Haem 6: Haemostasis and Bleeding disorders Flashcards
Describe the process of Haemostasis?
- Damage to endothelium leaves sub-endothelial structures exposed
- Platelet adhesion:
DIRECTLY - via Glp1a
INDIRECTLY - via binding to vWF via Glp1b (More important) - This leads to release of mediators ADP and Thromboxane A2 by platelets
- This promotes platelet aggregation and they attach to each other using the GlpIIb / IIIa receptor (aka fibrinogen recepton - fibrinogen can also bind to this receptor)
What are the 3 stages of the coagulations cascade?
- Initiation
- Amplication
- Propagation
Outline the initiation phase of the clotting cascade.
Damage to the endothelium results in exposure of tissue factor which binds to factor 7 and activates it to factor 7a
The tissue factor-factor 7a complex then activates factors 9 and 10
Factor 10a binds to factor 5a resulting in the first step of the coagulation cascade
Outline the amplification phase of the clotting cascade.
Activated factors 5 and 10 will result in the production of a small amount of thrombin
This thrombin will activate platelets
Thrombin will also activate factor 11 which activates factor 9
Thrombin also activates factor 8 and recruits more factor 5a
Factors 5a, 8a and 9a will bind to the activated platelet
Outline the propagation phase of the clotting cascade
Activated factors 5, 8 and 9 will recruit factor 10a
This results in the generation of a large amount of thrombin (thrombin burst)
This enables the formation of a stable fibrin clot
List some pro-coagulant factors in the body
Platelets
Endothelium
vWF
Coagulation cascade
List some anti-coagulant factors in the body
Fibrinolysis
Anti-thrombins
Protein C/S
Tissue factor pathway inhibitor
How can disorders of haemostasis be categorised and what do these mean?
Disorders of primary or secondary haemostasis
- Primary – platelet adhesion and aggregation (quantitative and qualitative defects)
- Secondary – coagulation cascade (inherited and acquired)
What are disorders of thrombosis caused by?
Due virchow’s triad
Inherited causes = Factor V leiden, Anti-thrombin deficiency and protein C/S deficiency
Accquired = HIT, malignancy and immobilisation
What is Virchow’s triad?
Stasis of blood flow
Endothelial injury
Hypercoagulability
What does a dysfunction in primary haemostasis cause? How can this be categorised?
Bleeding disorders (superficial bleeding)
Qualitative defect in platelets – von Willebrand disease
Quantitative defect in platelets – ITP, HIT (heparin induced thrombocytopaenia)
What does a dysfunction in secondary haemostasis cause? How can this be categorised?
Coagulation disorders (deep bleeding):
Inherited disorders – haemophilia A, haemophilia B
Acquired disorders – liver disease, vitamin K deficiency
What are some causes of platelet disorders ?
Decreased Number (Thrombocytopaenia)
- Decreased production
- Decreased survival (ITP)
- Increased consumption (DIC)
- Dilution
Defective Platelet Function
- Acquired (e.g. aspirin, end-stage renal failure)
- Congenital (e.g. thrombasthenia)
What are the different causes of platelet disorders?
Immune-Mediated
- Idiopathic
- Drug-induced (e.g. quinine, rifampicin, vancomycin)
- Connective tissue disease (e.g. rheumatoid arthritis, SLE)
- Lymphoproliferative disease
- Sarcoidosis
Non-Immune Mediated
- DIC
- MAHA
NB: this isnt really tested that much
What is the most common coagulation disorder and how is this inherited?
Von Willebrand disease - AD (mainly) (1/10,000)
What are the subtypes of vWD? main symptom?
Type I – AD, quantitative defect
Type II – AD, qualitative defect
Type III – AR, quantitative and qualitative defects
Superficial bleeds eg mucocutaneous bleeding
What can ix show in vWD?
↓platelet adhesion, ↓factor VIII (generally vWF prevents VIII breakdown in circulation), abnormal ristocetin
Clotting screen: ↓platelet count, ↑bleeding time, ↑APTT, normal PT
What are the differences and similarites between vWD and Haemophilia A?
Very similar to haemophilia A because there is a strong relationship between vWF and factor 8 (both go down together)
These cases will both present similarly however in vWD there will be REDUCED PLATELET ADHESION which you would not see in Haemophilia A
What are ddx to consider in vWD?
These present similarly however have different findings on ix:
Bernard-Soulier disease (large platelets) and
Glanzmann’s thrombasthaenia (normal ristocetin)
Mx of vWD?
Desmopressin, vWF and factor VIII concentrates
What is ITP? pathophysiology?
