Haemophilia A and B
Presentation 1. Woman known to be a carrier § Cord blood factor VIII will establish diagnosis
2. Sporadic cases § Often present around 1 year when toddlers become mobile § Cephalohaematoma or prolonged bleeding from the cord § Neither FVIII or IX cross the placenta § Circumcision in cultures where this is performed early § One third with severe will not bleed § Bruising from minor knocks on the cot or hand pressure § Dental eruption / lacerations
3. Mild cases § Bleeding after surgery / dental extraction
Epidemiology § 1:5000 live male births (Haemophilia B 1:30 000, most have unique mutation) § 30% have new mutations and no family history
Classification – ISTH § <1iu/dl = severe § 1-5iu/dl = moderate § >5iu/dl = mild § Exclude VWF type 2N if platelet type bleeding
Clinical features Joint disease § Ankles, knees and elbows most affected § Intracapsular bleeding leads to severe pain, swelling, stiffness inflammation. § Gradually resolves over days to weeks § Reason for joint bleeding possibly due to expression of TFPI by synovial membrane § Blood highly irritant and leads to synovial overgrowth, which is very friable leading to a vicious circle (patients have ‘target joints’) § Iron accumulation in chondrocytes then leads to rapid degenerative arthritis.
Muscle bleeding § Often in large load bearing groups (thigh, calf, buttocks and posterior abdominal wall) § Local pressure can lead to nerve entrapment (particularly the femoral nerve with iliopsoas bleeding § Causes a triad of groin pain, hip flexure and sensory loss over the femoral nerve distribution § Can lead to ischaemic necrosis and contracture formation (calf, forearm, peroneal muscles)
Haematuria § Rare – one or two episodes per decade § Can cause clot colic but usually resolves spontaneously
CNS § Uncommon but can occur after a slight head injury § Previously the commonest cause of death in haemophilia A
Oral bleeding § Can be dangerous as may lead to airway obstruction § Bleeding after tongue laceration can be troublesome due to fibrionlytic substances in saliva
Surgery § Invariably leads to dangerous haemorrhage often after an initial short-lived period of apparent haemostasis. § Haemorrhage can recur over a period of days or weeks.
Diagnosis § Prolonged APTT § Normal PT / TT / bleeding time / platelet count § Factor VIII clotting activity below 50 U/dL § Normal vWF antigen and ristocetin cofactor § Factor VIII antibodies should always be performed
Treatment § Prenatal diagnosis / carrier status § Genetic testing § Initially direct gene mutation analysis for Intron 22 inversion (45% in severe) and intron 1 (1-5%) – can be done by PCR on chorionic villous samples § If negative – linkage analysis for restriction fragment length polymorphisms or full mutation analysis § CVS weeks 10-13 § Amnio weeks 14-16 § Counselling § Current risks of factor therapy § Buddy system with parents of haemophilia children § Identify mutation in mother § CVS at 11-12 weeks (1-2% complications) or amnio at 15-20 weeks (0.5-1% complications) § Risk of miscarriage § IVF with preimplantation genetic haplotyping § Doesn’t require prior knowledge of mutation § Pregnancy and delivery § Check FVIII levels in mum and exclude associated bleeding disorders § Vaginal delivery preferred § Avoid prolonged 2nd stage labour § No ventouse or forceps if male baby § Check cord blood levels § Neonatal period § More counselling and education about when to seek medical attention § USS head to rule out ICH § Consider repeat scan in 7-10 days § Community visit by haemophilia nurse § Issue green card § Communicate with GP, paediatricians § Vaccine advise etc § Primary prophylaxis § Considerations § Who? § Usually only severe § When to start? § When they become more active, usually after 1 year § Inverse relationship between inhibitor development and age treatment started (Chalmers et al) § Venous access? § portacath § What product? § Record exposure days § Treatment intensity associated with increased inhibitors (Canal study)
Treatment recommendations – UKHCDO § General § Information and consent § Vaccinations against Hepatitis A and B § Hepatitis A not licensed for under 1s § Adminstered subcutaneously § Should be offered to carers preparing / injecting § Avoid exposure to blood / animal proteins § Mild haemophilia A and VWD should be treated with DDAVP and tranexamic acid whenever possible § Licensed products should be used within their product license unless there is a clear advantage to do otherwise § Specific § Haemophilia A § Recombinant factor VIII § Haemophilia B § Recombinant factor IX § High purity pd-FIX is the preferred alternative to PCC due to increased thrombotic risk with PCC § Inhibitors § rFVIIa or FEIBA § vWD § vWD containing concentrate – need to consider FVIII to VWF ratio § may prefer to avoid FVIII accumalation during repetitive dosing post-operatively § Factor XI deficiency § Pd-FXI concentrate or virally inactivated FFP § Pd-FXI has been shown to be associated with thrombosis § Dose should not increase FXI levels above 70 and tranexamic acid should not be given concurrently due to risk of thrombosis § Should avoid if a history of cardiovascular disease § Factor VII deficiency § rFVIIa § Factor II or X deficiency § No specific concentrates available § PCC § Factor V deficiency § Virally inactivated FFP § Factor XIII deficiency § Pd-FXIII concentrate § Fibrinogen deficiency § Pd-fibrinogen concentrate § Virally inactivated FFP or cryoprecipitate
