Introduction:

• It is a rare genetic disorder caused by missing or defective factor resulting in impairment of normal coagulation.
• Hemophilia A is due to Factor VIII deficiency or defect
• Hemophilia B (Christmas disease) is due to Factor IX deficiency or defect

Epidemiology:

• Incidence – Hemophilia A – 1/5,000 – 10,000 males
• Hemophilia B – 1/25,000 – 30,000 males
• At present there are 14,000 registered patients in India.

Etiology:

• Both factor 8 and factor 9 genes are located on chromosome X. Hence these diseases are inherited in X linked recessive pattern.
• In case of X-linked recessive inheritance, males are usually affected and females are carriers
• More than 1000 mutations have been described that lead to hemophilia.
• Commonest mutation involving Factor 8 gene is “Inversion and crossing over of intron 22 during meiosis”
• Other mutations include deletion, inversion, missense, non sense, insertion, and splicing mutations.
• 1/3^rd of mutations arise de-novo. These occur in germ cells of maternal grandfather, whose daughters will be carriers and whose grandsons will have 50% chance of having hemophilia.
• Mechanisms by which a female can become hemophiliac:
  • Inheritance of either homozygous or compound heterozygous factor 8 mutations
  • Inheritance of single factor 8 mutation with a 46 XO (Turner syndrome)
  • Markedly skewed inactivation of X chromosome.

Classification based on clinical severity:

Clinical Features:

• Recurrent hemarthrosis of large joints
  • Tissue factor pathway inhibitors are produced by synovial tissue. So joints are most common sites of bleeding
  • Median age to develop 1^st joint bleed is 1.8 years. (Generally when child starts to crawl/ walk)
  • Accounts for 75% of all bleeding episodes in hemophilia
  • Occurs especially in knees,ankles and elbows
  • Patient feels bleeding has started in joints (called as Aura of discomfort)
  • Hot, swollen, very painful joint (Bleeding continues till factor replacement/ till pressure in joints causes occlusion of bleeding vessels)
  • Sometimes there can be mild fever (Prolonged fever indicates infective etiology)
  • Swelling gradually subsides over days
  • As blood is highly irritant to synovium, and because of accumulation of iron in chondrocytes, recurrent attacks lead to
    • Synovitis
    • Synovial hypertrophy
    • Destruction of cartilage
    • Irregularities of articular contour leading to secondary osteoarthritis
    • Bony overgrowth
    • Subchondral cyst formation
    • Ankylosis of joint
    • Deformed and dysfunctional joint
  • Eventually there is immobility and muscle wasting
  • Because of vicious cycle of bleeding and synovial hypertrophy, a particular joint tends to become the “target joint” in an individual, where as other joints may be relatively spared
• Muscle hematoma in psoas and calf muscles
  • It causes pressure which in turn leads to ischemia, necrosis, fibrosis and contraction of muscle
  • Can lead to compartment syndrome which needs urgent fasciotomy
• Intracranial haemorrhage
  • Usually occurs following head injury, but can occur spontaneously
  • Leading cause of death in haemophiliac patients
  • Presents with headache which later leads to decreased sensorium.
  • Factor replacement should be given, prior to investigations such as CT/MRI.
• Bleeding from other sites
  • Continuous bleeding from wound/ circumcision site/ surgical site
  • Bleeding from sockets after dental extraction. Loss of deciduous teeth rarely causes excessive bleeding.
  • Epistaxis
  • Hemoptysis
  • Retroperitoneal bleeding
  • Hematuria- Mostly bleeding arises from renal pelvis
• Pseudotumors/ Blood cysts-
  • Occur in soft tissues or bone
  • They are painless masses containing viscous brownish fluid
  • 3 types
    • Type I- Simple cyst confined by tendinous attachment within the fascial envelop of a muscle.
    • Type II- Involves periosteum and bone, resulting in reabsorption of bone.
    • Type III- Subperiosteal bleed that separatesperiosteum from the bony cortex.
  • Avoid needle biopsies as infection and hemorrhage are common
• When examining these patients, note
  • Range of motion
  • Joint deformity
  • Swelling
  • Crepitus
  • Wasting
  • Instability of joints

