(37) Heritable bleeding disorders Flashcards
1
Q
The haemostatic balance is a balance between which 2 things?
A
Bleeding and clotting
2
Q
Primary haemostasis involves what?
A
Platelet aggregation and adhesion
3
Q
Secondary haemostasis involves what?
A
Coagulation (fibrin formation etc)
4
Q
When the is injury to a blood vessel wall, what happens initially?
A
- platelets adhere to site of vascular injury with help from von Willebrand factor, and become activated
- platelets aggregate and form a platelet plug/thrombus
- this goes on to activate fluid phase of clotting
5
Q
How does secondary (coagulation) haemostasis contribute to clotting?
A
A fibrin network is formed which stabilises the platelet plug to form a haemostatic clot
6
Q
Thromboxane is synthesises in the platelet. What is its function?
A
Thromboxane is a vasoconstrictor and a potent hypertensive - it facilitates platelet aggregation/activates more platelets
7
Q
The platelet releases dense granules from inside the cell. What do they all do?
A
They all contribute to positive feedback and enhancing the clotting process
8
Q
What is the function of the glycoprotein IIb/IIIa receptor on the platelet surface?
A
Receptor for fibrinogen - this enables platelets to stick together and supports aggregation
9
Q
What is the function of the glycoprotein Ib-V-IX receptor on the platelet surface?
A
Receptor for von Willebrand factor - supports primary platelet adhesion
10
Q
Anti-platelet drugs work against the mechanisms going on in the platelet. What are the used for?
A
Patients with thrombosis, MI, thrombotic stroke etc. and prevention of these disorders
11
Q
Aspirin is a type of anti-platelet drug. What does it do?
A
Inhibits cyclooxygenase (COX) which synthesises thromboxane
12
Q
Clopidogrel is a type of anti-platelet drug. What does it do?
A
Inhibits the ADP receptor on platelet cell membranes.
- requires CYP2C19 for its activation
- irreversibly inhibits the P2Y12 subtype of ADP receptor
- which is important in activation of platelets and eventual cross-linking by the fibrin
13
Q
IIb/IIIa antagonists are a type of anti-platelet drug. What do they do?
A
They inhibit the GpIIb/IIIa receptor on the surface of platelets - thus preventing platelet aggregation and thrombus formation
14
Q
Name 4 anti-platelet drugs
A
- aspirin
- clopidogrel
- dipyridamole
- IIb/IIIa antagonists
15
Q
Which enzyme converts fibrinogen to fibrin?
A
Thrombin - converts fibrinogen circulating in the plasma to fibrin
16
Q
What activates the extrinsic pathway?
A
Tissue factor (TF) - exposed on the surface of cells that are injured or activated
17
Q
When tissue factor is expressed, leading to the extrinsic pathway, what happens next?
A
Factor 7 is activated forming factor 7a, this cleaves factor 10 to factor 10a (common pathway)
18
Q
How is the intrinsic pathway started?
A
Activated when the blood is in contact with foreign surface - no need for substances outside of the blood
19
Q
The intrinsic pathway starts with activation of what?
A
Activation of factor 12 making factor 12a
20
Q
Activation of factor 12 is the first step in the intrinsic pathway. What happens next?
A
Factor 12a activates factor 11 forming factor 11a - this activates factor 9 forming factor 9a
21
Q
What happens after factor 9 is activated in the intrinsic pathway?
A
Factor 9a, together with the cofactor factor 8a, activates factor 10 to factor 10a
22
Q
When factor 10 is activated, what pathway does it become?
A
The common pathway
23
Q
What does factor 10a do?
A
Factor 10a together with cofactor factor 5a will enzymatically cleave prothrombin (factor 2) to thrombin
24
Q
What does fibrin do after it is cleaved from fibrinogen by thrombin?
A
It polymerases to form a fibrin network = fibrin clot
25
Are the extrinsic and intrinsic pathways completely separate?
No, they interact and work in conjunction with one another
26
What is the intrinsic pathway also called?
Contact activation
27
Name 3 tests in a coagulation screen
- prothrombin time
- activated partial thromboplastin time
- thrombin clotting time
28
How does the prothrombin time test work?
Evaluates the extrinsic pathway of coagulation (and the common pathway) - in order to activate the extrinsic clotting cascade, tissue factor is added and the time the sample takes to clot is measured optically
29
How does the activated partial thromboplastin time (APTT) work?
