Haemophilia

 

Original Editors - Alyssa Elliott, Chelsea Reinhart

Top Contributors - Chelsea Reinhart, Alyssa Elliott, Tarina van der Stockt, Kim Jackson, Mandy Roscher, Robin Tacchetti, Elaine Lonnemann, Lucinda hampton, Tony Lowe, WikiSysop, Jess Bell, Aminat Abolade and Stacy Schiurring  

Introduction

Haemophilia is a term that describes a rare – usually inherited- bleeding disorder that leads to haemorrhage in various body parts. It has various types and each type is different according to the factor that is deficient (1). It is also known as the royal disease(2).

Definition:

Haemophilia is the most commonly known haemorrhagic disorder causing bleeding due to defects in the coagulation factors. This leads to delay in the coagulation process post injury. Haemophilia is usually an X linked recessive inherited disease; but in some rare conditions it has been found to be acquired(3).

History of Haemophilia:

The observation of bleeding disorders in males happened early in the 2nd century. The Talmud stated that if 2 brothers had bled to death after circumcision then the next brother shouldn’t be circumcised. Also in the 12th century the Arabic physician al-Zahrāwī, known as Albucasis, described the death of male family members due to excessive haemorrhage after an injury (4).

The first medical description of haemophilia was made by the physician John Conrad Otto in the 19th century. He successfully linked this bleeding disorder to a sex linked inheritance; this was followed by another genetic description of haemophilia by Nasse in 1820. He stated that haemophilia is transmitted from carrier mothers to their male offspring. Finally, the term “haemophilia” appeared in 1928 in the University of Zurich by Hopff(4).

Genetic Inheritance:

The term sex-linked refers to genes on the Sex chromosomes (usually the larger chromosome “X”)(5).

Genetic inheritance can either be dominant or recessive.

Females (XX) carry two X chromosomes. If a female carries a normal X-chromosome and a mutated X-chromosome. If the gene is recessive the female will be a carrier and will not suffer from the condition.(6) There is a 50% chance she will pass on the mutated x chromosome to her children.

Males (XY) only carry one X chromosome. If a male inherits a mutated X-chromosome he will be affected by the condition whether it is dominant or recessive.

Figure 1: X linked Recessive Inheritance(7)

Prevalence of Haemophilia:

It was estimated that haemophilia was found in 1 in each 5000 male worldwide(8). In 2019 a meta-analysis found that the number is larger than previously estimated. The researchers found that there is around 1,125,000 males that have bleeding disorders. The study also revealed that in every 100 000 males there are 17.1 with haemophilia A and 3.8 with haemophilia B (9,10).

Types of Haemophilia:

Haemophilia is usually an inherited disease; but in rare cases it can be acquired.

Inherited haemophilia

The type of haemophilia is determined according to the protein factor that defected(11).There are three known types of haemophilia(12,13):

Table 1: Comparison between types of haemophilia

	haemophilia A	haemophilia B	haemophilia C
Known as	Classical / Standard haemophilia	Christmas haemophilia	Rosenthal’s disease
Protein factor affected	Factor VIII	Factor IX	Factor XI
Genetic Inheritance	X linked recessive	X linked recessive	Autosomal recessive
Gender Affected	Mostly males	Mostly Males	Females & males equally
Severity	Mild , Moderate and Severe	Mild , Moderate and Severe	Mild

Acquired haemophilia:

Acquired haemophilia is rare and occurs as the result from an autoimmune disease that attacks the protein clotting factors (especially factor VIII) and subsequently leads to manifestations similar to haemophilia A(12).

The Royal Disease

Queen Victoria was a carrier of haemophilia B. She passed the mutated gene to three of her children. Her two daughters became carriers and her son, Prince Leopold, had haemophilia. Queen Victoria’s children married many royals across Europe and Russia. Haemophilia B was spread among royals for many generations with royals being either a carrier or haemophilic(2,14,15).

Manifestations of Haemophilia:

Children with mild haemophilia do not show any manifestation except post-injury or dental extraction. Moderate and severe haemophilliacs may experience the following manifestations(16):

·  Mouth bleeding post-dental extraction or cut.

·  Nose bleedings

·  Un-stoppable haemorrhage after a small injury or cut

·  Blood in urine and stool due to haemorrhage in the kidney / bladder/ intensines or stomach

·  Haematoma

·  Joint Bleeding

·  Muscle Bleeding

Diagnosis of Haemophilia:

Screening Tests

1. Complete Blood Count (CBC):

CBC may appear normal in persons with haemophilia. If the patient has already experienced a massive haemorrhage, the CBC count may appear low(17).

2. Activated Partial Thromboplastin Time (APTT) Test:

The APTT test measures the duration of blood clotting by measuring the clotting ability of factor VIII, IX, XI and XIII. In patients with haemophilia, the results will show a prolonged clotting time(17).

3. Prothrombin Time (PT) Test

The PT test measures the duration of blood clotting by measuring the clotting ability of factor I, II, V, VII. In patients with haemophilia the results are normal (17).

