Bleeding Disorders Flashcards
Why might drug history be important in investigation of a bleeding disorder
Anti-coagulants such as warfarin may be taken
Why might a physical examination be important when investigating a bleeding disorder
Does the patient have any bruises are patterns associated with the disease
What four things must be considered when investigating a bleeding disorder
Bleeding history
Physical examination
Drug history
Basic Laboratory screening tests
Compare disorders of coagulation versus platelets
(Coagulation)
(5)
Delayed bleeding after trauma
Deep haematomas
Large and solitary ecchymoses (bruise)
Haemarthrosis (bleeding into joints)
80-90% males
Compare disorders of coagulation versus platelets
(platelets)
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
What is haemophilia A
An inherited blood disorder
Deficiency of factor VIII
Classic haemophilia
Type A haemophilia
What are some symptoms of Haemophilia A
Intracranial haemorrhage
Prolonged nosebleeds
Bruises easily
Warm, painful, swollen joint with decreased movement
GI haemorrhage
Write about haemophilia
(5)
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
What does a severe reduction in factor 8 mean?
(5)
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
Write about the history of haemophilia
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
What percentage of haemophilia cases are spontaneous mutations
30%
What percentage factor level is needed to prevent bleeding?
50%
What is considered mild haemophilia
(4)
5-40% factor
Usually diagnosed in adulthood
Bleeding uncommon -> often noticed post dental extraction surgery or serious accident
Joints not affected
What is considered moderate haemophilia?
(5)
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
What is considered severe haemophilia
(4)
Less than 1% factor
Early recognition before 1 years old
Bleeding frequent and spontaneous into muscles and joints
2-4 bleeds a month
How frequent is haemophilia
There are 860 haemophiliacs in Ireland
60 have a factor IX deficiency
Write about the molecular defects in Haemophilia 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
Write about the molecular defects of haemophilia B
Over 680 specific mutations identified
Large deletions increase the risk of inhibitor development
Mutation screening available through specialised DNA diagnostic labs
What lab results would indicate Haemophilia A or B
(4)
Normal PT
Prolonged APTT that corrects with mixing study
Abnormal factor VIII or IX factor assays (low)
Normal platelet function test
Write about correction tests/Mixing studies
(3)
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
Write about coagulation factor assays
(5)
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
How is haemophilia treated
(6)
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
What drugs are given to haemophiliacs upon admission?
(3)
Factor replacement
Analgesia -> NSAID (painkiller)
Tranexamic acid: antifibrinolytic
What is DDAVP
Desamino-D-vasopressin
How does tranexamic acid work
It’s an antifibrinolytic
It prevents the breakdown of blood clots
What infusions are haemophiliacs given
Infused with concentrated extended half life factor
What is the factor VIII extended half life product for infusion
Elocta
What is the factor FIX extended half life product for infusion
Alprolix
How are Haemophiliac infusions carried out
(3)
80% of haemophiliacs carry out their infusions at home
Dosage is based on weight
Don’t need 100% of factors, just above 50%
How does DDAVP work
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
What is the risk associated with factor infusions
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)
What is the recombinant factor VIII factor called
Elocta
What is the recombinant factor IX called
Alpolix
What recombinant product is given to patienets with factor VIII or IX inhibitors
Novoseven
What is the plasma derived product given to haemophiliacs
FEIBA
Write about DDAVP
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
What are currently the four ways of treating haemophiliacs
IV clotting factors
Prophylaxis treatment
PEGylated FVIII treatment
GENE therapy
Write about IV as a form of treatment
Expensive
Long term treatment
Some treatments not suitable for Haemophilia e.g. Desmopressin
Some are not effective in severe haemophilia
Write about prophylaxis treatment of haemphilia
Able to change the serious haemophilia to mild or moderate
Reduces the risk of joint damage
Write about PEGylated FVIII treatment
Low dose required for the treatment
better half life
Less probability of leading to an adverse immune reaction
Write about gene therapy
Target drug delivery
Ability to replace the defective cell
Short term treatment
Write about Emicizumab (Hemlibra)
(5)
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
Write about Concizumab
(3)
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
Write about fitusiran
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.
Write about gene therapy for haemophilia
(3)
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
What are AAVs
Adeno-associated virus
Small viruses that are not currently known to cause disease but can cause a very mild immune response
What was the first gene therapy for factor IX
Hemgenix
What was the first gene therapy for factor VIII
Roctavian
How frequent is von willebrand disease
(4)
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
What are the clinical signs of mild to moderate VWD
Bruising
Epistaxis
Prolonged bleeding from minor cuts
Menorrhagia
Bleeding following trauma or surgery
What can be seen in severe VWD
Same symptoms as mild to moderate
Hemarthrosis (FVIII is also reduced)
Bleeding into muscles
What does VWF do
Helps with platelet aggregation and adhesion to damaged endothelium
What are the three types of VWF disease
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)
Does VWF affect men or women
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
What are the two quantitative forms of VWD
Type 1 (75% of people) - partial deficiency
Type 2 (<5% of people) - complete deficiency
What is the qualitative form of VWD
Type 2 (20% of people)
Type 2A, 2B, 2M and 2N
What is VWD type 2A
Qualitative variants with decreased platelet-dependent function associated with the absence of high and intermediate molecular weight VWF multimers
What is VWD Type 2B
Qualitative variants with increased affinity for platelet GPIb
What is VWD type 2M
Qualitative variants with decreased platelet-dependent function not caused by the absence of high molecular weight VWF multimers
What is VWF type 2N
Qualitative variants with markedly decreased affinity for FVIII
How is VWD treated?
(4)
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
What determines you choice in VWD treatment
Type of VWD
Severity of the haemostatic challenge
Nature of the actual or potential bleeding
What are the four main methods of VWD treatment
Tranexamic acid (Cyklokapron)
Demopressin (DDAVP)
Von Willebrand’s Factor Replacement Therapy
Fibrin Glue
How does tranexamic acid work
(3)
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
How does desmopressin work
(5)
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
How does VWF replacement therapy work
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
How does fibrin glue work
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
What are the screening tests for VWD
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
What are the eight components of the VWD diagnostic test panel
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
New profalactic drugs
Emicizumab
Concizumab
fitusiran
