CRISBERT I. CUALTEROS, M.D. - hemophilia A & B
   
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CRISBERT I. CUALTEROS, M.D. (+63919)8586556
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What Is Hemophilia?

Hemophilia (heem-o-FILL-ee-ah) is a rare, inherited bleeding disorder in which your blood doesn’t clot normally. If you have hemophilia, you may bleed for a longer time than others after an injury. You also may bleed internally, especially in your knees, ankles, and elbows. This bleeding can damage your organs or tissues and, sometimes, be fatal.

People born with hemophilia have little to none of a protein needed for normal blood clotting. The protein is called a clotting factor. There are several types of clotting factors, and they work together with platelets to help the blood clot. Platelets are small pieces of blood cells that are formed in the bone marrow. They play a major role in blood clotting.

When blood vessels are injured, clotting factors help the platelets stick together to plug cuts and breaks at the site of the injury to stop the bleeding. Without clotting factors, normal blood clotting can’t take place. Sometimes people with hemophilia need injections of a clotting factor or factors to stop bleeding.

There are two main types of hemophilia. If you have hemophilia A, you have little to no clotting factor VIII (8). About 9 out of 10 people with hemophilia have type A. If you have hemophilia B, you’re missing or have low levels of clotting factor IX (9).

Hemophilia can be mild, moderate, or severe, depending on how much clotting factor is in the blood. About 7 out of 10 people who have hemophilia A have the severe form of the disorder. People who don’t have hemophilia have a factor VIII activity of 100 percent; people who have severe hemophilia A have a factor VIII activity of less than 1 percent.

In addition to being inherited, hemophilia also can be acquired, which means that you can develop it during your lifetime. It can develop if your body forms antibodies to the clotting factors in your bloodstream. The antibodies can block the clotting factors from working. Only inherited hemophilia is discussed in this article.

About 18,000 people in the United States have hemophilia. Each year, about
400 babies are born with the disorder. Hemophilia usually occurs nly in males (with very rare exceptions).

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Author: Hadi Sawaf, MD, Director, Pediatric Hematology-Oncology, Department of Pediatrics, St John's Hospital of Detroit; Clinical Assistant Professor, Wayne State University

Hadi Sawaf is a member of the following medical societies: American Academy of Pediatrics

Coauthor(s): Adonis Lorenzana, MD, Consulting Staff, Department of Pediatrics, St John Hospital and Medical Center; Lawrence Jardine, MD, Director of Hemophilia Treatment Center, Children's Hospital of Western Ontario

Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University

Author and Editor Disclosure

Synonyms and related keywords: hemophilia a, hemophilia b, factor VIII deficiency, FVIII deficiency, factor VIII hemophilia, factor IX deficiency, FIX deficiency, factor IX hemophilia, Christmas disease, angiostaxis, coagulation disorder, coagulation deficiency, bleeding disorder

Background

Hemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII (FVIII) and factor IX (FIX), respectively. They account for 90-95% of severe congenital coagulation deficiencies. The 2 disorders are considered together because of their similar clinical pictures and similar patterns of inheritance.

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF).

A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not appreciated at the time. In 1953, decreased factor FVIII in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors.

In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. This disease was distinct from "hemophilia" because mixing plasma from a patient with "true hemophilia" and one with Christmas disease, corrected the clotting time; thus, hemophilia A and B were differentiated.

In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

In the 1980s, the risk of transmitting viral contaminants in commercial FVIII concentrates became increasingly recognized. By the mid-1980s, most patients with severe hemophilia had been exposed to hepatitis A, B, and C viruses and human immunodeficiency virus (HIV). New viricidal techniques have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and C exposures. The present standard of using recombinant products in the treatment of hemophilia virtually eliminates the risk of viral exposure.

Pathophysiology

The role of the coagulation system is to produce a stable fibrin clot at sites of injury. The clotting mechanism has 2 pathways: intrinsic and extrinsic.

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation. In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates FIX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.

In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.

In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested.

FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly alter clot formation and, as a consequence, result in clinical bleeding.

