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1. DISEASE/DISORDER

Definition

Hemophilia is a group of congenital bleeding disorders characterized by low or absent clotting factors, which normally aid in bleeding resolution. The most common types are Hemophilia A (classic hemophilia) caused by decreased factor VIII and Hemophilia B (Christmas disease) caused by decreased factor IX.

Etiology

Hemophilia A and B are caused by defects in the genes for factor VIII and factor IX respectively, which are on the X chromosome. These are transmitted as X-linked recessive. 1 Sporadic cases are common and are responsible for up to 50% of cases of hemophilia A and 40 % of hemophilia B. 2

Epidemiology including risk factors and primary prevention

Hemophilia occurs most commonly in patients with family history of hemophilia with male predominance (due to its X-linked recessive inheritance). Hemophilia A occurs 1 in 5000 to 10,000 males birth (~60 % have severe disease). Hemophilia B occurs 1 in 25,000 to 30,000 males (~50% have severe disease).  Hemophilia affects all ethnic groups with no correlation found by race or geography. Approximately 30% of female carriers have lower than 40% factor VIII or IX clotting activity and may have abnormal bleeding.3, 4 Females need to be evaluated also for Von Willebrand disease, which is the most common bleeding disorder.

Patho-anatomy/physiology

Hemophilia results in abnormalities in the clotting cascade. Factor VIII and IX respectively are involved in the initiation and propagation of the hemostatic mechanism. This mechanism involves the interaction of platelets with the exposed thrombogenic endothelium mediated by collagen, which serves an adhesive function for platelets in the subendothelium, and the coagulation proteins to dock on activated platelets, resulting in fibrin generating concentrations of thrombin.5 Any resulting dysfunction in coagulation factors VIII and IX disrupt two processes: the formation of fibrin, which help stabilize the clot, and fibrinolysis inhibitor, which helps prevent clot breakdown.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The natural history of hemophilia varies with severity of the condition. Patients with severe hemophilia are more likely to have spontaneous bleeding as early as birth.

Initial sites of bleeding may change with age. 6

  • Infants- intracranial or extracranial bleeding, prolonged bleeding during circumcision or phlebotomy are common. Most patients with severe hemophilia (90%) will present with symptoms during the first year.
  • Children (6 m to 11 year)- Bruising, forehead hematomas, hemathrosis, other musculoskeletal bleeding, or young toddlers with frenulum and oral injuries are common. Children in this age group generally have mild or moderate disease.
  • Older children and adults –joints and muscles bleeding are common.

Specific secondary or associated conditions and complications

Formation of factor inhibitors occurs in 15-20 percent of patients. These are defined as antibodies to clotting factors.

Recurrent hemarthrosis may cause joint arthropathy, muscle atrophy, soft tissue contractures and functional disability.

Intracranial bleeding is relatively rare, affecting about 3-4% of patients with hemophilia at birth. 6,7

2. ESSENTIALS OF ASSESSMENT

History

A detailed history is essential. It should include patient age, sex, past medical history, birth history, bleeding history, family history, recent trauma or surgery. Past history should be directed to the type and location of bleeding, prior spontaneous bleeding, excessive bruising and/or bleeding with procedures (immunizations).5

Physical examination

Physical examination includes a full musculoskeletal evaluation of upper and lower limbs, including inspection, palpation, range of motion and strength. Inspection should be focused in evaluating for pallor, joint effusions, bruising, leg length discrepancy, joint deformity and limb/joint asymmetry. Palpate for joint tenderness in the joint or muscle (most commonly the quadriceps, hamstrings, iliopsoas, biceps and triceps) and possible effusion. Consider hemarthrosis in the presence of limited ROM, swelling, pain and warmth. Posture of the limb can suggest muscle hematoma; in case of iliopsoas it will present with flexed, internally rotated hip. History of trauma can guide the physician on specific examination.

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Patients with severe arthropathy and/or joint deformity can have issues affecting functional mobility and basic ADL’s. These patients should be evaluated for the need of assistive devices.

Cognitive state is usually not affected in the child-adolescent stage, but adults may present with mild cognitive dysfunction as the result of asymptomatic cerebral microbleeds.8

Laboratory studies

  1. Prothrombin time (PT), platelet count and bleeding time – Normal
  2. Activated partial thromboplastin time (aPTT) – Prolonged
    • If prolonged, mixing study is performed.
  3. Factor activity level (Factor VIII- Hemophilia A; Factor IX – Hemophilia B) provides a definite diagnosis
    • Mild: > 5%-40%
    • Moderate: 1-5%
    • Severe: <1%

Imaging

Musculoskeletal Ultrasonography (MSKUS): Point-of-care MSKUS is a fast, efficient, safe, and cost-effective imaging modality in early detection and management of hemarthrosis. It can detect bleeding in joints, synovial hypertrophy, cartilage damage, muscle hematoma, and evaluate periarticular structures (tendons, ligaments, muscles).9

Radiographs: Useful for adults with advanced joint disease. Several classifications have been developed based on radiographic findings (Arnold-Hilgartner, Petterson score). It identifies irregularity of joint space, joint effusion and epiphyseal overgrowth. It is insensitive to early changes and unreliable for cartilage or soft tissue evaluation.

