BLEEDING_DISORDERS

Hemostasis: BV Injury Tissue Factor Neural Blood Vessel Constriction Platelet Aggregation Primary hemostatic plug Coagulation Cascade Reduced Blood flow Platelet Activation Fibrin formation Stable Hemostatic Plug Haemostasis 11/16/2008 Thrombocytopenia 4 Coagulation cascade Intrinsic system (surface contact) XII XI XIIa Extrinsic system (tissue damage) Tissue factor XIa IX IXa VIII X VIIa VII VIIIa Xa Vitamin K dependant factors V II Va IIa (Thrombin) Fibrin Fibrinogen Coagulation Cascade: Intrinsic Path (XII,XI,IX,VIII) (aPTT) (Factor X) Common Path (V,II) (Thrombin) Extrinsic Path (VII) (PT) (TT) Fibrinogen  Fibrin (Fibrin & FDP) Platelets: • • • • • Contractile, adhesive, cell fragments. Bone marrow –Megakaryocytes Store coagulation factors & enzymes Surface Binding sites for fibrinogen Surface Glycoprotein Antigens. 7 Disorders of Hemostasis • Vascular disorders – Scurvy, easy bruising • Platelet disorders – Low number or abnormal function • Coagulation disorders – Factor deficiency. • Mixed/Consumption: DIC 8 Bleeding: Clinical Features 1. 2. 3. 4. • • Local - Vs - General, spontaneous . Hematoma & Joint bleed - Coagulation Skin/Mucosal Petechiae & Purpura – PLT wound / surgical bleeding – Immediate - (PLT) Delayed - (Coagulation) 9 Platelet Petechiae, Ecchymoses Coagulation Joint bl. 10 Petechiae & Echymoses -Platelet count 11 Sub Conjuctival Haemorrhage 12 Clinical Features of Bleeding Disorders Platelet Site of bleeding Skin Mucous membranes (epistaxis, gum, vaginal, GI tract) Coagulation Deep in soft tissue (joints,muscles) Petechiae Ecchymoses (“bruises”) Hemarthrosis / muscle bleeding Bleeding after cuts & scratches Bleeding after surgery or trauma Yes Small, superficial Extremely rare Yes Immediate, usually mild No Large, deep Common No Delayed (1-2days), often severe 13 BLEEDING DISORDERS 11/16/2008 Thrombocytopenia 14 Investigations • Platelet count • Bleeding time 2-9 minutes is time taken by a standard skin puncture to stop bleeding prolonged – defect in platelet number or function 15 Coagulation cascade Intrinsic system (surface contact) XII XI XIIa Extrinsic system (tissue damage) Tissue factor XIa IX IXa VIII X VIIa VII VIIIa Xa Vitamin K dependant factors V II Va IIa (Thrombin) Fibrin 16 Fibrinogen • Prothrombin time 11-15sec Prolonged – deficiency of factor VII, X, V, Prothrombin, Fibrinogen (Extrinsic and common pathway) • Activated Partial thromboplastin time 32-46sec Prolonged- of factor V, VIII, IX, X, XI, XII, Prothrombin, Fibrinogen (Intrinsic and common pathway) • Factor assays 17 Special Investigations: • Specific Factor Assays • Platelet function studies • Bone marrow examination – plt – Aggregometry – Adhesion studies 18 Vessel wall abnormalities • • • • • • Petechiae,purpura BT,PT,APTT-Normal Infections Drugs Scurvy , Ehlers-Danlos , Cushing Henoch-Schonlein purpura 19 Thrombocytopenia • Platelet count below the lower limit of the reference range( 100 x 10 9/ l ) • Symptomatic < 50 x 10 9 / l • < 30 x 10 9 / l menorrhagia, petechiae, spontaneous bruising • < 10 x 10 9 / l severe spontaneous bleeding including CNS 11/16/2008 Thrombocytopenia 20 Classification of thrombocytopenia 1.Decreased production Generalised disease of bone marrow Aplastic anemia, marrow infiltration, Disseminated Carcinoma Selective impairment of platelet production Drugs, Infections Megaloblastic anemia 11/16/2008 Thrombocytopenia 21 2.Increased destruction • Immune thrombocytopenia Autoimmune disorders platelet destruction due to antiplatelet antibodies • Idiopathic or primary • Secondary SLE, Viral Drug-Quinidine,Heparin,Sulfa • Non immune 11/16/2008 Thrombocytopenia 22 Idiopathic thrombocytopenic purpura Acute Chronic 11/16/2008 Thrombocytopenia 23 Molecular Mimicry: VZV Platelet 11/16/2008 Thrombocytopenia 24 MHCII Macrophage (APC) 11/16/2008 Thrombocytopenia 25 1. Phagocytosis MHCII Macrophage (APC) 11/16/2008 Thrombocytopenia 26 2. 