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HAEMOPHILIA

HAEMOPHILIA. Presenter: Dr Suzanna Mwanza Moderator: Dr Sambo. HISTORY. DM, male, 19 years old Diagnosed with Haemophilia type A in 1994 at the age of 2 years File records date from Feb 2008 when pt was 16 yrs old. 2008. 2009. 2010. 2011. HAEMOPHILIA A.

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HAEMOPHILIA

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  1. HAEMOPHILIA Presenter: Dr Suzanna Mwanza Moderator: Dr Sambo

  2. HISTORY • DM, male, 19 years old • Diagnosed with Haemophilia type A in 1994 at the age of 2 years • File records date from Feb 2008 when pt was 16 yrs old

  3. 2008

  4. 2009

  5. 2010

  6. 2011

  7. HAEMOPHILIA A • Hemophilia A is an X-linked recessive bleeding disorder attributable to decreased blood levels of functional procoagulant factor VIII • Hemophilia occurs in approximately 1:5,000 males, with 85% having factor VIII deficiency and 10–15% having factor IX deficiency • Hemophilia shows no apparent racial predilection, appearing in all ethnic groups

  8. COAGULATION CASCADE

  9. Clinical presentation • The severity of hemophilia is classified on the basis of the patient's baseline level of factor VIII because factor levels usually correlate with the severity of bleeding symptoms. • By definition, 1 international unit (IU) of each factor is defined as that amount in 1 mL of normal plasma referenced against a standard established by the World Health Organization (WHO); • thus, 100 mL of normal plasma has 100 IU/dL (100% activity) of each factor

  10. Factor concentrates are also referenced against an international WHO standard, so treatment doses are usually referred to in international units (IU). • The hemostatic level for factor VIII is >30–40% • The lower limit of levels for factors VIII in normal individuals is approximately 50%.

  11. Clinical presentation

  12. Sites of bleeding • The principal sites of bleeding in patients with hemophilia are as follows: • For joints, weight-bearing joints and other joints are affected (hallmark of hemophilia is hemarthrosis ) • Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. • Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.

  13. Sites of bleeding – Cont’d • In the genitourinary tract, gross hematuria may occur in as many as 90% of patients • In the GI tract, bleeding may complicate common GI disorders • Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia

  14. Laboratory features

  15. Treatment • Early, appropriate therapy is the hallmark of excellent hemophiliacare • When mild to moderate bleeding occurs, levels of factor VIII must be raised to hemostatic levels in the 35–50% range • For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity • Calculation of the dose of recombinant factor VIII (FVIII) is as follows: • Dose of FVIII (IU) = % desired (rise in FVIII) X body wt (kg) X 0.5 • FVIII 1 U/kg increases FVIII plasma levels by 2%. • The reaction half-time is 8-12 hours. Dosing interval 2-3/day

  16. Treatment • Before a patient with hemophilia is treated, the following information should be obtained: • the type and severity of factor deficiency, • the nature of the hemorrhage or the planned procedure, • the patient's previous treatments with blood products, • the presence and possible titers of inhibitors, and • the patient's previous history of desmopressin acetate (DDAVP) use (eg, in mild hemophilia A only) with the degree of response and clinical outcome

  17. Treatment

  18. Treatment – Cont’d

  19. Monitoring of treatment • Variations in responses related to patient or product parameters make determinations of factor levels important. • These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. • Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a hemophilia A factor level of 30% • Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an hemophilia A factor level of 50% • Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain a hemophilia A factor level of 80-90%

  20. Monitoring of treatment • Plasma levels are maintained higher than 40-50% for a minimum of 7-10 days. • Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration

  21. Treatment - desmopressin • With mild factor VIII hemophilia, the patient's endogenously produced factor VIII can be released by the administration of desmopressinacetate • In patients with moderate or severe factor VIII deficiency, the stored levels of factor VIII in the body are inadequate, and desmopressin treatment is ineffective • The risk of exposing the patient with mild hemophilia to transfusion-transmitted diseases and the cost of recombinant products warrant the use of desmopressin, if it is effective

  22. Prophylaxis • With the availability of recombinant replacement products, prophylaxis has become the standard of care for most children with severe hemophilia to prevent spontaneous bleeding and early joint deformities • The results of prophylaxis have been impressive in the prevention of chronic joint disease.

  23. Prophylaxis • Usually, such programs are initiated with the first joint hemorrhage. • The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years • Treatment is usually provided every 2–3 days to maintain a measurable plasma level of clotting factor (1–2%) when assayed just before the next infusion (trough level).

  24. Complications • Chronic arthropathy resulting in deformity • Development of an inhibitor to either factor VIII • Risk of transfusion-transmitted infectious diseases - hepatitis B and C, HIV • Allergic reactions with the use of cryoprecipitate, fresh-frozen plasma (FFP), and factor concentrates • Thrombosis or even acute myocardial infarctions have been encountered in patients using Prothrombin complex concentrate (PCC) products

  25. Inhibitors • The mixing of normal plasma with patient plasma results in correction of PTT • If correction does not occur on mixing, an inhibitor may be present • In 25–35% of patients with hemophilia who receive infusions of factor VIII a factor-specific antibody may develop • These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass; they are directed against the active clotting site and are termed inhibitors

  26. Inhibitors • The inhibitors occur at a young age (about 50% by age 10 y), principally in patients with less than 1% FVIII • In such patients, the quantitative Bethesda assay for inhibitors should be performed to measure the antibody titer • In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal and patient plasma in 2 hours at 37°C

  27. Inhibitor • By convention, • more than 0.6 BU is considered a positive result for an inhibitor, • less than 5 BU is considered a low titer of inhibitor, and • more than 10 BU is a high titer (neutralizing effectiveness of factor concentrate therapy to control bleeding)

  28. Treatment of inhibitors • The treatment of patients with inhibitors of FVIII is difficult. • Attempts to overwhelm the inhibitor with large doses of human FVIII have been tried in attempts to induce immune tolerance, especially if inhibitor concentrations are below 5 BU • Porcine FVIII, which has low cross-reactivity with human factor VIII antibody, has also been administered. • FVIII inhibitor-bypassing agents (FEIBA), including FIX complex, activated prothrombin complex concentrate (aPCC), and activated FVII has also been used. • Plasmapheresis, IVIG, or immunosuppressive therapy with cyclophosphamide and prednisone, have showed some success in achieving long-term control. • Rituximab with prednisone plus or minus the addition of mycophenolatemofetil when standard therapy has failed

  29. Recombinant factor VII • This activated recombinant FVII increases local formation of FXa, thrombin, and fibrin, to facilitate the formation of a hemostatic plug. • Factor VIIa, recombinant (Novo Seven) • Binds to exposed tissue factor and also directly activates FX • Dosing • Adult • 90 mcg/kg initial infusion IV over 2-5 min, with subsequent redosing q2-3h depending on bleeding severity • Pediatric • Determined according to body weight and not age

  30. END

  31. PATHOPHYSIOLOGY • Result in an insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade • After injury, the initial hemostatic event is formation of the platelet plug, together with the generation of the fibrin clot that prevents further hemorrhage • In hemophilia A , clot formation is delayed and is not robust. • Inadequate thrombin generation leads to failure to form a tightly cross-linked fibrin clot to support the platelet plug forming a soft friable clot • When untreated bleeding occurs in a closed space, such as a joint, cessation of bleeding may be the result of tamponade; in open wounds, profuse bleeding can result in significant blood loss

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