Investigations:

• Bleeding time – Normal
• Clotting time – Prolonged
• Prothrombin time – Normal
• Thrombin time – Normal
• Activated partial thromboplastin time – Prolonged. Corrected when mixed with equal volume of normal plasma.
• Plasma factor 8/factor 9 assay – Reduced levels (Normal – 50 – 150 IU/dL)
• Functional factor 8 coagulant activity- By one stage clotting assay or chromogenic assay.
• Factor 8 or Factor 9 mutation analysis-As certain mutations are associated with high risk of inhibitor development.
• USG of joints
  • Can detect joint hypertrophy
  • Low cost, non-invasive real time technique
  • It can detect extent and degree of soft tissue inflammation and amount of intra-articular fluid.
• MRI of joints- 
  • Most sensitive technique
  • Scoring system
    • 0- None
    • I- Minimal hemosiderin
    • II- Large amount of hemosiderin and cartilaginous erosion
    • III-Cartilage destruction, bone erosion, subchondral cyst
    • IV-Osteoarthritis with or without ankylosis
• Antenatal diagnosis
  • Chorionic villi sampling at 8-9 weeks of gestation and testing with factor VIII probes
  • Sexing of fetus at 6 weeks of gestation, using amniocentesis. If found to be male,fetal blood sampling is done at 20 weeks

Differential Diagnosis:For low Factor 8 levels

• Von Willebrand disease
• Acquired haemophilia
• Combined Factor 8 and factor 5 deficiency

Pretreatment Work-up: 

• History & Examination
• Type of Hemophilia
• PT
• APTT
• Factor level
• Severity
• Joints affected
• Blood Group and Rh Type
• Hemoglobin
• TLC, DLC
• Platelet count
• LFT: Bili- T/D      SGPT:       SGOT:       Albumin:     Globulin:
• Creatinine
• Hemophilia Chapter Number

Prophylaxis

• Prophylaxis should be the main stay of management
• Aim is to reduce severity of disease from severe haemophilia to moderate haemophilia.
• Should be given to all patients with severe haemophilia.
• Decreases number of bleeds and protects joints from progressive arthropathy.
• 2 types of prophylaxis:
  • Primary: Begun at 1-1.5 years, before the onset of joint bleeds or after 1^st joint bleed.
  • Secondary- Started at later age or after more than 1 joint bleeds but before the onset of proven joint bleed.
  • Tertiary: Started after development of joint disease, which aims to slow down the progression of joint disease.
• Dose (For both haemophilia A and B): F VIII – 20 – 40 IU/Kg (doses rounded up to nearest vial size), every second day or 3 days a week (So that trough level is > 1 IU/dL)
• Adults are less prone to spontaneous bleeding, hence lower dose (50% of dose) prophylaxis may be tried in them. But prophylaxis must ideally continue lifelong.
• Annual use of factor 8
  • Prophylaxis group- 6000 IU/kg
  • On demand group- 2500 IU/kg (Need goes on increasing as joint damage increases)
  • Prophylaxis appears difficult as cost of treatment is high. But studies which have taken into account number of working days, loss of pay due to hospitalization etc, have shown that giving prophylaxis is more economical.
• Risk of inhibitor development is less in patients on prophylaxis.
• Breakthrough bleeding must be treated according to site and severity until complete resolution.

Treatment:

