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Haematology revision

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Haematology revision Haematology revision Presentation Transcript

  • Topics
    • Physiology of haemostasis
    • Bleeding disorders (congenital)
    • Massive blood loss
    • DIC
    • Thrombosis
    • Anticoagulant drugs
  • Haemostasis needs… Platelets Vessel Wall Clotting Factors
  • FIG 1: Normal blood vessel Intima/media with endothelial cell basal membrane smooth muscle cells collagen fibers erythrocyte platelet lumen leukocyte
    • FIG 2
    • Injured blood vessel
    • Exposure of collagen
    • Adhesion of platelets mediated by vWF
    • Activation and de-granulation of platelets
    • Aggregation of platelets
    erythrocyte non-activated platelet lumen endothelial cell basal membrane activated collagen- boundplatelet collagen fibers smooth muscle cells
  • FIG 3 Platelet plug stabilization by fibrin lumen endothelial cell basal membrane erythrocytes activated platelets plug sealing and stabilization by fibrin formation
  • “ Intrinsic” System Collagen / Kallikrein Prekallikrein XII XIIa XI XIa IX IXa Ca 2+ X Xa Ca 2+ Phospholipid + VIII “ Extrinsic” System VII Tissue Factor VIIa + Tissue Factor Prothrombin Thrombin V + Phospholipid + Ca 2+ Fibrinogen Fibrin XIII XIIIa Cross Linked Fibrin Ca 2+ HMWK Final Common Pathway
  • Platelets
      • The job of platelets is to:
    • Form a plug in a breech in a blood vessel wall to arrest haemorrhage
    • Provide a phospholipid surface rich in negatively charged phospholipid for coagulation factors to interact (tenase and prothrombinase complexes).
  •  
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  • The starter motor…….. Switched off by Tissue Factor Pathway Inhibitor Provides initial Thrombin burst Factors measured in Prothrombin Time PT
  • The engine………….. Thrombin from initial burst back activates “intrinsic system” Fibrin then cross linked by XIII APTT TT
  • Natural anticoagulants
    • Protein C (activated by thrombin/thrombomodulin)
    • Protein S - cofactor for protein C
    • Protein C and S cleave factors V and VIII
    • Antithrombin inhibits Thrombin and Xa
    • TAT complexes removed by liver
    • Activity increased 000’s by heparin
  • Fibrinolysis Plasminogen Plasmin tPA or uPA Fibrin Fibrin degradation products Plasmin interaction with Fibrin is Lys residue dependent. TAFI removes such residues. TA and EACA act as Lys analogues. Circulating antiplasmin and PAI I inhibit this system. Their effect is not present in the milieu of the clot which protects tPA and Plasmin from their actions (If x-linked get D-D dimers)
  • Global coagulation tests
    • APTT : Kallikrein, HMWK, XII, XI, IX, VIII, X, V, II, I
    • “ intrinsic system”
    • PT : VII, X, V, II, I
    • “ extrinsic system”
    • TT : I
    • NB reason for 50:50 mix (inhibitors versus deficiency)
    • Protamine correction
    • Reptilase time
    • Specific factor assays
    • Bleeding time, PFA-100, TEG
  • CAUSES OF A PROLONGED PROTHROMBIN TIME
    • CONGENITAL
    • Coagulation factor deficiencies: VII, X, V, II, I
    • ACQUIRED
    • Hepatocellular disease
    • Vitamin K deficiency (II, VII, IX, X): obstructive jaundice, haemorrhagic disease of the newborn
    • Disseminated intravascular coagulation (DIC)
    • Massive blood transfusion
    • Warfarin (monitoring test based on PT)
    • Gross overheparinisation, some lupus anticoagulants
  • CAUSES OF A PROLONGED ACTIVATED PARTIAL THROMBOPLASTIN TIME
    • CONGENITAL