Clotting Factor Tests

Clotting factor tests are used to diagnosis haemophilia and its type and the degree of severity.  It measures the levels of factor VIII and IX (17).

Severity of haemophilia:

The severity of haemophilia is determined by the levels of clotting factor in the blood(17).

Table 2: Severity of haemophilia

Severity	Levels of Factor VIII or IX in the blood
Normal	50% to 100%
Mild haemophilia	Greater than 5% but less than 50%
Moderate haemophilia	1% to 5%
Severe haemophilia	Less than 1%

Medical Management:

Replacement Therapy

Concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B) are slowly injected into a vein to replace the missed clotting factor. These concentrates can be extracted from human blood or synthesized (recombinant clotting factor) (18).

Preventative (prophylactic) therapy

Preventative therapy encompasses the usage of replacement therapy on a regular basis to prevent bleeding(18).

Demand therapy

Demand therapy is a less intensive approach that encompasses the usage of replacement therapy only when the need arises. (18).

Complications of Replacement Therapy (18)

·  May develop antibodies that attack the clotting factor

·  Susceptible to viral infections from human clotting factors

·  Damage to joints, muscles, or other parts of the body resulting from bleeding as a result of delays in treatment

Other Types of Treatment

Other types includes Desmopressin (stimulates the production of the clotting factors), Antifibrinolytic Medicines and gene therapy(18).

Table 3: Recommended Treatment according to the severity of haemophilia

Severity of haemophilia	Recommended Medical Management
Mild haemophilia	Desmopressin No replacement therapy
Moderate haemophilia	Desmopressin Replacement therapy during bleeding / prevent bleeding prior certain activities  or surgeries
Severe haemophilia	Replacement therapy

Physical Therapy Management:

The National haemophilia  Foundation formed a physical therapy working group that created the best physical therapy practice for bleeding disorders including haemophilia (19).

The Medical and Scientific Advisory Council (MASAC) recommends physical therapy management in haemophilia because the most common manifestation is joint and muscle bleeding(20).

Joints that have recurrent bleedings in haemophilia are known as “Target Joints”. The most common target joints are knee, elbow, ankle, hip and shoulders (19).

The physiotherapy management of haemophilia is very similar to the management of Von Willebrand Disease.

Physical Therapy Evaluation

According to the MASAC; the purpose of an evaluation is to detect the musculoskeletal and activities limitations caused by haemophilia(21).

History and Interview (21):

The patient and/or the caregiver is interviewed and the history is taken:

·  Personal history.

·  Family history.

·  Bleeding history.

·  Medical and surgical history.

·  Pain history.

·  ADL concerns.

·  Occupational concerns.

Physical Examination

·  Palpation of joints at rest and during active range of motion to detect crepitus, synovitis, edema or temperature.

·  Girth measurement to assess edema/ muscle atrophy.

·  Atypical Joint End feel detection via passive range of motion.

·  Manual Muscle Testing to assess muscular strength.

·  Muscle Flexibility test.

·  Sensation and proprioception.

·  Balance and fall assessment.

·  Posture and alignment assessment.

·  Assessment of functional activities.

·  Gait analysis.

·  Neuromotor assessment.

·  Musculoskeletal Ultrasound.

Physical Therapy Treatment:

The recommended physical therapy program by MASAC for muscles and joints bleeding is different in each recovery phase. There are three recovery phases: Acute, Subacute and Chronic. All muscles follow a specific guidelines, except for iliopsoas muscle, and all physical therapy suggested protocols are performed post factor replacement medication as follows(22–24) :

Table 4: Physical Therapy Guidelines in Different Recovery Phases of haemophilia

	Acute Phase	Subacute Phase	Chronic	Precautions
Muscles Bleeding except iliopsoas	Main Problem: Present pain at rest and with movement	Main Problem : Limitations in ADL without increasing pain from baseline	Main Problem : ADL limitation but without pain	- Monitor for neurovascular compromise while Splinting - Caution with use of compression on affected muscle. - Use of heat modalities including ultrasound  with precautions - Ultrasound for blood absorption can be used with precautions.
	Physical Therapy Program: - No compression in case of neuromuscular symptoms. - No active movement or weight bearing till bleeding stoppage. - Splinting. - RICE: Rest, Ice, Compression & Elevation - TENS	Physical Therapy Program: - Splinting and assistive device to limit activity - Toe touch Weight bearing - Isometric contractions - Active range of motion - Positioning - AAROM without pain - TENS	Physical Therapy Program: - Full Weight Bearing without assistive devices - Positional stretching -  Active Range of Motion exercises - unrestricted lifting - Re-evaluation.
Iliopsoas Muscle Bleeding	Main Problem: pain presented at rest and with movement	Main Problem : ADL limitation without increase pain from baseline	Main Problem : ADL limitation but without pain	Monitor for femoral nerve palsy
	Physical Therapy Program : -   Bedrest -   Toe Touch Weight Bearing for household mobility -   Rest -   Opposite limb ROM Ankle pumps involved lower limb with pain avoidance	Physical Therapy Program: -   Toes touch weight bearing without increase in pain -   Isometric contractions -   Active Range Of Motion exercises to involved Lower limb without increase in pain -   Positioning with increasing hip extension Range Of Motion in supine and prone over pillows without increase in pain. -   therapeutic exercises for non-involved limb	Physical Therapy Program: -   Full Weight Bearing without  assistive devices -   positional stretches from prone position -   Active range of motion exercises -   Re-evaluation
Joint Bleeding	Main Problem: pain presented at rest and with movement	Main Problem : ADL limitation without increase pain from baseline	Main Problem : ADL limitation but without pain	-   Avoid aggressive exercise too early -   Monitor for nerve compression -   Use of heat modalities including ultrasound with precautions -    No return to sports or activity until pain-free full ROM and strength
	Physical Therapy Program : -   RICE (ice for 10-20 minutes every 1-2 hours) -    Splinting -    Non Weight Bearing using  assistive device	Physical Therapy Program : -    Continue RICE for pain and after exertion Splinting -   Night resting splint for protection -   Begin progressive weight bearing -   Activity modification to avoid pain -    Pain-free gentle active Range of motion -    Pain-free progressive strengthening	Physical Therapy Program : -   Dynamic splinting to increase ROM -   Active range of motion Progressive -   Strengthening as Open chain, closed chain and resistive band -   proprioceptive training -   Gentle joint mobilizations -   Modified functional activities -   Orthotics -   Reevaluations

