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2.2 Haematology > Bleeding Disorders > Flashcards

Bleeding Disorders Flashcards

1
Q

Why might drug history be important in investigation of a bleeding disorder

A

Anti-coagulants such as warfarin may be taken

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2
Q

Why might a physical examination be important when investigating a bleeding disorder

A

Does the patient have any bruises are patterns associated with the disease

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3
Q

What four things must be considered when investigating a bleeding disorder

A

Bleeding history
Physical examination
Drug history
Basic Laboratory screening tests

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4
Q

Compare disorders of coagulation versus platelets
(Coagulation)
(5)

A

Delayed bleeding after trauma

Deep haematomas

Large and solitary ecchymoses (bruise)

Haemarthrosis (bleeding into joints)

80-90% males

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5
Q

Compare disorders of coagulation versus platelets
(platelets)

A

Spontaneous bleeding or immediately after trauma

Mucosal bleeding

Petechiae rash

Small and multiple ecchymoses (bruises)

Persistent, profuse bleeding from superficial cuts

Equally in males and females

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6
Q

What is haemophilia A

A

An inherited blood disorder

Deficiency of factor VIII

Classic haemophilia

Type A haemophilia

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7
Q

What are some symptoms of Haemophilia A

A

Intracranial haemorrhage
Prolonged nosebleeds
Bruises easily
Warm, painful, swollen joint with decreased movement
GI haemorrhage

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8
Q

Write about haemophilia
(5)

A

Deficiency of FVIII, FIX, or FXI (rare)

Genes for FVIII and IX are X linked

Found almost exclusively in males

Females are carriers

Both FVIII and FIX have identical clinical presentation

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9
Q

What does a severe reduction in factor 8 mean?
(5)

A

Patient will need transfusions of factor 8

Can’t play sport

Childbirth is very dangerous

Surgery or getting a tooth removed is complicated

Usually diagnosed at birth as baby tends to be bruised upon birth

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10
Q

Write about the history of haemophilia

A

There were early mentions of bleeding up to 2000 years ago

Rabbi used to excuse a woman’s third son from being circumcised if the two older brothers died in circumcision

Circumcision also forbidden when a mother’s three elder sisters had sons who died from circumcision

Often called the Royal disease

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11
Q

What percentage of haemophilia cases are spontaneous mutations

A

30%

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12
Q

What percentage factor level is needed to prevent bleeding?

A

50%

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13
Q

What is considered mild haemophilia
(4)

A

5-40% factor

Usually diagnosed in adulthood

Bleeding uncommon -> often noticed post dental extraction surgery or serious accident

Joints not affected

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14
Q

What is considered moderate haemophilia?
(5)

A

1-5% factor

Diagnosed between 1 and 2 years old

Bleeding associated with minor injury

Can present like severe haemophilia with 4-6 bleeds a year

Can have joint problems

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15
Q

What is considered severe haemophilia
(4)

A

Less than 1% factor

Early recognition before 1 years old

Bleeding frequent and spontaneous into muscles and joints

2-4 bleeds a month

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16
Q

How frequent is haemophilia

A

There are 860 haemophiliacs in Ireland
60 have a factor IX deficiency

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17
Q

Write about the molecular defects in Haemophilia A

A

over 500 different mutations identified on chromosome X

5% caused by gene deletions
45% caused by intron 22 inversion
50% caused by point mutations

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18
Q

Write about the molecular defects of haemophilia B

A

Over 680 specific mutations identified

Large deletions increase the risk of inhibitor development

Mutation screening available through specialised DNA diagnostic labs

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19
Q

What lab results would indicate Haemophilia A or B
(4)

A

Normal PT

Prolonged APTT that corrects with mixing study

Abnormal factor VIII or IX factor assays (low)

Normal platelet function test

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20
Q

Write about correction tests/Mixing studies
(3)

A

Carried out on the prolonged screening test to determine if the prolongation is due to a factor deficiency or an inhibitor

Patient plasma is mixed with control normal plasma at a ratio of 1:4

The degree of correction is assessed at time 0 min and at time 60 mins

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21
Q

Write about coagulation factor assays
(5)

A

Clotting versus chromogenic assays

Assess degree of deficiency in a patient with haemophilia or other factor deficiency

Classify haemophilia as severe, moderate or mild

Determines the appropriate treatment

Identifies the causative mutation and determines the carrier status in family members

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22
Q

How is haemophilia treated
(6)

A

Factor replacement/DDAVP/Desmopressin for mild to moderate Haemophilia A
Home treatment/admit to ward
Analgesia (no aspirin, non-steroidal anti-inflammatory drugs etc)
Tranexamic acid: antifibrinolytic
Rest
Follow up appointment

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23
Q

What drugs are given to haemophiliacs upon admission?
(3)

A

Factor replacement

Analgesia -> NSAID (painkiller)