Evaluates the intrinsic pathway and the common pathway. A reagent is added that the blood with see as a foreign surface eg. silica - this activates factor 12.
Then a mixture of phospholipid (platelet substitute) and calcium - allowing to go beyond factor 11a
Time between adding phospholipid and calcium and clot forming is measured
30
How does the thrombin clotting time test work?
Only evaluates the final reaction of the whole pathway. An excess of thrombin is added to plasma in a test tube and time to form a clot is measured
31
In reality, normal haemostasis is not so simple and everything is interacting. What is evidence for this?
The fact that factor 12 deficiency is not a bleeding disorder and factor 11 deficiency is a variable and mild bleeding disorder
32
Why is factor 12 deficiency not a bleeding disorder?
As factor 11 can be directly activated by thrombin (so no need for factor 12)
Activated thrombin feeds back and activates other factors
33
Name 2 procoagulants
- platelets
| - clotting factors
34
Name 4 anti-coagulants
- protein C
- protein S
- anti-thrombin III
- fibrinolytic system
35
What is the importance of the anticoagulant system?
Need to break down a clot after healing has occurred so blood can flow normally again
36
What is protein S?
A cofactor for protein C
37
Which enzyme breaks down fibrin into fibrin degradation products?
Plasmin
38
What cleaves plasminogen into plasmin?
Tissue plasminogen activator (tPA)
39
Where does cleaving of plasminogen into plasmin by tPA occur?
On the surface of the fibrin clot
40
Why is it important not to have free plasmin circulating?
As it is a very potent digestive enzyme
41
Which protein inactivates plasmin?
Alpha 2-antiplasmin (it mops up excess plasmin to stop it digesting other things)
42
Where is there absence of alpha 2-antiplasmin?
Inside the clot - this means that plasmin can work inside the clot
43
What is tPA used for in medicine?
To get rid of a clot in MI for example (as it produces activated plasmin to break down fibrin clot)
44
What are the 2 types of categories of bleeding disorders?
- congenital or acquired
| - platelet/vessel wall defect (primary haemostasis) or coagulation defect (secondary haemostasis)
45
What is usually defected in congenital vs acquired bleeding disorders?
congenital = usually single gene defect, so single gene faulty
acquired = often multiple defects, usually secondary to something else/drugs
46
Briefly, what type of bleeding does platelet/vessel wall defects (primary) bleeding disorders cause?
Bleeding into skin and mucosal bleeding eg. nosebleeds
47
Briefly, what type of bleeding does coagulation defects (secondary) bleeding disorders?
Deep tissue bleeding into muscles and joints
Bleeding following trauma
48
How can you differentiate by taking a history between congenital and acquired bleeding?
Congenital = have problems since childhood
Acquired = correlates with something else going wrong with the patient
49
What do you need to know in a history when diagnosing a bleeding disorder?
- date of onset, previous episodes
- the pattern of bleeding
- response to surgery etc
- other systemic illnesses
- family history
- examination: pattern of bruising, signs of underlying disease, joints, muscles, skin
ect.
50
What do platelet/vessel wall defects all give rise to?
A prolonged bleeding time
51
What types of platelet/vessel wall defects are there?
- reduced number of platelets
- abnormal platelet function (drugs, aspirin)
- abnormal vessel wall
- abnormal interaction between platelets and vessel wall
52
Give an example of a disorder where there is an abnormal vessel wall (platelet/vessel wall defects)
Ehlers-Danlos syndrome
53
What is Ehlers-Danlos syndrome?
A group of rare inherited conditions that affect connective tissue - connective tissues provide support in skin, tendons, ligaments, blood vessels, internal organs and bones
54
Give an example of a condition where there is abnormal interaction between platelets and the vessel wall
Von Willebrand Disease
55
What is von Willebrand factor?
Primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. It is not an enzyme and, thus, has no catalytic activity
Like glue that sticks platelets to vessel wall, an adhesion protein
56
Give 4 types of bleeding in vascular/platelet defects
- petechiae and superficial bruises
- skin and mucosal membranes
- spontaneous bleeding
- bleeding immediate; prolonged and non-recurrent
57
Give 4 types of bleeding in coagulation defects
- deep spreading haematoma
- haemarthrosis
- retroperitoneal bleeding
- bleeding prolonged and often recurrent
58
`What is haemarthrosis?
