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pathological approach to bleeding disorders
- 1. PATHOLOGICAL APPROACH TO BLEEDING DISORDERS PRESENTOR: Dr. G. Geetha priya SRM institute of medical sciences Chennai. Dr.G.GEETHA PRIYA 1
- 5. Case scenario • 25 yrs male • C/o Excrutiating pain in knee, ankle with swelling and redness • Bleeding time- 4 mins • PT- 14 sec • APTT- 50 sec Dr.G.GEETHA PRIYA 5
- 6. Bleeding disorders Primary hemostatic disorders Platelet Vascular Secondary hemostatic disorders Deficiency/ Defective factors Factor inhibitors Excessive fibrinolysis Quantitative disorders Qualitative disorders Both qualitative and quantitative defects Dr.G.GEETHA PRIYA 6
- 7. PRIMARY HEMOSTATIC DISORDERS Dr.G.GEETHA PRIYA 7
- 8. Abnormalities in platelets Dr.G.GEETHA PRIYA 8
- 9. THROMBOCYTOPENIA DECREASED PLATELET PRODUCTION • Aplastic anemia • Megaloblastic anemia • MDS • Bone marrow failure syndromes • Marrow infiltration • Hypoplasia of megakaryocytes - Alcohol, viral infections, chemicals ABNORMAL PLATELET POOLING: Spleen disorders – congestive splenomegaly etc Dr.G.GEETHA PRIYA 9
- 10. INCREASED PLATELET DESTRUCTION/ CONSUMPTION IMMUNE MEDIATED ITP- Acute/Chronic Pregnancy Heparin induced Dengue NON-IMMUNE MECHANISMS Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Dr.G.GEETHA PRIYA 10
- 11. QUALITATIVE-PLATELET FUNCTION DISORDERS INHERITED • Bernard soulier syndrome • Glanzmann’s thrombasthenia • Von Willebrand’s disease • Gray platelet syndrome • Storage pool disease ACQUIRED • Dysprotienemia • Uremia • Drugs • Myeloproliferative disorders • MDS Dr.G.GEETHA PRIYA 11
- 12. BOTH QUALITATIVE AND QUANTITATIVE • Bernard Soulier Syndrome • Gray Platelet Syndrome • Wiscott Aldrich Syndrome Dr.G.GEETHA PRIYA 12
- 13. SECONDARY HEMOSTATIC DISORDERS Dr.G.GEETHA PRIYA 14
- 14. DEFICIENCY/ DEFECTIVE COAGULATION FACTORS INHERITED Hemophilia A( VIII Def) Hemophilia B (IX Def) Factor VII deficiency Factor XIII deficiency Hypofibrinogenemia/ dysfibrinogenemia Combined factor deficiency (factor V & VIII common) ACQUIRED Vitamin K deficiency Liver diseases DIC Oral anticoagulant therapy Massive transfusion Dr.G.GEETHA PRIYA 15
- 15. COAGULATION FACTOR INHIBITORS Inherited/ Acquired: Factor VIII inhibitors Other factors inhibitors (rare) Dr.G.GEETHA PRIYA 16
- 16. Increased fibrinolysis (RARE) • Quebec platelet disorder – Increased U-PA in alpha granules • Plasminogen Activator Inhibitor – 1 deficiency • Alpha 2 antiplasmin deficiency • Secondary causes: – Chronic liver disease – Various malignancies – DIC Dr.G.GEETHA PRIYA 17
- 17. KEY POINTS TO RECALL ABOUT VARIOUS BLEEDING DISORDERS Dr.G.GEETHA PRIYA 18
- 18. PLATLET FUNCTIONAL DISORDERS Dr.G.GEETHA PRIYA 19
- 19. Key Points To Recall Bernard Soulier syndrome: – Autosomal Recessive – Mild thrombocytopenia – GpIb defect – Giant platelets – Adhesion defect Dr.G.GEETHA PRIYA 20
- 20. Key Points Contd… Glanzmann’s thrombasthenia- – Autosomal Recessive – GpIIb/IIIa defect – Aggregation defect – Umbilical stump bleeding – Life long mucocutaneous bleeding Dr.G.GEETHA PRIYA 21
- 21. Key Points Contd… Von- Willebrand disease – Both platelet function and coagulation defect. – Types –I,II,III(Severe) – Reduced vWF and factor VIII deficiency (rapid degradation) Dr.G.GEETHA PRIYA 22
- 22. Key Points contd… • Wiscott- Aldrich Syndrome - Recurrent infections, eczema • Gray platelet syndrome- defective alpha granules • Storage pool defect- defective dense granules essential for secondary aggregation – Hermansky Pudlak syndrome –dense granule defect, Oculo cutaneous albinism – Chediak- Higashi Syndrome -Recurrent infections, albinism, photophobia, bleeding Dr.G.GEETHA PRIYA 23