CT: Non-contrast head CT is the study of choice to rule out intracranial bleeding.

MRI: High resolution for assessing hemarthrosis, synovial hypertrophy, deposits of hemosiderin, focal cartilage damage, bony destruction, subchondral bone and cysts, osseous pseudotumors and muscle bruising.7

Supplemental assessment tools

Genetic testing is offered at no cost to hemophilia individuals in US through participating Hemophilia Treatment Centers. This helps predict the risk of factor inhibitor formation and facilitates carrier identification in female family members. In suspected carriers, genetic testing is considered first line evaluation. Confirming or excluding carrier status is important both for managing the carrier herself and the offspring.6,10

Early prediction of outcomes

Children with recurrent hemarthrosis are at high risk of developing severe arthropathy and joint contractures later in life. Neuromuscular dysfunction can precede radiologic pathology of the affected joint.11 Higher grade of radiological arthropathy and deformity correlates with decrease torque of joint musculature.12

Environmental

Complete assessment of home and school environment for possible injury hazards at discharge planning.

Evaluation of sports activity and the use of sports safety equipment such as knee pads, elbow pads and helmets.13

Social role and social support system

All those involved in the care of a child with hemophilia should be informed about the diseases. The child’s caregivers, daycare providers, teachers, other school staff, and coaches should be prepared to contact parents and emergency services in case of injury13.

Professional issues

Bleeding history, physical exam and diagnostic testing should be consistent with the child’s development and level of activity. If suspected, physical abuse should be reported to the proper authorities for further investigation.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Current treatment aims to prevent musculoskeletal injuries and maintain the locomotor apparatus in optimal condition through rehabilitation and clotting factor replacement therapy. Rehabilitation requires a clinical evaluation of the patient’s physical state in order to develop a customized therapeutic program. Treatment objectives include: alleviate pain, improve joint range of motion and proprioception, prevent muscle atrophy, improve muscle power, recover balance and coordination, improve the functional capacity and gait, and ultimately reduce the frequency of joint bleeds and improve quality of life.7

At different disease stages

Pre-Bleed/Preventative Management:

  • Early prophylaxis with factor concentrates is the best method for preventing or reducing the risk of recurrent joint bleeds and arthropathy, and is typically administered for severely affected patients two to three times per week.14, 15
  • Due to cost, potential adherence challenges amongst adolescents, as well as the development of neutralizing autoantibodies (inhibitors) to FVIII/IX, new alternative therapies have become available that allow for subcutaneous administration and longer half-life. This includes humanized antibody mimicking FVIIIa function, small interfering RNAs, and gene therapy.16,17
  • Ancillary treatments include vasopressin and fibrinolysis inhibitors. DDAVP increases FVIII levels by 2.5-6 fold and can be used for hemorrhagic episodes in mild hemophilia A patients or before minor procedures. Antifibrinolytic drugs can be used prior to dental procedures and epistaxis, oral hemorrhage, or menorrhagia.16
  • Two studies showed no association of increased incidence of bleeding or joint outcome related to high impact sports or strenuous physical activity in patients receiving adequate prophylaxis.18, 19 However, the National Hemophilia Foundation recommends that patients engage in activities that it has stratified as “safe” or “moderate” while avoiding those that are “dangerous” such as football, lacrosse, and hockey.20 Each patient and sport should be evaluated prior to participation in addition to adequate adult supervision and prophylaxis.

Acute Hemarthrosis:

