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Hemophilia

Chapter · December 2015

DOI: 10.1016/B978-0-12-801238-3.05056-X

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 Hemophilia☆
J Schrader and M White, Creighton University, Omaha, USA
P Silberstein, Creighton University School of Medicine, Omaha, USA
Y Shiozawa, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Wake Forest University School of Medicine, Winston-
Salem, NC, USA
ã 2015 Elsevier Inc. All rights reserved.

Introduction 1
Definition 1
Classification 1
Consequences 1
Associated Disorders 2
Etiology 2
Epidemiology 2
Pathophysiology 2
Signs and Symptoms 2
Standard Therapies 2
Complications of Replacement Treatment 3
Experimental Therapies 3
References 3

Introduction

Hemophilias are a group of relatively rare bleeding disorders that are usually inherited, always in an X-linked fashion. Hemophilias
are subdivided into hemophilia A, which is a deficiency in clotting factor VIII, and hemophilia B, or Christmas disease, which is a
deficiency in clotting factor IX.

Definition

Hemophilia A is defined as a congenital deficiency in clotting factor VIII, and hemophilia B a congenital deficiency in clotting factor
IX. These hereditary deficiencies make it impossible to produce sufficient thrombin in the intrinsic pathway of the coagulation
cascade, resulting in bleeding.

Classification

The most common classification of hemophilia is based on the levels of circulating procoagulants. In severe hemophilia, there is
less than 1% of normal circulating clotting factors (<0.01 IU ml 1). Moderate hemophilia is diagnosed when there is 1–5% of
normal circulating clotting factors (0.01 to 0.05 IU ml 1). For mild hemophilia, circulating clotting factors are greater than 5%, but
less than 40% of normal (>0.05 to <0.40 IU ml 1) Handin (2001).

Consequences

The most common consequence of hemophilia is bleeding into a body structure. Most of the disability associated with this
condition is associated with joint destruction related to repeat hemarthrosis. Because of the treatment required, hepatitis or HIV
may be contracted secondary to infected blood products, although this problem is becoming less common due to increased blood
screening and the use of recombinant clotting factors.
The development of clotting factor inhibitors is a complication that can affect up to 25% of patients with hemophilia A, and
some with hemophilia B. It usually occurs in patients with the severe form of the disease that have received previous clotting factor
replacement therapy. It is an immune response that is generated against the replacement clotting factor VIII or factor IX.

☆
Change History: October 2014. Y Shiozawa made small edits in the text, updated Websites of the National Institutes of Health, and added Keywords, Abstract,
and ‘Complications of replacement treatment’ section.

Reference Module in Biomedical Research http://dx.doi.org/10.1016/B978-0-12-801238-3.05056-X 1

2 Hemophilia

Associated Disorders

Both hemophilia A and hemophilia B are associated with disorders that involve other defects in the coagulation cascade. Other
conditions that should be considered in those with bleeding problems are Von Willebrand’s disease, acquired hemophilia, other
clotting factor deficiencies (factor VII, V, X, or XI), or platelet disorders. The identification of these other conditions has important
prognostic and treatment implications.

Etiology

Hemophilia is an X-linked recessive disorder.

Epidemiology

The incidence of hemophilia A is 1 in 5000 male births, with approximately 30% of these individuals not having a family history of
this disorder. Its prevalence is 21 cases per 100 000 males, with 60% having severe disease. More than 300 abnormal clotting factor
VIII genes have been described Mannucci and Tuddenham (2001).
The incidence of hemophilia B is 1 in 30 000 male births, and its prevalence is 5 cases per 100 000 males, with 44% having
severe disease Roberts and Eberst (1993).

Pathophysiology

The gene for clotting factor VIII is located on the long arm of the X chromosome. It is 186 kb in length with 26 exons and
25 introns. Inversion of intron 22 accounts for 50% of all severe cases of hemophilia, and is present in 20% of all cases.
Approximately 30% of the mutations in this region are de novo. In the case of inherited hemophilia, males within the same
family have the same level of deficiency since they share the same defect Hoyer (1994).
The gene for clotting factor IX is 34 kb in length and composed of 8 exons and 7 introns. De novo point mutations account for
the majority of abnormalities in this gene that lead to hemophilia B Roberts and Eberst (1993).
Coagulation is a complex series of chemical reactions that allow the body to form a clot to prevent the further loss of blood.
Factors VIII and IX are located in the intrinsic arm of the coagulation cascade. The absence, or a decrease in the level, of either of
these factors will arrest the clotting process, leading to prolonged bleeding.

