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8. CP - Core Haematology > (37) Heritable bleeding disorders > Flashcards

(37) Heritable bleeding disorders Flashcards

1
Q

The haemostatic balance is a balance between which 2 things?

A

Bleeding and clotting

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2
Q

Primary haemostasis involves what?

A

Platelet aggregation and adhesion

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3
Q

Secondary haemostasis involves what?

A

Coagulation (fibrin formation etc)

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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
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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

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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

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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

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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

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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

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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

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11
Q

Aspirin is a type of anti-platelet drug. What does it do?

A

Inhibits cyclooxygenase (COX) which synthesises thromboxane

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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
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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

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14
Q

Name 4 anti-platelet drugs

A
  • aspirin
  • clopidogrel
  • dipyridamole
  • IIb/IIIa antagonists
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15
Q

Which enzyme converts fibrinogen to fibrin?

A

Thrombin - converts fibrinogen circulating in the plasma to fibrin

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16
Q

What activates the extrinsic pathway?

A

Tissue factor (TF) - exposed on the surface of cells that are injured or activated

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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)

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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

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19
Q

The intrinsic pathway starts with activation of what?

A

Activation of factor 12 making factor 12a

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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

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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

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22
Q

When factor 10 is activated, what pathway does it become?

A

The common pathway

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23
Q

What does factor 10a do?

A

Factor 10a together with cofactor factor 5a will enzymatically cleave prothrombin (factor 2) to thrombin

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24
Q

What does fibrin do after it is cleaved from fibrinogen by thrombin?

A

It polymerases to form a fibrin network = fibrin clot

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25
Q

Are the extrinsic and intrinsic pathways completely separate?

A

No, they interact and work in conjunction with one another

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26
Q

What is the intrinsic pathway also called?

A

Contact activation

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27
Q

Name 3 tests in a coagulation screen

A
  • prothrombin time
  • activated partial thromboplastin time
  • thrombin clotting time
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28
Q

How does the prothrombin time test work?

A

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

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29
Q

How does the activated partial thromboplastin time (APTT) work?

A

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

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30
Q

How does the thrombin clotting time test work?

A

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

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31
Q

In reality, normal haemostasis is not so simple and everything is interacting. What is evidence for this?

A

The fact that factor 12 deficiency is not a bleeding disorder and factor 11 deficiency is a variable and mild bleeding disorder

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32
Q

Why is factor 12 deficiency not a bleeding disorder?

A

As factor 11 can be directly activated by thrombin (so no need for factor 12)

Activated thrombin feeds back and activates other factors

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33
Q

Name 2 procoagulants

A
  • platelets

- clotting factors

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34
Q

Name 4 anti-coagulants

A
  • protein C
  • protein S
  • anti-thrombin III
  • fibrinolytic system
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35
Q

What is the importance of the anticoagulant system?

A

Need to break down a clot after healing has occurred so blood can flow normally again

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36
Q

What is protein S?

A

A cofactor for protein C

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37
Q

Which enzyme breaks down fibrin into fibrin degradation products?

A

Plasmin

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38
Q

What cleaves plasminogen into plasmin?

A

Tissue plasminogen activator (tPA)

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39
Q

Where does cleaving of plasminogen into plasmin by tPA occur?

A

On the surface of the fibrin clot

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40
Q

Why is it important not to have free plasmin circulating?

A

As it is a very potent digestive enzyme

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41
Q

Which protein inactivates plasmin?

A

Alpha 2-antiplasmin (it mops up excess plasmin to stop it digesting other things)

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42
Q

Where is there absence of alpha 2-antiplasmin?

A

Inside the clot - this means that plasmin can work inside the clot

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43
Q

What is tPA used for in medicine?

A

To get rid of a clot in MI for example (as it produces activated plasmin to break down fibrin clot)

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44
Q

What are the 2 types of categories of bleeding disorders?

A
  • congenital or acquired

- platelet/vessel wall defect (primary haemostasis) or coagulation defect (secondary haemostasis)

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45
Q

What is usually defected in congenital vs acquired bleeding disorders?

A

congenital = usually single gene defect, so single gene faulty

acquired = often multiple defects, usually secondary to something else/drugs

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46
Q

Briefly, what type of bleeding does platelet/vessel wall defects (primary) bleeding disorders cause?

A

Bleeding into skin and mucosal bleeding eg. nosebleeds

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47
Q

Briefly, what type of bleeding does coagulation defects (secondary) bleeding disorders?

A

Deep tissue bleeding into muscles and joints

Bleeding following trauma

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48
Q

How can you differentiate by taking a history between congenital and acquired bleeding?

A

Congenital = have problems since childhood

Acquired = correlates with something else going wrong with the patient

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49
Q

What do you need to know in a history when diagnosing a bleeding disorder?

A
  • 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.
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50
Q

What do platelet/vessel wall defects all give rise to?

A

A prolonged bleeding time

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51
Q

What types of platelet/vessel wall defects are there?

