Haematology 5 and 6 0900 Lecture Haemostasis Professor David Lane Film 1000 Lecture Abnormalities of Haemostasis Dr Carolyn Millar Department of Haematology Hammersmith Hospital Campus ID: 1045084
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1. 22 October 2012 Lectures: Haematology 5 and 60900 Lecture: Haemostasis: Professor David LaneFilm 10.00 Lecture: Abnormalities of Haemostasis: Dr Carolyn MillarDepartment of HaematologyHammersmith Hospital Campus(d.lane@imperial.ac.uk; c.millar@imperial.ac.uk)Year 2: Molecules Cells & DiseaseHaematology
2. Learning OutcomesThe student should be able to:1. Explain the normal haemostatic mechanisms including theinteraction of vessel wall, platelets and clotting factors2. Describe the clinical features of bleeding due to thrombocytopenia and coagulation disorders, respectively3. Describe the use of laboratory tests to assess haemostasis4. Know the principles of management of disorders of haemostasis
3. Abnormal HaemostasisWhat is abnormal bleeding?Why do people have abnormal haemostasis?Laboratory detection/prediction of abnormal haemostasisGenetics of common bleeding disordersTreatment of bleeding disorders
4. Minor bleeding symptoms are commonEasy bruising 12%Gum bleeding 7%Frequent nosebleeds 5%Bleeding after tooth extraction 2.5%Post operative bleeding 1.4%In womenMenorrhagia 23%Post partum bleeding 6%Family history 44%
5. Nosek-Cenkowska 1991History and Bleeding after tonsillectomynon bleeding %(228)Known bleeding disorderEasy bruisingFrequent bruisingEpistaxes>10mins Bruises >1 siteLarge bruises%(31)24363944.93.62.767686947393022Haematomata
6. A significant bleeding history: elementsEpistaxis not stopped by 10 mins compression or requiring medical attention/transfusion.Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.Heavy, prolonged or recurrent bleeding after surgery or dental extractions. Sadler 2005
7. Abnormal HaemostasisWhat is abnormal bleeding?Why do people have abnormal haemostasis?Genetics of hereditary bleeding disordersLaboratory detection/prediction of abnormal haemostasisGenetics of common bleeding disordersTreatment of bleeding disorders
8. Haemostatic Plug Formation: An OverviewVessel constrictionFormation of an unstable platelet plug -platelet adhesion -platelet aggregationStabilisation of the plug with fibrin -blood coagulationDissolution of clot and vessel repair -fibrinolysisResponse to injury
9. Abnormal HaemostasisLack of a specific factorFailure of production: congenital and acquiredIncreased consumption/clearanceDefective function of a specific factorGenetic defectAcquired defect – drugs, synthetic defect, inhibition
10. Haemostatic Plug Formation: An OverviewVessel constrictionFormation of an unstable platelet plug -platelet adhesion -platelet aggregationStabilisation of the plug with fibrin -blood coagulationDissolution of clot and vessel repair -fibrinolysisResponse to injuryPrimary haemostasis
11. plateletGlpIaVon Willebrand factorEndothelial cellsplateletGlpIbcollagenPlatelet adhesionPlatelet aggregationplateletplateletGlpIIb/IIIaplateletFibrinogen+Ca2+orRelease of ADP&thromboxane
12. Disorders of Primary HaemostasisPlateletsLow numbers: “thrombocytopenia”Bone marrow failure eg: leukaemia, B12 deficiencyAccelerated clearance eg: immune (ITP), DIC.
13. Auto-Immune Thrombocytopenic Purpura (auto-ITP)YYYYYYY............Yantiplateletautoantibodiessensitisedplateletmacrophagevvvvvv..YITP is a very common cause of thrombocytopeniasensitisedplatelet
14. 1. Failure of platelet production by megakaryocytes 2. Shortened half life of platelets3. Increased pooling of platelets in an enlarged spleen (hypersplenism) + shortened half lifeMechanisms (and causes) of Thrombocytopenia
15. Disorders of Primary HaemostasisPlateletsLow numbers: “thrombocytopenia”Bone marrow failure eg: leukaemia, B12 deficiencyAccelerated clearance eg: immune (ITP), DIC. Pooling and destruction in an enlarged spleenImpaired functionHereditary absence of glycoproteins or storage granules
16. Hereditary Platelet defectsPhospholipidmembraneOpen cannalicular systemmitochondriona granules:growth factorsfibrinogenfactor VvWFDense granules:ADPATPSerotoninCa2+GlycogenSurface glycoproteins:GpIaGpIIb/IIIaGpIbMicrotubules &actomyosin(Receptorfor thrombin)XGlanzmann’s thrombastheniaBernard Soulier syndromeStorage Pool diseaseXX
17. Disorders of Primary HaemostasisPlateletsLow numbers: “thrombocytopenia”Bone marrow failure eg: leukaemia, B12 deficiencyAccelerated clearance eg: immune (ITP), DIC. Pooling and destruction in an enlarged spleenImpaired functionHereditary absence of glycoproteins or storage granulesAcquired due to drugs: aspirin, NSAIDs, clopidogrel
18. Disorders of Primary HaemostasisPlateletsVon Willebrand FactorVon Willebrand diseaseHereditary decrease of quantity +/ function (common)Acquired due to antibody (rare)
