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Hemophilia itp lymphoma

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Hemophilia, itp, lymphoma

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Hemophilia itp lymphoma

  1. 1. DR SHIV DUBEY AIIMS Bhopal 11/19/17 1
  2. 2.  A 11 months/F child came to emergency with severe right knee joint pain and swelling. There is h/o easy bruising and blue spots over body. She has just started to stand with support and fell.  History ??  D/D  Investigations11/19/17 2
  3. 3. Differential Diagnosis  Clinically impossible to differentiate from Hemophilia B- FIX def- Christmas’ disease  Type 2N vWD, transmitted as an autosomal recessive trait, is characterized by mutations in VWF within the factor VIII binding domain. Affected patients present with low levels of factor VIII (usually 5 to 15 percent of normal), because of unimpeded proteolytic cleavage of factor VIII, along with a clinical pattern of bleeding similar to that seen in hemophilia A, rather than that associated with classical vWD Should be suspected in families in which an autosomal recessive (rather than X-linked) inheritance pattern is seen. 11/19/17 3
  4. 4. 11/19/17 4
  5. 5. Definition  Hemophilia- “love of bleeding”  Hemophilia A: X linked recessive hereditary disorder that is due to defective or deficient factor VIII 11/19/17 5
  6. 6. Incidence  It is the second most common inherited clotting factor abnormality (after von Willebrand disease)  1 in 5000-10000 live male births  No difference between racial groups 11/19/17 6
  7. 7. Pathophysiology  Sequential activation of a series of proenzymes or inactive precursor proteins (zymogens) to active enzymes, resulting in significant stepwise response amplification.  Two pathways: intrinsic and extrinsic measured by two lab tests 11/19/17 7
  8. 8. Pathophysiology  F VIII is a cofactor for intrinsic Xa  FvW is its carrier  Activated by Xa and thrombin  Inactivated by activated protein C in conjunction with protein S 11/19/17 8
  9. 9. Genetics  Transmitted by females, suffered by males  The female carrier transmits the disorder to half their sons and the carrier state to half her dtrs  The affected male does not transmit the disease to his sons (Y is nl) but all his dtrs are all carriers (transmission of defected X) 11/19/17 9
  10. 10. Genetics  Hemophilia in females  If a carrier female mates with an affected male there’s the possibility that half their daughters are homozygous for the disease  Other possibility: Turner syndrome (45,X0) with a defective X 11/19/17 10
  11. 11. Clinical manifestations  Frequency and severity of bleeding are related to F VIII levels Severity F VIII activity Clinical manifestations Severe <1% Spontaneous hemorrhage from early infancy Freq sp hemarthrosis Moderate 2-5% Hemorrhage sec to trauma or surgery Occ sp hemarthrosis Mild >5% Hemorrhage sec to trauma or surgery Rare sp bleeding  Coinheritance of prothrombotic mutations (i.e. Factor V Leiden) can decrease the risk of bleeding 11/19/17 11
  12. 12. Clinical Manifestations: Hemarthrosis  The most common, painful and most physically, economically and psychologically debilitating manifestation.  Clinically:  Aura: tingling warm sensation  Excruciating pain  Generally affects one joint at the time  Most commonly: knee; but there are others as elbows, wrists and ankles.  Edema, erythema, warmth and LOM  If treated early it can subside in 6 to 8 hs and disappear in 12 to 24 hs. 11/19/17 12
  13. 13. Clinical Manifestations: Hemarthrosis  Pathophysiology:  Bleeding probably starts from synovial vessels into the synovial space.  Reabsorption of this blood is often incomplete leading to chronic proliferative synovitis, where the synovium is more thickened and vascular, creating a “target joint” with recurrence of bleeding.  There is destruction of surrounding structures as well-bone necrosis and cyst formations, osteophytes  Terminal stage: Chronic Hemophiliac arthropathy: fibrous or bony ankilosing of the joint. 11/19/17 13
  14. 14. Clinical Manifestations Hematomas  Subcutaneous bleeding spreads in characteristic manner- in the site of origin the tissue is indurated purplish black and when it extends the origin starts to fade  Muscle hematomas: 1)calf,2)thigh,3)buttocks,4)fo rearms  Psoas hematoma- if right sided may mimic acute appendicitis 11/19/17 14
  15. 15. Clinical manifestations Intracranial hemorrhage  Leading cause of death of hemophiliacs  Spontaneous or following trauma  Suspect always in hemophilic patient that presents with unusual headache 11/19/17 15
