Haem 2S: Haemostasis and Thrombosis Flashcards
(105 cards)
1
Q
What are the procoagulation factors?
A
Primary haemostasis
- Platelets
- Endothelium
- vWF
Coagulation cascade
2
Q
What are the anticoagulation factors?
A
Natural inhibitors of thrombosis
- Anti-thrombin
- Protein C / Protein S
- Tissue Factor Pathway Inhibitor (TFPI)
Fibrinolysis
3
Q
Which 3 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
What are the Components of blood clot formation?
A
- Vascular endothelium
- Platelets
- Coagulation proteins
- White blood cells
5
Q
How is the Vascular Endothelium invovled in coagulation?
A
- The endothelium acts as a barrier which prevent exposure of pro-coagulant subendothelial structures
- Endothelial damage exposes these pro-coagulant substances which then triggers a haemostatic response
-
Endothelial cells also produce:
- Prostaglandins (PGI2)
- vWD
- Plasminogen activators (activate fibrinolysis)
- Thrombomodulin
- The exposure of subendothelial pro-coagulant factors leads to platelet aggregation at the site of damage
6
Q
Where are platelets produced?
A
- Produced in the bone marrow and originate from megakaryocytes
- Each megakaryocyte can produce up to 4000 platelets
- Platelets have a life span of 10 days (anti-platelet drugs halt platelet activity for 10 days)
- Clinical relevance: someone on aspirin needs surgery –> stop aspirin 7-10 days before surgery
- The production of platelets is regulated by a range of thrombopoietic factors (e.g. thrombopoietin, IL-6, IL-12)
- These can be given therapeutically to stimulate platelet production
7
Q
What is the structure of platelets?
A
- Glycoproteins = cell surface proteins via which platelets can interact with the endothelium, vWF and other platelets
- Dense granules contain energy stores (in the form of ATP and ADP)
- The presence of an ‘open canalicular system’ and ‘microtubules and actomyosin’ means that platelets are capable of massively expanding their surface area
8
Q
How do platelets migrate and adhere to the vascular endothelium?
A
- Two methods of adhesion:
- DIRECTLY – GlpIa
- INDIRECTLY – vWF via GlpIb
- Adhesion of platelets to exposed structures à release of ADP and thromboxane A2 à platelet aggregation
- Platelets attach to each other via GlpIIb/IIIa
- I.E. the fibrinogen receptor
9
Q
What is the Arachidonic Acid Pathway?
A
- Aspirin will irreversibly inhibit COX
- NSAIDs are different from aspirin because they reversibly block COX
10
Q
Which other receptors are important for platelet adhesion to the vascular endothelium?
A
- ADP receptors are also very important for platelet aggregation
- Examples of inhibitors: clopidogrel, ticagrelor
11
Q
What are the roles of Coagulation Proteins, White Blood Cells in coagulation?
A
- A fibrin mesh needs to be generated to reinforce the clot
- Intrinsic pathway = in-vitro during clotting studies
- Extrinsic pathway = the body
- Factor Xa is the rate-limiting step for fibrin formation
- Pathway triggered by trace amounts of thrombin (which is formed following the activation of the platelet plug)
12
Q
What are the effects of thrombin?
A
- Activates fibrinogen
- Activates platelets
- Activates pro-cofactors (Factor 5 and Factor 8)
- Activates zymogens (Factor 7, 11 and 13)
13
Q
What do the following link up to form?
- fibrinogen
- platelets
- pro-cofactors (Factor 5 and Factor 8)
- zymogens (Factor 7, 11 and 13)
A
- These all link together to form a prothrombinase complex à activation of prothrombin to thrombin
14
Q
What is the most important step of the coagulation cascade?
A
- KEY POINT: the MOST IMPORTANT step of the coagulation cascade is the generation of THROMBIN
15
Q
What is the final step of the coagulation cascade?
A
- Thrombin will catalyse the breakdown of fibrinogen to FIBRIN which is the final step in the coagulation cascade
16
Q
What are the phases of clotting?
A
- Factor 10a binds Factor 5a = 1st step of the coagulation cascade
- Factor V Leiden will not be able to bind Factor 5a to Factor 10a
- Activated platelet → thrombin burst (convert fibrinogen → fibrin)
17
Q
How does the rate of prothrombin activation change?
A
18
Q
What does PT and APTT refer to?
A
PT = INR = extrinsic pathway
APTT = intrinsic pathway
19
Q
Summarise the intrinsic extrinsic and common pathways of the coagulation cascade
A
20
Q
Which coagulation factors are Vitamin K-dependent? Where are these produced?
A
Vitamin K-dependent factors = 2, 7, 9, 10 (produced in the liver)
21
Q
Why is Vitamin K necessary in for the coagulation cascade?
A
Biological activation =
vitamin K is required as a co-enzyme for the gamma-carboxylation of the clotting factors
22
Q
Why might Abx reduce Vitamin K intake?
A
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
23
Q
Why might Abx reduce Vitamin K intake?
