Congenital bleeding disorders

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gives an overview of congenital bleeding disorders especially the more common ones - hemophilia and von willebrand disease

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  • Good Morning. I am Dr. Lesaca- Medina.
  • Who knows who this is?
    Who knows who this is? She is responsible for the most common severe congenital bleeding disorder. Queen of England in the … Queen Victoria
  • And these are her descendants who married into every royal family in Europe and spread the disease now known as Hemophilia. The Royal disease.
  • Congenital bleeding disorders

    1. 1. Congenital Bleeding Disorders Ma. Ysabel Lesaca-Medina, MD Pediatric Hematology-Oncology
    2. 2. Prince Leopold Born 1853
    3. 3. Princess beatrice, 9th child Princess louise Prince leopold, 8th child
    4. 4. Married to Princess Helene: 1882
    5. 5. Princess Alice Hemophilia carrier
    6. 6. London news: Death of the duke of albany March 27, 1884 Villa Nevada Morphine side effects
    7. 7. Prince charles Princess alice
    8. 8. Outline  What is and how does hemostasis occur?  How does one evaluate a patient presenting with bleeding?  What are the features of the Congenital Bleeding Disorders?  Hemophilia A, Hemophilia B  Von Willebrand Disease  Platelet function disorders  Rare Coagulation Factor Deficiencies
    9. 9. What is Hemostasis ?  Maintenance of fluid blood flow  Prevention of bleeding
    10. 10. Hemostasis – 3 stages 1. Vascular – vasoconstriction 1. Platelet (PRIMARY HEMOSTASIS) – Platelet plug formation 1. Coagulation (SECONDARYHEMOSTASIS) – Fibrin thrombus formation – Clotting factors
    11. 11. Intact vessel
    12. 12. Platelet Phase
    13. 13. platelet phase
    14. 14. Resting  activated platelets
    15. 15. Coagulation phase
    16. 16. Fibrin Clot
    17. 17. PTT
    18. 18. APTT
    19. 19. PT
    20. 20. TT
    21. 21. Factor XIII cross links fibrin
    22. 22. Clinical Evaluation of Bleeding patient
    23. 23. Clinical History
    24. 24. Detailed History  Symptoms:  Epistaxis gum bleeding, easy bruising, menorrhagia, hematuria, GI bleeding (platelet problem)  hemarthrosis, intramuscular bleed (coagulation problem)  Delayed onset bleeding (factor XIII problem)
    25. 25. Detailed History Response to hemostatic challenge: circumcision, surgery, phlebotomy, immunization, suture placement/removal Underlying medical conditions :  liver disease, renal failure, vitamin K deficiency Medications:  antiplatelet drugs, anticoagulants, antimetabolites, antibiotics
    26. 26. Detailed History  Family history:  similar symptoms  response to hemostatic challenge,  consanguinity  Menorrhagia  > 3 soaked pads /day  Flooding  Hb < 10g/L
    27. 27. Physical Examination
    28. 28. Physical Examination Petechiae < 2mm Purpura 2mm – 1 cm Hematoma Ecchymoses > 1 cm
    29. 29. Physical Examination HEMARTHROSIS
    30. 30. Physical Examination INTRAMUSCULAR BLEED, PSOAS
    31. 31. Laboratory evaluation
    32. 32. Laboratory Evaluation  Initial lab tests  CBC with platelet  PT (extrinsic)- VII, X, V, II, I  PTT (intrinsic)- XII, XI, IX, VIII, X, V,II, I  Further work up:  Thrombin time  PFA, platelet aggregation  Mixing Studies, clotting factor assays, VW antigen tests, urea clot lysis assay