Bleeding into joint spaces
59
In which type of defect is there prolonged but non-recurrent bleeding?
Vascular/platelet defects
60
In which type of defect is there prolonged and recurrent bleeding?
Coagulation defects
61
In which type of defect is there petechiae?
Vascular/platelet defects
62
In which type of defect is there spontaneous?
Vascular/platelet defects
63
What is petechiae?
Red or purple spots caused by bleeding into the skin
64
How can you differentiate between petechiae and angiomas?
Petechiae does not blanch with pressure whereas angiomas do
65
How can you differentiate between petechiae and vasculitis?
Petechiae is not palpable, it is flat on the skin. Unlike vasculitis
66
Give 2 features of petechiae
- does not blanch with pressure
| - not palpable
67
Nosebleeds are common in which disorders?
von Willebrand disease and other platelet disorders
68
What is mild type 1 vWF disease?
The most common type (1% of population) - normal structure of vwf but reduced amount
Reduced production of a normal molecule (high molecular weight polymer)
69
What is type 2 vWF disease?
Normal number of vwf but abnormal structure (low molecular weight polymer rather than high molecular weight so not as good 'glue')
70
What is type 3 vWF disease?
Rare, completely absent molecule, no vwf
71
What types of vWF disease are more severe?
type 1 and 2 = less severe
type 3 = severe
72
What type of inheritance pattern do the different types of vWF disease show?
type 1 and 2 = autosomal dominant
type 3 = recessive
73
Why might there be low levels of von Willebrand factor despite the gene being normal?
- increased clearance
- ineffective secretion
etc
(30-50% vwf)
74
von Willbrand is also a carrier protein for which factor around the blood stream?
Factor VIII
75
Why does factor 8 need a carrier (vwf)?
It has a short half life in circulation
76
Since vWF is also a carrier protein to factor 8, what other types of bleeding pattern do you get in vWF disease?
Deficiency of factor 8 means there is also haemarthrosis and muscle bleeds as well as mucosal bleeding such as nosebleeds
77
Which gender is affected more by vWF disease?
Men and women are affected equally
78
What is the most common heritable bleeding disorder?
Von Willebrand disease - associated with defective primary haemostasis
79
In VWF disease you get mucocutaenous bleeding including what in women?
Menorrhagia (heavy periods) and post partum bleeding (as well as postoperative bleeding etc), easy bruising
80
Which blood group has lower levels of von Willebrand factor?
Blood group O
81
What is the penetrance of vWF disease?
Variable penetrance for mild types
82
Why is diagnosis of mild vWF disease difficult?
Due to confounding factors
83
What treatment is there for Von Willebrand Disease?
- antifibrinolytics: tranexamic acid
- DDAVP (type 1 vWD)
- factor derived concentrates containing wWF (plasma-derived)
- vaccination against hepatitis
- COCP for menorrhagia
84
When particularly is tranexamic acid used in vWF disease?
When going to the dentists etc - good for mouth bleeding and nose bleeds
85
What type of substance is tranexamic acid?
An antifibrinolytic
86
What does DDAVP do? (used in type 1 vWD)
It releases vWF from its stores in endothelial cell so temporarily increase the vWF levels in the plasma
87
Continued use of DDAVP is associated with tachyphylaxis. What is this?
Acute rapid decrease in response to a drug after its administration. It can occur after an initial dose or after a series of small doses - lesser response in continued uses
88
What is ad adverse affect of DDAVP?
Can cause vasoconstriction so avoid in very young, elderly, heart problems etc
89
What is DDAVP also called?
Desmopressin
90
What is the reason for vaccinating against hepatitis in vWF disease?
As you might need to give blood products in the future
91
Deficiencies in single clotting factors are defects in what haemostasis?
Secondary haemostasis (coagulation)
92
What are the 2 most common single coagulation factor deficiencies?
Haemophilia A and B
93
Haemophilia A and B are deficiencies in which coagulation factors?
A = factor 8
B = factor 9
94
Is factor 12 deficiency a bleeding disorder?
No
95
Recessive coagulation factor deficiencies are more common in which communities?
Those where there is lots of consanguineous marriage
96
The haemophilias show which mode of inheritance?