• In a patient with serious bleed and if type of haemophilia is not known fresh frozen plasma (10ml/kg) may be given.
• Replacement must be given as early as possible (with onset of Aura), preferably at home to stop bleeding and minimize further complications.
• Dose calculation: 
  • Factor 8
    • Each unit/kg increases factor level by 2%.
    • Therefore bolus dose= Target increment in Factor 8 level x weight in Kg x 0.5
    • T ½ of factor 8 is 8-12hrs. Hence following loading dose repeat doses are administered every 8-12hrly (generally 12 hourly), adjusted to measured factor 8 levels.
  • Factor 9
    • Each unit/kg increases factor level by 1%.
    • Therefore bolus dose = Target increment in Factor 9 level x Weight in kg
    • Multiply this by 1.3 if recombinant factor 9 is given
    • Dose is repeated every 12 or 24 hrly (generally 24 hourly), based on factor 9 levels in blood.
• Targets
  • Minor bleeding (Hematomas in Noncritical Areas ; Hematuria ; Dressing Changes, Arthrocentesis ; Removal of Sutures and Drains)- 30%- To be maintained for 1-2 days
  • Severe bleeding (Muscle/ joint bleed/ Deep laceration Multiple tooth Extraction)- 50%- To be maintained for 2-3 days
  • Surgical procedures/ life threatening bleed/ any bleed with neurovascular compromise/ neck bleed/ GI bleed/ Retroperitoneal bleed- >80%- To be maintained for 7-14 days. 
  • These targets can be kept at 50% levels if there is significant resource constraint.
• If factors are not available cryoprecipitate can be used
  • Each bag contains about 70-80units of factor 8 in a volume of 30-40ml.
  • Usual dose- 1.25-1.75 bags /10 kg every 12 h for 1-3days
• Therapy should continue until complete hemostasis is achieved.
• Post operative therapy should continue for 10-14 days.
• Joint bleed-  follow RICE protocol(Treatment for first 24 hrs apart from factor replacement)
  • R- Rest
    • Immobilization and non-weight bearing.
    • Prevents rebleeding
    • Rest in functional position
    • Gentle mobilization must start at 48 hrs
    • Low intensity stretching exercises must start at 72hrs within the limits of pain. This causes distension of maturing scar while it is still plastic.
    • Walking aids must be provided for 1 week.
    • Weight bearing can start after 1 week.
    • Graduated physiotherapy (which includes daily exercises to maintain joint motion and muscle strength) with secondary prophylaxis must be done for minimum of 6-8 weeks.
  • I- Ice
    • Should be applied for 20min every 3 hrs up to 6hrs.
    • Prevent direct contact of ice with skin
    • Decreases inflammation, nerve conduction, and blood flow to injured area.
    • There is a risk of delayed coagulation due to decreased intra-articular temperature.
  • C- Compression and COX-2 inhibitors 
    • External pressure decreases joint space. Hence tamponade is created early and bleeding stops early.
    • COX-2 inhibitors such as Celecoxib/ Paracetamol can be given for pain. If persistent pain add tramadol/ morphine.
  • E- Elevation
    • Limb must be elevated above the level of heart.
    • Because of decreased capillary hydrostatic pressure and by gravity edema subsides.
  • Indications for joint aspiration (this must be done under factor cover)
    • No improvement after 24hrs of therapy. Presence of inhibitors must be excluded prior to attempting arthrocentesis.
    • Evidence of neurovascular compromise of limb
    • If there is evidence of infection (septic arthritis)
• Local treatment for bleeding from wounds
  • Application of pressure bandage
  • Hemostatic agents such as adrenalin and thrombin
  • Immobilization of wound with splints
• Tranexamic acid: 
  • Useful in treatment of bleeds in skin and mucosa. Not useful in preventing hemarthrosis
  • Can be used locally in dental surgeries
  • Contraindicated if there is hematuria.
• Pain management: Paracetamol, COX2 inhibitors and opioids are the options

Types of factors used for replacement:

• Purified factor VIII concentrates
  • Prepared using cryoprecipitate of pooled normal human plasma (2,000-20,000 donors)
  • Sterilized by heating in solution and by superheating to 80 degree C after lyophilisation and by exposure to solvent detergents, that destroy enveloped viruses such as HIV, HBV and HCV.
  • They contain significant amounts of vWF
• Recombinant Factor VIII
  • It is derived from recombinant DNA technology: Genes are inserted into cell lines. Cells are cultured and secreted factor is purified from the culture medium and final formulation is lyophilized.
  • 3 generations of factors
    • 1^st generation- Human albumin is added as stabilizer
    • 2^nd generation- No stabilizer is added
    • 3^rd generation- Manufactured without exposure to animal proteins. Hence no chances of transmission of prion diseases.
  • Unopened vial can be stored at room temperature for up to 30 months.
  • Once reconstituted, it should be stored at 2-8 degree C
• Extended action factors: t ½ is extended by following measures
  • Pegylation
  • Decreased intracellular degradation- Fc fusion and albumin fusion proteins
  • Enhanced interaction with vWF.