19. VWF has two functions in haemostasisBinding to collagen and capturing plateletsStabilising Factor VIIIFactor VIII may be low if VWF is very lowVWD is usually hereditaryDeficiency of VWF (Type 1 or 3)VWF with abnormal function (Type 2)Von Willebrand disease: A disorder of primary haemostasis
20. Disorders of Primary HaemostasisPlateletsVon Willebrand FactorThe vessel wallInherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
21. Ehlers Danlos syndrome
22. Disorders of Primary HaemostasisPlateletsVon Willebrand FactorThe vessel wallInherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disordersAcquired: Scurvy, Steroid therapy, Ageing (senile purpura), Vasculitis
23. Disorders of Primary HaemostasisPlateletsThrombocytopeniaDrugsVon Willebrand FactorVon Willebrand diseaseThe vessel wallHereditary vascular disordersScurvy, steroids, age
24. plateletplateletPrimary Haemostasis: platelet plugCollagenTissue Factorlumenplateletplateletplateletplatelet
25. plateletplateletVWD: failure of primary haemostasisCollagenTissue Factorlumenplatelet
26. Bleeding in disorders of primary haemostasisTypical primary haemostasis bleeding:Immediate Prolonged bleeding from cutsEpistaxesGum bleedingMenorrhagia Easy bruisingProlonged bleeding after trauma or surgeryThrombocytopenia – PetechiaeSevere VWD – haemophilia-like bleeding
27. Purpura and petechiae
28. Tests for disorders of primary haemostasisPlatelet countBleeding time (PFA100 in lab)Assays of von Willebrand FactorClinical observation
29. Haemostatic Plug Formation: An OverviewVessel constrictionFormation of an unstable platelet plug -platelet adhesion -platelet aggregationStabilisation of the plug with fibrin -blood coagulationDissolution of clot and vessel repair -fibrinolysisResponse to injurySecondary haemostasis
30. XXaXFibrinogenFibrinCrosslinked fibrinXIIIaXIIIProthrombinthrombin (IIa)IXaIXVIIIaPlCa 2+XIaXIXIIaXIICOMMON PATHWAYVaPlCa 2+thrombinBlood coagulationTissue factor(vessel damage)VIIaCa 2+EXTRINSIC PATHWAYVIIaCa 2+INTRINSIC PATHWAY
31. Fibrin mesh binds and stabilises platelet plug and other cells
32. Thrombin generation by the coagulation cascadeNormalHaemophiliaFactor VIII <1%TF trigger
33. Disorders of coagulation – bleeding patternDeficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formationThe role of the coagulation cascade is to generate a burst of thrombin which will convert fibrinogen to fibrin
34. Coagulation and secondary haemostasisThe primary platelet plug is sufficient for small vessel injuryIn larger vessels it will fall apartFibrin formation stabilises the platelet plugSo -
35. lumenHaemostasis: fibrin clot stabilising platelet plug
36. lumenHaemophilia: failure to generate fibrin to stabilise platelet plug
37. Deficiency of coagulation factor productionHereditary Factor VIII/IX: haemophilia A/BDisorders of Coagulation
38. Coagulation factor deficiencies are not all the sameFactor VIII and IX (Haemophilia)Severe but compatible with lifeSpontaneous joint and muscle bleedingProthrombin (Factor II)LethalFactor XIBleed after trauma but not spontaneouslyFactor XIINo excess bleeding at all
39. XXaXFibrinogenFibrinCrosslinked fibrinXIIIaXIIIProthrombinthrombin (IIa)IXaIXVIIIaPlCa 2+XIaXIXIIaXIICOMMON PATHWAYVaPlCa 2+thrombinBlood coagulationTissue factor(vessel damage)VIIaCa 2+EXTRINSIC PATHWAYVIIaCa 2+INTRINSIC PATHWAY
40. Deficiency of coagulation factor productionHereditary failure of productionFactor VIII/IX: haemophilia A/BAcquiredLiver diseaseDilutionAnticoagulant drugs – warfarinDisorders of Coagulation
41. Acquired coagulation disorders (1)Liver failure – decreased productionMost coagulation factors are synthesised in the liverDilutionRed cell transfusions no longer contain plasmaMajor transfusions require plasma as well as rbc and plateletsMore common in hospital practice
42. Deficiency of coagulation factor productionHereditary failure of productionFactor VIII/IX: haemophilia A/BAcquiredLiver diseaseDilutionAnticoagulant drugs – warfarinIncreased consumptionAcquiredDisseminated intravascular coagulation (DIC)Immune - autoantibodiesDisorders of Coagulation
43. Acquired coagulation disorders (2)ConsumptionDisseminated intravascular coagulation increased consumptionGeneralised activation of coagulation – Tissue factorAssociated with sepsis, major tissue damage, inflammation Consumes and depletes coagulation factorsPlatelets consumedActivation of fibrinolysis depletes fibrinogenDeposition of fibrin in vessels causes organ failure
44. Bleeding in coagulation disorderssuperficial cuts do not bleed (platelets)bruising is common, nosebleeds are rarespontaneous bleeding is deep, into muscles and jointsbleeding after trauma may be delayed and is prolongedfrequently restarts after stopping
45. Haemarthrosis – hallmark of haemophilia
46.
