Haemostasis Flashcards
1
Q
What is haemostasis?
A
The process involving the stoppage of blood flow through vessels following trauma.
2
Q
What are the three stages of haemostasis?
A
1) Vasoconstriction
2) Primary haemostasis
3) Secondary haemostasis
3
Q
What is vasoconstriction?
A
Vascular smooth muscle cells contract locally to limit blood flow to injured vessel.
4
Q
What is primary haemostasis?
A
Formation of unstable platelet plug at the site of damaged vessel wall (Involves platelet adhesion, and aggregation).
N.B: Provides surface for coagulation
5
Q
What is secondary haemostasis?
A
Formation of stable fibrin clot. (coagulation)
6
Q
What is fibronlysis?
A
Concerned with vessel repair, and dissolution of clot, respectively achieved by cell migration/proliferation and the enzymatic breakdown of fibrin – restores vessel integrity.
7
Q
What are the 3 main functions of haemostasis?
A
Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
Enable tissue repair
8
Q
What are platelets?
A
Platelets are non-nucleated, discoid, granule-containing cells
9
Q
Which cells are platelets derived from?
A
Megakaryocytes
10
Q
What is the circulating lifespan of platelets?
A
10 days
11
Q
How to platelets adhere to the damaged endothelial wall?
A
The plasma membranes contain glycoproteins that are responsible for platelet interactions, to which proceeding on from vessel wall damage, exposed collagen fibres facilitate a surface for platelet aggregation to the damage endothelium by directly binding onto glycoprotein-1A receptor.
12
Q
Which cell surface glycoprotein on platelets directly binds onto the endothelial wall?
A
Glycoprotein-1a receptor
13
Q
How do platelets indirectly bind onto the damaged endothelium?
A
By attaching to Von Willebrand factor (VWF), interacting with the glycoprotein-IB receptor
14
Q
What happens upon platelet adhesion to the damaged endothelial wall?
A
Platelet adhesion initiates activation and release of clotting factors from storage granules
ADP is also released
15
Q
What are the two storage granules in platelets?
A
Alpha and dense granules
16
Q
What two substances are mainly released upon platelet aggregation?
A
Thromboxane A2
ADP
17
Q
What is the precursor of thromboxane A2?
A
Arachidonic acid
18
Q
What is the function of thromboxane A2?
A
Stimulates platelet aggregation, and activation of new platelets (exhibits positive feedback)
-Also a vasoconstrictor
19
Q
Upon thromboxane and ADP action, what happens to the platelets?
A
Conformational change occurs (ADP-induced) in the GP2b/3a receptor (flip-flopping) to provide binding sites for fibrinogen
20
Q
What is the function of fibrinogen in primary haemostasis?
A
A soluble blood protein that links platelets together to form an unstable platelet plug
21
Q
What is thrombocytopenia?
A
Low numbers of platelets
22
Q
What are the common disorders of primary haemostasis?
A
Thrombocytopenia
Bone marrow failure: Leukaemia, B12 deficiency
ITP
Disseminated intravascular coagulation
Pooling and destruction in an enlarged spleen
Impaired function of platelets
Acquired (drugs)
23
Q
What are possible causes of bone marrow failure?
A
Leukaemia, B12 deficiency
24
Q
How can an impaired function of platelet activity lead to a disorder of primary haemostasis?
A
There is an hereditary absence of glycoproteins or storage granules (rare).
25
Which drugs are implicated in inducing a disorder of primary haemostasis?
Aspirin
NSAIDs
Clopidrogrel
26
What is immune thrombocytopenic purpura?
• Antiplatelet autoantibodies adhere to the sensitised platelet.
• This identifies the platelet to undergo phagocytosis by macrophages.
This causes a depletion of platelets.
• ITP is a common cause of thrombocytopenia.
27
What is Glanzmann's thrombocytopenia?
Refers to an abence of GP2b/3a receptor on platelets
28
What is Bernard Soulier Syndrome?
Absence of Gp1b receptors
29
What is storage pool disease?
Absence of dense granules
| -reduced ADP release
30
What is the mechanism of action of aspirin?
Aspirin inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX) - reduced platelet aggregation
31
How long does a single dose of aspirin typically last?
7 days
| Most of the platelets at the time of aspirin ingestion have been replaced by new platelets
32
What is the action of clopidogrel?
• Irreversibly blocks the ADP receptor (P2Y12) on the platelet cell membrane; thereby ADP-induced conformational change cannot occur.