Other agents: 

• Emicizumab- 
  • Recombinant humanized bispecific monoclonal antibody mimicking the co-factor function of activated Factor 8. 
  • It can be used for prophylaxis in patients both with and without inhibitors.
  • Licensed for use in children aged >2 years.
  • Dose- 1.5mg/Kg- Once a week
  • Side effect- thrombosis (especially when it is co-administered with prothrombin complex concentrates)
• Desmopressin (DDAVP)
  • It transiently raises factor VIII activity by  3 -5 times
  • Exact mechanism of action is not known.
  • Dose 0.3 µg/Kg- IV/SC over 15 min
  • Intransal spray- Children- 150mcg- in one nostril, Adults- 150mcg- in each nostril.
  • Peak response occurs 30-60min after dosing.
  • Patients with severe haemophilia do not respond to this treatment.
  • Patients are advised to restrict their fluid intake, otherwise it results in hyponitremia and convulsions
  • Repeated administration leads to decreased response. Generally response of 2^nd dose is 30% less than response to first dose. (tachyphylaxis)
• Novel intrinsic tenase
  • Cleavage of factor 10 occurs in presence of negatively charged phospholipids provided by the surface of activated or damaged cells.
• ALN-AT3- Antisence RNA to decrease synthesis of antithrombin in liver.
• Somatic gene therapy
  • Following vectors are being tried to transfer the normal genes
    • Non viral capsid
    • Adenoassociated virus
    • Replication deficient retrovirus
  • Difficult because factor 8 is large complex protein and it needs extensive post-translational modification with chaperons for normal functioning.
• Liver transplantation
  • Can result in complete cure of haemophilia
  • Also useful for chronic hepatitis which is often seen in old hemophiliacs

General measures

• Avoid aspirin and other NSAIDs which increase the risk of bleeding
• Avoid giving IM injections
• Avoid competitive contact sports.
• Racket sports, athletics and swimming are encouraged. It promotes musculoskeletal development and general good health.
• Maintain central venous access device or AV fistula, so that factor replacement can be done easily at home. Initially teach parents. At 8-12 years teach children using these access devices.
• Parents must be taught about dosage calculation, preparation, storage and administration of factor concentrates.
• Vaccinations against hepatitis A and B must be given. This should be given by subcutaneous route with smallest gauze needles (Number 26)
• Physiotherapy for strengthening of muscles around joints. This decreases the risk of repeated bleeding.
• Ankle guards and arch support for patients with ankle arthropathy.
• To facilitate appropriate management in emergency situations, all patients must carry easily accessible identification card/letter, indicating
  • Diagnosis
  • Severity of bleeding disorder
  • Inhibitor status
  • Type of treatment product used
  • Initial dosage of treatment for severe, moderate and mild bleeding.
  • Contact information of treating physician/ clinic.

Surgical interventions

• Operative removal of entire mass of pseudotumor. If not completely removed, recurrence is common.
• Evacuation of intracranial bleed if needed
• For haemophilic arthropathy
  • Functional bracing- Allows joints to move but limits movements at the ends of range where the synovium can be pinched. This can prevent further bleeding.
  • Synovectomy- Needed when persistent chronic synovitis results in recurrent bleeds
  • Orthoscopic/ surgical synovectomy- Removal of inflamed and thickened synovial tissue. Although frequency of bleeding decreases, there is no improvement in joint mobility.
  • Chemical (Rifampicin, Oxytetracyclin, osmic acid, theotepa, D-Pencillamine)/ radionuclide (Rhenium-186, Gold-198, Dysprosyum-160, yyatrium-90, Phosphorous-32) synovectomy- Compared to surgical synovectomy, this is less invasive with less hospitalization and less factor consumption.
  • Varlousarthodosis procedure
  • Joint replacement (Total knee replacement)- Treatment of choice for patients with severe knee arthropathy. Abolishes pain and corrects deformities.
• Fasciotomy- If intramuscular bleed leads to neuromuscular compromise