- 23. GRAY PLATELET SYNDROME Dr.G.GEETHA PRIYA 24
- 24. Key Points contd… • Hemophilia A -X linked Recessive, factor VIII deficiency • Hemophilia B- X linked Recessive, factor IX deficiency • Vitamin K deficiency and liver diseases- factors II, VII, IX, X affected • DIC- consumption coagulopathy. All factors and platelets will be reduced. Dr.G.GEETHA PRIYA 25
- 25. APPROACH TO BLEEDING DISORDERS Clinical history Platelet count & Peripheral smear Bleeding time Depending on history and results so far: – Further tests for primary hemostasis – Further tests for secondary hemostasis Dr.G.GEETHA PRIYA 26
- 26. CLINICAL HISTORY • H/O to confirm a bleeding disorder: – Spontaneous bleeding – Excessive bleeding after minor trauma/ post surgery/ dental extractions – Treatment for IDA – Need for repeated blood transfusion • H/O to distinguish inherited & acquired disorders: – History of symptoms from childhood – Family history Dr.G.GEETHA PRIYA 27
- 27. Clinical History FINDINGS DISORDERS OF COAGULATION DISORDERS OF VESSEL/ PLATELET Deep dissecting hematoma/ hemarthrosis Common Rare Delayed bleeding Characteristic Rare Bleeding from superficial cuts Rare Common Mucocutaneous bleed Rare Common Menorrhagia , Epistaxis Rare Common History to distinguish primary and secondary hemostatic disorders: Dr.G.GEETHA PRIYA 28
- 28. CLINICAL HISTORY History to ascertain the cause: • Liver disease/ Renal disease • Vitamin K therapy • Prolonged antibiotic therapy • Anticoagulant therapy • Snake bite, sepsis & other causes of DIC Dr.G.GEETHA PRIYA 29
- 29. CLINICAL HISTORY • Frequent infections – Wiscott Aldrich syndrome – Chediak Higashi syndrome (albinism also) – Various causes of pancytopenia • H/o antecedent infection – Dengue, Acute ITP Dr.G.GEETHA PRIYA 30
- 30. PERIPHERAL SMEAR STUDY (FINGER PRICK SMEAR IDEAL) Dr.G.GEETHA PRIYA 31
- 31. RBC findings to be looked for 1. Fragmented RBC, microsphercytes, nRBC – DIC/TTP 2. Target cells, macrocytes- liver disease- splenomegaly 3. Macro ovalocytes, basophilic stippling- megaloblastic anemia 4. Agglutination, spherocytes- Evans syndrome 5. Tear drop cells, nRBC-myelofibrosis 6. Malarial parasite Dr.G.GEETHA PRIYA 32
- 32. WBC findings to be looked for 1. Atypical cells/ blast- lymphoma/ leukemia 2. Reactive lymphocytes- dengue/ malaria 3. Neutrophilia, toxic changes- sepsis 4. Hypersegmented neutrophils- megaloblastic anemia 5. Hypolobated/ hypo granular neutrophils, ring neutrophils, pseudo pelger huet cells- MDS 6. Severe leucopenia with lymphocyte preponderance- marrow suppression. Dr.G.GEETHA PRIYA 33
- 33. Platelet findings to be looked for 1. Platelet count 2. Giant platelets- Gray platelet syndrome, Bernard Soulier, May Hegglin Anomaly, splenectomy, recovery from dengue / sepsis, SLE, ITP 3. Small platelet- Wiscott Aldrich Syndrome 4. Reduced uptake of stain- Gray Platelet Syndrome 5. Discrete round platelets without clumps- Glanzmann’s Thrombasthenia Dr.G.GEETHA PRIYA 34
- 35. Bleeding time • Test for primary haemostasis • Normal bleeding time – 2 to 6 minutes • Prolonged in platelet and vascular disorders • Not an ideal test – technical variations • Not prolonged in all cases of primary hemostasis disorders • Being replaced by Platelet function analyser–100 in many centres Dr.G.GEETHA PRIYA 36
- 36. PLATELET FUNCTION ANALYSER (PFA- 100) • In vitro system for measuring platelet functions as well as vWF function • Whole blood is aspirated through a membrane with an aperture.(mimics injured blood vessel) • Membrane is coated with collagen and ADP/ epinephrine • Full obliteration of the aperture – closure time • Sensitive for adhesion and aggregation abnormalities • Not useful in vascular disorders. Dr.G.GEETHA PRIYA 37
