Hemophilia A and B

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

Print this page

This article have been viewed 1385 times

Chapter 60 Hemophilia A and B

Manuel Carcao, Paul Moorehead, David Lillicrap

Table 60-1 Factor VIII Mutant Genotype and Inhibitor Risk in Previously Untreated Hemophilia A Patients

Multidomain deletions	≈75%
Light chain nonsense mutns	30%-40%
Intron 22 inversion	20%-25%
Single domain deletions	15%-25%
Small non-A run insertions/deltns	15%-20%
Heavy chain nonsense mutns	10%-20%
Factor VIII missense mutns	<10%
Small A run insertions/deltns	<5%
Splicing mutns	<5%

Table 60-2 Methods of Factor VIII Measurement

Hemophilia Carrier Detection and Prenatal Diagnosis

As an X-linked recessive trait, hemophilia most often manifests in males. However, females may be affected by the condition in two ways: through bleeding caused by low clotting factor levels and through transmission of the trait to later generations as a hemophilia carrier.

Women who are heterozygous carriers of a hemophilic mutation may have low levels of the implicated clotting factor. This depends on the ratio of inactivation of the hemophilic and normal X chromosomes, a random process that occurs early during embryonic development. If there is markedly skewed inactivation of the normal X chromosome, the plasma level of FVIII or FIX may be correspondingly reduced, and the carrier female may have evidence of a bleeding disorder. Thus FVIII or FIX levels should be determined in all potential carrier females before adolescence when they might first manifest with menorrhagia. A low plasma level of FVIII or FIX is predictive of the carrier state, and the lower the level, the more probable the carrier diagnosis.

Aside from using clotting factor levels to determine carrier status and bleeding risk, the most definitive approach to carrier diagnosis is to use molecular genetics to identify the causative FVIII or FIX mutation. Although carrier detection studies originally used analysis of linked polymorphisms to track mutant alleles, advances in sequencing technology now enable relatively easy access to direct mutation detection.

Ideally, carrier detection should be performed after puberty but before the woman is contemplating starting a family. In many countries, testing for the carrier status of genetic disease is prohibited before adolescence so that the girl can participate in discussions of testing options.

With current molecular genetic testing strategies, the results of mutation analyses are available within a few days in urgent circumstances. However, most often, results are returned within a few weeks.

Causative mutations in the FVIII or FIX genes are found in more than 95% of carriers. If a mutation is not found, it is possible that the mutation is deep within an intron or involves a distant transcriptional element.

Prenatal diagnosis of hemophilia should begin with an evaluation of the fetal sex, which can usually be determined through an ultrasound examination. If the fetus is female, no additional studies should be performed. If the fetus is male, molecular genetic analysis can be used to identify the hemophilic mutation. Fetal DNA can be isolated from chorionic villus samples obtained after 11 weeks of gestation or from amniocytes obtained by amniocentesis from 12 to 34 weeks. The risk of miscarriage with both of these procedures is approximately 1%. If the studies are being used for decision making concerning therapeutic abortion, the tests should be performed as soon as possible. Determination of the hemophilic status of the fetus will also help plan for delivery, although consensus about the optimal obstetric management of an affected baby is lacking. Finally, recent studies suggest that free fetal DNA can be isolated from the mother’s blood, with levels increasing towards term. Examination of this material for the presence of Y chromosome sequences would allow definitive sex determination.

Table 60-3 Differential Diagnosis of a Low Factor VIII Level

FV, Factor V; FVIII, factor VIII; vWD, von Willebrand disease.

Figure 60-1 CLINICAL OUTCOME OF CHRONIC SEVERE HEMOPHILIC ARTHROPATHY.

This picture shows the legs of a 55-year-old patient with severe hemophilia A who is a wheelchair user. After a lifelong experience of multiple hemarthroses, the patient has very limited mobility. His ankles and knees show deformities, and his leg muscles are markedly atrophic because of lack of use.

Hemophilic Pseudotumors

Pseudotumors are a rare but very problematic complication in hemophilia. The most common type of pseudotumor arises as a result of repeated hemorrhages into a muscle with insufficient resorption of blood between hemorrhages. Pseudotumors become walled-off cystic structures surrounded by a fibrous membrane. They may become multivacuolated over time, and parts may become calcified. These cystic lesions frequently expand into adjacent structures, leading to their destruction. Skeletal fractures and bony deformities may arise from such lesions. Another and rarer type of pseudotumor, generally only seen in adult patients, arises from within the bone itself and is often secondary to subperiosteal bleeding. This type of pseudotumor is typically observed in the long bones of the lower extremities and in the pelvis. Pseudotumors arising distally are more common in young children and most often occur in the hand. Pseudotumors may be associated with pain from rapid growth or nerve compression.