Tranexamic acid: antifibrinolytic

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24
Q

What is DDAVP

A

Desamino-D-vasopressin

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25
Q

How does tranexamic acid work

A

It’s an antifibrinolytic

It prevents the breakdown of blood clots

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26
Q

What infusions are haemophiliacs given

A

Infused with concentrated extended half life factor

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27
Q

What is the factor VIII extended half life product for infusion

A

Elocta

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28
Q

What is the factor FIX extended half life product for infusion

A

Alprolix

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29
Q

How are Haemophiliac infusions carried out
(3)

A

80% of haemophiliacs carry out their infusions at home

Dosage is based on weight

Don’t need 100% of factors, just above 50%

30
Q

How does DDAVP work

A

DDAVP can release the factor 8 bound to VWB factor to be used for coagulation

This will only work in mildly affected patients who still have some factor 8

31
Q

What is the risk associated with factor infusions

A

30% of patients will develop an inhibitor to factor 8

This is a lot less common in factor 9 as it is a smaller molecule

Long-term management involves attempting to eradicate inhibitors by administering high dose FVIII (Or FIX)

32
Q

What is the recombinant factor VIII factor called

A

Elocta

33
Q

What is the recombinant factor IX called

A

Alpolix

34
Q

What recombinant product is given to patienets with factor VIII or IX inhibitors

A

Novoseven

35
Q

What is the plasma derived product given to haemophiliacs

A

FEIBA

36
Q

Write about DDAVP

A

Releases VWF/FVIIII from endothelial cells

Brings a rise in FVIII levels of 2-4 times after 30-60 minutes (IV) or 60-90 minutes (intranasal)

Brings about enhanced platelet adhesion due to increased vWF

Useful for mild haemophiliacs with an FVIII activity greater than 5%

Often given prior to minor surgery or dental work

Trial dose is needed to ensure adequate response

Can cause cardiovascular complication in older patients

37
Q

What are currently the four ways of treating haemophiliacs

A

IV clotting factors

Prophylaxis treatment

PEGylated FVIII treatment

GENE therapy

38
Q

Write about IV as a form of treatment

A

Expensive
Long term treatment
Some treatments not suitable for Haemophilia e.g. Desmopressin
Some are not effective in severe haemophilia

39
Q

Write about prophylaxis treatment of haemphilia

A

Able to change the serious haemophilia to mild or moderate

Reduces the risk of joint damage

40
Q

Write about PEGylated FVIII treatment

A

Low dose required for the treatment

better half life

Less probability of leading to an adverse immune reaction

41
Q

Write about gene therapy

A

Target drug delivery
Ability to replace the defective cell
Short term treatment

42
Q

Write about Emicizumab (Hemlibra)
(5)

A

A recombinant, humanised bispecific monoclonal antibody

Restores function of the missing activated FVIII by binding FIXa and FX to facilitate effective haemostasis in Haemophiliacs A

Used as routine prophylaxis to prevent or reduce frequency of bleeding in Haemophiliacs of all ages with or without factor VIII inhibitors

Subcutaneous injection taken either once a week, every 2 weeks or every 4 week

Can be given to children under 1 years old as they don’t need a IV/port

43
Q

Write about Concizumab
(3)

A

Haemostatic rebalancing agent that binds to the Kunitz-2 domain of tissue factor pathway inhibitor, one of the molecules that contributes to downregulation of coagulation thereby preventing TFPI from binding to and blocking the factor Xa active site

When TFPI inhibitory activity is decreased, sufficient FXa is produced by the FVIIa-tissue factor complex to achieve haemostasis

On the basis of this mechanism of action, concizumab is expected to be equally effective in haemophilia A and B, regardless of inhibitor status

44
Q

Write about fitusiran

A

A novel small interfering (si)RNA therapy in development, subcutaneous treatment for people with haemophilia A and B, with or without inhibitors, typically every other day for haemophilia A and 2-3 times a week for
haemophilia B.

Fitusiran is designed to treat haemophilia A and B by depleting AntiThrombin.

During the first trial, 25 out of 38 (66 per cent) participants with inhibitors who received fitusiran injections had zero bleeds after nine months, compared to one out of 19 (5 per cent) who were given an on-demand bypassing agent.

Research on patients without inhibitors found 40 out of 79 (51 per cent) of those given the monthly jabs experienced no bleeds, compared to 2 out of 40 (5 percent) in the other group, according to the findings published in The Lancet Haematology.

However, potential side effects such as blood clotting and liver damage require
further investigation, the researchers said.