This is when autoantibodies are generated against platelets
Platelets tagged by antibodies are then destroyed in the reticuloendothelial system
Causing an immune mediated thrombocytopaenia
What are the different types of ITP + who is more likely to get it?
Acute = children 1:1 (m:f)
Chronic (relapsing-remitting disease) = adults 1:3 (m:f)
What are the features of acute ITP? mx?
Generally occurs in children with preceding infection
Mx:
- Can be severe but SELF-LIMITING
- Treatment with steroids and IVIG if platelet count ↓↓↓, major bleeding
What are the features of chronic ITP? mx?
More likely in adults, 3:1 female ratio
No trigger
Long-term relapsing-remitting
Mx:
Treatment with steroids, IVIG or splenectomy
What is Haemophilia A and what is the inheritance?
X-linked recessive, Factor VIII deficiency (intrinsic pathway)
What are the clinical features + ix findings in Haemophillia A
Spontaneous, deep bleeding, haemarthrosis (IMPORTANT), lots of bleeding after dental extractions (IMPORANT)
Normal platelet count, normal bleeding time, ↑APTT, normal PT
Which Haemophillia is more common A or B? How can you differentiate between these two?
Haemophillia A > B
Clinically there is no way to differentiate - only possible by factor VIII or IX assay
What is Haemophilia A mx?
Factor VIII concentrate
What is Haemophilia B and what is the inheritance?
X-linked recessive, Factor IX deficiency (intrinsic pathway)
What are the key features of Haemophilia B?
Spontaneous, deep bleeding, haemarthrosis (IMPORTANT), lots of bleeding after dental extractions (IMPORANT)
Normal platelet count, normal bleeding time, ↑APTT, normal PT
What is Haemophilia B mx?
Factor IX concentrate
What is Vitamin K important for?
For synthesis of factors II, VII, IX and X, protein C/S (natural anticoagulants)
What are some common causes of vitamin K deficiency?
Secondary to malabsorption, warfarin (MOST COMMON), antibiotic therapy
What factor is the first to be depleted in vitamin K deficiency and why?
Factor VII - has the shortest halflife
What are the ix findings in vitamin K deficiency? mx?
Ix - Normal platelet count, normal bleeding time, ↑APTT, ↑PT (affects both extrinsic and intrinsic pathways)
Management – vitamin K replacement, PCC (Prothrombin complex concentrate), FFP (Fresh frozen plasma)
What are some differentials to consider in vitamin K deficiency?
Differentials include liver disease (↓platelet count), scurvy (corkscrew hair)
What is the most common inherited prothombotic disorder? what is its mode of inheritance?
Factor V Leiden - AD
What are the key features of Factor V leiden? mx?
Resistance to protein C -> failure to degrade factor V -> hypercoagulable state
Predisposition to venous thromboembolism (arterial thromboembolism rare)
Mx = long-term anticoagulation
What is thrombin used for? what opposes this action?
Covert fibrinogen into fibrin hence increases coagulation
Anti-thrombin acts against this and decreases coagulation
What is the inheritance of anti-thrombin deficiency?
AD
What are the key features of anti-thrombin deficiency?
Carries highest risk of thrombosis - IMPORTANT
Develop thromboembolism in unusual locations (e.g. splenic or mesenteric veins)
Anti-thrombin assay used to make diagnosis
Key differentials include protein C/S deficiency
Mx of anti-thrombin / protein C/S deficiency?
Management – long-term anti-coagulation with warfarin(AVOID WARFARIN IN PROTEIN C/S) and argatroban
Which patients are most likely to suffer from warfarin-induced skin necrosis?
Protein C/S deficiency - Paradoxical blood clotting.
Blood clots block the blood vessels and cause necrosis, where an area of skin is destroyed.
Inheritance of Protein C/S deficiency?
Autosomal dominant
A 19-year-old boy comes in with an acutely swollen knee. He does not recollect any trauma.
He has been known to have history of bleeding after dental extraction. What is the most likely factor deficiency?
Factor X
Factor VII
Factor IX
Factor VIII
Factor XI
Factor VIII - Haemophilia is the dx A or B
A is way more common, no way to clinically distinguish
What is the most common inherited Thrombophilia?
VWD
Hereditary Activated Protein C Resistance
Anti-Thrombin Deficiency
Hemophilia B
Protein S Deficiency
Hereditary Activated Protein C Resistance - This is simply there to throw you off -> it’s referring to Factor V Leiden
Describe the extrinc,intrinsic and common pathways of coagulation