Signs and Symptoms

Patients with the severe form of hemophilia are usually diagnosed shortly after birth. Signs of the condition include large
cephalhematomas or profuse bleeding after circumcision.
Patients with milder forms of the disease usually present later in life. Presenting symptoms include pain, followed by swelling in
a weight bearing joint, such as a knee, hip, or ankle. The swelling and pain are caused by hemarthrosis, which is bleeding into the
joint space. The hemarthrosis causes irritation and inflammation of the synovium, with repeated episodes resulting in erosion of
the articular cartilage, fibrosis, joint ankylosis, and muscle atrophy. Bleeding can occur in any joint following a trauma Mannucci
and Tuddenham (2001).
While bleeding associated with hemophilia can occur at any site in the body, the most catastrophic bleeding is within the central
nervous system. Other complications associated with this condition include skeletal muscle hematomas, epistaxis, gastrointestinal,
and genitourinary bleeding Hoyer (1994).

Standard Therapies

The standard treatment for hemophilia involves replacement of clotting factor VIII in hemophilia A and replacement of clotting
factor IX in hemophilia B.

Agent Name Discussion

Antihemophilic factor VIII Antihemophilic factor VIII, a recombinant DNA derivative of factor VIII, is the preferred agent for the treatment of
hemophilia A. Replacement of factor VIII allows for the activation of Factor X that, together with activated Factor IX,
 Hemophilia 3

Antihemophilic factor IX
complex
Recombinant factor VII
Desmopressin (DDAVP)
Aminocaproic Acid
converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, which combines with factor XIII to form
a clot. The dose of antihemophilic factor VIII, which is usually 25–50 U/kg, is dictated by the severity of bleeding.
Antihemophilic factor IX complex is used to treat hemophilia B. This agent replaces factor IX that is needed in the intrinsic
clotting cascade. The usual dose of antihemophilic factor IX is 25–50 U/Kg administered i.v.
Recombinant factor VII is used for the treatment of either hemophilia A or hemophilia B to control bleeding episodes.
It promotes hemostatsis by activating the extrinsic pathway of the clotting cascade. It combines with tissue factor to
promote the activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa. The usual dose of
recombinant factor VII is 90 mg i.v. every 2 h until adequate hemostasis is achieved.
Desmopressin, which causes a dose-dependent increase in plasma clotting factor VIII and plasminogen activator, is used
to terminate a bleeding episode or to reduce bleeding associated with surgery. It is used primarily for the treatment of
mild hemophilia. The usual dose of desmopressin is 0.3 mg kg 1 i.v. 30 min prior to a surgical procedure. This agent
can also be given intranasally at a dose of 300 mg 2 h prior to surgery.
Aminocaproic acid is used primarily for the treatment of oral mucosal bleeding resulting from local fibrinolytic activity to
control bleeding associated with dental procedures. It competitively inhibits activation of plasminogen, reducing
fibrinolysin without inhibiting clot lysis. The usual dose of aminocaproic acid is 4–5 g i.v. for the first hour, followed by
continuous infusion at 1–1.25 g h 1 until the bleeding stops. Aminocaproic acid can also be administered orally.

Complications of Replacement Treatment

1) Development of antibodies (inhibitors) against the clotting factors

• 20-30% of hemophilia A patients and 2-5% of hemophilia B patients develop antibodies.
• Once antibodies are developed, high doses of clotting factors or switching to other clotting factors is required.
2) Virus infection
• Clotting factors can still cause viral infections (e.g. HIV, hepatitis), since they are isolated from human blood.
• The risk of viral infection has declined due to the improvement of blood screening and donor blood quality (vaccinated
donors), and the use of recombinant clotting factors.
3) Damage to joints and muscles
• Treatment delay can cause bleeding into a joint and surrounding organs, resulting in inflammation and eventual joint
deformity.

Experimental Therapies

Gene therapy for the treatment of hemophilia has been attempted. The goal of therapy is not to restore full levels of circulating
clotting factors but to stimulate enough clotting factor production to minimize bleeding episodes Roth and Tawa (2001).

References
Journal Citations
Hoyer LW (1994) Hemophilia A. New England Journal of Medicine 330(1): 38–47.
Mannucci PM and Tuddenham EG (2001) The hemophilias-from royal genes to gene therapy. New England Journal of Medicine 344: 1773.
Roberts HR and Eberst ME (1993) Current management of hemophilia. Hematology/Oncology Clinics of North America 7(6): 1269–1280.
Roth DA and Tawa NE Jr (2001) Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe Hemophilia A. New England Journal of Medicine 344(23):
1735–1742.

Book Citations
Handin R (2001) Disorders of Coagulation and Thrombosis. In: Braunwald E (ed.) Harrison’s Principles of Internal Medicine, 15th edn., pp. 751–758. USA: McGraw-Hill.

Relevant Websites
www.hemophilia.org – This website, which is maintained by the national Hemophilia Foundation, has information on research funding and resources related to hemophilia.
https://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/ – This site, which is maintained by the National Institutes of Health, provides information on hemophilia.

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