Development of inhibitors in haemophilia patients

Introduction:

• Inhibitors are antibodies against factor VIII and IX
• They are mostly IgG4 subtype.
• They are directed against A2 and C domains of factor 8    
• 20% of haemophilia A develop antibodies by age 5-8 years
• 3% of haemophilia B develop antibodies by age of 5-8 years.

Mechanisms of action:

• Preventing factor 8 interaction with vWF, thereby decreasing the t ½
• Impairing the release of factor 8a from vWF after thrombin activation
• Preventing C2 domain from binding to the phospholipid
• Preventing A2 domain interaction with factor 9, which results impaired tenase activity
• Catalysis of proteolysis of protein 8

Clinical features

• Bleeding which will not stop with routine factor replacement
• Bleeding, different from those of haemophilia- Generally bruising, retroperitoneal bleed, muscle hematoma, GI and urogenital bleeds
• No relationship exists between Bethesda titres and severity of bleeding.

Risk factors for development of inhibitors

• Increased disease severity
• Early exposure to factor 8 concentrates
• Genetic factor- Family history of inhibitors, gene defect such as inversion and crossing over, Absence of HLA Cw5 antigen
• African Americans and Latinos
• Microsatellite polymorphisms in the promoter region of IL-10 gene
• G308A polymorphism in the promoter region of TNF- Alpha gene.
• Use of continuous infusion for factor replacement
• Use of recombinant factor 8. Products containing vWF are less likely to produce inhibitors than highly purified products. (As vWF has immunomodulatory function)

Assessment:

• Mixing study
  • Abnormal clotting times are not corrected by adding normal plasma, either by immediate or incubated mix.
• Bethesda assay
  • Patient’s plasma is diluted such that, when patient’s plasma is mixed with equal volume of normal pooled plasma, the factor 8 activity in the mixture decreases by 50%
  • Nijmegen assay- pH of the sample over 24hrs of incubation is maintained at 7.4.
  • Procedure of the assay is complicated.
  • Inhibitor titres of >0.6 BU/ml must be taken as significant.
• When to test?
  • If patients show poor response to factor replacement treatment
  • Till 20 exposure days- Every 3^rd exposure day or every 3 months, whichever is earlier
  • 21-150 exposure days- Every 3-6 monthly
  • After 150 exposure days- Once in 6 months for severe haemophilia A and for others once a year.

Classification

• Low titre inhibitors- <5 BU/ml (Can be managed with higher doses of factors)
• High titre inhibitors ≥ 5BU/ml (With complete withdrawal of factors, titres may become undetectable.. But with subsequent exposure these patients mount memory response, resulting in very high inhibitor titres. This process is called as anamnesis. These patients need immune tolerance induction)

Treatment (For both haemophilia A and B):

• In the event of bleeding
  • Tranexamic acid
  • Higher doses of deficient factor (8/9)- To be given every 4 hrs initially, then as per schedule tailored to APTT or factor 8 levels.
  • DDAVP trial- Useful in mild haemophilia A (Not useful in haemophilia B)
  • Factor Eight Inhibitor Bypassing agent (FEIBA)/ Activated prothrombin complex concentrate (APCC)
    • 75-100 IU/Kg- every 6-12 hrly to maximum dose of 200mg/kg/day
    • Useful in haemophilia B as well.
  • Human Recombinant FVIIa
    • 90-120microgm/kg- every 2hr for 3 doses/ till complete hemostasis achieved
    • It is not proteolytically active by itself and does not therefore produce systemic activation of coagulation when infused
    • F VIIa complexes with tissue factor at site of injury inducing local hemostasis
    • The process is independent of the F VIII or F IX and is not affected by inhibitors to F VIII and F IX
  • Emicizumab
    • Monoclonal antibody that binds to factor IXa and X and brings them together, hence factor IXa converts factor X to Xa.
    • Normally this is the function of factor 8
    • Loading dose- 3mg/kg/week- SC for 4 weeks, then maintenance of 6mg/kg- once in 4 weeks.
    • When used with APCC, higher of thrombotic events
    • Now being used for patients without inhibitors as well, as prophylaxis.

