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

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

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-

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

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

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

COAGULATION CASCADE

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

• 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%.

Clinical presentation

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.

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

Laboratory features

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

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

Treatment

Treatment – Cont’d

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%

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

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

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.

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).

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

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

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

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)

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

• 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

END

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