Hemophilia in children

Author(s): Edwardo Ramos, MD, Juan Galloza, MD, Juan Perez, MD, Isabel Rutzen, MD, Natalia Betances, MD

Originally published:09/15/2015

Last updated:09/15/2015

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, with about 30% of cases being new spontaneous mutations.1 X-linked recessive transmission means that all daughters of an affected father will be carriers, sons of carrier mothers have a 50% chance of inheriting the disease, and daughters of carrier mothers have a 50% chance of being carriers.

Epidemiology including risk factors and primary prevention

Hemophilia occurs most commonly in patients with family history of hemophilia and will have a male predominance due to its X-linked recessive association. Hemophilia A, which is more common, occurs in 1:5000 male births, whereas hemophilia B occurs in 1:30,000 male births.2 Hemophilia is found throughout all ethnic groups with no correlation found by race or geography. Actual genes for factor VII and IX are on the X chromosome which could make females affected as carriers if factor levels are below 60%.3 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.2 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 regard to disease classification and clinical features. This classification is based on residual factor levels which correlate with bleeding severity. Bleeding episodes may be seen as soon as in utero, and intracranial bleeding, prolonged bleeding during circumcision or phlebotomy should raise flags regarding hemophilia diagnosis. Most patients with severe hemophilia (90%) will present with symptoms during the first year. Depending on severity of the disease, patients will present with recurrent episodes of traumatic or spontaneous bleeding. Recurrent bleeding into joints can progress to joint arthropathy and contractures causing severe disability.3

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 which may cause joint deformity, muscle atrophy, soft tissue contractures and chronic arthropathy.

Intracranial bleeding is relatively rare.5

2. ESSENTIALS OF ASSESSMENT

History

A detailed history is essential. It should include patient age, sex, past medical 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).2

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 and joint deformity. 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.6

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%
    • Moderate: 1-5%
    • Severe: <1%

Imaging

Radiographs: Useful for adults with advanced joint disease. Several classifications have been developed based on radiographic findings (Arnold-Hilgartner, Petterson score). Used to identify irregularity of joint space, joint effusion and epiphyseal overgrowth.

Ultrasonography: this is appropriate in the early stages of the disease. It can detect bleeding in joints, synovial hypertrophy, and cartilage damage. It is the most useful diagnostic test in evaluating muscle hematoma.3

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

MRI: It has high resolution for assessing hemarthrosis, synovial hypertrophy, deposits of haemosiderin, focal cartilage damage, bone damage, subchondral bone and cysts, osseous pseudotumors and muscle bruising.3

Supplemental assessment tools

Genetic testing is usually reserved for cases in which factor testing is not definitive and can be targeted to the specific mutation in the proband.7 In suspected female carriers, genetic testing is considered first line evaluation. This is useful for the evaluation of the carrier and the offspring.8 Prenatal chromosomal analysis is uncommon. It is useful in the identification of disease in a fetus from a female carrier.

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.9 Higher grade of radiological arthropathy and deformity correlates with decrease torque of joint musculature.10

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.11

Social role and social support system

All those involved in the care of a child with this condition should be informed about the diseases. The child’s babysitters, daycare providers, teachers, other school staff, and coaches should be prepared to contact parents and emergency services in case of injury11.

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. The objectives of the treatment are to alleviate the pain, recover the range of movement in the joint, 
prevent muscle atrophy, improve muscle power and strength, 
recover proprioception, 
prevent sequelae and deformities, improve the functional abilities, 
maintain an appropriate pattern of movement when walking, 
reduce the frequency of joint bleeds, and 
improve the quality of life.3