33
Which receptor is blocked by clopidogrel?
P2Y12 receptor (ADP)
34
What is Von Willebrand disease?
In Von Willebrand disease, there is a hereditary decrease of quantity of VWF, in severe cases there is a deficiency of factor VIII. The cause is typically associated with an autosomal inheritance pattern.
35
Which cells are responsible for the synthesis of VWF?
• VWF is a multimeric glycoprotein that is synthesised by endothelial cells and megakaryocytes, circulating in the plasma.
36
What is the function of VWF?
• This mediates the adhesion of platelets to sites of injury, thus promoting platelet-platelet aggregation by binding onto the glycoprotein-1b receptor.
37
What clotting factor is VWF a specific carrier?
Factor VIII
38
What type 1 and 3 VW disease?
Deficiency of VWF
39
Which type of Von Willebrand disease is concerned with abnormal function of VWF?
Type 2
40
Which hereditary disorders influence disorders of the vessel wall?
• Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders (RARE).
41
What are the acquired causes of disorders of the vessel wall?
Steroid therapy, ageing (senile purpura), vasculitis, scurvy (Vitamin C deficiency).
42
How do steroids cause damage to the vessel wall?
Steroids can develop atrophy of the collagen fibres supporting the blood vessels in the skin
43
What is senile purpura?
Senile purpura is dark purple well-defined margins commonly distributed on the extensor surfaces of the arms and dorsum of the hand.
44
What are the clinical features of disorders of primary haemostasis?
* Immediate
* Prolonged bleeding from cuts
* Nose bleeds (Epistaxis): Prolonged > 20 minutes.
* Gum bleeding: Prolonged
* Heavy menstrual bleeding (menorrhagia)
* Bruising (ecchymosis) may be spontaneous/easy
* Prolonged bleeding after trauma or surgery
45
What are petechia and purpura?
Thrombocytopenia – petechiae Petechia and purpura are caused by bleeding under the skin. (Can occur in vascular disorders).
Purpura do not blanch when pressure is applied Diagnostic of meningitis.
46
What is the average radius of petechia?
Less than 3mm
47
What is the average radius of purpura?
3-10mm
48
What is the average radius of ecchymosis?
>10mm
49
What investigations are conducted
1. Platelet count, platelet morphology
2. Bleeding time (PFA100 in lab)
3. Assays of VWF.
4. Clinical observation
5. Note –coagulation screen (PT, APTT) is normal (except more severe VWD cases where FVIII is low)
50
What is the normal range of a platelet count?
100-400 x 10^9/L
51
Which platelet count range is associated with no spontaneous bleeding, but bleeding witj trauma?
40-100 x 10^9/L
52
Which platelet count range is associated with spontaneous bleeding?
10-40 x 10^9/L
53
Which platelet count is associated with severe spontaneous bleeding?
<10x10^9/L
54
What treatment is available for disorders of primary haemostasis?
Replacing missing factor/platelet e.g. VWF containing concentrates
Stop drugs such as aspirin or NSAIDs
55
What treatment is available for ITP?
Immunosuppression using prednisolone and splenectomy for ITP
56
What pharmacological treatment is used for the treatment of Von Willebrand disease?
Desmopressin
57
How does desmopressin work in terms of treating Von Willebrand disease?
This is a vasopressin analogue with a notable 2-5 fold increase in VWF and factor VIII.
58
What is the function of tranexamic acid>
Is a synthetic derivative of lysine Works by binding to plasminogen, thereby behaving as a competitive inhibitor by preventing plasminogen from binding to lysine residues of fibrin.
• Plasminogen cannot be activated into plasmin Fibrin is not lysed. This inhibits fibrinolysis.
59
What is the main role of coagulation?
To generate thrombin, this converts fibrinogen into insoluble fibrin
60
What are the hereditary causes of coagulator factor deficiency?
Factor VIII/IX
| Haemophilia A/B respectively
61
What are the common acquired causes of coagulation factor deficiency?
```
Liver diseases
Anticoagulant drugs (Warfarin, direct oral anticoagulants)
```
Dilution
Increased consumption: DIC and autoantibodies
62
Which clotting factors are synthesised upon the carboxylation of glutamic acid residues by vitamin K?
II,
VII,
IX,
X
63
How does dilution cause a coagulation factor deficiency?
Blood transfusion following haemorrhage (inadequate replacement of platelets). Transfusion does not contain plasma or clotting factors.