Frequency

United States

Hemophilia A is much more common than hemophilia B. The prevalence of hemophilia is 1 case per 5,000 males; 80-85% of these cases are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities. Approximately 17,000 persons have hemophilia in the United States. About 60% of cases are severe.

International

Hemophilia has a worldwide distribution.

Race

Hemophilia affects all racial groups.

Sex

Both Hemophilia A and B are X-linked recessive disorders; therefore, they affect males almost exclusively. Reports of affected females are rare, and these cases are attributed to extreme lyonization or the presence of 2 independent mutations.

Age

Significant deficiency in FVIII or FIX may be evident in the neonatal period and continue through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia.



Physical

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which typically is the result of vasculitis or abnormalities in the number or function of platelets.

Hemophilia is classified according to the clinical severity as mild, moderate, or severe. Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% FVIII activity and bleed only after significant trauma or surgery.

Table 1. Severity, Factor Activity, and Hemorrhage Type

Classification Factor Activity, % Cause of Hemorrhage
Mild

>5

Major trauma or surgery
Moderate 1-5 Mild-to-moderate trauma
Severe <1 Spontaneous, hemarthrosis


 

Causes

Both of these disorders are inherited in an X-linked recessive pattern. The genes for FVIII and FIX are located on the long arm of the X chromosome in bands q28 and q27, respectively. The factor VIII gene is one of the largest genes; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kD. It includes 3 A domains, 1 B domain, and 2 C domains. Factor IX contains 415 amino acids and has a molecular weight of 57,000 d. The gene that encodes this protein is 33 kb and contains 8 exons and 7 introns.

Numerous mutations in the gene structure have been described. Genetic abnormalities include genetic deletions of variable size, abnormalities with stop codons, and frame-shift defects. Recent data suggest that 45% of severe hemophilia A cases result from an inversion mutation. Several hundred mutations with different amino acid substitutes have been described in hemophilia B. These mutations include partial and total deletions, missense mutations, and others that result in the decreased or absent production of factor IX or the production of an abnormal protein. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

 



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Hemophilia C
Von Willebrand Disease


Lab Studies

 

  • Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. Severe hemophilia is easily identified with a significantly prolonged aPTT.
  • Bleeding times, prothrombin times, and platelet counts are normal.
  • The diagnosis is based on functional assay results for FVIII and FIX. Usually, immunoassay of these factors is not required for diagnosis, but it assists in identifying dysfunctional coagulation problems in some patients with hemophilia.
  • Usually, vWF is also measured. The combination of low FVIII and low vWF may indicate vWF deficiency as the primary diagnosis.
  • Because FVIII and FIX are large molecules that do not cross the placenta, the diagnosis can be made at birth by means of quantitative assay of coagulation factors in the cord blood.
  • Early diagnosis of FIX deficiency is complicated by the physiologic reduction of vitamin K–dependent factors in young infants.
  • Other laboratory evaluations in the patient with hemophilia are a periodic screening for the presence of FVIII or FIX inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. This may be less important in populations who receive only recombinant product.

 

Other Tests

 

  • Fetal testing
    • If the mutation is known, then restriction fragment length polymorphism (RFLP) can be performed on chorionic villous or amniocentesis samples.
    • Inversion of the factor VIII gene can be detected by Southern blot.
    • If the mutation is not known, gene sequencing can be done.
  • Carrier testing
    • A reduced factor VIII C to vWF antigen ratio below 0.7 is suggestive of carrier status.
    • Direct genetic testing for known gene mutation is more accurate.
    • Linkage analysis by RFLP in multiple family members can be used.
    • Factor IX level is often normal in factor IX carriers.
    • Direct mutation analysis is available in several laboratories for unknown factor VIII or IX mutations.

 



Medical Care

Current treatment of patients with hemophilia requires a comprehensive multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Comprehensive care clinics are supported by evidence of better access to care, less morbidity, and better overall outcome.

Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability. For most mild hemorrhages, dose calculations are directed toward achieving an FVIII activity level of 30-40% or FIX activity level of 30% and clotting factor activity of at least 50% in severe bleeds (eg, major dental surgery, major surgery, trauma) and 80-100% in life-threatening hemorrhage.

Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work. Patients are treated with prophylaxis or intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.

In most countries with access to recombinant product, prophylaxis is primary, ie, therapy is started in patients as young as 1 year and continues into adolescence. A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. In situations in which this is not feasible, secondary prophylaxis, ie, therapy after a target joint has been established to prevent worsening of the joint, is instituted for a defined period. Dosing is designed to maintain trough levels greater than 2%. This usually requires the administration of FVIII 3 times per week or FIX 2 times per week.

The treatment of hemophilia may involve the management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, and treatment of patients with factor inhibitors.

Management of hemostasis

Hemostasis is achieved with replacement therapy aimed at correcting the coagulation factor deficiency. The dose and frequency of administration are calculated as outlined in Table 2.

Table 2. Replacement Therapy Dose Calculations

Factor

Half-Life, h

Increase After 1 U/kg, %

Required Activity for Common Bleeding, %

VIII

8-12

2

40

IX

24

1

30

Management of bleeding episodes

  • Musculoskeletal bleeding
    • The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.
    • Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.
    • Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.
    • Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply.
    • Aseptic necrosis of the femoral head can be complications in hip joint hemorrhages. Administer adequate replacement therapy for at least 3 days.
    • Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.
    • Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension.
    • Ultrasonography in the involved region may demonstrate a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.
    • Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII or FIX.
    • Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.
  • Oral bleeding
    • Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.
    • Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.
    • Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.
    • Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.
  • GI bleeding
    • GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause.
    • Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII coagulant or FIX.
  • Intracranial bleeding
    • Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare.
    • If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.
    • All head injuries must be managed with close observation and investigated by imaging such as CT or MRI.
    • Prophylactically infuse the factor.
    • In addition, if the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Factor replacement products and medications

  • FVIII products
    • A variety of products are available for replacement therapy. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia A and B because of the lack of safe viral elimination and concerns regarding volume overload. Many plasma-derived FVIII concentrates are commercially available.
    • Various purification techniques are used to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation.
    • Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of the presence of inhibitor appear to be unwarranted.
    • With wider availability of improved products (stability, purity) use of continuous infusion of factors has increased incrementally. Continuous administration of antihemophiliac factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods of time.
    • Besides improved hemostasis, continuous infusions decreases the amount of factor used, which can result in significant savings.
    • The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery.
    • In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.
  • Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP)
    • DDAVP is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia.
    • It stimulates a transient increase in plasma FVIII levels and results in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures.
    • It can be administered intravenously at a dose of 0.3 mcg per kilogram of body weight.
    • Its peak effect is observed in 30-60 minutes.
    • A concentrated DDAVP intranasal spray is available. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.
    • Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed.
    • The major adverse effects of DDAVP are asymptomatic facial flushing and hyponatremia.
  • Antifibrinolytics
    • Aminocaproic acid (Amicar), or EACA, is administered to patients with hemophilia to control mucosal bleeding, such as oral bleeding or bleeding after dental extractions.
    • It neutralizes fibrinolytic activity in the saliva.
    • With the cloning of FVIII and FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy is an area of intense research, and human trials are underway.

Table 3. Replacement Therapy for Hemorrhage in Hemophilia A and B

Site of Bleeding

Required Factor Level, %

Dose in Hemophilia A

Dose in Hemophilia B

Joint 30-50   30-40 U/kg q2d
Muscle 40-50 20-40 U/kg/d 40-60 U/kg q2d
Oral mucosa 50, add EACA 25 U/kg 50 U/kg
Epistaxis 80-100, then 30 until healed 40-50 U/kg, then 30-40 U/kg/d 80-100 U/kg, then 70-80 U/kg q2d
GI tract 100, then 30 until healed 40-50 U/kg, then 30-40 U/kg q 80-100 U/kg, then 70-80 U/kg q2d
Genitourinary tract 100, then 30 until healed 40-50 U/kg, then 30-40 U/kg/d 80-100 U/kg, then 70-80 U/kg q2d
CNS 100, then 50-100 for 10-14 d 50 U/kg, then 25 U/kg q12h or continuous infusion 100 U/kg, then 50 U/kg/d
Trauma or surgical site 100, then 30-50 until healed 50 U/kg, then q12h or continuous infusion 100 U/kg, then qd

Prophylactic factor infusions

Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic regimes of factor concentrate infusions that take place at home and are usually given by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to the joint. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method. But this approach is not universally accepted, with only about one half of children with hemophilia A and one third of children with hemophilia B receiving this treatment modality in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability, repeated venipunctures, cost, and others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects.