Pseudotumors are usually diagnosed by radiological means (ultrasonography or MRI). A pseudotumor may be misdiagnosed as a neoplasm (e.g., Ewing sarcoma or osteosarcoma) or as an infection (e.g., osteomyelitis or tuberculous abscess). Biopsy of such lesions is contraindicated because of the potential for significant bleeding or infection. Small pseudotumors, particularly distal ones or pseudotumors in patients with inhibitors, are often treated conservatively with aggressive clotting factor replacement along with immobilization of the affected limb.

Unfortunately, in some instances, factor replacement alone is insufficient, and complete surgical excision is needed. This carries potential morbidity and even mortality and should only be undertaken by skilled surgeons in conjunction with appropriate hemophilia specialists. Attempts have been made at embolization of such pseudotumors, and radiation therapy has been successfully used for treatment of small pseudotumors of the hand.

Compartment Syndrome

A compartment syndrome arises when a bleed (usually trauma induced) occurs into a closed (encapsulated) space, such as the forearm or calf. The capsule restricts exit of blood, thereby raising the pressure within the compartment. This ultimately results in compression of blood vessels and obstruction of blood flow, leading to tissue ischemia and the potential for nerve and muscle damage. Compartment syndrome is characterized by severe pain and swelling, limb pallor, paresthesias, and reduced movement of the limb. Without treatment, a compartment syndrome may lead to permanent neuropathy, tissue necrosis, and even loss of the limb. This emergency condition requires urgent factor replacement and potentially surgical decompression (fasciotomy).

Table 60-4 Hemophilia A and B

	Scores	Reference
Clinical	World Federation of Hemophilia Joint score (Gilbert score)	Gilbert, Semin Hematol, 1993
	The modified WFH joint score Colorado PE-1 and PE-0.5	Manco-Johnson et al, Haemophilia, 2000
	HJHS (Hemophilia Joint Health Score)	Feldman et al, Arthritis Care Res, 2011
Plain radiography	Arnold-Hilgartner	Arnold and Hilgartner 1977
	Pettersson	Petterson et al, Acta Paediatrica, 1981
MRI	Progressive Denver scoring system	Nuss et al, Haemophilia, 2000
	Additive European scoring system	Lundin et al, Haemophilia, 2004
	Single compatible IPSG MRI scoring system	Doria et al, Haemophilia, 2008

IPSG, International Prophylaxis Study Group; MRI, magnetic resonance imaging; WFH, World Federation of Hemophilia.

Home Care

Hemophilic treatment is best administered in the patient’s home. Having a patient or other caregiver able to administer factor allows for prompt treatment of bleeds and facilitates prophylaxis. Teaching patients and families how to administer clotting factor concentrate is labor intensive and usually falls to the dedicated hemophilia clinic nurse. It often takes a long time before families become skilled at factor delivery. Most boys with hemophilia older than the age of 3 years can be treated at home after the parents are taught how to administer factor. In some children, poor venous access precludes routine factor delivery; these children often require implantation of a CVAD such as a port-a-cath or creation of an AVF. The teaching of home care is complex. Good sterile technique is critical to avoid CVAD or AVF infections. Later in life, children can be taught how to self-administer factor through peripheral veins. This is generally done in children between the ages of 8 and 12 years of age.

Table 60-5 Recommendations for Clotting Factor Replacement

CNS, Central nervous system; GI, gastrointestinal; GU, genitourinary; rFIX, recombinant factor IX; rFVIII, recombinant factor VIII.

Hip Joint Bleeds

Hemorrhage into the hip joint is uncommon compared with other joints. However, the clinical features of hip bleeds are less distinctive than those of more exposed joints, and it is possible that the incidence of hip bleeding is underestimated. Patients with a hip bleed maintain the hip joint in a partially flexed position, the position of lowest pressure. This position is similar to that seen in patients with an iliopsoas muscle bleed, causing these entities to be confused.

The management of acute hemarthrosis of the hip joint is somewhat different from that of other joints because of the vascular anatomy of the hip joint, which renders the head of the femur vulnerable to ischemia in the context of a bleed, causing raised intraarticular pressure.

Pain in the hip joint region may be caused by a range of conditions (hip joint bleed, iliopsoas muscle bleed, bleeds of surrounding muscles, retroperitoneal bleed, and appendicitis). Consequently, without appropriate imaging, a hip joint bleed may be easily misdiagnosed. Ultrasonography remains the preferred modality for investigation of hip pain because plain radiographs lack sufficient sensitivity to detect a hip joint bleed. Persistent pain despite appropriate factor replacement may indicate impending avascular necrosis and urgent consideration for joint aspiration by an experienced interventionalist (using ultrasound guidance) or by a surgeon. Graded physiotherapy should be instituted when symptomatic improvement is observed. Follow-up imaging studies (MRI, bone scan, or both) should be considered for assessment of avascular necrosis.

Related

Hematology Diagnosis and Treatment