Chapter 60: Hemophilia

Epidemiology

1. Hemophilia A is a congenital X-linked recessive bleeding disorder characterized by deficient or defective coagulation factor VIII

2. Overall incidence: 1 in 10,000 males

3. Annual incidence estimated at approximately 500 male births

4. Hemophilia A observed in all ethnic and racial groups

Work-up

1. Bleeding time of PFA-100—usually normal

2. Prothrombin time (PT)—normal

3. Activated partial thromboplastin time (aPTT)—usually prolonged except in certain cases of mild hemophilia; it is corrected by the addition of an equal volume of normal plasma

4. Factor VIII coagulant activity—low

   1. Classification of severity

      Table Graphic Jump Location

      |Download (.pdf)|Print

      Factor VIII Coagulant
      Activity	Severity	Bleeding Episodes
      <1%	Severe	Spontaneous and traumatic bleeding, predominately in joints/muscles
      1–4%	Moderate	Severe bleeding after trauma
      ≥5%	Mild	Bleeding, infrequent, usually after surgery or trauma

5. Factor VIII von Willebrand Factor antigen (FVIII VWF:Ag) and FVIII Ristocetin cofactor (FVIII VWF:RCo)—normal

6. The 1-stage FVIII coagulant assay is the most widely used method for the determinations of the FVIII clotting activity because of its reproducibility, simplicity, and low cost. In many centers, particularly in Europe, use for the chromogenic assay to determine FVIII levels is more frequent. The results obtained with both assays usually correlate with each other. No significant differences in the results between the 2 methods have been detected in normal donors and in those with chronic liver disease (Chandler WL et al. Am J Clin Pathol 2003;120:34–39). However, discrepancies in the assays are observed in patients with mild hemophilia who have missense mutations (Verbruggen B et al. Haemophilia 2008;14(Suppl 3):76–82). Very low FVIII coagulant activities can sometimes be better diagnosed by a chromogenic assay

7. Differential diagnosis of an isolated prolongation of a PTT (Ragni MV, Kessler CM, Lozier JN. Clinical aspects and therapy for hemophilia. In Hoffman R, Benz EJ, eds. Hematology Basic Principles and Practice. Philadelphia, PA: Church Livingstone Elsevier; 2009:1918)

   1. Heparin use

   2. Factor VIII deficiency or inhibitor to factor VIII

   3. von Willebrand disease (VWD)—especially the type II-N variant of VWD

   4. Factor IX deficiency or inhibitor to factor IX

   5. Factor XI deficiency or inhibitor to factor XI

   6. Factor XII deficiency

   7. Contact factor deficiency or inhibitor

   8. Lupus anticoagulant

   9. Factor VIII and factor XI deficiency; factor VIII and factor XII deficiency

Treatment Options

1. Factor VIII replacement

2. Desmopressin acetate

3. Antifibrinolytic therapy

4. Topical agents

5. Platelet concentrates

6. Recombinant Factor VIIIa

7. Prothrombin complex concentrates (PCC)

Acute bleeds should be treated early (immediately, or as soon as possible within 2 hours of onset). Home therapy should be used to manage uncomplicated mild bleeding episodes (eg, hemarthrosis, small muscle bleeds), while more severe bleeds should be evaluated in the clinic or hospital setting, if needed, with subsequent management as needed under the care of a hematologist with expertise in hemophilia care. Patients should avoid use of drugs affecting platelet function;—that is, aspirin or aspirin-containing compounds, or nonsteroidal antiinflammatory drugs (NSAIDs). Use of acetaminophen-containing analgesics is a safe alternative. If possible, intramuscular injections should be avoided, unless performed under coverage of clotting factor VIII

Regimen for Factor VIII Replacement

1. Factor VIII concentrates available in the United States

    

   Recombinant Factor VIII Products

   Product (Manufacturer)

   Recombinate (Baxter Healthcare Corporation)

   ReFacto (Wyeth Pharmaceuticals Inc.)