Treatment in patients with factor inhibitors

Inhibitors to FVIII develop in 25-35% of children with severe hemophilia A; inhibitors to FIX develop in 1-3% in children with hemophilia B. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII. Both patient- and product-specific factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development (FVIII and FIX). Also, inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development. As for recombinant FVIII products, no new inhibitors have been known to develop in previously treated patients, and inhibitors develop in as many as 30% of previously untreated patients (PUPs). In PUPs, the titer of the inhibitors is low in half and transient in one third.

In the treatment of patients with low-titer FVIII inhibitors (<5 Bodansky units [BU]), bleeding can be controlled with human FVIII administered at standard or higher doses. In patients with high-titer inhibitors, immune tolerance induction (ITI) may be used to reduce or suppress the inhibitor. Therapeutic options include standard or activated prothrombin complex concentrate (PCC); recombinant factor VIIa (NovoSeven); and porcine FVIII (Hyate:C), if no cross-reacting antibodies are present. In patients with high-titer FIX inhibitors, ITI is less successful compared with that in patients with FVIII inhibitors. Therapeutic options are the same for these patients as for those with FVIII inhibitors, with the same doses. Patients with hemophilia B and inhibitors can have anaphylactic reactions to FIX infusions.

Gene transfer therapy

Previous clinical trials have suffered from transient, subtherapeutic expression of human FVIII transgenes. More recently, porcine FVIII retroviral gene was successfully transferred into genetically immunocompetent hemophilia A mice. FVIII expression was sustained beyond 10 months.

 

Consultations

A genetic counselor may be consulted. Genetic testing for hemophilia A and B is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

Annual dental evaluation is recommended. A neurologist and neurosurgeon should be consulted when necessary, and consultation with an orthopedic surgeon should be considered in situations involving significant or repeated hemarthrosis.

 

Activity

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning.



 

Drug Category: Hemostatic agent

 

These are used in the treatment of excessive bleeding in the oral mucosa that results from local fibrinolytic activity.

Drug Name Aminocaproic acid (Amicar)
Description Competitively inhibits activation of plasminogen, reducing fibrinolysin without inhibiting clot lysis. Widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal.
Adult Dose 5 g PO first h followed by 1-1.25 g/h for about 8 h or until bleeding stops
4-5 g IV first h followed by continuous infusion at 1-1.25 g/h; continue for 8 h or until bleeding stops
Pediatric Dose 100-200 mg/kg PO initially, followed by a maintenance dose of 100 mg/kg q6h; not to exceed 30 g
100 mg/kg or 3 g/m2 IV initially, followed by continuous infusion of 33.3 mg/kg/h or 1 g/m2/h; not to exceed 18 g/m2/d
Contraindications Documented hypersensitivity; evidence of active intravascular clotting process; can be lethal in patients with DIC (important to differentiate hyperfibrinolysis and DIC)
Interactions Coadministration with estrogens may increase in clotting factors, leading to a hypercoagulable state
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Do not administer unless diagnosis of hyperfibrinolysis is definite; caution in cardiac, hepatic, or renal disease

 

 

Drug Category: Antihemophilic agent, hemostatic agent, vasopressin analog, synthetic

 

These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.