    • Coagulation factor deficiencies: XII, XI, IX, VIII, X, V, II, I
    • ACQUIRED
    • Hepatocellular disease
    • Vitamin K deficiency
    • Disseminated intravascular coagulation
    • Massive blood transfusion
    • Heparin (monitoring test based on APTT)
    • Lupus anticoagulants
  • CAUSES OF A PROLONGED THROMBIN TIME
    • CONGENITAL
    • Dys/hypofibrinogenaemia
    • ACQUIRED
    • Hepatocellular disease: dys/hypofibrinogenaemia
    • Disseminated intravascular coagulation:
      • hypofibrinogenaemia
      • FDPs
    • Heparin
  • Haemophilia
    • A = reduced VIII; B = reduced IX
    • Both sex-linked recessive
    • Queen Victoria
    • Intronic rearrangements, point mutations, gene deletions
    • Haemophilia A 1 in 10,000 male infants
    • Prolonged APTT (normal PT and TT)
    • Mild Rx: Tranexamic acid, DDAVP (not HB)
    • Severe Rx: factor replacement recombinant or pooled donor
    • Home prophylaxis
    • Past problem with HIV, now HCV ??? CJD
  • Von Willebrand’s Disease Functions of VWF: 1. Sticks to platelets (GPIb) 2. Sticks to collagen in subendothelium (Important in small blood vessel lesions; high shear stress) 3. Binds to and protects VIII (labile) Therefore in VWD see long APTT (low VIII) and bleeding where VWF platelet interaction important
    • Type 1: mild- moderate quantitative deficiency
    • Type 2: qualitative changes (functional)
    • Type 3: severe deficiency
    • Type 2N : reduced VIII binding in isolation
    • Type 2A : absent HMW multimers
    • Type 2B : increased affinity for platelet GPIb
    • Type 2M : HMW multimers present
    Von Willebrand’s Disease
    • Treatment options
    • DDAVP, antifibrinolytics
    • NB DDAVP causes fluid retention.
    • Intermediate purity VIII concentrate
    • (NB type I may “auto-correct” in pregnancy)
    Von Willebrand’s Disease
  • Massive blood loss
    • Defined as loss of more than one circulating volume in 24 hours or 50% blood volume loss within 3 h or a rate of loss of 150 ml/min
    • Coagulopathy is multifactorial:
    • Loss of factors only once 80% of volume replaced
    • Dilution of factors during fluid resuscitation
    • Inhibitory effect of some colloids on clotting factors
    • DIC secondary to trauma
    • Acidosis
    • Hypothermia (enzymes) (blood warmer)
  • Assessment of loss
    • <25% loss : Tachycardia is often (but not always) one of the first signs; blood pressure may be normal. Pulse pressure is often narrow. Capillary refill will be at upper end of normal. Respiratory rate will be increased.
    • 25-40% loss : Tachycardia, hypotension, prolonged capillary refill, tachypnoea, oliguria and altered mental state.
    • >40% loss: the patient will be shocked. Bradycardia, hypotension, prolonged capillary refill, abnormal respiratory rate, anuria and possibly coma.
    • Regular checks of FBC and PT,APTT,TT and Fibrinogen
    • Aim for platelets > 50x10 9 /l or >100x10 9 /l if polytrauma or CNS injury
    • Aim for fibrinogen >1g/l
    • Aim for PT and APTT <1.5x control times
    • FFP 15ml/kg
    • Cryoprecipitate 2 packs (=10 old packs) if fibrinogen fails to correct with FFP
    • ? rVIIa
    • Stainsby D, MacLennan S, Hamilton PJ. Management of massive blood loss: a template guideline. Br J Anaesth. 2000 Sep;85(3):487-91.
    Massive blood loss
  • Disseminated intravascular Coagulation
    • “… ..an acquired syndrome characterised by the intravascular activation of coagulation with loss of localisation arising from different causes.
    • DIC can originate from and cause severe damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.”