  • First line treatment is clotting factor replacement therapy. Rapid administration has shown to reduce the severity of the bleeding episode.7
  • Arthrocentesis should be avoided in the absence of factor therapy. It can be considered in painful joints after failure of conservative therapy.
  • Compressive bandage, static orthotics for joint immobilization, elevation, and avoidance of weight-bearing should be implemented for up to 7 days.21,22
  • Ice reduces pain, but it can delay healing, thus is indicated only within the first 6 hours of an acute bleed. Electrical stimulation can also reduce pain.22,23
  • Proper analgesia with NSAIDs, preferably COX-2 inhibitors are indicated.
  • Isometric exercises can be started to overcome the arthrogenic inhibition and accelerated atrophy that may occur.
  • Chronic Hemarthrosis: characterized by destructive synovitis, joint destruction, osteophyte formation, and ultimately hemophiliac arthropathy. 15 When tolerated, start a supervised physiotherapy program aiming to preserve muscle strength and functionality to pre-bleeding level.1,7,12
  • Progress to active range of motion (AROM) or very careful assisted active range of motion (AAROM) and avoid passive range of motion (PROM) to prevent further hemarthrosis. Balance, coordination, and proprioceptive exercises are beneficial.
  • Dynamic orthotics for pain control or functional restoration.
  • Hydrotherapy may be more effective than land exercises for pain relief.
  • Pulsed high-intensity laser therapy has been found to significantly reduce pain, improve function compared to placebo laser in children with mild to moderate hemophiliac arthropathy.24 Non-invasive synovectomy using radiation or chemical agents is indicated in refractory synovitis.14 It does not require major coverage with coagulation factors.
  • Surgical synovectomy can be performed either by open or arthroscopic approach with complete excision of the hypertrophic synovial membrane. The procedure requires more use of coagulation factors.13
  • Joint arthroplasty of the hip and knee or arthrodesis of the ankle can be considered in cases of severe deformity.

Coordination of care

A multidisciplinary approach is recommended in these patients. Primary care physician, hematologist, physiatrist, genetic counselor, physical and occupational therapist, and orthopedic surgeons are involved in the treatment. The physiatrists input is important to the patient from the point of diagnosis throughout their lifespan. It should be involved in the assessment, education and treatment of the condition.1

Patient & family education

Parents and family must: learn how to recognize signs of bleeding and be prepared for bleeding episodes; know the location of nearest certified Hemophilia Treatment Center; and be oriented about national and international support organizations.

The patient should wear a medical ID bracelet or necklace to alert any care providers about his hemophilia.13

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based

  1. Hemophilia Joint Health Score (HJHS) – is a physical examination tool appropriate for monitoring joint change over time or assessing efficacy of treatment regimens. It is useful when there is a need for orthopedic intervention, or as an outcome measure of physiotherapy interventions.25
  2. Arnold-Hilgartner classification – is a plain radiograph grading system for hemophilic arthropathy of the knee.
  3. Functional Independence Score in Hemophilia (FISH) – a performance-based assessment tool to objectively measure an individual’s functional ability.
  4. Hemophilia Activities List (HAL/PedHAL) – measures the impact of hemophilia on self-perceived functional abilities in patients.

Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Children with hemophilia are particularly vulnerable to loss of physical conditioning and becoming overweight or obese as a result of restrictions on their activity.6 Regular exercise to stimulate normal psychomotor development should be encouraged to promote toned  muscles and healthy bone mineral density, develop balance and coordination, and improve fitness.1 The role of an exercise program for the child and adult following episodes of bleeding is best discussed before the child has a joint bleed.25 Education improves compliance and patient-provider communication. Prophylactic hematological treatment makes it possible to advise patients to take part in a sport, provided that certain basic safety conditions are obeyed.7

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

A bispecific antibody, emicizumab, (FVIIIa mimetic) demonstrated efficacy in a phase 3 trial in patient with hemophilia and inhibitors. New approaches using modified factor VIII molecules are being tested for prevention and eradication of inhibitor antibodies in hemophilia A. 26

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Although several protocols exist for factor therapy prophylaxis, there are still gaps in the evidence-based knowledge regarding the patient selection, dosage and duration of treatment. Recommendations for prophylaxis should still be tailored to each individual case.1