- 38. Tests for platelet function disorders • Platelet aggregation assays- ADP, Ristocetin, arachidonic acid, collagen • Platelet adenine nucleotide content and release assay Dr.G.GEETHA PRIYA 39
- 39. PLATELET AGGREGATION ASSAYS • ADP aggregation - interpretation 1. Before addition of ADP 2. At the time of addition of ADP 3. Change of shape of platelet 4. Primary wave 5. Secondary wave Dr.G.GEETHA PRIYA 40
- 40. ADP- Higher concentration Dr.G.GEETHA PRIYA 41
- 41. Platelet aggregation test ADP/ Collagen/ Ristocetin Absence of 1o aggregation to ADP/ Collagen and transient response to Ristocetin Gp IIb/IIIa measurement Glanzmann’s thrombesthenia Absence of 20 aggregation response to ADP/ Collagen and normal to Ristocetin Normal aggregation with ADP/ Collagen but not with Ristocetin vWF assay Normal Measure Gp Ib Bernard Soulier Abnormal vWD Dr.G.GEETHA PRIYA 42
- 42. Absence of 20 aggregation response to ADP/ Collagen and normal to Ristocetin Aggregation response to AA Abnormal Aggregation to Endoperoxidase analogue Normal Cyclooxygenase deficiency, Aspirin Abnormal Granule content- ADP-ATP Normal - TXA2 defect/ abnormal Ca flux Abnormal -SPD Normal Granule content of ATP- ADP Normal Defect in Ca flux Abnormal SPD Dr.G.GEETHA PRIYA 43
- 43. Tests of coagulation phase • PT • APTT • Thrombin time First line • Fibrinogen assay Dr.G.GEETHA PRIYA 44
- 44. Prothrombin time Normal value- 11-16 sec Prolonged in: • Oral anticoagulants (vit K antagonist) • Liver disease • DIC • Factor deficiency / defect / inhibitors of VII, X, V, prothrombin Dr.G.GEETHA PRIYA 45
- 46. Activated Partial Thromboplastin Time Normal value- 26-40 sec Prolonged in: • Deficiency of intrinsic & common pathway factors • Liver diseases • vWD • Heparin/ anticoagulants • Non-specific circulating anticoagulant • DIC Dr.G.GEETHA PRIYA 47
- 48. Thrombin Time Normal value- 15-19 sec Prolonged in : • Hypo/ dysfibrinogenaemia • Heparin • Raised FDP • Paraproteinemia Dr.G.GEETHA PRIYA 49
- 50. APTT -PROLONGED PT- NORMAL Dr.G.GEETHA PRIYA 51
- 51. APTT- Prolonged PT- Normal Mixing studies Abnormal- inhibitors Lupus anticoagulant Negative -specific work up Positive -Lupus anticoagulant Corrected Repeat APTT after 2 hrs ProlongedNormal Factor deficiency -factor assay Late acting inhibitorDr.G.GEETHA PRIYA 52
- 52. PT- PROLONGED APTT- NORMAL Dr.G.GEETHA PRIYA 53
- 53. PT-Prolonged APTT- Normal Mixing studies Abnormal -Inhibitor Correction -Factor assay Dr.G.GEETHA PRIYA 54
- 54. PT- PROLONGED APTT - PROLONGED Dr.G.GEETHA PRIYA 55
- 55. PT/ APTT- Increased TT NORMAL Vitamin K deficiency Liver diseases Deficiency of common pathway factors Combined factor deficiences PROLONGED Fibrinogen deficiency Disfibrinogenemia DIC Fibrin polymerisation defect Dr.G.GEETHA PRIYA 56
- 56. TT - prolonged Reptilase time Prolonged Fibrinogen functional assay Reduced Normal FDP / D- dimer Increased- DIC Normal- fibrin polymerisation defect Hypo / dysfibrinogenemia Dr.G.GEETHA PRIYA 57
- 57. PT- NORMAL APTT- NORMAL Dr.G.GEETHA PRIYA 59
- 58. PT- Normal APTT- Normal Factor XIII deficiency Excess fibrinolysis Mild von Willebrand disease Disorders of platelet function Vascular disorders Normal haemostasis Dr.G.GEETHA PRIYA 60
- 59. Factor XIII deficiency PT- Normal APTT- Normal Clot solubility test Clot not dissolved Clot dissolved Factor XIII deficiency Other causes Dr.G.GEETHA PRIYA 61
- 60. Case scenario • 25 yrs male • C/o Excrutiating pain in knee, ankle with swelling and redness • Bleeding time- 4 mins • PT- 14 sec • APTT- 50 sec • Thrombin time- 15 sec Dr.G.GEETHA PRIYA 62