  16. 16. Clinical manifestations Others  Gastrointestinal Bleeding:  Mucous Bleeding: Epistaxis, gum bleeding.  Genitourinary Bleeding: Frequently severe hemophiliac can experience hematuria and a structural lesion should be ruled out. 11/19/17 16
  17. 17. Laboratory diagnosis Deficit can be quantitative or qualitative General Lab: prolonged aPTT, nl PT and BT Mixing studies: aPTT corrects with normal plasma –if there are no factor VIII antibodies present Clotting assays: F VIII activity, expressed in % of normal DecreasedQUANTITATIVE Immunoassays: “Cross Reactive Material” Positive- there is an antigen similar to the F VIII protein- QUALITATIVE 11/19/17 17
  18. 18. Carrier detection and Antenatal diagnosis  Family history: if we follow the inheritance pattern a female is a carrier if she:  Has an hemophilic father  Has two hemophilic sons  Has one hemophilic son and has a family history  Has a son but no family history, there is a 67% chance that she is. 11/19/17 18
  19. 19. Carrier detection and Antenatal diagnosis For prenatal diagnosis: DNA testing on choronic villi samples obtained by biopsy at week 12 11/19/17 19
  20. 20. Treatment General Considerations  Avoidance of aspirin and NSAIDs if at all possible sometimes it is difficult because of the painful hemarthrosis  No IM injections  Counseling for patient and family, both genetic and psychosocial, encouraging normal socialization 11/19/17 20
  21. 21. Treatment Factor replacement Replacement of F VIII is the cardinal step to prevent or reverse acute bleeding episodes  Dosing: Replacement products can be given on the basis of body weight or plasma volume ( aprox 5% of body weight)  1 U/ml = 100% factor activity  Practically 1 unit of F VIII/kg increases F VIII about 0.02 U/ml  In a severe hemophiliac, to raise F VIII to 100% activity or 1 U/ml, we need 50 U/kg  Redosing is based on half life: 8-12 hs  Monitoring of Factor activity is crucial during therapy 11/19/17 21
  22. 22. Treatment Factor replacement  Choice of treatment: is based on  Purity of the factor (how concentrated or “purified” the factor is)  Safety  Cost  Nowadays most used therapies are believed to be effective and relatively safe 11/19/17 22
  23. 23. Treatment Factor replacement Sources of F VIII  Plasma • FFP was used as the only replacement therapy until 1960s. • Not really much effective since it could only raise f VIII to 20%, by giving the patient many liters • Usually patients experienced severe volume overload (luckily furosemide was introduced around this time) • Patients used to have to spend most of their time in the hospital 11/19/17 23
  24. 24. Treatment Factor replacement  Cryoprecipitate • By mid 1960s Pool et al demonstrated that cold insoluble material obtained from plasma contained high levels of F VIII and fibrinogen, achieving a major advance in hemophilia treatment • 1 unit of FFP prepared by cryoprecipitate contains 50-120 U of VIII  Plasma Derived f VIII prepared by monoclonal antibodies. 11/19/17 24
  25. 25. Treatment Factor replacement  Before 1985 all plasma derived products were highly contaminated by blood borne virus such as HIV, HBV and HCV which is now incredibly reduced by the introduction of donor screening and viral inactivation techniques such as pasteurization, solvent detergent treatment and ultrafiltration.  However, there is still some theoretical concern about non lipid coated parvovirus, HAV and prion disease such as Creutzfeld- Jakob 11/19/17 25
  26. 26. Treatment Factor replacement  Recombinant F VIII • First generation: derived from hamster cell culture. Contains human albumin for stabilization (possible source of viral contamination) • Second Generation: Mutated F VIII, lacking B domain (no role in clotting) that can be stabilized by sucrose “albumin free” 11/19/17 26
  27. 27. Treatment Factor replacement  Target level and duration of treatment: depend of severity and site of bleeding Site of hemorrhage Desired F VIII level Duration of treatment (days) Hemarthrosis 30-50 1-2 Superficial intramuscular hematoma 30-50 1-2 GI tract 50 7-10 Epistaxis 30-50 Until resolved Oral Mucosa 30-50 Until resolved Hematuria 30-100 Until resolved CNS 50-100 At least 7-10 days Retropharyngeal 50-100 At least 7-10 days Retroperitoneal 50-100 At least 7-10 days 11/19/17 27
  28. 28. Treatment Others  Fibrin Glue  Contains fibrinogen, thrombin and factor XIII  It’s placed in the site of injury and stabilizes clot  Used in dental procedures and after circumcision  Antifibrinolyitic Agents  Epsilon aminocaproic acid  Inhibit fibrinolysis by inhibiting plasminogen activator  Adjuvant therapy for dental procedures  Contraindicated in hematuria  Desmopressin  Transient increase in F VIII levels in pts with mild hemophilia(2-4 times above baseline)  Mechanism: release from endothelial storage sites  Has spared many hemophiliacs of blood borne products in the 1970s  Repeated administration results in a diminished response- tachyphylaxis  Side effects: hyponatremia, facial flushing and headache 11/19/17 28