A
  • reduced number of platelets
  • abnormal platelet function (drugs, aspirin)
  • abnormal vessel wall
  • abnormal interaction between platelets and vessel wall
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52
Q

Give an example of a disorder where there is an abnormal vessel wall (platelet/vessel wall defects)

A

Ehlers-Danlos syndrome

53
Q

What is Ehlers-Danlos syndrome?

A

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
Q

Give an example of a condition where there is abnormal interaction between platelets and the vessel wall

A

Von Willebrand Disease

55
Q

What is von Willebrand factor?

A

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
Q

Give 4 types of bleeding in vascular/platelet defects

A
  • petechiae and superficial bruises
  • skin and mucosal membranes
  • spontaneous bleeding
  • bleeding immediate; prolonged and non-recurrent
57
Q

Give 4 types of bleeding in coagulation defects

A
  • deep spreading haematoma
  • haemarthrosis
  • retroperitoneal bleeding
  • bleeding prolonged and often recurrent
58
Q

`What is haemarthrosis?

A

Bleeding into joint spaces

59
Q

In which type of defect is there prolonged but non-recurrent bleeding?

A

Vascular/platelet defects

60
Q

In which type of defect is there prolonged and recurrent bleeding?

A

Coagulation defects

61
Q

In which type of defect is there petechiae?

A

Vascular/platelet defects

62
Q

In which type of defect is there spontaneous?

A

Vascular/platelet defects

63
Q

What is petechiae?

A

Red or purple spots caused by bleeding into the skin

64
Q

How can you differentiate between petechiae and angiomas?

A

Petechiae does not blanch with pressure whereas angiomas do

65
Q

How can you differentiate between petechiae and vasculitis?

A

Petechiae is not palpable, it is flat on the skin. Unlike vasculitis

66
Q

Give 2 features of petechiae

A
  • does not blanch with pressure

- not palpable

67
Q

Nosebleeds are common in which disorders?

A

von Willebrand disease and other platelet disorders

68
Q

What is mild type 1 vWF disease?

A

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
Q

What is type 2 vWF disease?

A

Normal number of vwf but abnormal structure (low molecular weight polymer rather than high molecular weight so not as good ‘glue’)

70
Q

What is type 3 vWF disease?

A

Rare, completely absent molecule, no vwf

71
Q

What types of vWF disease are more severe?

A

type 1 and 2 = less severe

type 3 = severe

72
Q

What type of inheritance pattern do the different types of vWF disease show?

A

type 1 and 2 = autosomal dominant

type 3 = recessive

73
Q

Why might there be low levels of von Willebrand factor despite the gene being normal?

A
  • increased clearance
  • ineffective secretion
    etc
    (30-50% vwf)
74
Q

von Willbrand is also a carrier protein for which factor around the blood stream?

A

Factor VIII

75
Q

Why does factor 8 need a carrier (vwf)?

A

It has a short half life in circulation

76
Q

Since vWF is also a carrier protein to factor 8, what other types of bleeding pattern do you get in vWF disease?

A

Deficiency of factor 8 means there is also haemarthrosis and muscle bleeds as well as mucosal bleeding such as nosebleeds

77
Q

Which gender is affected more by vWF disease?

A

Men and women are affected equally

78
Q

What is the most common heritable bleeding disorder?

A

Von Willebrand disease - associated with defective primary haemostasis

79
Q

In VWF disease you get mucocutaenous bleeding including what in women?

A

Menorrhagia (heavy periods) and post partum bleeding (as well as postoperative bleeding etc), easy bruising

80
Q

Which blood group has lower levels of von Willebrand factor?

A

Blood group O

81
Q

What is the penetrance of vWF disease?

A

Variable penetrance for mild types

82
Q

Why is diagnosis of mild vWF disease difficult?

A

Due to confounding factors

83
Q

What treatment is there for Von Willebrand Disease?

A
  • antifibrinolytics: tranexamic acid
  • DDAVP (type 1 vWD)
  • factor derived concentrates containing wWF (plasma-derived)
  • vaccination against hepatitis
  • COCP for menorrhagia
84
Q

When particularly is tranexamic acid used in vWF disease?

A

When going to the dentists etc - good for mouth bleeding and nose bleeds

85
Q

What type of substance is tranexamic acid?

A

An antifibrinolytic

86
Q

What does DDAVP do? (used in type 1 vWD)

A

It releases vWF from its stores in endothelial cell so temporarily increase the vWF levels in the plasma

87
Q

Continued use of DDAVP is associated with tachyphylaxis. What is this?

A

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
Q

What is ad adverse affect of DDAVP?

A

Can cause vasoconstriction so avoid in very young, elderly, heart problems etc

89
Q

What is DDAVP also called?

A

Desmopressin

90
Q

What is the reason for vaccinating against hepatitis in vWF disease?

A

As you might need to give blood products in the future

91
Q

Deficiencies in single clotting factors are defects in what haemostasis?