47. Intramuscular injections should be avoided
48. How serious is haemophilia?Carol Birch 1937
49. Clinical Distinction Between Bleeding due to Platelet and Coagulation DefectsPlatelet/VascularSuperficial bleeding into skin, mucosal membranesBleeding immediateafter injuryCoagulationBleeding into deeptissues, muscles,jointsDelayed, but severebleeding afterinjury. Bleedingoften prolongedThis is a simplistic distinction. Note thateither defect can be life threatening
50. Tests for coagulation disordersScreening tests (‘clotting screen’)Prothrombin time (PT)Activated partial thromboplastin time (APTT)Full blood count (platelets)Factor assays (for Factor VIII etc)Tests for inhibitors
51. IXIIFibrinogenFibrinPKHMWKXIXIIVIIaTFVIIIXVCONTACTPTAPTTTTIIa
52. IIFibrinogenFibrinVIIaTFXVPROLONGED APTT in HAEMOPHILIAIXXIXIIVIIIPT 10.6s (9.6-11.6)APTT 85s (26-32)TT 16s (15-19)PT(extrinsic)APTT(intrinsic)
53. Bleeding disorders not detected by routine clotting tests Mild factor deficiencies von Willebrand disease Factor XIII deficiency (cross linking) Platelet disorders Excessive fibrinolysis Vessel wall disorders Metabolic disorders (e.g. uraemia) (Thrombotic disorders)
54. Haemostatic Plug Formation: An OverviewVessel constrictionFormation of an unstable platelet plug -platelet adhesion -platelet aggregationStabilisation of the plug with fibrin -blood coagulationDissolution of clot and vessel repair -fibrinolysisResponse to injuryFibrinolysis
55. Disorders of FibrinolysisDisorders of fibrinolysis can cause abnormal bleeding but are rareHereditary antiplasmin deficiencyAcquired drugs such as tPADisseminated intravascular coagulation
56. Abnormal HaemostasisWhat is abnormal bleeding?Why do people have abnormal haemostasis?Laboratory detection/prediction of abnormal haemostasisGenetics of common bleeding disordersTreatment of bleeding disorders
57. Haemophilia: a sex linked recessive disorderXYXXXXXY100%50%120%95%XY1%XXXXXY65%60%110%Unaffected femaleUnaffected maleCarrier femaleAffected male
58. Von Willebrand disease: an autosomal dominant disorderUnaffected femaleUnaffected maleAffected femaleAffected male
59. Genetics of common bleeding disordersHaemophiliaSex linked recessive (SLR)Von Willebrand diseaseAutosomalType 2, (Type 1) ADType 3 ARAll the rest (V, X etc.)Autosomal recessive (AR) And therefore much less common
60. Abnormal HaemostasisWhat is abnormal bleeding?Why do people have abnormal haemostasis?Laboratory detection/prediction of abnormal haemostasisGenetics of common bleeding disordersTreatment of bleeding disorders
61. Treatment of abnormal haemostasisFailure of production/functionReplace missing factor/plateletsProphylacticTherapeuticStop drugsImmune destructionImmunosuppression (eg prednisolone)Splenectomy for ITPIncreased consumptionTreat causeReplace as necessary
62. Factor replacement therapyPlasmaContains all coagulation factorsCryoprecipitateRich in Fibrinogen, FVIII, VWF, Factor XIIIFactor concentratesConcentrates available for all factors except factor V.Recombinant forms of FVIII and FIX are available.Principles of Treatment of HaemostaticDisorders Causing BleedingPlatelet replacement therapyPooled platelet concentrates available
63. Using factor replacement therapytime (hours)factorlevel (%)0257510050036241224489660VIIIIX
64. Additional haemostatic treatmentsDDAVPTranexamic acidFibrin glue/spray
65. Desmopressin (DDAVP)Vasopressin derivative 2-5 fold rise in VWF-VIII (VIII>vWF)Releases endogenous stores -Hence only useful in mild disorders Dose 0.3µg/kg i.v300µg i.n.Peak response30-60 mins60-90 mins
66. Mannucci 1992Repeated DDAVP doses and Factor VIII
67. Tranexamic acidInhibits fibrinolysisWidely distributed – crosses placentaLow concentration in breast milkIntravenous: 0.5g tdsOral: 1.5g tdsMouthwash: 1g (10ml 5%) qdsUseful adjunctive therapy.
68. Normal haemostasis: a state of equilibriumCoagulation factors,plateletsFibrinolytic factors,anticoagulant proteinsHaemostasis and Thrombosis: a Balance
69. BleedingFibrinolytic factors,anticoagulant proteinsCoagulation factors,platelets
70. ThrombosisFibrinolytic factors,anticoagulant proteinsCoagulation factors,platelets