  29. 29. Treatment Gene Therapy  Hemophilia is an ideal disease to target for gene therapy since it is caused by mutations in a single identified gene.  A slight increase in factor activity can make a severe hemophilic in mild.  Tight regulation of gene expression is not essential.  Many animal models trials have been studied, being the main problems encountered: immunogenicity and short gene expression.  To date 3 hemophilia A trials in human (aprox 20 patients): transient increase of factor VIII activity and good safety profile.  Main issue remains: finding of a gene delivery system which is nonimmunogenic so as to allow for long term expression.11/19/17 29
  30. 30. Course and prognosis  Replacement therapy has its complications and includes:  Development of F VIII antibodies  Liver disease resulting from hepatitis B and C  Infection with HIV 11/19/17 30
  31. 31. So… WHY IS IT CALLED THE ROYAL DISEASE?!!? 11/19/17 31
  32. 32. History Why the Royal disease?  This is because Queen Victoria, Queen of England from 1837 to 1901, was a carrier.  Most likely a spontaneous mutation since the duke of Kent (her father) was not affected and her mother did not have any affected children from the previous marriage.  Her eighth child, Leopold, had hemophilia and suffered from frequent hemorrhages. These were reported in the British Medical Journal in 1868.  Leopold died of a brain hemorrhage at the age of 31, but not before he had children. His daughter, Alice, was a carrier and her son, Viscount Trematon, also died of a brain hemorrhage in 1928.  The British family descends from Victoria’s first child Edward who was not affected. Hence this house is disease free. 11/19/17 32
  33. 33. History Why the Royal disease?  Beatrice, Victoria’s youngest child had two hemophilic sons and a daughter- Victoria Eugene that was a carrier  She introduced the hemophilia gene into the Spanish royal family by marrying king Alfonso XIII.  By this time, Queen Victoria’s blood was recognized as “defective” and the king may have been warned about Eugene’s carrier state. However, Royalty was more important than X chromosomes. 11/19/17 33
  34. 34. History Queen Victoria’s pedigree Spanish House Russian House British House 11/19/17 34
  35. 35. Case 11/19/17 35
  36. 36.  A 3 year/F came in OPD with red spots/rash over lower limbs since morning. She is perfectly fine, no H/O Fever. There is H/O URI some 3 weeks back. Next ??  Examination – Normal  Investigations – PC-20k  TLC/Hb-N 11/19/17 36
  37. 37. Idiopathic (Autoimmune) Thrombocytopenic Purpura(ITP)  The most common cause of acute onset of thrombocytopenia in an otherwise well child  A recent history of viral illness is described in 50-65% of cases of childhood ITP 11/19/17 37
  38. 38. ITP (cont.)  1 - 4 wk after exposure to a common viral infection  The peak age is 1-4 yr.  ITP seems to occur more often in late winter and spring after the peak season of viral respiratory illness. 11/19/17 38
  39. 39. ITP (Pathophysiology)  An autoantibody directed against the platelet surface develops with resultant sudden onset of thrombocytopenia  After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on splenic macrophages, ingested, and destroyed 11/19/17 39
  40. 40. ITP (Pathophysiology)(cont.) 11/19/17 40
  41. 41. ITP (Pathophysiology)(cont.)  Most common viruses have been described in association with ITP, including Epstein-Barr virus  In some patients ITP appears to arise in children infected with Helicobacter pylori or rarely following the measles, mumps, rubella vaccine 11/19/17 41
  42. 42. Clinical Manifestations (Cont.)  The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of generalized petechiae and purpura  Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 × 109/L). 11/19/17 42
  43. 43. Clinical Manifestations (cont.) 11/19/17 43
  44. 44. Clinical Manifestations (cont.) 11/19/17 44
  45. 45. Clinical Manifestations (Cont .)  The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, or remarkable lymphadenopathy suggests other diagnoses 11/19/17 45
  46. 46. Prognosis  Severe bleeding is rare (<3% of cases)  In 70-80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo  Fewer than 1% of patients develop an intracranial hemorrhage.  Approximately 20% of children who present with acute ITP go on to have chronic ITP 11/19/17 46
