Heritable bleeding disorders Flashcards
Haemostasis
- Haemostasis exists in a balance between bleeding and clotting
Breech of vasointegrity =
- Initial vasoconstriction, then activation of platelets at the site of vascular injury = adhere to the area of damaged vessel become activated and aggregate to form a plug
- Coagulation is then activated, and a fibrin plug is formed
glycoprotein 1b9
- receptor for vWF
Extrinsic pathway of coagulation cascade
- Activated first
- Exposure of tissue factor, binds + activates factor V11
- Factor V11a activates factor X
- Xa + Va cleaves prothrombin to produce thrombin
- formation of fibrin from fibrinogen
Intrinsic pathway of coagulation cascade
- Involved when blood gets into contact with a foreign surface
- When thrombin is generated it feedbacks and directly activates factor XI
Common pathway
Where the intrinsic and extrinsic pathways of the coagulation cascade interact.
- can’t get fibrin without activation of Factor X
Fibrinolysis
- Plasma proteins circulate and become active when required
- plasmin breaks down cross-linked fibrin into fibrin degradation products
- Plasmin is generated by the action of tissue plasminogen activator on inert plasminogen
Bleeding disorder types
- Congenital – usually single gene defect
- Acquired – often multiple defects
- Platelet/vessel wall defect - mucosal and skin bleeding - easy bruising, petechial rash, heavy periods, nose/gum bleeds.
- Coagulation defect – deep muscular bleeds, following trauma
What to ask when taking a history of a patient with bleeding
- Ask about previous bleeding
- Response to challenges
- Severity of bleeding
- Systemic illness
Appropriate investigations for patients with bleeding
- Firstly - FBC and blood film
- Coagulation screen and Clauss fibrinogen
- Prothrombin time (PT) = measuring extrinsic pathway, APTT = measuring intrinsic pathway
- vWF profile
- If all normal and suspicion remains – FXIII assay and assay of alpha2anti-plasmin
A coagulation screen includes the following tests
- Prothrombin Time (PT)
- Activated Partial Thromboplastin Time (APTT)
- Fibrinogen
Normal coagulation screen results
- Prothrombin Time (PT) = 10–14 seconds
- Activated Partial Thromboplastin Time (APTT) = 22–36 seconds
- Clauss Fibrinogen = 1.5–4.5 g/l
Platelet/vessel wall defects
- All give rise to prolonged bleeding time
- Abnormal vessel walls due to scurvy
- vWD - abnormal interaction between platelets and cell walls
Children with meningococcal meningitis get what?
- Will get petechial rash, often because their blood platelet count drops and/or platelets are not working normally
Von Willebrand Disease - 3 types
Type 1 = reduced production of normal molecule = deficiency of protein = milder bleeding disorder – MOST COMMON BLEEDING DISORDER, F=M
- Type 2 = normal amount of abnormal molecule = still a mild disease but more manifestations than type 1
- Type 3 = absence of molecule = severe
Von Willebrand factor (vWF)
- VWF synthesised and stores in endothelial cells
- acts as a glue for platelet aggregation to vessel walls
- acts as a carrier protein for FVIII and prolongs the life of it in the circulation
Presentation of vWD
- Associated with defective primary haemostasis; skin and mucosal bleeding
- Mucocutaneous bleeding including menorrhagia (heavy periods)
- Postoperative and post-partum bleeding
Treatment of vWD
- Antifibrinolytics - tranexamic acid
- DDAVP (desmopressin) - promotes release of vWF from storage granules
- Factor concentrates containing vWD (plasma derived)
Haemophilia
- X linked recessive; expressed in males and carried by females – most common clotting factor deficiencies
- A = Factor VIII deficiency – 1/5000
- B = Factor IX deficiency; less common
- Severity level is consistent between family members
Factor levels in haemophilia
- Normal Factor VIII/IX = 50—100%;
- Mild = 6-50%;
- Moderate = 1-5%;
- Severe = <1%
Types of bleed in haemophilia
- Spontaneous/post traumatic
- Joint bleeding = haemarthrosis
- Muscle haemorrhage in neck - threat to airways
- Leads to MSK disability
Treatment of Haemophilia
- Severe = replacement of missing clotting protein
- Mild/moderate - DDAVP
- Factor concentrates
- Anti-fibrinolytic agents
Why does DDAVP not work for Haemophilia B
- factor IX not carried in circulation by vWF
Complications of treatment
- TTI = transfusion transmitted infections
- Inhibitor development, HA>HB - factor being infused does not work
How is the inhibitor eradicated
- Immune tolerance induction = child is exposed to factor VIII over a long time