A
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
24
Q
Why might Abx reduce Vitamin K intake?
A
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
25
Why might Abx reduce Vitamin K intake?
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
26
Why is bile necessary to absorb vitamin K?
Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
27
Why might Abx reduce Vitamin K intake?
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
28
Why might a bile duct obstruction reduce vitamin K absorption?
Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
29
Why might Abx reduce Vitamin K intake?
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
30
Why is bile necessary to absorb vitamin K?
Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
31
Why might Abx reduce Vitamin K intake?
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
32
Why might Abx reduce Vitamin K intake?
Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
33
Why is bile necessary to absorb vitamin K?
Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
34
What does the term fibrinolysis mean?
Blood Clot Removal
35
Where is Tissue plasminogen activator (tPA) produced? What is its role?
Tissue plasminogen activator (tPA) is produced by the endothelium (converts plasminogen to plasmin)
36
Which conditions is tPA sometimes used to treat?
tPA is sometimes given in stroke, MI and peripheral vascular disease
37
What else can activate plasminogen to plasmin?
Urokinase
38
What can inhibit tPA and urokinase?
tPA and urokinase are inhibited by plasminogen activator inhibitor 1 & 2
39
What is plasmin inhibited by?
Plasmin is inhibited by:
* Alpha-2 antiplasmin
* Alpha-2 macroglobulin
40
What is an important inhibitor of fibrin breakdown?
**Thrombin-activatable fibrinolysis inhibitor (TAFI)** is an important inhibitor of fibrin breakdown
41
Summarise the process of fibrinolysis
```
RED = inhibitory effect
BLUE = stimulatory effect
```
42
Name the Physiological anticoagulants
* Antithrombins (ATs)
* Protein C and S
* Tissue factor pathway inhibitor (TFPI)
43
What do Antithrombins bind to? How is this then excreted?
Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine
44
How many types of antithrombin are there? Which is the most active?
There are FIVE types of antithrombin but the most active is AT-III
45
The deficiency of which Physiological anticoagulant is the MOST THROMBOGENIC condition?
deficiency of antithrombin
46
Which factors must be inactivated to stop thrombin?
To stop thrombin, F5a and F8a need to be inactivated
47
Which factors must be inactivated to stop thrombin?
To stop thrombin, F5a and F8a need to be inactivated
48
How is thrombomodulin activated?
by thrombin
49
How do proteins C and S inactivate factors V and VIII?
50
Name 2 causes of APC (activated protein C), resistance
* Mutated F5 (Factor V Leiden) → prothrombotic
* High levels of Factors 8
51
How does Tissue factor pathway inhibitor (TFPI) cause anticoagulation?
Inhibits F7a
52
Name some genetic causes of excessive bleeding
Platelet abnormalities
Blood vessel wall abnormalities
Clotting factor deficiencies (i.e. haemophilia)
**Excessive clot breakdown**
53
Name some acquired causes of excessive bleeding
Liver disease
Vitamin K deficiency
Autoimmune disease (platelet destruction)
Trauma
Anticoagulants/antiplatelets
54
Name some genetic causes of Excessive thrombosis *[may be transient; i.e. MI]*
Clotting factor inhibitor deficiencies
Decreased fibrinolysis
55
Name some acquired causes of Excessive thrombosis *[may be transient; i.e. MI]*
Atherosclerosis
56
Name the broad categories of disorders of haemostasis
57
What are the Clinical features of bleeding disorders?
58
How do you differentiate between platelet disorders and coagulation disorders?
* Platelet = petechiae, purpura
* Coagulation = heamarthrosis
* Microscopy
59
When is Tx required in platelet disorders?
*Tx required when platelet count drops \<30x109/L*
60
Why must you always inspect blood film under a microscope to differentiate between platelet and coagulation disorders?
* **Pseudothrombocytopaenia** = platelets clump together creating an erroneously low platelet count
* **Grey Platelet Syndrome** (you see large platelets)
61
What is heparin? How are its levels monitored?
Heparin = AT-III potentiator (monitor levels with F Xa assay)
62
How are platelet disorders broadly grouped?
63
What is Clopidogrel?
Clopidogrel = ADP-R blocker → reduce Glp2b/3a crosslinking
64
Name some COX inhibitors. How do they work?
COX inhibitors (aspirin, NSAIDs) → reduce TXA2 production
65
How is are the different causes of thrombocytopenia grouped?
* Immune-Mediated
* Non-Immune Mediated
* Idiopathic Immune Thrombocytopaenic Purpura (ITP)
66
Give some Immune-Mediated causes of Thrombocytopaenia
* Idiopathic
* Drugs (e.g. rifampicin, vancomycin)
* Sarcoidosis
* connective tissue disease (e.g. rheumatoid arthritis, SLE)
* Lymphoproliferative disease
67
Give some non-Immune-Mediated causes of Thrombocytopaenia
* DIC
* MAHA
68
What is Idiopathic Immune Thrombocytopaenic Purpura (ITP)? What is its major clinical feature?