   Kogenate FS (Bayer HealthCare LLC)

   Helixate FS (CSL Behring LLC)

   Advate (Baxter Healthcare Corporation)

   Xyntha (Wyeth Pharmaceuticals Inc.)

    

   Plasma-derived FVIII Products

   Hemophil-M (Baxter Healthcare Corporation)

   Monoclate-P (CSL Behring LLC)

    

   Plasma-derived FVIII Products with Von Willebrand Factor

   Alphanate (Grifols Biologicals Inc.)

   Humate-P (CSL Behring LLC)

   Koāte-DVI (Talecris Biotherapeutics, Inc.)

Toxicity

1. Infection—HIV and hepatitis C with chronic liver disease: Seen in most patients who received factor VIII and IX concentrates before 1985

2. Development of an inhibitor: 25–30%

3. Redness at injection site: <1%

4. Dizziness: <1%

5. Hypersensitivity reaction (hives, urticaria, wheezing, chest tightness, and arthralgia): Rare

6. Hypertension: Rare

Notes

Recombinant products are the preferred products for treatment of patients with hemophilia A. All recombinant products appear to be comparable in efficacy, risk of infection, and risk of inhibitor development

The potential advantage of second-generation recombinant products is higher specific activity and stability without added serum albumin, further reducing the potential risk of transmissible infectious agents

With third-generation recombinant products, animal components have been removed from the culture media. ReFacto and rAHF-PFM Advate are manufactured and formulated without human or animal proteins

If recombinant factor VIII is not available, a plasma-derived concentrate can be used, but with an inherent risk of potential infection from transmissible agents. Whenever possible, patients should store their own products at home and bring them to emergency facilities for immediate treatment of trauma

Indications

To prevent bleeding and limit existing hemorrhage in patients with hemophilia A or factor VIII deficiency

Efficacy

Eighty-five percent of bleeding episodes are treated successfully with 1–2 infusions (rated excellent or good hemostasis) (Keeling D et al. Haemophilia 2008:14:671–684). Of course, target joints, that is, joints in which repeated hemorrhages occur, may require more aggressive or longer treatment

Regimen: Desmopressin Acetate (DDAVP) DDAVP (Desmopressin Acetate) (1-Deamino-8-D-Argine Vasopressin) Stimate (Intranasal Preparation)

Dunn AL et al. Haemophilia 2000;6:11–14

Hemophilia of Georgia (Georgia, USA). April 2008 (no 14) World Federation of Hemophilia monograph

Lethagen S. Semin Thromb Hemost 2003;29:101–105

Intravenous Use

Test dose:

1. Measure factor VIII levels before the infusion

2. Desmopressin acetate, 0.3 mcg/kg (not to exceed 20 mcg) intravenously in 50 mL 0.9% sodium chloride injection (0.9% NS) over 15–30 minutes

   • Rapid administration may be accompanied by hypotension

3. Measure factor VIII levels 1–2 and 4 hours after the infusion. Expect a 2–5-fold increase in factor VIII levels, persisting for 6–12 hours

Therapeutic dose:

Desmopressin acetate, 0.3 mcg/kg (not to exceed 20 mcg) intravenously in 50 mL 0.9% NS over 30 minutes. Infusion may be repeated every 12–24 hours for 2–4 doses

Note: Tachyphylaxis with serious hyponatremia can occur with repeated doses. If possible, limit use to 1 dose daily to avoid tachyphylaxis. If administering more than 4 doses, monitor daily serum sodium levels and measure VWF levels

Intranasal Use

Desmopressin acetate nasal spray, 1.5 mg/mL

Test dose:

Because of marked variability in response to desmopressin acetate nasal spray, all patients should be tested before therapeutic use

1. Measure factor VIII levels before administration

2. Patient weight <50 kg: desmopressin acetate 1 spray (150 mcg) intranasally in 1 nostril

   Patient weight ≥50 kg: desmopressin acetate 2 sprays (300 mcg) intranasally; 1 spray in each nostril