Recombinant products eg. Advate, benefix, novoseven
§ Gene inserted into a cell line (eg. Baby hamster kidney cell – helixate, Chinese hamster ovary cell – recombinate) § Cells are cultured § Secreted factor is purified from the culture medium § Human/ animal products have been used in the culture media and albumin has been used as a stabaliser, therefore there is still potential risk of infection transmission § 3rd generation products eg. Benefix, advate do not know contain any animal product § Refacto is B domain depleted FVIII – this domain is dispensible for haemostatic activity but the domain depleted molecule is much more stable and albumin is not necessary for stabilisation § Most undergo a viral inactivation step, although no recombinant products have been known to transmit infection
Fractionated products eg. PCC, fibrinogen, FXI § TTI was a major problem with these products prior to the introduction of viral inactivation steps in the 1980s § Donor selection, screening and testing, testing of plasma pools and dual viral inactivation (eg. Heating or solvent detergent) have reduced this and probably overcoes the theoretical risk of prion transmission, and current products have an excellent safety record. § Parvovirus and hepatitis A are resistant to viral inactivation by SD methods
Non-fractionated blood products § The concentration of clotting factors and efficacy of viral inactivation is lower compared to fractionated products, therefore these products should be considered second choice and only used if concentrates that have undergone dual inactivation are not available § The only exception is in FXI deficiency, when inactivated non-UK FFP may be preferred to FXI concentrate due to its thrombotic potential § Platelet function disorders should receive HLA-matched products
Desmopressin § Synthetic analogue of vasopressin § Should document response prior to treatment § Can be used in mild-moderate haemophiliacs or VWD to increase FVIII levels to 3-5 fold above baseline § Can also improve primary haemostasis and has proven useful in some platelet defects § Can be given iv, sc or intranasally § Typical regimen 0.3 mcg/kg body weight IV over 20 mins with 1g tranexamic acid § Maximal effect 30min after IV / 1h after sc dose § Half life of FVIII around 8h § Side effects include haed ache and facial flushing § Attention needs to be paid to fluid balance and sodium levels esp post-op § Need to restrict fluid intake once taken as risk of hyponatraemia (which can cause fitting) § Contraindicated in the elderly as can precipitate arterial thrombosis
Treatment principles § On-demand § Prophylaxis § Intermittent eg. Post surgery § Continuous § FVIII 25-40iu/kg 3/ week (FIX 25-40iu/kg 2/week) § Recovery and half life study annually § Adults don’t usually require continued prophylactic regimes § FVIII – 1iu/kg = increment of 2iu/dl § FIX – 1iu/kg = increment of 1iu/dl § No documented evidence of different viral transmission rates between rFVIII and rFIX, bur rFIX not licensed for <6yrs
Formula Dose for FVIII = Weight x increment / 2 Formula Dose for FIX = weight x increment (If rFIX = weight x increment x 1.3, because of diminished recovery of this product)
General organisation of haemophilia care § Multidisciplinary team (physicians, nurses, social workers, laboratory scientists, physiotherapists) § Orthopaedic and dental surgeon § National service specification § 24h emergency treatment for haemophiliac patients § Full records should be kept of all treatments whether given at home or in hospital § Genetic counselling § Carrier detection § Antenatal diagnosis § Specialised care for HIV and Hep C infection § Special medical card
Complications if untreated § Haemophilic arthropathy § Pseudotumours § Compartment syndrome § Deep seated bleeds eg. Iliopsoas § CNS bleeds
Inhibitors § IgG 4 subtype § Nearly always in children within first 25days of treatment § 20% cumulative risk by age 8 § Normally high titre with brisk amanestic response § Risk factors: § Haemophilia A > B § Severe disease § Genetic lesion in FVIII gene (particularly large deletions / stop codons) § Immunogenotype § Immunological challenges § Ethnicity (more likely in afrocarribeans and Hispanics) § Positive family history § Age of exposure (young > older) § Intensity of exposure § May occur in previously treated patients § Usually low titre with little amanesis § CANAL cohort study § Prophylaxis may be protective because it reduces intensity of treatment § Increased incidence with early treatment disappears when corrected treatment intensity § Product with high vWF may be protective § Bethesda assay most commonly used § 1 BU is the quantity of antibody that neutralises 50% of FVIII or IX in normal plasma § Low titre <5 BU / High >5 § Low responders remain at low level and can be treated with high doses of factor VIII concentrate § High responders have a sharp an amnestic rise in antibody 5-8 days after FVIII treatment and need alternative treatment
