B7 - Disorders of homeostasis Flashcards
What causes bleeding
- Abnormalities of vasculature
○ E.g. structural, connective tissue disorders
○ Surgeons have to close the vessels properly- Defects of primary haemostasis - platelet disorders
- Defects of secondary haemostasis
○ Procoagulant protein deficiency - Accelerated breakdown of clot
○ hyperfibrinolysis
Common causes of thrombocytopaenia
○ Impaired bone marrow function
§ Myelodysplasia
§ Leukaemia
§ Bone marrow infiltration
○ Hypersplenism (sequestration) (e.g. chronic liver disease)
○ Acts as a storage site for platelets
○ Increased platelet destruction
§ Severe sepsis/DIC
§ TTP/HUS syndrome
§ Immune thrombocytopaenic purpura (ITP)
§ Autoimmune conditions (SLE, antiphospholipid syndrome)
§ Viral infections (HIV, EBV, hepatitis C, H. pylori)
§ Pre-eclampsia
○ Drug-induced (heparin, gold, quinine)
Immune (Idiopathic) thrombocytopaenic purpura (ITP)
- Isolated thrombocytopaenia (remainder of blood count and coagulation testing normal). Diagnosis of exclusion - no gold standard diagnostic test
- Present with petechiae, epistaxis, bleeding gums
- Pathogenesis
○ Increased platelet destruction - antibody effect
○ Inhibition of megakaryocyte platelet production via the production of specific IgG autoantibodies by the patients B cells - Presentation
○ Children usually present with sudden severe thrombocytopaenia a few weeks after viral infection
§ Usually clears on it’s own
○ Adults often present with more gradual onset and more gradual recovery, many do not fully resolve
○ Treatment options include steroids, intravenous immunoglobulin (IV Ig), splenectomy, rituximab, TPOmimetics
Platelet function in haemostasis
- Circulating platelets bind to sub-endothelial matrix through platelet surface receptors
○ Glycoprotein 1b/IX/V complex via non-Willebrand factor (VWF)
○ GPVI binding collagen
○ GP1a/IIa- Platelets are activated by collagen, thrombin
- Activated platelets
○ Change shape
○ Release their granules (which contain substances such as ADP, TXA2, fibrinogen, VWF)
○ Express glycoprotein IIb/IIIa (fibrinogen receptor) - on the surface in a functional form - ADP and TXA2 recruit other platelets to help from a platelet plug
Abnormal Platelet Function
- Congenital
○ GP Ib IX-V defect (Bernard-Soulier Syndrome)
○ GP IIb/IIIa defect (Glanzmann’s thrombasthaenia)- Acquired - usually caused by drugs
○ Aspirin - irreversibly inhibits enzyme
○ Clopidogrel - inhibits ADP receptor
○ Dipyridamole
○ Non-steroidal anti-inflammatories
○ Uraemia
- Acquired - usually caused by drugs
Bleeding disorders and secondary haemostasis
- Inherited ○ Haemophilia ○ Von-Willebrand disease - Acquired ○ Liver disease ○ Vitamin K deficiency ○ Renal disease ○ Warfarin ○ DIC ○ Massive transfusion
Congenital deficiency of clotting factor
- Congenital deficiencies described for all except tissue factor
- Factor XII deficiency not associated with bleeding
○ All others are - Bleeding potentially due to
○ Quantitative defect
○ Qualitative defect
○ Combined
- Factor XII deficiency not associated with bleeding
Haemophilia
- Rare
- Severe bleeding
○ Diagnosed as infants
○ Spontaneous haemarthrosis, muscle haematoma, intracranial haemorrhage, internal bleeding - Types
○ Haemophilia A: FVIII deficiency
○ Haemophilia B: FIX deficiency (Christmas disease) - Haemophilia A and B of comparable severity, bleed with similar frequency
- Inheritance is X linked recessive: predominantly effects males, females are usually carriers
- Severe bleeding
Haemophilia A
FVIII deficiency
Haemophilia B
FIX deficiency (Christmas disease)
Diagnosis of haemophilia/bleeding disorders
- Most important screening test is clinical history
○ Personal bleeding history
○ Drugs
○ Family history- Laboritory screening test
○ Activated partial thromboplastin time (APTT) (prolonged)
○ Normal PT, platelet count and fibrinogen - Severe is FIX or FVIII level of <1%
- Laboritory screening test
Haemophilia Management
- Recombinant (manufactured) FVIII (or IX) replacement for procedures or treatment of bleeds (levels increased from 1% to 50%-100)
- For people with severe disease - prophylaxis (routine FVIII (or IX) replacement 2-3 times per week) for newly diagnosed children
○ Eg. Constantly bleeding into knee may cause arthritis etc. - In the 1980’s-90’s haemophiliacs given FVIII from blood donors - group of men with medically-acquired hepatitis C and HIV. ALL current patients in Australia given recombinant product
- All patients should carry a card detailing the diagnosis, severity and usual treatment
- For people with severe disease - prophylaxis (routine FVIII (or IX) replacement 2-3 times per week) for newly diagnosed children
bleeding caused by platelet defects
mucocutaneous bleeding
bleeding caused by clotting factor defects
deep tissue bleeding
Von-Willebrand Disease VWD
- Most common inherited bleeding disorder
- Von-Willebrand Protein
○ Role in primary haemostasis
○ Carrier protein for FVIII - Autosomal dominant, 1% population
○ Equal males/females
○ May be family history of bleeding - May have mild bleeding tendency
○ Epistaxis, mucosal bleeding, menorrhagia, easy bruising
○ Many are diagnosed after haemorrhage following tooth extraction or tonsillectomy
- Von-Willebrand Protein
types of von willebrand disease
○ Type 1 - decreased quantity of VWF - mild
○ Type 2 - decreased function of VWF
○ Type 3 - rare, sever deficiency of VWF due to inheriting two mutated genes (one from each parent) presents as haemophilia with similar style bleeding to a severe case
