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
von willebrand disease diagnosis
○ May or may not have a prolonged APTT (VWF carrier protein for FVIII)
○ Specific tests to diagnose ‘von-Willebrand screen’
§ VWF antigen
§ VWF function (collagen binding, ristocetin cofactor)
§ Factor VIII levels (VWF carrier protein for FVIII)
○ Normal >50%, abnormal <30%, 30-50%?
von willebrand disease management
○ Depend on severity of bleeding
○ DDAVP (desmopressin)
§ IV infusion that increases release of VWF from storage granules in platelets and endothelium
§ Duration of effect 4-6 hours max so must be given on the same day as the procedure
§ Burst of VWF into circulation
§ Good for simple surgeries eg. Tooth extraction
○ Tranexamic acid tablets (or mouthwash)
§ Stabilise fibrin clot, may be taken for the first 4-5 days after procedure
○ Biostate
§ For severe deficiency (type 3) or non-responders to DDAVP plasma-derived product prepared from blood donors that contains FVIII and VWF
§ Needs to be given on the same day as the procedure
§ Or for major surgeries or severe bleeding disorders
○ DDAVP (desmopressin)
§ IV infusion that increases release of VWF from storage granules in platelets and endothelium
§ Duration of effect 4-6 hours max so must be given on the same day as the procedure
§ Burst of VWF into circulation
§ Good for simple surgeries eg. Tooth extraction
○ Biostate
§ For severe deficiency (type 3) or non-responders to DDAVP plasma-derived product prepared from blood donors that contains FVIII and VWF
§ Needs to be given on the same day as the procedure
§ Or for major surgeries or severe bleeding disorders
○ Vit K deficiency
§ Essential for activity of several carboxylase enzymes within hepatic cells, necessary for activation of factors II, VII, IX, X
§ Vit K1 - dietary (green leafy vegies)
§ Vit K2 - synthesised by gut flora
§ Deficiency
1. Neonatal ‘haemorrhagic disease of the newborn’ all neonates are vit K deficient: IM vitamin K at birth - public health scheme to prevent haemorrhagic disease of the newborn
2. Adults
a) Any cause of malnutrition, malabsorbtion (coeliac disease, inflammatory bowel, short bowel, cystic fibrosis etc.)
§ Laboritory diagnosis
□ Prolonged PT
□ Normal fibrinogen and normal/prolonged APTT (because of factors 2 ad 10)
Neonatal ‘haemorrhagic disease of the newborn
all neonates are vit K deficient: IM vitamin K at birth - public health scheme to prevent haemorrhagic disease of the newborn
vit K deficiency lab diagnosis
□ Prolonged PT
□ Normal fibrinogen and normal/prolonged APTT (because of factors 2 ad 10)
Massive transfusion
- Defined as replacement by transfusion of >50% of blood volume in 12-24 hours
- In adult usually >10 units of packed cells
- Dilution of clotting factors, platelets
- Lab tests: prolonged INR, prolonged APTT, low fibrinogen, low platelets
- Coagulopathy potentiated by acidosis, hypothermia
- Many institutions now have massive transfusion protocol e.g. after 4 units packed cells, give 1 unit FFP
Disseminated Intravascular Coagulation (DIC)
- Systemic process where the blood is exposed to procoagulant factor (e.g. tissue factor)
Massive thrombin generation, widespread coagulation, followed by fibrinolysis and depletion of clotting factors
DIC causes
- Causes ○ Acute § Sepsis § Severe trauma § Complications of pregnancy (amniotic fluid embolism, placental abruption, fetal death in utero) § Snake bite § Acute leukaemia (particularly promyelocytic) ○ Chronic (compensated) § Cancer
DIC clinical presentation
○ Bleeding (64%), including spontaneous bleeding from cannula sites
○ Renal dysfunction (25%)
○ Hepatic dysfunction (19%)
○ Respiratory dysfunction (16%)
○ Shock (14%)
○ Thromboembolism (7%)
○ Central nervous system involvement (2%)
thrombosis
- Too little breakdown, too much clot formation
- Risk factors - Virchow’s Triad
○ Endothelial injury
○ Abnormal blood flow
○ Hypercoagulability (too many clotting proteins, to thicker blood flow) - Clinical features of deep vein thrombosis
○ Usually in leg
○ Usually red swollen and painful
- Risk factors - Virchow’s Triad
diagnosis of Deep vein thrombosis
