both coagulation and fibrinolysis is triggered by?
Sepsis (MOST COMMON); trauma (e.g. head injury, fat embolism); obstetric complications (abruptio placentae, amniotic fluid embolism); malignancy; vascular disorders; reaction to toxin (e.g. snake venom); immunological disorders (e.g. severe allergic reaction, transplant rejection)
137
What is the mechanism of DIC?
- There is systemic activation of coagulation.
- This results in intravascular deposition of fibrin and then thrombosis of small, midsize vessels with organ failure.
- Systemic activation also leads to depletion of platelets and coagulation factors. This leads to bleeding.
138
What is the pathogenesis of DIC?
Release of thromboplastic material into the cogaulation leads to activation of thrombin which activates the coagulation cascade. (look at diagram in notes)
139
In DIC, what happens to APTT, PT, TT and fibrinogen?
Increased APTT, increased PT, increased TT, decreased fibrinogen
140
Plasmin (as part of the fibrinolytic pathway) degrades fibrin (and fibrinogen), resulting in...
FDPs
141
In DIC what happens to FDP and what does it indicate?
FDP increases. Indicates the presence of plasmin.
142
What does the release of thromboplastic material into the coagulation activate?
Leads to activation of thrombin
143
What are the clotting study results in DIC (APTT, PT, TT, fibrinogen, FDP, platelets, schistocytes)
```
o Prolonged APTT
o Prolonged PT
o Prolonged TT
o Decreased fibrinogen
o Increased FDP
o Decreased platelets
o Schistocytes
```
144
Why does DIC produce schistocytes?
Due to fragmentation of red blood cells as they pass through the fibrin mesh in the small blood vessels
145
What is the treatment of DIC?
Treatment of underlying disorder; anticoagulation with heparin; platelet transfusion; FFP; coagulation inhibitor concentrate (APC concentrate)
146
Why does liver disease lead to bleeding disorders?
- Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
- Inadequate intake or absorption of dietary vitamin K deficiency (inadequate intake or absorption)
- Dysfibrinogenaemia
- Enhanced haemolysis (decreased alpha-2 antiplasmin)
- DIC
- Thrombocytopaenia due to hypersplenism
147
What to consider in the management of haemostatic defects in liver disease?
Treatment for prolonged PT/PTT; treatment for low fibrinogen; treatment for DIC
148
What is the treatment for prolonged PT/PTT in the management of haemostatic defects in liver disease?
Vitamin K 10mg o.d. x 3 days - usually ineffective; FFP infusion; 25-30% of plasma volume (1200-1500ml); immediate but temporary effect
149
What is the treatment for low fibrinogen in the management of haemostatic defects in liver disease?
Cryoprecipitate (1 unit/10kg)
150
What is the treatment for DIC (elevated D-dimer, low factor VII, thrombocytopenia) in the management of haemostatic defects in liver disease?
Replacement therapy
151
Oral vitamin K (2 mg) has also been shown to be effective in reducing raised INRs without omission of warfarin. IV vitamin K has also been shown to be a safe and effective method of warfarin reversal. True or false?
True
152
When there is vitamin K deficiency due to warfarin overdose, what should you do if INR is therapeutic - 5?
Lower or omit next dose of warfarin; resume warfarin therapy when INR is therapeutic
153
What is therapeutic INR for patients on anticoagulant therapy?
For patients who are on anticoagulant therapy, the therapeutic INR ranges between 2.0 to 3.0. INR levels above 4.9 are considered critical values and increase the risk of bleeding.
154
When there is vitamin K deficiency due to warfarin overdose, what should you do if INR is 5 - 9 and no bleeding?
Lower or omit next dose of warfarin; resume warfarin therapy when INR is therapeutic. Omit dose of warfarin and give vitamin K (1-2.5 mg PO). For rapid reversal: vitamin K 2-4 mg PO (repeat).
155
When there is vitamin K deficiency due to warfarin overdose, what should you do if INR is > 9 and no bleeding?
Omit dose of warfarin; vitamin K 3-5 mg PO; repeat as necessary. Resume therapy at lower dose when INR therapeutic
156
When there is vitamin K deficiency due to warfarin overdose, what should you do if INR is > 20 and bleeding?
Omit warfarin; vitamin K 10mg slow IV infusion; PCC (or recombinant human factor VIIa); repeat vitamin K injections every 12 hours as needed
157
What is management of vitamin K deficiency due to warfarin overdose dependent on?
INR
158
What contains the vitamin-K dependent clotting factors?
Prothrombin complex concentrate
159
Warfarin is on its way out, what is coming to the forefront?
NOACs/DOACs
160
What is the benefit of warfarin?
We can rapidly reverse the bleeding
161
What are tissue factor pathway inhibitors (initiation phase of coagulation pathway)?
TFPI, Nematode Anticoagulant Protein C2 (NAPc2).
162
What are factor IX a inhibitors (thrombin generation phase of coagulation pathway)?
IXa inhibitors, IXa antibody
163
What are protein C activators (thrombin generation phase of coagulation pathway)?
APC, thrombomodulin
164
What are examples of factor Xa inhibitors (thrombin generation phase of coagulation pathway)?
Fondaparinux, rivorxaban, abixaban, etc.
165
What are examples of thrombin inhibitors (thrombin activity phase of coagulation pathway)?
Hirudin, bivalirudin, argatroban, melagatran, dabigatran