There are also some modalities and physical therapy tools that have been researched across the years to help patients with haemophilia.(25).

Kinesio Tape

It was shown the Kinesio tape plays a role in haemophilia by supporting the muscles, allowing joint movement with support, decreasing pain and decreasing hematoma(26).

Video 4: How to treat a bruise / haematoma / swelling of the quadriceps using kinesiology tape

Transcutaneous Electrical Neurostimulation (TENS)

It was shown that TENS has an impact on reducing pain for patients with haemophilia. It is applied as a low intensity electrical impulse to stimulate peripheral nerves. That inhibits pain information transmission along nerves (27).

Manual Therapy

Manual therapy such as fascial therapy, passive mobilization and stretching; manual orthopaedic therapy and proprioception training are recommended for physical therapy management for cases with haemophilia (28,29), but joint traction as a manual therapy technique (30) .

haemophilia is a congenital X-linked bleeding disorder in which blood does not properly clot. It is categorized as a disorder of haemostasis. haemostasis, the stopping of bleeding after a blood vessel is injured, normally is divided into two separate processes—primary and secondary haemostasis. In haemophilia, secondary haemostasis (which essentially results in the formation of a fibrin clot) is defected. Thus, deficient clotting is due to an abnormality of the functional plasma-clotting proteins, factors VIII and IX, that are involved in this process.

Differential Diagnosis

It is important to ensure haemophilia is properly diagnosed. Below are other medical issues or impairments that may present similarly and if not diagnosed appropriately could lead to a variety of medical issues.

• Nerve impingement: A person with haemophilia may experience bleeding into the iliacus muscle or the psoas. Bleeding in these areas can apply pressure to the femoral nerve branch that supplies the skin of the anterior thigh and a person may have loss of sensation.
• Appendicitis: A person with haemophilia may have symptoms that mimic appendicitis when they have muscle bleeding on the right side in their lower abdomen.
• Disseminated Intravascular Coagulation (DIC)
  
• Von Willebrand Disease (VWD)
• Thrombocytopenia
  

Case Reports/ Case Studies

1. Girardi D da M, Silva DRA, Villaça PR, Souza CE, Fonseca LG, Bastos DA, Hoffa PMG. Acquired haemophilia A in a patient with advanced prostate cancer. Journal of Autopsy & Case Reports. 2015;5(2):55-59.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584669/

2. Iioka F, Shimomura D, Nakamura F, Ohno H, Yada K, Nogami K, Shima M. Long-term treatment course of a patient with mild haemophilia A who developed a high titre factor VIII inhibitor. Journal of Haemophilia. 2014;20(6):e402-e404.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232888/

3. Janbain M, Leissinger CA, Kruse-Jarres R. Acquired haemophilia A: emerging treatment options. Journal of blood medicine. 2015;6:143-150.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431493/

Resources

• National haemophilia Foundation: https://www.haemophilia.org/

• Genetics Home Reference page for haemophilia: https://ghr.nlm.nih.gov/condition/haemophilia

• CDC page for haemophilia: http://www.cdc.gov/ncbddd/haemophilia/

• Information for people with haemophilia: http://www.cdc.gov/ncbddd/haemophilia/people.html

• haemophilia Federation of America: http://www.haemophiliafed.org/

• Merck Manual Professional Version: haemophilia: http://www.merckmanuals.com/professional/hematology-and-oncology/coagulation-disorders/haemophilia

• Merck Manual Consumer Version: haemophilia: http://www.merckmanuals.com/home/blood-disorders/bleeding-due-to-clotting-disorders/haemophilia

• Steps for Living - haemophilia: https://stepsforliving.haemophilia.org/basics-of-bleeding-disorders

References

see adding references tutorial.