Principles of Treatment § Screening § Mutation analysis to identify patients at high risk § Prophylaxis § Routine laboratory assessment with either trough levels or half-life studies § If suboptimal recovery – Bethesda assay § On-demand § Severe / moderate A- Screened with Bethesda after every 5th exposure day (ED) until the 20th ED, then 3-6 monthly up to the 150th ED, then annually § Severe/ moderate B – screening frequency as for A. The first 20 doses for high risk mutation should be given in a setting with resus facilities due to risk of anaphylaxis with B inhibitors § Prior to invasive procedures § Increase frequency of break through bleeding § Poor clinical or laboratory response to factor replacement § Mild § Screened after a period of intensive replacement therapy, esp. if high risk mutation § All new inhibitors should be notified to the National Haemophilia Database § Treatment of bleeding § low titre (<10BU) § high dose FVIII (recombinant or plasma) § high titre (>10BU) § FEIBA 100u/kg bd § rFVIIa 90mcg/kg 2 hour § Immune tolerance Induction § Should be considered as early as possible § Bleeding should be treated with novoseven to avoid an anamnestic rise in inhibitor titre § Should be deferred until titre <10BU, may take 3-6 months § Should be continued as long as there is a convincing downward trend in titres § Should be discontinued if no fall after 6 months § Should ideally be entered into a trial § High dose – Bonn regimen § 100iu/kg bd § 86% response rate § Low dose – Dutch protocol § 25iu FVIII alternate days § <40 BU 6 months, >40BU 19 months § Success = BU <2, recovery >50%, hallf-life >6 hours, no anamnesis § 87% response rate § Modified high dose with immunoadsorption, steroids, IVIG and immunosupression – Malmo protocol § Immunoadsorption by plasmapharesis and protin A immunoadsorption if >10 BU § High dose FVIII for 9-37 days § Success = normal recovery, normal half-life § 62.5% response rate
§ Principles of high dose immune tolerance induction § Allow BU to fall <5, by treating bleeding episodes with novoseven § FEIBA induces anamnesis in 30% § Phase 1 § High dose FVIII bd until anamnesis occurs (about 1 week) § End is determined by evidence of undetectable Bethesda after 3 day washout period § Phase 2 § Usually 3x duration of initial phase § High dose FVIII daily § End determined by formal half-life study after 3 day wash out with a result >6 hours § If < 6hours, re-establish 2nd phase for further 4-6 weeks § Phase 3 § Low dose 40-50iu/kg 3/ week § Half life study initially, 3 monthly for 6-12 months, thereafter 6 monthly
§ Prepare business case for appropriate funding § Predictors of outcome § Younger age § Short time between development and starting immunetolerance § Titre <10 § Low historical peak titre § Interruption free period of immuetolerance
Molecular genetics § Spans 190-kb pairs on X chromosome § Processed mRNA specifies a protein of 2351 AA which is made in liver, spleen and lymph nodes § 19 AA N-terminal leader is removed on secretion § Domains § A1 - (a1) - A2 - B - (a2) - A3 - C1 - C2 § Thrombin cleaves in 3 places leaving a heterotrimer § A1 A2 A3 - C1 - C2 § APC cleaves in another 2 places in the A1 and A2 domains destroying protein
§ Around 50% of mutations are due to major inversion that occurs frequently during male gametogenesis § The long arm of X has nothing to pair with and intrachromosomal pairing occurs because there are three copies of a gene designated F8A (one in intron 22 and 2 telomeric to it) § Means that the FVIII gene is divided in 2
§ Inversion 22 accounts for 20% of all and 45% of severe § Inversion 1 is the next most common – 1-5% of severe
Carriers § 85% can be detected by measuring VIII and vWF levels – will tend to have disproportionately low VIII compared to vWF
Haemophilia A in females § Due to a haemophiliac marrying a cousin § Severe menstrual bleeding which normally responds to FVIII replacement § Also described in Turner syndrome
§ 50% of carriers have VIII levels low enough to be classified as mild haemophilia requiring precautions to cover surgery. § Carriage can occur due to sperm mutation in the father without a family history
Haemophilia B § Simpler protein than Factor VIII § Recombinant factor IX is now available § benefix § More difficult to make as requires post translational processing § Formula = Dose = wt x increment / 0.9 § Longer half life 18h § only need daily dosing after surgery § only need prophylaxis twice a week § Inhibitors less common, partly because it’s a smaller molecule and thus has fewer epitopes § Inhibitor development can be associated with allergy and anaphylaxis § Occurs in about 3%
§ Haemophilia B LEYDEN § Severe childhood haemophilia which improves at puberty § Possibly due to influence of testosterone § Several different mutations in the LEYDEN specific region § Disrupt binding of proteins which initiate or enhance gene transcription § Probably steroid responsive elements upstream of the promoter mutations
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