3. Measure factor VIII levels 2 and 4 hours after administration. Expect a 2–5-fold increase in factor VIII levels, persisting for 6–12 hours

Therapeutic dose:

Patient weight ≤50 kg: Desmopressin acetate 1 spray (150 mcg) intranasally in 1 nostril

Patient weight ≥50 kg: Desmopressin acetate 2 sprays (300 mcg) administer intranasally, 1 spray into each nostril

Administer desmopressin acetate nasal spray before a procedure, and repeat every 12–24 hours for 2–4 doses

Note: Tachyphylaxis with serious hyponatremia can occur with repeated doses. If possible, limit use to 1 dose daily to avoid tachyphylaxis

Subcutaneous Use^✫

Test dose:

1. Measure factor VIII levels before the infusion

2. Desmopressin acetate 0.2–0.3 mcg/kg (not to exceed 20 mcg) subcutaneously

3. Measure factor VIII levels 1 hour and 4 hours after administration. Expect a 2–5-fold increase in factor VIII levels, persisting for 6–12 hours

Therapeutic dose:

Desmopressin acetate 0.2–0.3 mcg/kg (not to exceed 20 mcg) subcutaneously

Note: Tachyphylaxis with serious hyponatremia can occur with repeated doses. If possible, limit use to 1 dose daily to avoid tachyphylaxis

Indications

1. Synthetic analog of vasopressin indirectly release factor VIII/VWF from endothelial cell storage sites

2. dDAVP is useful in patients with mild hemophilia with factor VIII levels >5% who have shown through pretesting to be responsive to its infusion

Efficacy

On the basis of 3 small studies, a rise in factor VIII coagulant activity to >3 times baseline and normal hemostasis were seen in 80% of patients

Toxicity

Usually well tolerated, desmopressin acetate has the advantage of posing no risk of transmitting bloodborne viruses

1. Vasodilation with associated flushing and hypotension after rapid administration: Occasional

2. Headache: Usually transient and probably dose-related, and may resolve with dose reduction

3. Tingling: Occasional

4. Hypotension: Uncommon and usually mild

5. Hypertension: Uncommon and usually mild

6. Tachycardia: Uncommon

7. Volume overload: Uncommon

8. Hyponatremia: Caused by ADH

Note: Tachyphylaxis with serious hyponatremia can occur with repeated doses if desmopressin acetate is administered over a prolonged period:

1. Limit administration to once daily or less frequently

2. Restrict water intake

3. Monitor daily serum sodium levels

Notes

A trial of desmopressin acetate at the time of diagnosis assesses an individual's response pattern

Once a test dose is known to be successful, desmopressin acetate can be used without subsequently testing for responsiveness

Adults should be advised to limit fluid intake to 1000 mL for 24 hours after desmopressin acetate use

Adverse event reports describe thrombosis including MI after DDAVP administration; thus, it should be used with caution in patients with unstable angina, MI, etc

Antifibrinolytic Therapy: Antifibrinolytic Agent (Epsilon-Aminocaproic Acid, Eaca Amicar)

Cooksey MW et al. Br Med J 1966;2:1633–1634

Djulbegovic B et al. Am J Hematol 1996;51:168–170

Mannucci PM. N Engl J Med 1998;339:245–253

Mannucci PM. Blood 2001;97:1915–1919

Reid WO et al. Am J Med Sci 1964;248:184–188

Stajčić A. Int J Oral Surg 1985;14:339–345

Aminocaproic acid 50 mg/kg orally^✫ every 6 hours for 7–10 days (maximum dosage: 24 g/24 hours) after dental surgery or extraction

Efficacy

In small case studies in which aminocaproic acid is given after factor VIII replacement in patients undergoing dental extractions, hemostasis was excellent in 90% of cases and good in 10%. In the studies in which aminocaproic acid is given alone in patients undergoing dental extractions, only 8% required subsequent factor replacement

Toxicity

1. Nausea: Common

2. Vomiting: Common

3. Abdominal pain: Occasional

4. Diarrhea: Occasional

5. Thrombotic complications: Rare

Indications

1. As an antifibrinolytic agent that is often used along with factor VIII products for invasive dental work or for the treatment of mouth bleeds

