CP7-4 heritable bleeding disorders

Question 1

What is balanced in the hemostatic balance?

Answer 1

Bleeding and clotting

Question 2

How are hemostatic plugs formed?

Answer 2

primary hemostasis of aggregation of platelets and secondary hemostasis of coagulation with thrombin and fibrin combines to form a clot

Question 3

What does factor X become when it is activated (I.e. becomes factor Xa)?

Answer 3

A protease enzyme that cleaves factor II

Question 4

Which clotting cascade is tissue factor involved in?

Answer 4

The extrinsic pathway

Question 5

How does tissue factor contribute to the extrinsic clotting pathway?

Answer 5

Factor VII becomes activated and then activates factor X with calcium

Question 6

When does factor XII become activated in the intrinsic pathway?

Answer 6

When it comes in contact with a foreign surface

Question 7

What tests can be done to look at how quick clotting pathways work?

Answer 7

Prothrombin time - speed of extrinsic pathway
Activated partial thromboplastin time - speed of intrinsic pathway
Thrombin clotting time - adding thrombin to plasma and seeing how long a clot takes to form
Euglobulin lysis time

Question 8

What are two procoagulant components?

Answer 8

Platelets
Clotting factors

Question 9

What are 4 anti-coagulant components?

Answer 9

Protein C
Protein S
Anti+thrombin III
Fibrinolytic system

Question 10

How many defects are usually caused by congenital bleeding disorders?

Answer 10

Usually 1

Question 11

How many defects are usually caused by acquired bleeding disorders?

Answer 11

Usually multiple

Question 12

What defect is usually caused by disorders affecting platelets/vessel wall?

Answer 12

Mucosal and skin bleeding

Question 13

What can coagulation defects cause?

Answer 13

Deep muscular and joint bleeds and bleeding following trauma

Question 14

What investigations can be done into potential bleeding dirsorders?

Answer 14

FBC and blood film
Coagulation screen and Clauss fibrinogen screen
D-dimer if suspicious of acquired disorder
Von Willebrand profile
Coagulation factor assays including FVIII and FIX
Inhibitor assays
Platelet function tests

Question 15

What are further non-routine investigations into bleeding disorders if other tests are normal but suspicion remains?

Answer 15

FXIII assay
Assay of alpha2antiplasmin

Question 16

What are examples of bleeding disorders?

Answer 16

Thrombocytopenia
Disorders of platelet function
Von Willibrand disease
Factor XIII deficiency
Mild coagulation factor deficiency
Vascular disorders
(Rarely) disorder of fibrinolysis

Question 17

What are some defects that can lead to prolonged bleeding times?

Answer 17

Reduced number of platelets
Abnormal platelet function
Abnormal vessel wall
Abnormal interaction between platelets and vessel wall

Question 18

What are petechiae rashes?

Answer 18

Rashes as a result of bleeding into the skin which do no blanch with pressure and are non palpable

Question 19

What is the most common mild bleeding disorder?

Answer 19

Von willibrand disease

Question 20

What is the function of Von Willebrand factor?

Answer 20

Helps platelets stick to the vessel wall by interacting with collagen in the wall

Question 21

Type 1 and most type 2 Von Willebrand disease is inherited through which inheritance pattern?

Answer 21

Autosomal dominant

Question 22

Type 3 Von Willebrand disease is inherited through what inheritance pattern?

Answer 22

Autosomal recessive

Question 23

What clotting factor is Von Willebrand factor part of?

Answer 23

Factor VIII

Question 24

What care complications of VWD?

Answer 24

Defective haemostasis
Variable reduction in VIII levels
Mucocutaneous bleeding including menorrhagia in women
Increased postoperative and postpartum bleeding

Question 25

Who is more symptomatic with VWD? Men or women?

Answer 25

Women - both affects by VWD but women usually have more symptoms

Question 26

What are confounding factors which affect diagnosis of mild VWD?

Answer 26

Contraceptive pill Increased exercise Psychological stress

Question 27

Which blood group has lower vWF levels?

Answer 27

Group O

Question 28

How is VWD treated?

Answer 28

With antifibrinolytics like tranexamic acid With DDAVP if type 1 With factor concentrates containing vWF (either derived from plasma or recombinant) Vaccination against hepatitis In women combined oral contractile pill or inuterine system to increase progesterone hormones for menorrhagia

Question 29

What clotting factors have hereditary deficiencies? How common are each?

Answer 29

XII - relatively common XI - rare IX haemophilia B - uncommon VIII haemophilia A - uncommon VIII vWD- common VII, X, V, II, I & XIII - very rare

Question 30

Why is factor XII deficiency common but not usually a problem?

Answer 30

Deficiency of factor XII doesn’t usually cause clinical bleeding problems

Question 31

What factor deficiencies are inherited autosomally?

Answer 31

XII XI

Question 32

What factor deficiencies are inherited in a sex linked recessive inheritance pattern?

Answer 32

IX and VIII haemophilia A&B respectively

Question 33

Who is more likely to be affected by haemophilia?

Answer 33

Men as women have two X chromosomes which acts as a protective factor although they are still carriers

Question 34

What is the epidemiology in men of haemophilia A and B?

Answer 34

A = 1 in 5000 B = 1 in 30,000

Question 35

What factor deficiency/defect is inherited autosomal dominantly?

Answer 35

vWD - factor VIII

Question 36

What factor deficiencies/defects are inherited in an autosomal recessive inheritance pattern?

Answer 36

I, II, V, VII, X, XIII

Question 37

What is the pattern of severity between family members?

Answer 37

Severity is consistent

Question 38

What percentage of haemophilia cases are due to de novo mutations?

Answer 38

Around 30%

Question 39

What percentage of factor VIII or IX, compared to normal levels, are found in each severity of haemophilia? (Mild/moderate/severe)

Answer 39

Mild = 6-50% of normal Moderate = 1-5% of normal Severe = <1% of normal

Question 40

What are symptoms of mild haemophilia?

Answer 40

Won’t usually have spontaneous bleeds but will have increased bleeding after surgery or trauma

Question 41

What type of bleeds occur in people with haemophilia?

Answer 41

Spontaneous bleeds Post traumatic bleeds Joint bleeding aka haemarthrosis Muscle haemorrhage Soft tissue bleeding Life threatening bleeding

Question 42

How is haemophilia treated/managed?

Answer 42

Replacement of missing clotting protein either in demand or by prophylaxis DDAVP if mild/moderate haemophilia A Factor concentrates (usually recombinant) Anti fibrinolytic agents Vaccination for hepatitis A and B

Question 43

What are some transfusion transmitted infections that can complicate haemophilia?

Answer 43

Hepatitis A, B and C (and G) HIV Parvovirus vCJD

Question 44

How does inhibitor development complicate treatment of haemophilia?

Answer 44

Shortens half life of factor replacement therapy leading to poorer clinical response and poor recovery

Question 45

How is inhibitor development in haemophilia treated/prevented?

Answer 45

With specialised management of bleeds Emicizumab prophylaxis Eradication of inhibitor e.g with immune tolerance

Question 46

What is emicizumab?

Answer 46

A SC injected humanised bispecific monoclonal antibody which bridges FIXa and FX to restore function of missing FVIIIa and is not expected to be affected by or induce inhibitors/inhibition to help treat haemophilia A

Question 47

What are some new haemophilia treatments being developed?

Answer 47

Gene therapy EHL products AntiTFPI antibodies AT mRNAi