- 61. • Mixing studies- APTT corrected Dr.G.GEETHA PRIYA 63
- 62. • Factor assay – Factor VIII deficient Dr.G.GEETHA PRIYA 64
- 63. • Assess vWF, Ristocetin aggregation Dr.G.GEETHA PRIYA 65
- 68. PT- Increased APTT- Normal Bleeding Severe factor VII deficiency No bleeding Mild factor VII deficiency Oral anticoagulant therapy Dr.G.GEETHA PRIYA 70
- 69. PT- Increased APTT- Increased Bleeding / no bleeding DIC Liver diseases Lupus anticoagulant Dr.G.GEETHA PRIYA 71
- 70. Bleeding PT- Normal APTT- normal BT- Normal Factor XIII deficiency Dysfibrinogenemia BT- Increased Platelet disorders Dr.G.GEETHA PRIYA 72
- 71. APTT- Increased PT- Normal Bleeding Injury related Factor XI deficiency Mild hemophilia A/B Vit k deficiency Warfarin theraphy unprovoked Minor - vWD Major Severe hemophilia A/B Severe type 3 vWD Acquired vWD Factor VIII deficiency No bleeding Deficiency of factor XII, HMWK,PK Lupus anticoagulant Presence of heparin Dr.G.GEETHA PRIYA 73
- 72. Classification of hemostatic disorders- ACQUIRED THROMBOCYTOPENIA: Hypersplenism, drug induced, hypoplastic marrow, DIC, TTP/HUS, autoimmune and alloimmune VITAMIN K DEFICIENCY: Malabsorption syndrome, hemorrhagic disease of new born, malnutrition. ACQUIRED ANTIBODIES AGAINST COAGULATION FACTORS: Against factor V , VIII, XIII, APLA syndrome HEMTOLOGICAL DISORDERS: Acute leukemia, myelodysplasia , monoclonal gammopathies, essential thrombocythemia DIC: Sepsis, malignancies, pregnancy DRUGS: Antiplatelet agents, anticoagulants, antithrombins, thrombolytics, hepatotoxic, nephrotoxic drugs VASCULAR: Non palpable purpura, Vit C deficiency, palpable purpura LIVER DISEASE / RENAL DISEASEDr.G.GEETHA PRIYA 74
- 73. INHERITED DEFICIENCY OF COAGULATION FACTORS: Hemophilia A, Hemophilia B, Von Willibrand disease, factor II, V, VII, X, XI, XIII deficiency PLATELET DISORDERS: Glanzmann thrombasthenia, Bernard- Soulier syndrome, platelet granule disorders FIBRINOLYTIC DISORDERS: PAI-1 deficiency, alpha 2 antiplasmin deficiency VASCULAR: Hemorrhagic telangietasiaa CONNECTIVE TISSUE DISORDERS :Ehlers Danlos syndrome Dr.G.GEETHA PRIYA 75
- 74. Disorders of platelet/ VWD Disorders of coagulation Epistaxis Gingival hemorrhage Oral mucosal membrane Bleeding to razor nicks Menorrhagia Tooth extraction Early bleed Superficial cuts Deep seated bleed Hematemesis Hemoptysis Hematuria Post partum hemorrhage Habitual abortions- factor XIII deficiency, APLA Hemarthrosis Delayed bleed Dr.G.GEETHA PRIYA 76
- 75. Low platelet count CBC, PS No abnormality of other blood cells ITP, drugs, infections, dengue Abnormality of other blood cells Hemolysis , schistocytes TTP/HUS DIC Coagulation profile NORMAL HUS/TTP ABNORMAL DIC Abnormal leucocytes Leukemia, myelodysplasia Bone marrow examination pancytopenia Aplastic anemia, megaloblastic anemia, hyperspleenism Bone marrow examination Dr.G.GEETHA PRIYA 77
- 76. Normal platelets VFW analysis Abnormal-vWD Normal Platelet aggregation Abnormal primary wave to Ristocetin Enhanced T2B vWD/ Platelet type vWD Decreased- Bernard soulier ADP/Collagen/ TXA2 Glanzmann thrombesthenia Abnormal secondary wave Electron microscopy Dense bodies Alpha granules Alpha granules and dense bodies Dr.G.GEETHA PRIYA 78
- 77. DISORDERS OF COAGULATION INHERITED • Hemophilia A • Hemophilia B • Von Willebrand disease • Factor V deficiency • Hypofibrinogenemia/ Afibrinogenemia ACQUIRED • DIC • Haemorrhagic disease in new born • Liver diseases Dr.G.GEETHA PRIYA 79
- 78. Low platelet count Peripheral smear (finger prick) Associated RBC features Associated WBC features Associated platelet features Dr.G.GEETHA PRIYA 80