Drug Name Desmopressin (DDAVP, Stimate)
Description Main effect is enhancement of water reabsorption in the kidney and smooth muscle constriction. Causes dose-dependent increase in plasma FVIII and plasminogen activator.
Adult Dose IV: 0.3 mcg/kg slow infusion 30 min before procedure
Intranasal: 300 mcg (1 spray per nostril) 2 h before surgery; may repeat use, depending on clinical situation
Pediatric Dose 0.3 mcg/kg IV slow infusion; may repeat prn; administer 30 min before procedure; maximum dose is 20 mcg.
>12 years:
<50 kg: 150 mcg intranasally (1 spray in each nostril)
>50 kg: 300 mcg intranasally (1 spray in each nostril)
Repeat use is determined by clinical situation; administer 2 h before surgery
Contraindications Documented hypersensitivity; avoid in type IIB or platelet-type von Willebrand disease, hemophilia A ( <5%), hemophilia B; avoid intranasal route with mucosal changes (congestion, obstruction, scarring)
Interactions No known interactions related to antihemophilic effect
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Predisposition to thrombus formation; conditions associated with fluid and electrolyte imbalance (eg, cystic fibrosis)

 

 

Drug Category: Antihemophilic agent; blood product or recombinant DNA derivative

 

These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.

Drug Name Antihemophilic factor (Alphanate, Hemofil M, Humate-P, Koate-HP, Koate-HS)
Description FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.
Adult Dose 20-50 U/kg/dose
IV q12-24h; higher doses may be used (eg, 50-75 U/kg with high inhibitor titers); individualize doses according to clinical situation; may administer more frequently in special circumstances
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; documented hypersensitivity to mouse proteins
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Viral contamination and infection remotely possible but unlikely because of prescreening; risk of hemolysis with anemia in blood groups A, B, and AB is due to trace amounts of A and B isohemagglutinins

 

 

Drug Category: Antihemophilic agent; blood product derivative

 

These used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.

Drug Name Factor IX Complex (Konyne 80, Profilnine Heat-Treated, Proplex SX-T, Proplex T)
Description Replaces deficient FIX and other factors in the complex. AlphaNine and Mononine contain only FIX. BeneFix is a recombinant product.
Adult Dose 20-50 U/kg IV; individualize doses according to clinical situation; may administered higher doses and qd or more frequently in special cases Patients who are also receiving FVIII: 75-100 U/kg IV q6-12h
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; liver disease, DIC, fibrinolysis
Interactions Increased risk of thrombosis (FIX complex) with aminoproic acid (delay aminocaproic acid dose by 8 h)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Viral contamination and infection remotely possible but unlikely because of prescreening; caution in liver disease

Drug Name Recombinant factor VII (NovoSeven, NiaStase)
Description Indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. Promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, FIX to factor IXa, and factor II to factor IIa.
Adult Dose 90 mcg/kg IV q2h until hemostasis is achieved or treatment is judged inadequate; for patients with or without inhibitors; may use 35-120 mcg/kg, depending on the severity of the clinical situation; duration of administration has not been well established
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy A - Safe in pregnancy
Precautions Viral contamination and infection remotely possible but unlikely because of prescreening



 

Deterrence/Prevention

 

  • Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII or FIX with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.
  • Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge needle.
  • Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia.
  • Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

 

Complications

 

  • Hemorrhagic complications: Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Results with prophylactic therapy administered 2-3 times weekly, starting when patients are young, have been encouraging. Coagulation factor inhibitor to FVIII develops in about 30% of patients with severe hemophilia A, less often in those with severe hemophilia B (2%), and rarely in those with moderate or mild hemophilia.
  • Nonhemorrhagic complications: Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses were infected with HIV or hepatitis A, B, or C viruses. With new methods of purification and improved screening of donors, these infectious complications now are important only historically. But even with these methods, some viruses (eg, parvovirus B19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include those causing Creutzfeldt-Jacob disease. Also, chronic liver disease is a significant problem in patients with hepatitis C virus infection.

 

Patient Education

 

  • In infants, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation.
  • Encourage the patient to engage in appropriate exercise.
  • Advise the patient against participating in contact and collision sports.
  • For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.

 



Medical/Legal Pitfalls

 

  • Hemorrhagic manifestations of a coagulopathy, such as hemophilia, may be mistaken for signs of child abuse.

 



Media file 1:  Coagulation system.
Click to see larger picture Click to see detailView Full Size Image
 
Media type:  Graph


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Hemophilia A and B excerpt

Article Last Updated: Aug 15, 2006

   

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