    33. 33. DDX, based on initial screen ↑ PT Normal plt, Normal PTT ↑ PTT Normal plt, Normal PT ↑ PT,PTT Normal plt •Early Liver Disease •Early Vit K Def •F VII Def •F VIII def (hemophilia or VWD) •F IX, XI, XII def •Inhibitors •Late Liver Disease •Late Vit K deficiency •Massive Transfusion
    34. 34. ↑ PTT, TT Normal PT, Normal plt All normal Platelet dec Heparin - activates AT III  AT III inactivates thrombin - PTT more sensitive to heparin VWD Platelet fxn d/o Mild factor def (VIII, IX, XI, XIII ) Collagen Disorder Vitamin C def CAMT, TAR,BSS WAS, GPS ITP Infection CAMT = Congenital Amegakaryocytic Thrombocytopenia BSS = Bernard Soulier Syndrome TAR = Thrombocytopenia with Absent Radius GPS = Gray Platelet Syndrome WAS = Wiskott Aldrich Syndrome
    35. 35. Out Patient Clinic Time
    36. 36. 6 year/ M  Needs dental extraction; sent for hematologic clearance  History of easy bruisability  Mother and aunts report easy bruisability and strong menses  2 cousins died during delivery of unknown cause
    37. 37.  Labs  CBC Normal  PT Normal  PTT 39.3 (23 – 33 secs)
    38. 38. DDX, Normal plt, Normal PT prolonged PTT,  Dec Factor VIII due to  Hemophilia A  VWD  Dec Factor IX, XI, XII  Lupus anticoagulant or other coagulation factor inhibitors
    39. 39.  Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)  VWF : 1.2 u/ml (0.5 – 1.5 u/ml)
    40. 40. Hemophilia A, mild Diagnosis
    41. 41. HEMOPHILIA  Essentials  Factor VIII (or IX ) deficiency  X-linked (2/3) or spontaneous mutation (1/3)  Sxs: Bruising, soft tissue bleeding, hemarthrosis  Labs: Prolonged PTT + dec factor VIII (or IX) levels
    42. 42. HEMOPHILIA  Most common severe congenital bleeding disorder  Prevalence  Hemophilia A (Factor VIII)  1 / 10,000 males  Hemophilia B (Factor IX)  1 / 50,000 males
    43. 43. HEMOPHILIA – severity classification  Factor VIII – reported in units / ml ( 1 unit/ml = 100% factor activity) - Normal range: 0.5 – 1.5 IU/ml (50 – 150%) Classification - Severe (60% of cases) : < 1% factor VIII (spontaneous bleeding) - Moderate : 1 to < 5% - Mild : 5 – 50 % ( only with trauma and surgery)
    44. 44. HEMOPHILIA- Lab findings  PTT (normal plt; normal PT)  Dx is confirmed by Factor Assay  F VIII ( with normal VWF ) = Hemophilia A  Dec F IX = Hemophilia B
    45. 45. HEMOPHILIA- S/Sx  Severe Hemophiliacs  Usually initial presentation in 1st 2 years of life ( severe bruising and joint bleeds)  40 – 50% present in the 1st month of life  1- 4% present in the neonatal period (birth trauma)
    46. 46. HEMOPHILIA  Mild or Moderate  Boys  Trauma related bruising or bleeding  Excessive bleeding following surgery or dental extraction  Girls ( carriers ) ~ Often with Factor VIII < normal  Mild bruising or bleeding  Heavy menstrual periods
    47. 47. HEMOPHILIA-Cxs  Hemarthroses  If recurrent  joint destruction  Intracranial hemorrhage  Leading cause of death among hemophilliacs  Intramuscular hematomas  Compartment syndrome  muscle and nerve death ( anterior forearm, anterior tibial compartment)
    48. 48. HEMOPHILIA-Cxs • Infection • HIV, Hep B, Hep C • Not at risk, With current donor screening and viral inactivation of factor concentrates, • But still at risk for: • Hepatitis A • Creutzfeld-Jakob Disease • Parvovirus B-19 • Recommend Hep A and Hep B vaccines for all pxs
    49. 49. HEMOPHILIA-Cxs • Acquired antibody to Factor VIII • Antibody that inactivates F VIII function • Develops in • 30% of pxs with severe hemophilia • < 5% of Hemophilia B
