Lecture 29 - Bleeding disorders Flashcards
External bleeds
trauma
Internal bleeding:
haemophilia, aneurysm rupture, drug-induced, gastro-intestinal
What does not require treatment
minor bleeds - bruising menorhaggia, epistaxis (nose bleeds)
Common triggers of induced bleeding
Trauma Surgery Aneurysm rupture Sepsis Drugs (anticoagulants, aspirin)
Abdominal aortic aneurysm
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
What is Disseminated Intravasculat Coagulation
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
Primary causes of spontaneous bleeding
coagulation factor deficiency or haemophila (severe)
vitamin K deficiency
thrombocytopaenia (mild)
Which are Vitamin K dependent clotting factors and how do they assist coagulation?
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
Vitamin K epoxide reductase
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.
What is targetted by Warfarin?
c1 subunit of Vitamin K epoxide reductase
Enzymes which are vitamin K dependent and work efficiently when bound to a negatively charged membrane via Ca2+ and Gla -domains
TF & 7a converts 10-10a
F9a and 8a converts 10 to 10a
F10a and 5a complex converts prothrombin to thrombin
How does warfarin work
reduction for Vitamin K epoxide reductase
Vitamin K deficiency
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
Haemophila A
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
Haemophilia B
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
Prothrombin time (PT)
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
When is prothrombin time prolongued
in f7 deficiency
Activated partial thromboplastin time (APTT)
Uses silica as trigger
intrinsic
prolongued in F8,9,11, and 12 deficiency
-also sensitive to common pathway: F5. 10, Prothrombin and fibrinogen deficiency
Inheritance pattern of X-linked recessive disease such as haemophila A or B
50% chance that son is affected by haemophila
50% chance that daughter is carrier
Bleeding associated with Haemophilia
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
Von Willebrand disease
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
What is the vWF
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
Bleeding associated with vWD
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
are coagulation factor deficiencies autosomal dominant or recessive?
All factor deficiencies are autosomal recessive
describe coagulation factor deficiencies in terms of
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
What is thrombocytopenia
loss of blood/dysfunction of platelets
causes of thrombocytopenia
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
Bleeding in thrombocytopenia or thrombasthenia
Easy bruising Gum bleeds Epistaxis (nosebleeds) Menorrhagia Petechiae (bleeding from skin microvasculature)
Treatment for thrombocytopenia
focuses on underlying cause
corticosteriods fro ITP (thrombocytopenia purpura)
Platelet transfusions
-splenectomy