○ Presentations to ED with suspected DVT: 20% have DVT and 80% have other cause
○ DVT cannot be safely diagnosed or excluded on history/exam alone
○ Diagnosis involves
§ Assessment of pre-test probablity of DVT - clinical prediction guide
□ D dimer - measures broken down fragments of cross linked fibrin from a clot
® Any reason for having activated thrombosis will increase D dimer measurement
® If your D dimer is normal, DVT can be excluded
® If D dimer is high it is not necessarily DVT
□ Ultasonography USS
thrombosis risk factors
○ Endothelial injury
○ Abnormal blood flow
○ Hypercoagulability (too many clotting proteins, to thicker blood flow)
fibrinolysis
- At the time that the clot is broken down all the fibrin strands are cross linked
- Cross linked fragments of broken down blood clot are measured with d dimer
d-dimer
- Plasmin breaks down cross-linked fibrin to d-dimers (product of fibrinolysis)
- Occur after a thrombin has formed
- Found in VTE and post-operatively, DIC, infection, malignancy, trauma
- Not specific and cannot be used to confirm a diagnosis of DVT
Why measure D-dimer - High negative predictive value, low positive predictive value
Clinical features of Pulmonary Embolism (PE)
- Chest pain, shortness of breath, cough, palpitations, syncope, differential diagnosis
○ Chest infection
○ Cardiac failure
○ Malignancy
Natural history of Venous thromboembolism
- Usually starts in the calf veins
- Majority is symptomatic DVT are proximal
- Pulmonary embolism (PE) usually arise from proximal DVT - some of the clot breaks of and travels to cause a PE
- ~ 50% of untreated symptomatic proximal DVT are expected to cause symptomatic PE
- ~10% of symptomatic PE are rapidly fatal
- ~30% of untreated symptomatic non-fatal PE will have a fatal recurrence
Treatment of VTE - aims
- Relieve symptoms
- Prevent PE (DVT patients)
- Prevent death (PE patients)
- Prevent recurrence
- Prevent complications - post-phlebitic syndrome (DVT), pulmonary hypertension (PE)
- Anticoagulation is the mainstay of treatment
Antithrombin
- Genetics encode how much we produce
- Major inhibitor of thrombin, Xa and other serine proteases in coagulation cascade e.g. Ixa
- Heparin cofactor
○ Slowly inactivates thrombin in abense of heparin
○ More potent in presence of haperin - Active sites
○ Reactive centre - cleaved by thrombin
○ Heparin binding iste - Inherited autosomal dominant, variable clinical penetrance
○ One acquired defective copy of the gene is sufficient - Acquired causes include liver disease, warferin theraoy, protein loss (e.g. nephrotic syndrome), DIC
heparin effect on anti-thrombin
- Heparin cofactor
○ Slowly inactivates thrombin in abense of heparin
More potent in presence of haperin
antithrombin deficiency inheritance
- Inherited autosomal dominant, variable clinical penetrance
○ One acquired defective copy of the gene is sufficient
protein C deficiency
- Vitamin K dependant protein synthesised in the liver
- Autosomal dominant inheritance
- Anticoagulant effect only after activation to activated protein C (aPC)
- aPC inactivates Va and VIIIa
- Effect markedly enhanced by protein S
- aPC also has anti-inflammatory action, protects endothelial barrier function and enhances fibrinolysis
Protein S deficiency
- Autosomal dominant I heritance of deficiency
- Vit K dependant
- Co factor for protein C system
- Acquired deficiency in pregnancy, OCP, liver disease, certain drugs, HIV infection
Factor V leiden mutation
- Point mutation in factor 5 gene
- Arginine to glutamine at position 506
- Protein C is unable to inactivate factor V
- ‘activated protein C resistance’ - factor 5 is not switched off by protein C like it should be
- Only 5% of heterozygotes for FVL will experience VTE
- Risk factor, does not mean these people will have problems with clotting
Prothrombin gene mutation
- Prothrombin is the precursor for thrombin
- G20210A transition in 3’ untranslated region of gene is risk factor for thrombosis
- Heterozygous carriers have 30% higher plasma prothrombin levels
- Mechanism: altered mRNA processing or decay rate
- Risk factor for blood clotting, does not necessarily mean this people will have clotting issues