A

Secondary haemostasis (coagulation)

92
Q

What are the 2 most common single coagulation factor deficiencies?

A

Haemophilia A and B

93
Q

Haemophilia A and B are deficiencies in which coagulation factors?

A

A = factor 8

B = factor 9

94
Q

Is factor 12 deficiency a bleeding disorder?

A

No

95
Q

Recessive coagulation factor deficiencies are more common in which communities?

A

Those where there is lots of consanguineous marriage

96
Q

The haemophilias show which mode of inheritance?

A

Sex linked recessive (X-linked)

97
Q

Which laboratory defect would VIII haemophilia, VIII von Willebrand Disease, XI deficiency etc. cause?

A

Abnormal APTT

98
Q

What laboratory defect would factor VII deficiency cause?

A

Abnormal PT

99
Q

What laboratory defect would factor X deficiency cause?

A

Abnormal APTT and PT

100
Q

What laboratory defect would factor I (fibrinogen) deficiency cause?

A

Abnormal APTT, PT, and TCT

101
Q

How many people do the haemophilias affect?

A

haemophilia A = 1 in 5,000 males

haemophilia B = 1 in 30,000 males

(females are carriers)

102
Q

What is the chance of a son having haemophilia if the mum is a carrier?

A

50%

103
Q

What factor 8 level would you expect in a haemophilia-affected son?

A

2%

104
Q

What factor 8 level would you expect in a haemophilia-carrier daughter?

A

50%

105
Q

Haemophilia is a defect in intrinsic pathway factors meaning which clotting time is prolonged?

A

ATTP

106
Q

How many cases of haemophilia are new mutations? (new mutation in factor 8 gene)

A

30%

107
Q

What about haemophilia is consistent between family members?

A

Severity level

108
Q

What is the normal range of factor VIII or IX level?

A

50%-150%

109
Q

What is the factor 8/9 level in mild haemophilia?

A

6%-50%

110
Q

What is the factor 8/9 level in moderate haemophilia?

A

1%-5%

111
Q

What is the factor 8/9 level in severe haemophilia?

A

Less than 1%

112
Q

What type of bleeding do you get in haemophilia?

A
  • spontaneous/post-traumatic
  • haemarthrosis
  • muscle haemorrhage
  • soft tissue
  • life threatening bleeding eg. intracranial, bleeding into airways
113
Q

What is haemophilic arthropathy?

A

Bleeding into joints eg. knees causing swelling and bony deformities and muscle wasting

114
Q

What is involved in the treatment of haemophilia?

A
  • 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
Q

What supportive measures are taken in the case of joint and muscle bleeds in haemophilia?

A
  • icing
  • immobilisation
  • rest
  • physiotherapy
116
Q

What is the purpose of hepatitis vaccination in haemophilia?

A

In the case of needed plasma-derived products as treatment

117
Q

DDAVP is ineffective in which type of haemophilia?

A

Haemophilia B - so always treat with factor concentrate

118
Q

What are some potential complications of treatment of haemophilia?

A

Transfusion-transmitted infection

  • hep A, B, C….G
  • HIV
  • parovirus
  • vCJD

Inhibitor development

119
Q

Inhibitor development may occur in treatment of haemophilia. What is this?

A

Development of antibodies against factor 8/factor 9 - renders treatment useless

120
Q

Which type of haemophilia is inhibitor development most common in?

A

Incidence = 25% in haemophilia A

More rare in haemophilia B (inhibitors to factor 9 are rare)

121
Q

What does inhibitor development in haemophilia treatment result in?

A

Poor recovery and/or shortened half life of factor replacement therapy - poor clinical response to treatment

122
Q

When does inhibitor development occur?

A

Mostly early in course of condition (10 exposure days) - unusual to develop after 150 days

123
Q

If inhibitor development happens in haemophilia treatment, what is required?

A

Specialised management of bleeds - usually keep levels between 60-100%

Try to eradicate inhibitor - process is called immune tolerance

124
Q

Immune tolerance is the process of eradicating the inhibitor of factor 8/9. How is it done?

A

Give very high doses of factor 8 so immune system stops recognising it as a foreign protein

125
Q

What are the appropriate investigations into bleeding disorders?

A
  • 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
Q

What are some problems with blue-top bottle? (pre-analytical errors)

A
  • partial fill tubes

- vacuum leak and citrate evaporation

127
Q

What are some problems with phlebotomy? (pre-analytical errors)

A
  • heparin contamination
  • wrong label
  • slow fill
  • underfill
  • vigorous shaking
128
Q

What are some laboratory errors? (pre-analytical errors)

A
  • delay in testing
  • prolonged incubation at 37 degrees
  • freeze/thaw deterioration
129
Q

What is thromboplastin?

A

An enzyme released from damaged cells, especially platelets, which converts prothrombin to thrombin during the early stages of blood coagulation

8. CP - Core Haematology (11 decks)

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