Prophylaxis in patients with inhibitors: Any one can be used

• APCC- 85 Units/Kg- 3 times a week
• Rec Factor VIIa- 90-270microgram/Kg-
• Emicizumab Daily

Methods to decrease inhibitor levels

• Plasmapheresis
  • Helps in removal of antibodies
  • Adsorption of antibody on an affinity column (Sepharose A) can be done during plasmapheresis.
• IV. Immunoglobulins
• Immunosuppression
  • 1^st line: Steroids with Oral Cyclophosphamide
  • 2^nd Line: Any of the following along with steroids
    • Cyclosporine
    • Tacrolimus
    • Mycophenolate
    • Rituximab
    • CVP chemotherapy regimen
• Immune tolerance induction (ITI)
  • Daily doses of factor 8 until inhibitor titre is undetectable
  • Sometimes this is combined with CVP chemotherapy protocol
  • Types of regimens used
    • High dose (Molmo): 100U/kg-BD until inhibitor level decreases to 1BU/ml, then 150U/kg- OD until factor 8 t ½ becomes normal.
    • Low dose: 50U/kg- OD or on alternate days
    • Netherland protocol- 25U/kg-OD
  • Most patients achieve tolerance in 6-12 months
  • ITI must be given only if inhibitors interfere with prophylaxis or treatment of bleeds.
  • If inhibitor titres go up >500 BU/ml after starting ITI, ITI can be abandoned.
  • Allow the inhibitor titres to fall below 10BU/ml before starting ITI. Till that that time, RecVIIa may be used.
  • Central line is necessary prior to starting ITI.
  • Inhibitor levels should be checked every week during ITI initially, then once a month.
  • Dose tapering should be considered if inhibitor titres are negative on 2 successive occasions. 
  • If inhibitor reappears during tapering, factor 8 should be restarted at previous dose.
  • After stopping routine prophylaxis should be continued.
  • Better results are seen with
    • <20 BU/ml at the start of therapy
    • Historic peak of <200 BU/ml
    • Prophylaxis dose <50IU/kg/day- 3 times a week
    • Peak titre on ITI- <250 BU/ml
    • Uninterrupted ITI
    • Less number of exposure days
    • Use of vWF containing concentrates

Special Situations:

• Haemophilia carriers:
  • Factor levels are nearly 50%
  • Ratio of VWF antigen level to Factor 8 coagulant activity is increased.
  • Specific mutations can be detected by molecular tests.
  • Prenatal diagnosis has to be offered to them.
  • Asymptomatic but may have increased bleeding tendency.
  • Factor replacement is necessary if surgical or invasive procedures are planned.
  • Daughters of haemophiliac fathers are obligatory carriers.
  • Daughters of haemophilia carrier mother have 50% chance of becoming carrier.
  • Some may have low factor levels due to extreme lyonization.
  • May have menorrhagia, which can be controlled with tranexamic acid and hormonal therapy.
  • Factor 8 levels increase significantly during pregnancy, hence factor replacement is not necessary. But it is better to do measurement of factor levels at baseline and in 3^rd trimester.
  • Infant has a high risk of intracranial bleed- hence avoid vacuum extraction/ forceps delivery
  • LSCS is preferred over vaginal delivery
  • Factor replacement is needed if neuroaxial anaesthesia is planned. (Target factor level- >100U/dL- maintain this for 3 days)

• Acquired haemophilia- Refer to acquired coagulation disorders section.