* Autoantibodies generated against platelets
* Platelets tagged by antibodies and destroyed in reticuloendothelial system (liver, spleen, & bone marrow / anywhere with macrophages)
* Non-blanching petechiae
69
Compare the *Features of Acute & Chronic ITP*
70
Summarise the Tx of ITP
It depends on platelet count and symptoms
71
How does ITP present in children vs adults?
* Childhood ITP is usually ACUTE (usually following a previous illness)
* Childhood ITP is usually SEVERE (but it is self-limiting and resolves without any treatment)
* In adults, ITP is usually chronic and indolent
72
How does IVIG work?
o IVIG works by competing with the anti-platelet antibodies
73
Name some other classic clinical signs of thrombocytopenia
o Haematomas and subconjunctival haemorrhages are features of thrombocytopaenia
74
Why is it important to look at the blood film in patients with thrombocytopaenia?
It is important to look at the blood film in patients with thrombocytopaenia because there are various causes of thrombocytopaenia that can be diagnosed from the blood film
* Vitamin B12 deficiency
* Acute leukaemia (i.e.Auer rods in AML)
75
How are coagulation factor disorders grouped?
* acquired
* inherited
76
Name some inherited causes of coagulation factor disorders
* Haemophilia A and B
* Von Willebrand disease
* Other factor deficiencies
77
Name some acquired causes of coagulation factor disorders
* Liver disease
* Vitamin K deficiency / Warfarin
* DIC
78
What is Haemophilia?
* Congenital deficiency of Factor 8 or 9;
* X-linked
* Characterised by deep bleeding into joints and muscles
79
What is the cause of haemophilia?
Caused by isolated abnormality in the INTRINSIC pathway
80
What happens to the APTT and PT in haemophilia?
* Prolonged APTT
* Normal PT
81
What is the Tx of haemophilia?
Treatment = **clotting factor replacement** is required for life
82
How do you distinguish between haemophilia A and B clinically?
clinically indistinguishable
83
What are the clinical Features of haemophilia A and B?
* Haemarthroses (fixed joints) → most COMMON
* Soft tissue haematomas (e.g.muscle atrophy, shortened tendons) & ecchymoses
* Other sites of bleeding (e.g. urinary tract, CNS, neck)
* Prolonged bleeding after surgery or dental extractions
84
Compare the inheritance, incidence and severity of haemophilia A and B
85
What is von Willebrand Disease
* The most common coagulation disorder (incidence: 1/10,000)
* Autosomal dominant
86
What are the main clinical features of von Willebrand Disease
o Clinical features = **mucocutaneous bleeding**
87
How is von Willebrand Disease classified?
* Type 1 = PARTIAL quantitative deficiency
* Type 2 = QUALITATIVE deficiency
* Type 3 = TOTAL quantitative deficiency
T3 is very similar to haemophilia A (strong relationship between vWF and factor 8)
Binding of factor 8 to vWF protects factor 8 from being destroyed in the circulation
88
Describe how a) vWF antigen b) vWF activity c) multimer
varies by each type of von Willebrand Disease
89
What are the Sources of Vitamin K? Where in the body is it synthesised?
* Green vegetables
* Synthesised by intestinal flora
90
How is warfarin reversed?
***PCC** (Prothrombinase Complex Concentrate)*
91
What is vitamin K required for synthesis of?
* Factors 2, 7, 9 and 10
* Protein C, S and Z
92
What are the causes of vitamin K deficiency
* Malnutrition
* Malabsorption
* Biliary obstruction (reduces absorption of Vit-K)
* Antibiotic therapy (kills gut flora)
* Warfarin
93
What is the Tx for vitamin K deficiency?
* VitaminK
* FFP
94
What is Disseminated Intravascular Coagulation (DIC)
* Emergency
* Activation of both coagulation and fibrinolysis is triggered
95
What can trigger activation of both coagulation and fibrinolysis in DIC?
96
What is the Mechanism of DIC?
* Systemic activation of coagulation → deposition of fibrin in small blood vessels (which can cause kidney damage, brain damage and damage to the extremities requiring amputation)
* The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding
97
what is the Pathogenesis of DIC?
release of thromboplastic material into the coagulation
→ activation of thrombin
→ activates coagulation cascade
98
What do Clotting studies in DIC show?
99
What is the Treatment of DIC?
* Treatment of underlying disorder
* Anticoagulation with heparin
* Platelet transfusion
* FFP
* Coagulation inhibitor concentrate (Activated Protein C concentrate)
100
Why does liver disease lead to bleeding disorders?
101
What is the Management of Haemostatic Defects in Liver Disease?
102
What is the Mx of Vitamin K deficiency due to warfarin overdose?
* Management dependant on INR measurement
* Prothrombin complex concentrate (PCC) contains the vitamin K-dependent clotting factors
103
How do you manage high INR values?
104
How do you manage high INR values in bleeding patients?
105
Name some Novel Anticoagulants?
* Warfarin is on its way out and **NOACs/DOACs** are coming to the forefront
* The benefit of warfarin is that we can rapidly reverse the bleeding