64
What is disseminated intravascular coagulation?
* Generalised activation of coagulation – tissue factor
* Associated with sepsis, major tissue damage, inflammation
* Consumes and depletes coagulation factors
* Platelets consumed – thrombocytopenia
* Activation of fibrinolysis depletes fibrinogen – raised D-dimer (a breakdown product of fibrin).
* Deposition of fibrin in vessels causes organ failure.
65
What breakdown product of fibrin can be measured?
D-dimer
66
Which factor is deficient in haemophilia A?
Factor VIII
67
Which factor is deficient in haemophilia B?
Factor IX
68
Which haemophilia is sex linked?
Haemophilia B
69
What is the hallmark of haemophilia?
Haemarthrosis - the spontaneous bleeding of the joints
70
What impact does intramuscular injections have on patients with haemophilia?
Leads to an extensive haematoma
71
Which clotting factor deficiency is considered to be lethal?
Prothrombin (Factor II)
72
Which clotting factor deficiency is associated with non-spontaneous bleeding after trauma?
Factor XI
73
Which clotting factor deficiency is associated with no bleeding at all?
Factor XII
74
What are the clinical features of coagulation disorders?
* Superficial cuts do not bleed (Platelets plug is sufficient to stop bleeding, stabilisation does not occur in large vessels given that there is insufficient fibrin)
* 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.
75
Where does bleeding typically occur in individuals with a platelet/vascular disorder?
Superficial bleeding into skin, mucosal membranes
76
Where does bleeding typically occur in individuals with a coagulation disorder?
Bleeding into deep tissues ,muscles, joints.
| Delayed, but severe bleeding after injury.
77
What tests are conducted for coagulation disorders?
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Full blood count (for platelets)
Coagulation factor assays (For FVIII etc),
78
Which pathway does prothrombin time measure?
Measures the integrity of the extrinsic pathway
79
Which chemical substance is added to blood samples to chelate calcium and prevent clotting?
Sodium citrate
80
What is added to blood samples to initiate the coagulation cascade?
Tissue factor and phospholipid (recombinant thromboplastin)
81
What clotting factors directly influence prolongation of prothrombin time?
```
Factors:
V
VII
X
II
Fibrinogen
```
82
What is used to measure anticoagulant therapy using warfarin?
Prothrombin time, results are expressed as the international normalised ratio (INR).
83
What pathway is measured by the activated partial thromboplastin time (APTT)?
Measures the integrity of the ‘intrinsic pathway’, performed by the contact activation of factor XII by contact activity (silica or kaolin).
84
An isolated prolonged APTT, and normal PT suggests what?
* Haemophilia A (factor VIII deficiency)
* Haemophilia B (Factor IX deficiency)
* Factor XI deficiency
* Factor XII deficiency Does not result in bleeding.
85
If both PT and APPT are prolonged consider?
* Liver disease
* Anticoagulant drugs e.g., warfarin
* DIC (Platelets and D dimer)
* Dilution following red cell transfusion.
86
How are coagulation factors replaced?
* Plasma (Fresh frozen plasma FFP) Contains all coagulation factors.
* Cryoprecipitate Rich in fibrinogen, FVIII, VWF, Factor XIII
* Factor concentrates Concentrates available for all factors except factor V (Use FFP). Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
87
What is fresh frozen plasma?
Contains all coagulation factors
88
What is contained within cryoprecipitate?
Rich in fibrinogen, FVIII, VWF, Factor XIII
89
What are the 3 forms of novel treatment for haemophilia?
Gene therapy
Bis-specific antibodies (Haemophilia)
RNA silencing
90
How do bispecific antibodies work?
Emiciizumab binds to factor IXa and factor X, these mimic the procoagulant function of FVIII.
91
What is thrombosis?
Thrombosis is the local coagulation or clotting of blood in part of the circulatory system.
• Intravascular & inappropriate coagulation
• Venous
• Obstruction to blood flow
92
What are the presenting symptoms of a pulmonary embolism?
2. Hypoxia
3. Shortness of breath
4. Chest pain - Pleuritic chest pain worsening during deep inhalation
5. Haemoptysis Coughing up blood
6. Sudden death
93
What type of heart failure is concerned with a pulmonary embolism?
Right-sided heart failure
94
What are the symptoms of deep vein thrombosis?
```
Deep vein thrombosis (DVT) is the development of a blood clot in a major deep vein in the leg, thigh, pelvis or abdomen Impaired venous blood flow.
