haemophilia
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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HAEMOPHILIA
Presenter: Dr Suzanna Mwanza
Moderator: Dr Sambo
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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
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2008
DATE BLEEDING SITE TREATMENT PROPHYLASIS LAB RESULTS
15.02.08 Lt ankle FVIII 1000U (18U/kg) FEIBA 1000U (18U/kg)
13.06.08 Intra-abd FVIII; FEIBA PT – 16 secAPTT- 55 secPI – 88.75%INR – 1.11
05.09.08 FVIII; FEIBA
03.10.08 Rt hip (Psoas) FVIII; FEIBA (3/7)Prednisolone
09.10.08 FVIII assay <1%(50-150%)
19.11.08 FVIII; FEIBA
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2009DATE BLEEDING SITE TREATMENT PROPHYLASIS LAB RESULTS
09.02.09 Finger joints FVIII; FEIBA
26.02.09 Epistaxis FVIII; FEIBA
06.03.09-09.05.09
FVIII 2000U (33.3U/kg) FEIBA 1500U (25U/kg) X 4/7
PT:14.5-20.5secAPTT:75.7-95.2secPI:83.5-90.3%INR:1.12-1.63
20.09.09-14.11.09
Lt ring, little fingers
FVIII 3000U (50U/kg)FEIBA 3000U (50U/kg)
PT:16.0 -16.6 secAPTT:55.6-80 secPI:78.3-81.3%INR:1.24
28.20.09 FVIII assay <1%
006.12.09 Lt ankleRestricted movement –Lt fingers
No FVIII PT:15.7secAPTT:67.5 secPI:82.8%INR:1.2-
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2010DATE BLEEDING SITE TREATMENT PROPHYLASIS LAB RESULTS
09.01.10 FVIII 3000UFEIBA 3000U X 3/7
FVIII assay <1%FVIII inhibitor – 15.4 Bethesda
02.03.10 Right external oblique hematoma
FVIII 3000UFEIBA 3000U X 2/7
18.03.10 PT: 27.5 secAPTT:90.0 secPI:47.0%INR:2.16
30.04.10 Lt big toe FVIII 3000UFEIBA 3000U
27.07.10 FVIII 2500UFEIBA2500U
22.11.10 Lt big toeLt littl finger
FVIII 3000UFEIBA 3000U
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2011DATE BLEEDING SITE TREATMENT PROPHYLASIS LAB RESULTS07.01.11 Lt ankle FVIII 3000U
FEIBA 3000U07.04.11 FVIII assay <1%
06.05.11-20.05/11
Bilat subconjuctival haemorrage;Hemoperitoneum;Severe anaemia;Septicaemia (salmonelosis)
No FVIII/FEIBAPacked cells - 4Cryoprecipitate-11FFP - 6PrednisoloneCiprofloxacin
Hb 6.3U/S – Rt common femoral & popliteal thrombosis;Heamatoma posterior to bladder
21.05.11 FVIII 4000UFEIBA 4000U
PT:15.4 secAPTT: 77.5 secPT:78.2%INR:1.31
02.06.11-26.07.111
FVIII 4000U (62.5U/kg)FEIBA 4000U (62.5U/kg) X 6/7
26.07.11 U/S Abd haematoma resolved
05.09.11 Rt knee FVIII; FEIBA
12.09.11-19.09.11
HaemoperitoneumSevere anaemia
FVIII X 3Packed cells – 4FFP -15Cefotaxime/CiproPrednisolone
Hb: 6.3
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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
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COAGULATION CASCADE
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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
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• 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%.
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Clinical presentation
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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.
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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
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Laboratory features
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Treatment
• Early, appropriate therapy is the hallmark of excellent hemophilia care
• 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
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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
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Treatment
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Treatment – Cont’d
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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%
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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
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Treatment - desmopressin
• With mild factor VIII hemophilia, the patient's endogenously produced factor VIII can be released by the administration of desmopressin acetate
• 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
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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.
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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).
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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
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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
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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
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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)
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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 mycophenolate mofetil when standard therapy has failed
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• 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
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END
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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