Lecture 29 - Bleeding disorders

Question 1

External bleeds

Answer 1

trauma

Question 2

Internal bleeding:

Answer 2

haemophilia, aneurysm rupture, drug-induced, gastro-intestinal

Question 3

What does not require treatment

Answer 3

minor bleeds - bruising menorhaggia, epistaxis (nose bleeds)

Question 4

Common triggers of induced bleeding

Answer 4

Trauma
Surgery
Aneurysm rupture 
Sepsis
Drugs (anticoagulants, aspirin)

Question 5

Abdominal aortic aneurysm

Answer 5

progressive dilation of the abdominal aorta inferior to the renal and above the iliac arteries
common in men - over 60
prevalence is lower in women (1-2%)
high risk of rupture if too large
-AAA Rutpure associated with major internal bleeding and 50% mortality

Question 6

What is Disseminated Intravasculat Coagulation

Answer 6

infection causes sepsis - causes TF exposure - systemic coagulation leads to microvascular clots and consumption of clotting factors and platelets leads to bleeding. - mulitple organ failure

Question 7

Primary causes of spontaneous bleeding

Answer 7

coagulation factor deficiency or haemophila (severe)
vitamin K deficiency
thrombocytopaenia (mild)

Question 8

Which are Vitamin K dependent clotting factors and how do they assist coagulation?

Answer 8

F7, F9,F10, Prothrombin, protein C and protein S

• post-translational modification of glutamic acid to gamma- carboxyglutamic acid
• Gla binds to negatively charged phospholipids - provided activated platelets via Ca2+
• This increases the catalytic efficiency of the limited proteolysis dramatically

Question 9

Vitamin K epoxide reductase

Answer 9

Vitamin K epoxide reductase (VKOR) is an enzyme (EC 1.1.4.1) that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes.

Question 10

What is targetted by Warfarin?

Answer 10

c1 subunit of Vitamin K epoxide reductase

Question 11

Enzymes which are vitamin K dependent and work efficiently when bound to a negatively charged membrane via Ca2+ and Gla -domains

Answer 11

TF & 7a converts 10-10a
F9a and 8a converts 10 to 10a
F10a and 5a complex converts prothrombin to thrombin

Question 12

How does warfarin work

Answer 12

reduction for Vitamin K epoxide reductase

Question 13

Vitamin K deficiency

Answer 13

rare
causes by fat malabsorption
may occur in liver disease
may occur in new born infants
can occur due to oral anticoagulants - overdosage
associated with sever bleeding
can be reversed by vitamin K administration

Question 14

Haemophila A

Answer 14

deficiency of F8
Cofactor conversion of F10 to 10a (instrinsic)
consolidation phase of thrombin generation
x-linked recessive
female carrier, male offspring at risk
relatively rare

Question 15

Haemophilia B

Answer 15

Deficiency of F9 - Xmas disease
F9 converts F10 to 10a (Instrinsic)
consolidation phase of thrombin generation
x-linked recessive
female carrier, male offspring at risk
relatively rare

Question 16

Prothrombin time (PT)

Answer 16

Uses TF as trigger
measures factors in extrinsic pathway
prolongued in F7 deficiency
-also sensitive to common pathyway - FV, F10, prothrombin and fibrinogen deficiency
-used in the INR monitoring of oral anti-coagulants - warfarin

Question 17

When is prothrombin time prolongued

Answer 17

in f7 deficiency

Question 18

Activated partial thromboplastin time (APTT)

Answer 18

Uses silica as trigger
intrinsic
prolongued in F8,9,11, and 12 deficiency
-also sensitive to common pathway: F5. 10, Prothrombin and fibrinogen deficiency

Question 19

Inheritance pattern of X-linked recessive disease such as haemophila A or B

Answer 19

50% chance that son is affected by haemophila

50% chance that daughter is carrier

Question 20

Bleeding associated with Haemophilia

Answer 20

severe
spontaneous bleeding into the muscle and joints in particular
Easy bruising
Risk for cerebral haemorrhage
May need prophylactic treatment with recombinant or plasma factor concentrates (VIII or IX)
Patient may develop inhibitor against factor concentrates

Question 21

Von Willebrand disease

Answer 21

deficiency of vWF
most common inherited bleeding disorder
Types 1,2,3
1- heterozygous disease (autosomal dominant)
2- functional deficiency(autosomal dominant)
Type 3: complete deficiency (autosomal recessive)
Platelet type: mutation in GP1
Bleeding severity dependent on type

Question 22

What is the vWF

Answer 22

Large multimeric glycoprotein
stablilised F8
involved in platelet adhesion and aggregation
deficiency is quantitative(1,3) or qualitative (2)
Produced by endothelial cell in Weibel-Palade bodies
and by megakaryocytes

Question 23

Bleeding associated with vWD

Answer 23

Mild to severe depending on type
Menorrhagia, nose bleeds and bleeding after tooth extractions common
easy bruising
risk of GI bleeding, petechiae (capillary bleeding in the skin), muscular or joint bleeding if more severe
-may need treatment with plasma concentrate of vWF, demopressin (DDAVP - releases vWF from endothelium - type 1 disease) or platelets

Question 24

are coagulation factor deficiencies autosomal dominant or recessive?

Answer 24

All factor deficiencies are autosomal recessive

Question 25

describe coagulation factor deficiencies in terms of

Answer 25

FVII: Rare; Variable bleeding severity
FXI: Relatively common in certain populations; Mild bleeding
FXII: Rare, phenotypically normal Phenotypically normal
FX: Rare; Severe bleeding
FV: Rare; Severe bleeding
Prothrombin: Very rare; severe bleeding
Fibrinogen: Rare; Mixed phenotype (30% bleeding, 30% thrombosis, 40% normal)
FXIII: Rare; Severe bleeding, miscarriage, poor wound healing

Question 26

What is thrombocytopenia

Answer 26

loss of blood/dysfunction of platelets

Question 27

causes of thrombocytopenia

Answer 27

acquired: leukemia, blood loss, DIC, drug induced, immune thrombocytopenia purpura

Inherited
- congenital amegakaryotic thrombocytopenia (CAMT; severe)
fanconis anaemia - haematological malignancy and bone marrow failure
- Glanzmann thrombasthenia, mutation in alpha 2 beta 3
-bernard -soulier syndrome deficiency of GP1

Question 28

Bleeding in thrombocytopenia or thrombasthenia

Answer 28

Easy bruising
Gum bleeds
Epistaxis (nosebleeds)
Menorrhagia
Petechiae (bleeding from 					      skin microvasculature)

Question 29

Treatment for thrombocytopenia

Answer 29

focuses on underlying cause
corticosteriods fro ITP (thrombocytopenia purpura)
Platelet transfusions
-splenectomy