1. Phagocytosis Destruction MHCII Macrophage (APC) 11/16/2008 Thrombocytopenia 27 Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis MHCII Macrophage (APC) 11/16/2008 Thrombocytopenia 28 Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis Altered processing MHCII Macrophage (APC) 11/16/2008 Thrombocytopenia 29 Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis Altered processing Peptides MHCII 3. Macrophage (APC) 11/16/2008 Thrombocytopenia 30 Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis Altered processing Peptides MHCII 3. Macrophage (APC) 11/16/2008 Thrombocytopenia 4. Abnormal Presentation 31 Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis Altered processing CD4+ T cell Activation MHCII TcR Peptides 3. Macrophage (APC) 11/16/2008 Thrombocytopenia 4. Abnormal Presentation of a platelet autoantigen 32 Acute ITP • Most often in children 2 – 6 yrs • Most often 1 – 3 wks after viral infection eg; chicken pox, rubella, CMV, viral hepatitis • Platelet count < 20 x 10 9 / l • Abrupt onset of bleeding • Self limited • Therapy- none steroids ( severe thrombocytopenia) 11/16/2008 Thrombocytopenia 33 Chronic ITP • • • • • • Adults 20 – 40 yrs F: M = 3 : 1 Onset insidious Antecedent infection unusual Platelet count 30-80 x 10 9 / l .BT-prolonged Therapy- Steroids Splenectomy Spontaneous remission uncommon 11/16/2008 Thrombocytopenia 34 Clinical features • Bleeding into skin,mucous membrane bleeding into CNS rare • Easy bruising • Splenomegaly & lymphadenopathy rare 11/16/2008 Thrombocytopenia 35 Lab findings • Platelet count -low • Bone marrow Megakaryocytes- increased immature forms+ • BT Prolonged • PT & PTT normal Thrombotic microangiopathies TTP • Fever,thrombocytopenia Microangiopathic hemolytic Anemia,neurologic deficits, renal failure • Hyaline thrombi • PT,APTT-Normal • Platelet transfusion is contraindicated • vWF metalloprotease absent 11/16/2008 HUS • Microangiopathic HA, Thrombocytopenia • Renal failure • GI bleed • E.coli Thrombocytopenia 37 Defective platelet function • Bernard-soullier syndrome – gp Ib-IX • Glanzmann’s thrombasthenia- IIbIIIa 11/16/2008 Thrombocytopenia 38 COAGULATION DISORDERS • Acquired Vitamin K deficiency –factors II,VII,IX,X -Liver disease DIC • Hereditary Deficiency of Factor VIII (Haemophilia A) Deficiency of Factor IX (Christmas Disease/Haemophilia B) 11/16/2008 Thrombocytopenia 39 Haemophilia • Congenital deficiency -Factor VIII(A) or IX(B) • Bleeding – Haematoma, joint. • Gene on X chromosome. – (Carrier females, Males suffer) • Prolonged PTT but normal PT. • FFP or Factor replacement – Life long. 11/16/2008 Thrombocytopenia 40 11/16/2008 Thrombocytopenia 41 Hemophilia A • Reduction in the amount or activity of factor VIII • X linked recessive disorder • Males, homozygous females Pathogenesis Factor VIII gene on long arm of X Deletion / point mutation Decreased VIII levels 11/16/2008 Thrombocytopenia 42 • Clinical severity is related to the concentration of deficient factor • Severe < 1 % of normal Moderate- 2-5% of normal Mild 6-50% of normal In severe cases symptoms commences by 2 yrs of age mild cases-adolescences 11/16/2008 Thrombocytopenia 43 11/16/2008 Thrombocytopenia 44 Clinical features • • • • • Hemarthrosis - commonly knee joint, muscle atrophy pain + destruction of joint & deformities easy bruising & massive haemorrhage after trauma Petechiae absent 11/16/2008 Thrombocytopenia 45 Investigations • Bleeding time, platelet count, P T – normal • Prolonged PTT • Definitive diagnosisSpecific factor assay 11/16/2008 Thrombocytopenia 46 Treatment • Fresh blood, fresh plasma • Recombinant Factor VIII concentrate 11/16/2008 Thrombocytopenia 47 Hemophilia B • Factor IX deficiency • Less common X linked recessive Clinically indistinguishable from Hemophilia A Diagnosis by factor assay 11/16/2008 Thrombocytopenia 48 Von Willebrands Disease • Deficiency of Von Willebrand factor (vWF) • Factor VIII is complexed with large multimers of vWF in circulation,and maintains its stability • Activity can be assayed by RISTOCETIN AGGLUTINATION TEST • Autosomal dominant • Autosomal recessive Rare 11/16/2008 Thrombocytopenia 49 Clinical features • common inherited bleeding disorder • Spontaneous bleeding from mucous membrane, excessive bleeding from wounds, menorrhagia • BT-prolonged, platelet count-normal • vWF levels by Ristocetin activity-reduced • Secondary FVIII decrease- increased aPTT 11/16/2008 Thrombocytopenia 50 Nail bed - Hematoma •Red •Blue/Grey •Brown 11/16/2008 Thrombocytopenia 51 Contusion - Hematoma 11/16/2008 Thrombocytopenia 52 Bleeding-Coagulation disorder •Deep bleeding •Haematoma •Joint bleeds •Joint deformity 11/16/2008 Thrombocytopenia 54 Disseminated Intravascular Coagulation Activation of both coagulation and fibrinolysis Triggered by • Sepsis • Trauma – Head injury – Fat embolism • Obstetrical complications – Amniotic fluid embolism – Abruptio placentae • Malignancy • vascular disorders • Reaction to toxin (e.g. snake venom, drugs) • Immunologic disorders – Severe allergic reaction – Transplant rejection 11/16/2008 Thrombocytopenia 55 Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Intravascular deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels with organ failure 11/16/2008 Bleeding Thrombocytopenia 56 • three natural anticoagulants: antithrombin (AT), protein C (PC), and protein S (PS). 11/16/2008 Thrombocytopenia 57 Pathogenesis of DIC Release of thromboplastic material into circulation Coagulation Fibrinogen Thrombin Fibrinolysis Plasmin Consumption of coagulation factors; presence of FDPs  aPTT  PT  TT  Fibrinogen Presence of plasmin FDP,D dimer, Fibrinopeptides,monomer Intravascular clot  Platelets Schistocytes 58 Fibrin Monomers Fibrin(ogen) Degradation Products 11/16/2008 Fibrin Clot (intravascular) Plasmin Thrombocytopenia Initial Evaluation of a Bleeding Patient 1 Normal PT Abnormal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare) 11/16/2008 Thrombocytopenia 59 Initial Evaluation of a Bleeding Patient 2 Abnormal PT Normal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare) 50:50 mix is normal Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, 11/16/2008 DIC) Thrombocytopenia 60 Initial Evaluation of a Bleeding Patient 3 Abnormal PT Abnormal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) 11/16/2008 Thrombocytopenia Liver disease, vitamin K deficiency, warfarin, DIC 61 Initial Evaluation of a Bleeding Patient 4 Normal PT Normal PTT Urea solubility Abnormal Factor XIII deficiency Normal Consider evaluating for: Abnormal fibrinolysis (a2 anti-plasmin def) 11/16/2008 Elevated FDPs Platelet disorder Vascular disorder Thrombocytopenia 62 Summary: • Haemostasis – Blood vessels+ Platelets + Coagulation • Traumatic & Spontaneous bleeding. • Disorders are Congenital or Acquired • Screening tests: BT, CT, PT, PTT, Platelet count. • Platelet disorders–Skin/Mucosa Coagulation disorders- Deep bleeds, joint. 11/16/2008 Thrombocytopenia 63