2. Not recommended for treatment of most internal hemorrhages

Notes

1. Aminocaproic acid should not be administered to a patient with evidence of an active intravascular clotting process or hematuria of upper urinary tract origin, or when taken at the same time as factor IX complex concentrates or antiinhibitor coagulant concentrates

2. Contraindicated in patients with bleeding from the upper urinary tract because clots that do not lyse may cause ureteral obstruction

3. For intermittent use only, because long-term use may lead to thrombosis

SUPPORTIVE CARE

Topical agents: A wide variety of topical hemostatic agents are available to help control surgical bleeding. These include gelatin sponges, collagens, fibrin sealants, and thrombin preparations (see table: adapted from Kessler CM, Ortel TL. Thromb Haemost 2009;101:15–24)

Purified human plasma-derived thrombin (Evithrom; J&J Wound Management) and recombinant thrombin (Recothrom; Bristol-Myers Squibb) are approved for use as topical adjunctives to achieve surgical hemostasis. Clinical trials have demonstrated that these human-thrombin products possess equivalent efficacy and safety; with an improved immunogenicity profile (ie, antithrombin, anti-V antibodies and bleeding/thromboembolic complications) compared to bovine-derived thrombin products

Platelet concentrates: Platelet concentrates are not used in hemophilia except rarely in patients with inhibitors in high titers who are bleeding and do not respond to factor concentrates rituximab, desmopressin acetate, or other interventions. Platelets also are used in patients with ITP, HIV, or portal hypertension secondary to hepatitis C liver disease especially if there is active bleeding

Special Therapeutic Approaches DENTAL CARE

Considerations before dental procedures:

1. Routine examinations and cleaning generally can be performed without prophylactically increasing factor VIII levels

2. Adequate coverage (ie, factor VIII concentrate, antifibrinolytic therapy, or both) should be given before and possibly after a dental appointment in patients who need the following

   1. Deep cleaning or scaling because of heavy plaque and/or calculus accumulation in which bleeding would be induced

   2. Block local anesthesia or mandibular block

   3. Dental extractions, especially multiple procedures or other surgery

Suggested therapy:

1. Multiple dental extractions or other surgery:

   1. Loading dose: Calculate the units of factor VIII needed to raise the level to ≈50% in plasma. Factor VIII products should be reconstituted according to a manufacturer's instructions. The loading dose should be diluted according to a manufacturer's instructions and administered over a period of ≤5 minutes (maximum infusion rate 10 mL/min) 1 hour before a dental extraction or other surgery

   2. Maintenance dose: Further administration of factor VIII is usually not required, but can be repeated every 12 hours if bleeding recurs. Factor VIII products should be dissolved according to a manufacturer's instructions and administered over a period of ≤5 minutes (maximum infusion rate 10 mL/min)

2. When surgery is performed, in addition to factor VIII:

   1. Initial dose: Aminocaproic acid 3000 mg orally 4–6 hours after a dental procedure

   2. Maintenance dose: Aminocaproic acid 50 mg/kg every 6 hours or 4 times per day for 7 days after dental work is completed

For additional information and indications, refer to notes in Hemophilia A: Factor VIII Replacement

Brewer AK et al. Haemophilia 2003;9:673–677

Brewer AK. Haemophilia 2008;14(Suppl 3):119–121

Stajčić A. Int J Oral Surg 1985;14:339–345

Considerations before surgery:

1. Preadmission studies: CBC, inhibitor screen

2. Mini-PK study to establish response to factor VIII concentrate

3. At least 1 week before a surgical procedure, notify the Blood Bank about approximate amounts of factor VIII required

4. Notify special Hematology Department that frequent assays will be required during the week of surgery

Suggested therapy:

1. Factor VIII bolus administration protocol

   Hemophilia of Georgia (Georgia, USA): Protocols for the treatment of hemophilic and Von Willebrand disease April 2008(14). World Federation of Hemophilia Monograph