REFERENCES

  1. Srivastava, A., A. K. Brewer, E. P. Mauser-Bunschoten, N. S. Key, S. Kitchen, A. Llinas, C. A. Ludlam, J. N. Mahlangu, K. Mulder, M. C. Poon, and A. Street. “Guidelines for the Management of Hemophilia.” Haemophilia 19.1 (2013): E1-E47. Print.
  2. Hoots, WK, Shapiro A, Heiman M. ( August 23, 2019) Genetics of hemophilia A and B. Retrived from https://www.uptodate.com/contents/genetics-of-hemophilia-a-and-b?search=hemophylia+etiology&source=search_result&selectedTitle=5%7E150#H1283462643
  3. Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [Updated 2017 Jun 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  4. K onkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. 2000 Oct 2 [Updated 2017 Jun 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  5. Zimmerman, B., and L. A. Valentino. “Hemophilia: In Review.” Pediatrics in Review 34.7 (2013): 289-95.
  6. Hoots, WK, Shapiro A. (July 16, 2019) Clinical manifestations and diagnosis of hemophilia. Retrived from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hemophilia?search=hemophilia&topicRef=1311&source=see_link
  7. No author published. ( 2019, August 30). Hemophilia. Retrived from https://www.cdc.gov/ncbddd/hemophilia/facts.html
  8. Zanon, Ezio, Renzo Manara, Marta Milan, Barbara Brandolin, Daniela Mapelli, Rodica Mardari, Sandra Rosini, and Piero Amodio. “Cognitive Dysfunctions and Cerebral Microbleeds in Adult Patients with Haemophilia A: A Clinical and MRI Pilot-study.” Thrombosis Research4 (2014): 851-55. Print.
  9. Bakeer, N., Shapiro, A. “Merging into Mainstream: The evolution of the role of point-of-care musculoskeletal ultrasound in hemophilia.” f1000research PMID: 31431824. Published online July 2019. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619375/
  10. Goodeve, A. C. “Advances in Carrier Detection in Haemophilia.” Haemophilia4 (1998): 358-64.
  11. Pietri MM, Frontera WR, Pratts IS, Súarez EL. “Skeletal muscle function in patients with hemophilia A and unilateral hemarthrosis of the knee.” Archives Physical Medicine and Rehabilitation. 1992 Jan;73(1):22-8.
  12. Strickler EM, Greene WB. “Isokinetic torque levels in hemophiliac knee musculature”. Archives Physical Medicine and Rehabilitation. 1984 Dec;65(12):766-70.
  13. No Author Published. (2019, August 31). Living with Hemophilia. Retrieved from http://www.nhlbi.nih.gov/health/health-topics/hemophilia
  14. Knobe K, Berntorp E. “Haemophilia and joint disease: pathophysiology, evaluation and management.” Journal of Comorbidity. 2011;1(1):51–59.
  15. Lobet S, Hermans C, Lambert C.Optimal management of hemophilic arthropathy and hematomas.Journal of Blood Medicine. 2014 Oct 17;5:207-18.
  16. Lanzkowsky P. Manual of Pediatric Hematology and Oncology. 5th London: Elsevier.c2011. Chapter 13, Hemostatic Disorders; p378-418.
  17. Shima M, Lillicrap D, Kruse-Jarres R. Alternative therapies for the management of inhibitors. Haemophilia. 2016; 22(5):36-41.
  18. Ross, C., N. A. Goldenberg, D. Hund, and M. J. Manco-Johnson. “Athletic Participation in Severe Hemophilia: Bleeding and Joint Outcomes in Children on Prophylaxis.” Pediatrics 124.5 (2009): 1267-272.
  19. Tiktinsky R, Kenet G, Dvir Z, et al. Physical activity participation and bleeding characteristics in young patients with severe haemophilia. Haemophilia. 2009; 15:695-700.
  20. Anderson A, Forsyth A. National Hemophilia Foundation. Playing it Safe. 2005. Available online: http://www.hemophilia.ca/files/PlayingItSafe.pdf.
  21. De la Corte-Rodriguez H, Rodriguez-Merchan EC. The current role of orthoses in treating hemophiliac arthropathy. Haemophilia. 2015 August 7; 21(6):723-730.
  22. Atilla B and Guney-Deniz H. Musculoskeletal treatment in hemophilia. EFORT Open Rev. 2019 June 3;4(6):230-239.
  23. Rodriguez-Merchan EC. Treatment of musculo-skeletal pain in hemophilia. Blood Rev. 2018 March; 32(2):116-121.
  24. Mohamed El-Shamy S & Ashraf Abdelaal Mohamed Abdelaal. Efficacy of pulsed high-intensity laser therapy on pain, functional capacity, and gait in children with haemophiliac arthropathy. Disability and Rehabilitation. 2018 February; 40(4)462-468.
  25. Feldman, Brian M., Sharon M. Funk, Britt-Marie Bergstrom, Nichan Zourikian, Pamela Hilliard, Janjaap Van Der Net, Raoul Engelbert, Pia Petrini, H. Marijke Van Den Berg, Marilyn J. Manco-Johnson, Georges E. Rivard, Audrey Abad, and Victor S. Blanchette. “Validation of a New Pediatric Joint Scoring System from the International Hemophilia Prophylaxis Study Group: Validity of the Hemophilia Joint Health Score.” Arthritis Care & Research2 (2011): 223-30.
  26. Callaghan MU, Sidonio R, Pipe S. Novel therapeutics for hemophilia and other bleeding disorders. Blood 2018;132(1):23-30)

Original Version of the Topic

Edwardo Ramos, MD, Juan Galloza, MD, Juan Perez, MD, Isabel Rutzen, MD, Natalia Betances, MD. Hemophilia in Children. Oriiginal Publication Date: 09/15/2015.

Author Disclosure

Yuxi Chen, MD
Advisory Board Honorarium and Research Grant paid to institution, Ipsen;
Monika Desai, MD
Nothing to Disclose
Dara Jones, MD
Nothing to Disclose