  47. 47. Prognosis(cont.)  The outcome/prognosis may be related more to age, as:  ITP in younger children is more likely to resolve  The development of chronic ITP in adolescents approaches 50%. 11/19/17 47
  48. 48. Laboratory Findings  Severe thrombocytopenia (platelet count <20 × 109/L) is common, and platelet size is normal or increased, reflective of increased platelet turnover  In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should be normal. 11/19/17 48
  49. 49. Laboratory Findings(cont.)  Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes 11/19/17 49
  50. 50. Diagnosis/ Differential Diagnosis  Autoimmune thrombocytopenia may be an initial manifestation of : 1. SLE 2. HIV infection 3. Common variable immunodeficiency 4. Lymphoma(rarely) 11/19/17 50
  51. 51. Treatment  Platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present (Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets) 11/19/17 51
  52. 52. Treatment (cont.)  Initial approaches to the management of ITP include the following: 1. No therapy other than education and counseling of the family and patient for patients with minimal, mild, and moderate symptoms, as defined earlier.  This approach is:  Far less costly  Side effects are minimal 11/19/17 52
  53. 53. Treatment(cont.) 2.Intravenous immunoglobulin (IVIG).  IVIG at a dose of 0.8- 1.0 g/kg/day for 1-2 days induces a rapid rise in platelet count (usually >20 × 109/L) in 95% of patients within 48 hr.  IVIG appears to induce a response by downregulating Fc-mediated phagocytosis of antibody-coated platelets. 11/19/17 53
  54. 54. Treatment(cont.) 2.Intravenous immunoglobulin (IVIG).(cont.) IVIG therapy is :  Expensive  Time-consuming to administer  After infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis. 11/19/17 54
  55. 55. Treatment(cont.) 3.Intravenous anti-D therapy. For Rh positive patients: IV anti-D at a dose of 50-75 μg/kg causes a rise in platelet count to >20 × 109 /L in 80-90% of patients within48-72 hr. 11/19/17 55
  56. 56. Treatment(cont.) 4. Prednisone.  Doses of prednisone of 1-4 mg/kg/24 hr Corticosteroid therapy is usually continued for 2-3 wk or until a rise in platelet count to >20 × 109/L has been achieved, with a rapid taper long-term side effects of corticosteroid therapy: 1. Growth failure 2. Diabetes mellitus 3. Osteoporosis 11/19/17 56
  57. 57. Treatment(Cont.)  The role of splenectomy in ITP should be reserved for 1 of 2 circumstances. 1. The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) 2. Whose symptoms are not easily controlled with therapy 3. Life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP 4. Platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids 11/19/17 57
  58. 58. All Options  Steroids  IVIg / anti-D  Rituximab (anti-CD20)  Cyclophosphamide  Danazol  Accessory splenectomy  H. pylori eradication 11/19/17 58
  59. 59. Hematopoietic Malignancies Lymphoma is a general term used for proliferations that arise as discrete tissue masses. Leukemia is used for neoplasms that present with widespread involvement of the bone marrow and the peripheral blood(usually). 59
  60. 60. What is Lymphoma Malignant lymphoma is a term given to tumors of the lymphoid system and specifically of lymphocytes and their precursor cells i.e. Cancer of the lymphatic system.  Many lymphomas are known to be due to specific genetic mutations. 60
  61. 61. 61
  62. 62.  Associated with EBV infection mainly with mixed cellularity type.  High socio economic status.  Prolonged use of of human growth hormone. 11/19/17 62
  63. 63.  Most common presentation is asymptomatic lymph node enlargement, typically in the neck.  Cervical lymphnodes are involved in 80% cases.  Mediastinal involvement is seen in about 50% cases. They produce symptoms like chest pain, cough and dyspnoea.  Other less common symptoms are : Pruritis, alcohol induced pain over involved lymphnodes, nephrotic syndrome, erythema nodosum, cerebellar degeneration, immune hemolytic anaemia, thrombocytopenia, hypercalcemia. 11/19/17 63
  64. 64. 2008 WHO Classification of Hodgkin Lymphoma 64
  65. 65. Reed-Sternberg cell 65
  66. 66. Ann Arbor Staging System  Stage I: Single lymph node region (I) or single extralymphatic organ or site (IE)  Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE)  Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE)  Stage IV: multiple/disseminated foci involved with > 1 extralymphatic organs (i.e. bone marrow)  or (B) designates absence/presence of “B” symptoms *(E) Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow 66
  67. 67. Stage I Stage II Stage III Stage IV Staging of lymphoma A: absence of B symptoms B: fever, night sweats, weight loss 67
  68. 68. 68
  70. 70. THANK YOU! 11/19/17 70