Recent advances:

Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A 

Valoctocogene Roxaparvovec is an adeno associated virus based gene therapy used for treatment of Hemophilia A. It contains Factor VIII complementary DNA which is driven by a liver-specific promoter. The efficacy and safety of this therapy was tested by Ozelo et al in a multicenter trial. Overall 134 participants with severe hemophilia who were on prophylactic factors received 6x 10¹³ vector genomes per Kg body weight. At about 50 weeks after this infusion, the avarage factor levels were 41.9 IU/dL. About 85% participants had rise in alanine aminotransferase levels which was treated with immunosuppressants. 

https://doi.org/10.1056/NEJMoa2113708   

Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B 

FLT180a (verbrinacogenesetparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. This therapy was tested in patients with severe hemophilia B. All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. At a median follow-up of 27.2 months, sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. 

https://doi.org/10.1056/NEJMoa2119913

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A

Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor–imposed half-life ceiling. In this phase 3 study involved patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. In group A (133 patients), the median annualized bleeding rate was 0. In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. 

https://doi.org/10.1056/NEJMoa2209226

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A 

Present study included 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. At week 104, the mean annualized treated bleeding rate decreased by 84.5% from baseline. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. 

https://doi.org/10.1056/NEJMoa2211075 

Rondaptivon pegol as a treatment for severe and nonsevere hemophilia A 

The VWF-binding aptamer rondaptivon pegol increases plasma levels of VWF/FVIII. Nineteen adult patients with hemophilia A received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. 

https://doi.org/10.1182/blood.2022016571 

Marstacimab in haemophilia 

Marstacimab is a human monoclonal antibody targeting tissue factor pathway inhibitor. It was evaluated in patients with haemophilia A or B, with or without inhibitors. Overall, 80.8% experienced treatment related adverse events. Annual bleed rate during treatment was significantly reduced versus an external on-demand control group. Marstacimab was safe and well tolerated. 

https://doi.org/10.1111/bjh.18420

Concizumab in Hemophilia with Inhibitors

Concizumab is a novel subcutaneous prophylactic therapy for hemophilia. It is a hemostatic rebalancing agent that binds to the Kunitz-2 domain of tissue factor pathway inhibitor. In the explorer7 trial, it was evaluated for its safety and efficacy in patients with inhibitors. Patients were divided into different groups, some receiving concizumab prophylaxis and others not. The primary analysis showed that the annualized bleeding rate in the group without prophylaxis was significantly higher than in the group receiving concizumab prophylaxis (11.8 vs. 1.7 episodes). Patients on concizumab had an overall median annualized bleeding rate of 0 episodes. There were no reported thromboembolic events after concizumab therapy restart. 

https://doi.org/10.1056/NEJMoa2216455

Factor VIII inhibitor titers in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis

In a retrospective follow-up study of patients with hemophilia A (PwHA) carrying current or historical factor VIII (FVIII) inhibitors, emicizumab prophylaxis was associated with a marked decrease in inhibitor titers. Among 19 PwHA with FVIII inhibitors at the initiation of emicizumab prophylaxis, 17 experienced a significant reduction in inhibitor titers, with a median follow-up of 71 months. In two patients, titers were slightly elevated initially but decreased in the long term. Among six patients with negative inhibitor status at the switch to emicizumab, five maintained negative titers, while one experienced inhibitor recurrence, which decreased over time. The study suggests that FVIII inhibitor titers tend to decrease spontaneously during emicizumab prophylaxis, emphasizing the importance of regular follow-up to manage breakthrough bleeds.

https://doi.org/10.1007/s12185-023-03667-y

Emicizumab prophylaxis in patients with acquired haemophilia A

In this phase 2 clinical trial, emicizumab, a factor VIIIa mimetic antibody, was investigated as a prophylactic treatment to prevent bleeding in patients with acquired hemophilia A during the first 12 weeks after diagnosis. The study included adult patients who had not previously received immunosuppression. Emicizumab was administered subcutaneously, and no immunosuppression was given during the study period. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. The study found that emicizumab prophylaxis significantly reduced the mean bleeding rate, with 70% of patients experiencing no bleeding events. Adverse events were generally manageable, and the low number of thromboembolic events, severe infections, and fatalities observed are promising.