• Painful leg
• Swelling
• Red
• Warm
• May embolise to lungs
• Post-thrombotic syndrome
N.B: DVT can lead to a pulmonary embolism and cause long standing damage due to venous valve incompetence
```
95
What is Virchow's triad?
1. Blood Dominant in venous thrombosis
2. Vessel wall Dominant in arterial thrombosis
• Proteins active in coagulation are expressed on the surface of endothelial cells and their expression is altered in inflammation (TM, EPCR, TF).
3. Blood flow Contributes to both arterial and venous thrombosis.
• Reduced flow (stasis) increases the risk of thrombosis (Surgery, long-haul flights and pregnancy).
96
Which fibrinolytic factors lead to reduced in thrombosis?
Antithrombin
Protein C
Protein S
97
How does an antithrombin deficiency cause thrombosis?
Inherited antithrombin deficiency (thrombopenia), leads to a reduced inactivation of factor IIa and Xa.
98
Which plasminogen inhibitor is produced by the placenta during pregnancy?
PAI-2
99
Which clotting factor rises during pregnancy?
Factor VIII
100
How does Factor V Leiden contribute towards thrombosis?
Factor V activity increases through a single point mutation in the factor V gene.
Factor V Leiden results in increasing Factor V resistivity to inactivation by protein C (inherited 7% heterozygotes).
101
How do myeloproliferative disorders contribute towards thrombosis?
Increase platelets
102
Which factors are inactivated by antithrombin?
Thrombin and factor Xa
103
Which drug potentiates the action of antithrombin?
Heparin
104
What is the function of Protein C?
• Thrombin binds to thrombomodulin on the endothelial cell surface resulting in protein C activation to Activated Protein C (APC). APC inactivates factors Va and VIIIa in the presence of co-factor protein S.
105
Which factors are inactivated by Protein C?
Factors Va, and VIIIa.
106
Which inherited thrombophillic trait has the greatest impact on mortality?
Antithrombin
107
What is the mechanism of heparin?
* The mechanism of action of heparin concerns the indirect action of potentiating the action of antithrombin, leading to the inactivation of factors Xa and IIa (thrombin).
* Heparin is administered intravenously or by subcutaneous injection.
108
How is unfractionated heparin administered?
Intravenously
109
How is thrombin inactivated by unfractionated heparin?
Heparin binds to antithrombin and thrombin (long chains wraps itself around thrombin)
110
How is factor Xa inactivated by unfractionated heparin?
Heparin directly binds to antithrombin only, giving alterations to the active site leading to a greater affinity for target factor.
111
What are the two forms of heparin?
Unfractionated heparin
| Low molecular weight heparin (LMWH)
112
How is LMWH administered?
Subcutaneously
113
What is the action of LMWH?
* Contain pentasccharide sequence for binding antithrombin, given the shorter chains, LMWH is directed against factor Xa.
* Predictable dose response in most cases so does not require monitoring (cF UFH).
114
What compound is warfarin derived from?
Coumarin
115
What is the function performed by warfarin?
Behaves as a vitamin K antagonist, interfering with the carboxylation of glutamic acid residues, and thereby interrupting the synthesis of factors II, VII, IX, and X
116
How is the action of Warfarin reversed?
• Reversed slowly by Vit K administration Takes several hours to work.
• Reversed rapidly by infusion of coagulation factors:
PCC (Prothrombin complex concentrate – contains factors II, VII, IX and X)
FFP (Fresh frozen plasma).
117
What are side effects of warfarin?
Bleeding
Skin necrosis
Purple toe syndrome
Embryopathy
118
What is the normal unanticoagulated INR?
1.0
119
What is the target INR range for warfarin?
2-3
120
How can patients become resistant to Warfarin treatment?
```
Lack of patient compliance
• Measure warfarin levels
• Proteins Induced By Vitamin K Absence (PIVKA)
Diet Increased vitamin K intake.
Increased metabolism (Cytochrome p450)
Reduced binding (VKORC1)
```
121
Which DOACs target factor Xa?
Rivaroxaban
Apixaban
Edoxaban
122
Which DOAC targets factor IIa?
Dabigatran
123
Compare the onset of Warfarin with a DOAC?
Slow v Rapid
124
Compare the dosage of Warfarin with a DOAC?
Variable v Fixed
125
Which type of anticoagulant should be avoided in an individual with a mechanical prosthetic heart valve?
DOACs