Sex linked recessive (X-linked)
97
Which laboratory defect would VIII haemophilia, VIII von Willebrand Disease, XI deficiency etc. cause?
Abnormal APTT
98
What laboratory defect would factor VII deficiency cause?
Abnormal PT
99
What laboratory defect would factor X deficiency cause?
Abnormal APTT and PT
100
What laboratory defect would factor I (fibrinogen) deficiency cause?
Abnormal APTT, PT, and TCT
101
How many people do the haemophilias affect?
haemophilia A = 1 in 5,000 males
haemophilia B = 1 in 30,000 males
(females are carriers)
102
What is the chance of a son having haemophilia if the mum is a carrier?
50%
103
What factor 8 level would you expect in a haemophilia-affected son?
2%
104
What factor 8 level would you expect in a haemophilia-carrier daughter?
50%
105
Haemophilia is a defect in intrinsic pathway factors meaning which clotting time is prolonged?
ATTP
106
How many cases of haemophilia are new mutations? (new mutation in factor 8 gene)
30%
107
What about haemophilia is consistent between family members?
Severity level
108
What is the normal range of factor VIII or IX level?
50%-150%
109
What is the factor 8/9 level in mild haemophilia?
6%-50%
110
What is the factor 8/9 level in moderate haemophilia?
1%-5%
111
What is the factor 8/9 level in severe haemophilia?
Less than 1%
112
What type of bleeding do you get in haemophilia?
- spontaneous/post-traumatic
- haemarthrosis
- muscle haemorrhage
- soft tissue
- life threatening bleeding eg. intracranial, bleeding into airways
113
What is haemophilic arthropathy?
Bleeding into joints eg. knees causing swelling and bony deformities and muscle wasting
114
What is involved in the treatment of haemophilia?
- replacement of missing clotting protein (on demand for mild/moderate or prophylaxis for severe)
- DDAVP (mild/moderate haemophilia A)
- factor concentrates
- antifibrinolytic agents
- hepatitis A and B vaccination
115
What supportive measures are taken in the case of joint and muscle bleeds in haemophilia?
- icing
- immobilisation
- rest
- physiotherapy
116
What is the purpose of hepatitis vaccination in haemophilia?
In the case of needed plasma-derived products as treatment
117
DDAVP is ineffective in which type of haemophilia?
Haemophilia B - so always treat with factor concentrate
118
What are some potential complications of treatment of haemophilia?
Transfusion-transmitted infection
- hep A, B, C....G
- HIV
- parovirus
- vCJD
Inhibitor development
119
Inhibitor development may occur in treatment of haemophilia. What is this?
Development of antibodies against factor 8/factor 9 - renders treatment useless
120
Which type of haemophilia is inhibitor development most common in?
Incidence = 25% in haemophilia A
More rare in haemophilia B (inhibitors to factor 9 are rare)
121
What does inhibitor development in haemophilia treatment result in?
Poor recovery and/or shortened half life of factor replacement therapy - poor clinical response to treatment
122
When does inhibitor development occur?
Mostly early in course of condition (10 exposure days) - unusual to develop after 150 days
123
If inhibitor development happens in haemophilia treatment, what is required?
Specialised management of bleeds - usually keep levels between 60-100%
Try to eradicate inhibitor - process is called immune tolerance
124
Immune tolerance is the process of eradicating the inhibitor of factor 8/9. How is it done?
Give very high doses of factor 8 so immune system stops recognising it as a foreign protein
125
What are the appropriate investigations into bleeding disorders?
- FBC and blood film
- coagulation screen and Clauss fibrinogen (D-dimer if suspicion of acquired disorder)
- Von Willebrand profile
- coagulation factor assays eg. FVIII/FIX
- inhibitor assays
- platelet function tests
- FXIII assay and alpha 2-antiplasmin assay
126
What are some problems with blue-top bottle? (pre-analytical errors)
- partial fill tubes
| - vacuum leak and citrate evaporation
127
What are some problems with phlebotomy? (pre-analytical errors)
- heparin contamination
- wrong label
- slow fill
- underfill
- vigorous shaking
128
What are some laboratory errors? (pre-analytical errors)
- delay in testing
- prolonged incubation at 37 degrees
- freeze/thaw deterioration
129
What is thromboplastin?
An enzyme released from damaged cells, especially platelets, which converts prothrombin to thrombin during the early stages of blood coagulation