   1. Loading dose (approximately 2 hours before surgery): Calculate the units of factor VIII needed to raise plasma levels to ≈80–100% of normal, prepare products according to the manufacturer's instructions, and administer over a period of ≤5 minutes (maximum infusion rate = 10 mL/min)

   2. Maintenance dose: Begin with approximately one-half the loading dose of factor VIII. Prepare products according to the manufacturer's instructions and administer over a period of ≤5 minutes (maximum infusion rate = 10 mL/min) every 12 hours. Adjust dose according to measured factor VIII levels to maintain factor VIII levels >50% for the next 10–14 days or until general healing is complete. Factor VIII levels should be checked daily. Since the half-life of factor VIII is 8–12 hours, assays should be performed near the end of a 12-hour dose interval

2. Factor VIII continuous infusion administration protocol

Hay CR et al. Blood Coagul Fibrinolysis 1996;7(Suppl 1):15–19

Martinowitz U et al. Br J Haematol 1992;82:729–734

Rationale for adjusted continuous infusion is by avoiding the peaks and troughs in clotting factor levels seen with bolus injection regimens, a steady-state concentration of the factor may reduce the amount of concentrate used and be more convenient. However, dosing guidelines for continuous infusion of factor VIII are not currently established, and no products are currently licensed for this route of administration

Suggested protocol:

1. Loading dose (approximately 2 hours before surgery): Factor VIII 40–50 units/kg prepared according to the manufacturer's instructions and administered by intravenous injection

Maintenance dose (begin continuous infusion immediately after a loading dose):

1. Factor VIII 4 units/kg per hour intravenously as a continuous infusion. Dissolve factor VIII in 0.9% sodium chloride injection (0.9% NS). Mix an amount of factor VIII sufficient for infusion over 8 hours. Use a pump with compatible disposable (administration sets) capable of accurately administering small volume rates

2. One hour after a continuous infusion is started, measure the patient's plasma factor VIII

3. Ensure the patient's factor VIII level is ≥70% before sending to surgery

4. Monitor with daily factor VIII assays

5. Maintain factor VIII level at >70% for the first 48 hours after surgery

6. 48 hours after surgery, decrease infusion to maintain a factor VIII level of 50–60%

7. On postoperative day 5, discontinue the continuous infusion. The factor VIII level should be between 40–60% when infusion is discontinued

8. When infusion is discontinued, begin intravenous bolus administration every 12 hours over a period of ≤5 minutes (maximum infusion rate = 10 mL/min) to keep levels between 40% and 50%. Continue for ≥5–7 days, depending on surgery (example: hip replacement in which physical therapy required)

Considerations before procedure:

Factor VIII concentrate should be administered to achieve a factor VIII level ≥50% before invasive diagnostic procedures such as lumbar punctures, arterial blood gas measurements, bronchoscopy with brushings or biopsy, colonoscopy with biopsy, upper gastrointestinal endoscopy, or cardiac catheterization

Suggested therapy:

Loading and maintenance doses: Calculate the amount of factor VIII needed to raise the level to ≥50% in plasma, prepare products according to the manufacturer's instructions, and administer over a period of ≤5 minutes (maximum infusion rate = 10 mL/min). The dose may be repeated hours later if bleeding ensues

Hermans C et al. Haemophilia 2009;15:639–658

Definition of prophylaxis

1. Primary prophylaxis: long-term continuous factor VIII administration started after the first joint bleed and before the age of 2 years, or before the age of 2 years in the absence of clinically evident joint bleeds

2. Secondary prophylaxis: long-term continuous factor VIII administration started after 2 or more joint bleeds or at an age >2 years. Short-term prophylaxis is defined as intermittent continuous (“around-the-clock”) administration for patients with frequent bleeds

3. On-demand therapy: treatment given when bleeding occurs

Prophylaxis in children

1. A number of retrospective cohort or prospective observational studies and two recent randomized controlled studies gave indicated benefit of primary or early secondary prophylaxis