https://doi.org/10.1016/S2352-3026(23)00280-6

Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Hemophilia A

Moroctocogalfa is a recombinant Factor VIII.  This multicenter, open-label, post-approval study assessed the safety and efficacy of moroctocogalfa in 50 Indian patients with moderate or severe congenital hemophilia A. Administered three times weekly for up to 8 weeks, moroctocogalfa prophylaxis demonstrated a mean annualized bleeding rate of 0.79, with no participants developing factor VIII inhibitors. The mean annualized total factor consumption was 287,432 IU per participant, and the treatment was well tolerated with no adverse events leading to dose reductions, discontinuations, or serious adverse events reported. 

https://doi.org/10.1007/s12288-022-01587-1

Giroctocogene fitelparvovec gene therapy for severe hemophilia A

In the ongoing Alta study, interim results up to 214 weeks after treatment with giroctocogenefitelparvovec, a recombinant AAV vector-based gene therapy for severe hemophilia A, show promising safety and efficacy outcomes. Increases in liver enzymes were the most common treatment-related adverse events, resolving with corticosteroid administration, and few serious adverse events were reported. At the highest dose level, participants achieved mean circulating FVIII activity levels of 42.6% at week 52 and 25.4% at week 104, with low rates of bleeding events observed. No liver masses, thrombotic events, or confirmed inhibitors were detected. 

https://doi.org/10.1182/blood.2022018971

Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A

This phase 3, open-label study evaluated the efficacy and safety of once-weekly efanesoctocog alfa in children younger than 12 years with severe hemophilia A. Seventy-four male patients were enrolled, receiving a weekly dose of 50 IU/kg for 52 weeks. No factor VIII inhibitors developed, and most adverse events were nonserious. The median annualized bleeding rate was 0.00, with 64% of patients experiencing no treated bleeding episodes and 95% of bleeding episodes resolving with a single injection. Efanesoctocog alfa maintained high factor VIII activity, effectively preventing bleeding in this patient population.

https://doi.org/10.1056/NEJMoa2312611

Fitusiran prophylaxis in people with hemophilia A or B

A phase 3, open-label study assessed the efficacy and safety of fitusiran, a subcutaneous small interfering RNA therapeutic targeting antithrombin, in males aged ≥12 years with hemophilia A or B (PwHA/B). Participants, including those with and without inhibitors, transitioned from prior bypassing agent (BPA) or clotting factor concentrate (CFC) prophylaxis to once-monthly 80 mg fitusiran. The study found a significant reduction in annualized bleeding rate (ABR), with median ABRs decreasing from 6.5/4.4 (BPA/CFC) to 0.0 with fitusiran. Additionally, 63.1% of participants experienced no treated bleeds with fitusiran, compared to 16.9% with BPAs/CFCs. Two participants had thromboembolic events, aligning with known risks.

https://doi.org/10.1182/blood.2023021864

Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B

In a phase 3 open-label study, fidanacogene elaparvovec, a gene therapy for hemophilia B, was evaluated in 45 men with severe hemophilia B. The treatment significantly reduced the annualized bleeding rate by 71%, from 4.42 episodes at baseline to 1.28 after therapy (P=0.008), demonstrating both noninferiority and superiority to prophylactic treatment. After 15 months, the mean factor IX activity reached 26.9%. While 62% of participants required glucocorticoids due to elevated liver enzymes or decreased factor IX levels, no serious adverse events or thrombotic complications occurred. 

https://doi.org/10.1056/NEJMoa2302982

Etranacogene dezaparvovec gene therapy for haemophilia B

The phase 3 HOPE-B trial evaluated the long-term efficacy and safety of etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment. Adult males with severe or moderately severe haemophilia B received a single infusion of etranacogene dezaparvovec and were followed for a median of 26.51 months. Compared to the lead-in period, mean adjusted annualised bleeding rate (ABR) significantly decreased, with at least 67% of participants experiencing no bleeding during each 6-month period after gene therapy. Factor IX activity remained stable and sustained, with most participants expressing endogenous factor IX and remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified, and treatment-related adverse events were manageable. 

https://doi.org/10.1016/S2352-3026(24)00006-1