    50. 50. Antibody to factor VIII • Quantified by Bethesda units • 1 Bethesda unit – inactivates 50% of F VIII function • TREATMENT: • < 5 B.U. • Increase dose of F VIII • > 5 BU • Bypass agents: prothrombin complex conc ; FVII • ITI (immune tolerance induction)
    51. 51. HEMOPHILIA- Tx General aim of Mx: correct factor VIII to w/in normal limits  prevent or stop bleeding Mild May respond to desmopressin (ADH) - Releases endothelial stores of VWF Most still need exogenous F VIII after
    52. 52. HEMOPHILIA-Tx • Factor VIII dose • Non-life/limb threatening bleed • 20 to 30 u/kg  40 – 60% F VIII activity • Large hemarthrosis and life/limb threatening bleed • 50 u/KG  100% F VIII activity • Cryoprecipitate • 100 u F VIII / unit • e.g. 10 kg child –> 20 u/kg = • 200 u F VIII -> 2 u cryoppt) • (FFP (contains factor IX) – used for Hemophilia B)
    53. 53. HEMOPHILIA-Tx  Prophylaxis  Preventive F VIII infusions  2 to 3x, weekly  To achieve F VIII level >1%  Expensive  Initiate after 1st joint bleed  Do not start before 6 months of age – increases risk of inhibitor devlpt
    54. 54. HEMOPHILIA TREATMENT in the pipe line GENE THERAPY
    55. 55.  NEXT PATIENT please…
    56. 56. 13 / female Cc: menometrorhagia  Easy bruising and occasional epistaxis since childhood  Gum bleeding on toothbrushing  No previous BT  Iron supplement in the past
    57. 57.  Family History  Maternal grandmother and mother with epistaxis and heavy menses  3 brothers and 2 sisters normal
    58. 58.  Hb 114  Platelet 300 (150 – 450)  PT : normal; 12.9 sec INR 1.1  PTT : normal; 32.5 (23.5 – 33.5)
    59. 59. ↑ PTT, TT Normal PT, platelet All normal Platelet dec Heparin VWD Platelet fxn d/o Mild factor def (VIII, IX, XI, XIII ) Collagen Disorder Vitamin C def CAMT, TAR,BSS WAS, GPS ITP 2 Infection
    60. 60.  VIII  0.48 u /ml (0.5 – 1.5 u/ml)  VWF Ag  0.20 u /ml (0.5 – 1.5 u/ml)
    61. 61. VonWillebrand Disease, type 1 DIAGNOSIS
    62. 62. Von Willebrand Disease  Most common inherited bleeding disorder (Prevalence: 1% - by lab def’n; only 10% symptomatic)  Quantitative or Qualitative deficiency of vWF  Easy bruising / epistaxis from childhood / menorrhagia Dr. Erik Von Willebrand, 1926
    63. 63. Diagnosis  Criteria  VWF Ag < 30%  Or VWF Ag 30-50% , in patient with clinical symptoms supportive of VWF
    64. 64. The Von Willebrand Factor  Protein in plasma  Function 1. Tethers platelets to damaged endothelium 2. Binds and protects Factor VIII Endothelial cells w/stored VWF
    65. 65. vWD
    66. 66. vWD- Classification  Type 1  Classic ; 80% of patients  Partial quantitative deficiency  Type 2  Dysfunctional VWF- qualitative  Type 3  Nearly COMPLETE deficiency
    67. 67. vWD-Inheritance  Mostly AD ; can be AR  Theoretically, equal males and females  But more females dxd (menorrhagia)  Can be acquired  rare  Hypothyroidism, Wilms tumor, Cardiac disease, Renal disease or SLE / Valproic acid  Most often caused by Ab to VWF
    68. 68. vWD- S/Sx  Increased bruising and excessive epistaxis  Prolonged bleeding with trauma or surgery  Menorrhagia  Significant menorrhagia from menarche  prompt investigation for congenital bleeding d/o
    69. 69. vWD-Labs  Initial screen: - PT normal - PTT sometimes prolonged > in type 3 (factor VIII dec) - Platelet sometimes dec > in types 2 and 3  Most of the time: PT, PTT, platelet --- NORMAL  Blood type ‘O’ – normally lower vWF