    • ISTH definition
  • Clinical features
    • Mucosal oozing, bleeding from surgical wounds or indwelling canulae
    • Multi organ failure secondary to microthrobi (and hypovolaemia)
  • Causes of DIC
    • Conditions associated with overt DIC
    •  sepsis/severe infection (any organism)
    •  trauma (e.g. polytrauma, neurotrauma, fat embolism)
    •  organ destruction (e.g. severe pancreatitis)
    •  malignancy
    • massive blood loss with inadequate fluid replacement therapy
    •  vascular abnormalities
    • (e.g. Kassbach-Merrit syndrome)
    •  severe hepatic failure
    •  severe toxic or immunological reactions
    • (e.g. recreational drugs, transfusion reactions, transplant rejection)
  • Diagnosis Diagnostic algorithm for the diagnosis of overt DIC Does the patient have an underlying disorder known to be associated with overt DIC? ( If yes, proceed; if no, do not use this algorithm )  Order global coagulation tests (platelet count, PT, fibrinogen, soluble fibrin monomers (SFM) or fibrin degradation products (FDP).  Score coagulation test results: Platelet count (>100=0; <100=1, <50=2) Elevated FDP or SFM ( no increase=0; moderate increase=2; strong increase=3 ) Prolonged PT ( by <3 seconds=0; >3 but <6 seconds=1; >6 seconds=2 ) Fibrinogen level (>1g/l=0; <1g/l=1) Score >=5 compatible with overt DIC Score <5 suggestive (not affirmative) of non-overt DIC; repeat tests in 1-2 days
  • Management of DIC
    • TREAT THE CAUSE
    • Fluid resus as needed, antibiotics if sepsis
    • If bleeding or need surgery give FFP, Platelets, Cryoprecipitate
    • (Aim Platelets>50x10 9 /l, PT and APTT < 1.5x normal)
    • If thrombotic manifestations eg. Dermal ischaemia consider low dose heparin infusion.
  • Thromboembolic disease and anticoagulation
  • Venous thromboembolism DVT PE A Leading cause of morbidity and mortality
  • Natural History of DVT Rare under 16 years Annual incidence 30/100,000 40 years Annual incidence 90/100,000 60 years Annual incidence 260/100,000 80 years
  • Natural History of DVT >80% of symptomatic DVT are proximal 20% of isolated calf will spread proximally PE usually arises from proximal DVT Most patients with proximal DVT have asymptomatic PE and visa versa
  • Natural History of DVT 10% of symptomatic PE are fatal 30% of untreated symptomatic non-fatal PE will have a fatal recurrence
  • Pathogenesis
    • Virchow’s Triad:
    • Venous stasis
    • Endothelial changes (damage)
    • Hypercoagulability
  • Risk Factors for DVT Previous VTE Age Pregnancy Obesity Inherited Thrombophilia Malignancy Oestrogens Immobility Trauma Surgery Antiphospholipid antibodies
  • Treatment of VTE Heparin for a minimum of 5 days(followed by warfarin) Low molecular weight (occasionally unfractionated) Increases action of Antithrombin on Xa (and IIa) Overlap for 2 days with INR>2 on warfarin NB renal function Side effects: Bleeding, HIT, osteoporosis.
  • Heparin NB arterial lines !!!!!!!
  • Heparin
    • Unfractionated
    • monitor with APTT (ratio 1.5-2.5 - base on patient’s baseline)
    • reversal by stopping infusion and very rapid with protamine sulphate
    • can be hard to anticoagulate some children due to low antithrombin levels
    • bolus then continuous infusion
    • Low molecular weight
    • less monitoring
    • once or twice daily administration
    • more reliable pharmacokinetics (NB renal excretion)
    • Only partially reversible
    • anti-Xa levels - 4h post dose
    • Treatment 0.5-1; Prophylaxis 0.1-0.3 IU/ml
  • Warfarin II, VII, IX, X, protein C and S are vitamin K dependent. NB C and S fall first so overlap with heparin (Warfarin induced skin necrosis) Peri-surgical management of patients on warfarin
  • Treatment of bleeding/excess anticoagulation on warfarin INR 3-6 (target 2.5); INR 4-6 (target 3.5) Reduce dose or stop; restart when INR<5 INR 6-8 No or minor bleeding Stop warfarin; restart when INR<5
  • Treatment of bleeding/excess anticoagulation on warfarin INR>8; No or minor bleeding Stop warfarin; restart when INR<5 If other risks for bleeding give 0.5-2.5mg vitamin K orally
  • Treatment of bleeding/excess anticoagulation on warfarin Major bleeding Stop warfarin Give Prothrombin complex concentrate Give vitamin K oral or i.v. PCC – II; VII; IX; X – discuss dose with haematologist DO NOT USE FFP IF PCC AVAILABLE UNLESS IT IS CONTRAINDICATED
  • Other anticoagulant agents
    • Aspirin
    • Clopidogrel
    • Abciximab
    • NSAIDS
    • Fibrinolytics
  • Antiphospholipid Syndrome
    • An autoimmune disorder characterised by
    • the occurrence of :
    • thromboembolism (venous and/or arterial); and/or
    • obstetric morbidity; along with
    • the persistent production of antiphospholipid antibodies.
  • Questions