At different disease stages

  1. First line treatment is clotting factor replacement therapy. Rapid administration has shown to reduce the severity of the bleeding episode.3
  2. Arthrocentesis should be avoided in the absence of factor therapy. It can be considered in painful joints after failure of conservative therapy.
  3. Proper analgesia. NSAIDs, preferably COX-2 inhibitors are indicated. Physical modalities such as ice, and electrical stimulation.1
  4. Orthoses for pain control or functional restoration.
  5. When tolerated, a supervised physiotherapy program aiming to preserve muscle strength and functionality to pre-bleeding level.1,3,10
  6. If active bleeding, start with isometric exercises to overcome the arthrogenic inhibition and accelerated atrophy that may occur.
  7. 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 joint bleed.
  8. Early prophylaxis with factor concentrates is the best method for preventing or reducing the risk of recurrent joint bleeds and arthropathy.12
  9. Participation in sports is allowed in these patients under appropriate coaching and supervision. There is no association of increased incidence of bleeding or joint outcome related to high impact sports in patients receiving adequate prophylaxis.14 Individual characteristics of each patient and each sport should be evaluated prior to recommendations.
  10. Non-invasive synovectomy using radiation or chemical agents is indicated in refractory synovitis.12 It does not require major coverage with coagulation factors.
  11. Surgical synovectomy consists in conducting as complete a surgical excision as possible of the hypertrophic synovial membrane. This procedure can be performed either by open or arthroscopic approach.13
  12. Contrary to non-invasive synovectomy, the surgical synovectomy requires more use of coagulation factors to undergo the procedure.13
  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

  1. Parents should learn how to recognize signs of bleeding and be prepared for bleeding episodes when they occur.
  2. The patient should wear a medical ID bracelet or necklace to alert any care providers about his hemophilia.11
  3. Patients and family should know the location of nearest certified Hemophilia Treatment Center.
  4. Patients and family should be oriented about national and international support organizations.

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.15
  2. Arnold-Hilgartner classification – is a plain radiograph grading system for haemophilic 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.16 Regular exercise to stimulate normal psychomotor development should be encouraged to promote strong muscles, 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.15 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.3

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

There are ongoing clinical trials showing promising results for the use of gene therapy to treat hemophilia. One trial has shown an increase in factor function and decreased bleeding episodes with minimal side effects for the 4 years the patients were followed.17

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. Zimmerman, B., and L. A. Valentino. “Hemophilia: In Review.” Pediatrics in Review 34.7 (2013): 289-95. Print.
  3. No Author Published. (2014, August 26). Hemophilia. Retrieved from http://www.cdc.gov/ncbddd/hemophilia/facts.html.
  4. Corte-Rodriguez, Hortensia De La, and E. Carlos Rodriguez-Merchan. “The Role of Physical Medicine and Rehabilitation in Haemophiliac Patients.” Blood Coagulation & Fibrinolysis 24.1 (2013): 1-9. Print.
  5. Franchini, Massimo, and Pier Mannuccio Mannucci. “Hemophilia A in the Third Millennium.” Blood Reviews 27.4 (2013): 179-84. Print.
  6. 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 Research 134.4 (2014): 851-55. Print.
  7. No Author Published. (2014). Hemophilia Carrier Testing. Retrieved from http://www.stepsforliving.hemophilia.org/basics-of-bleeding-disorders/genetics-of-bleeding-disorders/hemophilia-carrier-testing.
  8. Goodeve, A. C. “Advances in Carrier Detection in Haemophilia.” Haemophilia 4.4 (1998): 358-64.
  9. 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.
  10. Strickler EM, Greene WB. “Isokinetic torque levels in hemophiliac knee musculature”. Archives Physical Medicine and Rehabilitation. 1984 Dec;65(12):766-70.
  11. No Author Published. (2013, July 31). Living with Hemophilia. Retrieved from http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/livingwith
  12.  Knobe K, Berntorp E. “Haemophilia and joint disease: pathophysiology, evaluation and management.” Journal of Comorbidity. 2011;1(1):51–59
  13. Lobet S, Hermans C, Lambert C.Optimal management of hemophilic arthropathy and hematomas.Journal of Blood Medicine. 2014 Oct 17;5:207-18.
  14. 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.
  15. 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 & Research 63.2 (2011): 223-30.
  16.  Hoots K, Shapiro A. (2014, December 3). Treatment of Hemophilia. Retreived from http://www.uptodate.com/contents/treatment-of-hemophilia?source=search_result&search=treatment+of+hemophilia&selectedTitle=1~122
  17. St. Jude Children’s Research Hospital. Dose-Escalation Study of a Self-Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2015 Mar 17]. Available from: http://clinicaltrials.gov/show/NCT00979238 NLM Identifier: NCT00979238.

Author Disclosure

Edwardo Ramos, MD
Speaker Honorarium, Allergan

Juan Galloza, MD
Nothing to Disclose

Juan Perez, MD
Nothing to Disclose

Isabel Rutzen, MD
Nothing to Disclose

Natalia Betances, MD
Nothing to Disclose

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