    70. 70. VWD  Bleeding time - prolonged  Platelet function analyzer – prolonged closure time  vWF assay - Definitive test
    71. 71. vWD -Treatment  VWD types 1 and 2  Desmopressin  Releases vWF from endothelial stores  IV or intranasal ( high concentration spray )  Variable response  measure VIII and vWF 60 minutes after  May cause fluid shifts (hyponatremia seizures )  Tachyphylaxis occurs (stored VWF limited)  Further therapy with VWF concentrate or cryoprecipitate
    72. 72. VWD -treatment  Intermediate purity F VIII concentrates  Cryoprecipitate
    73. 73. AdjunctiveTreatment  Antifibrinolytic agents (Tranexamic acid / E-aminocaproic acid )  Prevents plasminogen  plasmin  For mucosal bleeding  Topical thrombin and fibrin glue  Estrogen containing contraceptive tx  For menorrhagia
    74. 74. Rare Coagulation Disorders
    75. 75. Rare coagulation disorders  Other congenital coagulation factor deficiencies  Afibrinogenemia /hypofibrinogenemia  Deficiencies of factor V, VII, X, XI, XIII  Combined, occur in 1-500,000 to 1:2,000,000  Autosomal recessive  Most common : Factor VII def  Causes most bleeding sxs: Factor X and Factor XIII def
    76. 76. Rare coagulation disorders  S/Sx  Umbilical stump bleeding  Delayed cord separation  Intracranial or intestinal hemorrhage  Muscle hematomas  Easy bruising  Prolonged bleeding ff heelprick
    77. 77. Inherited platelet Disorders
    78. 78. Inherited platelet disorders  Decreased number and abn function  Bernard Soulier Syndrome (BSS)  Wiskott Aldrich Syndrome (WAS)  Gray Platelet Syndrome (GPS)  Normal number but abn function  Glanzman Thrombasthenia (GT)  Storage Pool Disorder (SPD)
    79. 79. Dec # and abn platelet fxn Defect S/Sx Labs BSS No GPIb/IX plt receptor -> defective binding to VWF ARecessive Bruising/ bleeding from infancy Moderate thrombocytopenia Large platelets GPS Alpha granule deficiency Severe bruising bleeding from early age Mild thrombocytopenia Large gray/Agranular platelets
    80. 80. GLANZMANN THROMBASTHENIA Defect S/Sx Labs Normal number Normal morph Platelet GP IIb/IIIA (fibrinogen receptor) – FAILS TO AGGREGATE ARecessive Severe spont’ mucosal bleeding Presents in infancy BT Flow cytometry Plt aggregation
    81. 81. SUMMARY
    82. 82. Summary  Hemostasis  3 stages  Vasoconstriction  Platelet phase  Coagulation phase  Congenital bleeding disorders  Hemophilia A, B  VWD  Rarer coagulation disorders  Inherited platelet disorders
    83. 83. Summary  Suspect a congenital bleeding disorder  Symptoms presenting in early infancy/childhood  Similar symptoms in family members  Consanguinity  Most common disorders  Hemophilia  VWD
    84. 84. Summary  Do coagulation screen  Deranged PTT only  Think…  Hemophilia – hemarthrosis/intramuscular bleed  VWD – bruising / petechiae, epistaxis  Platelet, PT, PTT all normal  Think…  VWD  Platelet function disorder  Mild coagulation disorders
    85. 85. Hemophilia A or B (factor VIII /IX def) VWD (VWF def or abn) Inheritance X linked De novo (1/3) AD (few AR) S/Sx Easy bruisability Hemarthrosis Soft tissue bleed Menorrhagia Easy bruisability Epistaxis Menorrhagia Labs Prolonged PTT Normal plt, PT, PTT < Prolonged PTT (few) > Confirmatory test Factor VIII /IX assay VWF assay Treatment Desmopressin (for mild Hemophilia A) Recomb Factor VIII /IX Cryoprecipitate /FFP Desmopressin Intermediate purity FVIII Cryoprecipitate

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