45
Q

Write about gene therapy for haemophilia
(3)

A

March 2020 gene therapy was used for the first time to treat a person with haemophilia in Ireland

It is hoped that the effect of the gene therapy infusion will last for many years and possibly for a lifetime

The trial uses adeno-associated virus (AAV) to deliver the gene intravenously to the liver of the Haemophilia B patient where it provides a new “working copy” of the genes for clotting factor protein

46
Q

What are AAVs

A

Adeno-associated virus

Small viruses that are not currently known to cause disease but can cause a very mild immune response

47
Q

What was the first gene therapy for factor IX

A

Hemgenix

48
Q

What was the first gene therapy for factor VIII

A

Roctavian

49
Q

How frequent is von willebrand disease
(4)

A

Most common inherited bleeding disorder

1,644 people diagnosed in Ireland

1% of the world’s population -> many with mild who don’t need treatment

As many as 9 out of 10 people with VWD have not been diagnosed

50
Q

What are the clinical signs of mild to moderate VWD

A

Bruising
Epistaxis
Prolonged bleeding from minor cuts
Menorrhagia
Bleeding following trauma or surgery

51
Q

What can be seen in severe VWD

A

Same symptoms as mild to moderate
Hemarthrosis (FVIII is also reduced)
Bleeding into muscles

52
Q

What does VWF do

A

Helps with platelet aggregation and adhesion to damaged endothelium

53
Q

What are the three types of VWF disease

A

Deficiency of VWF (most common type) -> treated with desmopressin

Abnormal and dysfunctional VWF (treatment with factor VIII concentrate)

VWF is absent (treatment with factor VIII concentrate)

54
Q

Does VWF affect men or women

A

Affects both but women have more noticeable symptoms

However women tend to brush this off and never get it checked

Many Irish people have the mild disease

55
Q

What are the two quantitative forms of VWD

A

Type 1 (75% of people) - partial deficiency
Type 2 (<5% of people) - complete deficiency

56
Q

What is the qualitative form of VWD

A

Type 2 (20% of people)

Type 2A, 2B, 2M and 2N

57
Q

What is VWD type 2A

A

Qualitative variants with decreased platelet-dependent function associated with the absence of high and intermediate molecular weight VWF multimers

58
Q

What is VWD Type 2B

A

Qualitative variants with increased affinity for platelet GPIb

59
Q

What is VWD type 2M

A

Qualitative variants with decreased platelet-dependent function not caused by the absence of high molecular weight VWF multimers

60
Q

What is VWF type 2N

A

Qualitative variants with markedly decreased affinity for FVIII

61
Q

How is VWD treated?
(4)

A

DDAVP promotes release of VWF from endothelial cells but 25% don’t respond and it doesn’t work for type 2B or 3

VWF concentrate for DDAVP non responders (Wilate)

Tranexamic acid, fibrin glue (prevents breakdown of clot)

OCP, hysterectomy

62
Q

What determines you choice in VWD treatment

A

Type of VWD
Severity of the haemostatic challenge
Nature of the actual or potential bleeding

63
Q

What are the four main methods of VWD treatment

A

Tranexamic acid (Cyklokapron)

Demopressin (DDAVP)

Von Willebrand’s Factor Replacement Therapy

Fibrin Glue

64
Q

How does tranexamic acid work
(3)

A

Slows the breakdown of blood clots

It is used to prevent or treat bleeding from mucous membranes, such as the inside of the mouth, nose, gut or uterus

It may be given before dental work, for nose bleeds or prolonged menstrual bleeding

65
Q

How does desmopressin work
(5)

A

A synthetic hormone which is not made form blood products

Administration intravenous infusion over 30 mins

Test dose is always given at diagnosis to document a positive response

Also available as a nasal spray for at home use

Sometime person won’t respond to DDAVP so plasma-derived factor containing factor 8 and Von willebrand;s factor must be used

66
Q

How does VWF replacement therapy work

A

Factor VIII/VWF concentrate is given into a vein to replace the missing VWF to allow clotting to take place

It is made from pooled human plasma, which is screened for viruses

67
Q

How does fibrin glue work

A

Made from synthetic copies of two proteins: fibrinogen and thrombin, which are normally found in the body. Fibrin glue can be put directly to the site of bleeding

It is especially useful in tooth extractions

68
Q

What are the screening tests for VWD

A

FBC -> Type 2B or pseudo can present with low platelets

Coagulation screen/fibrinogen to rule out other coag defects -> PT, TT and fibrinogen should be unaffected but APTT will be prolonged

69
Q

What are the eight components of the VWD diagnostic test panel

A

Factor VIII
VWF: Ag (antigen level)
VWF: RCo (Ristoctin cofactor activity)
VWF: CB (Collagen binding activity)
VWF: VIIB (Factor VIII binding assessment)
RIPA (Ristocetin induced platelet aggregation)
VWF Multimer analysis
VWF Mutation analysis

70
Q
A
71
Q

New profalactic drugs

A

Emicizumab
Concizumab
fitusiran

2.2 Haematology (38 decks)

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