   1. On the U.S. Joint Outcome Study (JOS), the efficacy of prophylaxis (25 units/kg) every other day in preventing joint damage was compared with an enhanced episodic infusion schedule (factor VIII 40 units/kg at joint bleed onset, 20 units/kg at 24 and 72 hours, and 20 units/kg every 48 hours thereafter until complete recovery) in 65 children (mean age: 1.6 years). Early prophylaxis resulted in 93% of patients having normal index-joint structure on MRI at 6 years compared with 55% of those in the on-demand treatment group

   2. The Evaluation Study on Prophylaxis—a randomized Italian trial (Espirit) compared children on prophylaxis (factor VIII 25 units/kg 3 times per week) with dose adjustments to maintain trough FVIII levels >1% with patients who received on demand treatment (factor VIII ≥25% units/kg per day until recovery). At 10 years follow-up, there was a lower median frequency of joint bleeds among those who received prophylaxis

Prophylaxis in adults

1. Prophylaxis in adults has been less well studied than prophylaxis in children. There have been 6 published studies (preliminary results from 4 of 6 studies) on the effects of secondary prophylaxis in adolescent or adult hemophiliacs. All have studies indicated secondary prophylaxis markedly reduces the number of bleeding episodes in the joints and other sites¹

2. Regimens used for prophylaxis in adults^1,2,3,4

   1. FVIII at a dose of 25–40 units/kg 3 times per week, or every other day

   2. FVIII 15–25 units/kg 2 to 3 times per week

   3. FVIII 50 units/kg weekly initially; increase the dose or frequency according to a patient's bleeding pattern

   4. Factor IX (hemophilia B patients) 25–40 units/kg twice per week

3. The Medical and Scientific Advisory Council of the U.S. National Hemophilia Foundation (MASAC has recommended prophylaxis as the standard of care for severe hemophilia in all age groups)

4. The optimal and most cost-effective dosage, administration interval, and duration of prophylaxis are still unknown

HEMOPHILIA CARRIERS AND PRENATAL DIAGNOSIS

Detection^1,2

1. Only females can be carriers

2. Obligatory carriers

   1. All daughters of a man with hemophilia

   2. Mothers of 1 son with hemophilia and at least 1 other family member with hemophilia (brother, maternal grandfather, uncle, nephew, or cousin)

   3. Mother of 1 son with hemophilia and a family member who is a carrier of hemophilia gene (ie, mother, sister, maternal grandmother, aunt, niece, or cousin)

   4. Mothers of 2 or more sons with hemophilia

3. Possible carriers

   1. Daughters of a carrier

   2. Mothers of 1 son with hemophilia who have no other family members who either have or are carriers of hemophilia

   3. Sisters, mothers, maternal grandmothers, aunts, nieces, and female cousins of carriers

4. Clotting factor levels in hemophilia carriers

   1. The expected mean clotting factor levels in hemophilia carriers is 50% of the concentration found in the unaffected population. However, because of exonization (ie, random suppression of one of the two X chromosomes) a wide range in clotting factor levels is found (ie, <1% to >150%)

   2. Other factors (eg, ABO blood types, pregnancy, stress hormones, etc) may influence the level of FVIII activity

5. Bleeding symptoms in carriers (reference 1, below)

   1. Carriers with clotting factor levels of <50% may have an increased risk of bleeding. The risk of bleeding roughly correlates inversely with levels of FVIII/IX, the lower the level, the greater the risk of bleeding. In most cases, clinical symptoms are comparable to those with mild hemophilia, except that carriers may bleed excessively after menstruation or after surgery or delivery. When bleeding occurs, carriers must be treated similarly as those with hemophilia

Prenatal diagnosis

1. Invasive methods^3,4

   1. Chorionic villus sampling

      1. Method of choice for prenatal diagnosis of hemophilia

      2. Performed at 11–14 weeks gestation under ultrasound guidance

      3. Permits diagnosis in first trimester

      4. DNA obtained from sample screened for FVIII intron 22 inversion. If negative, direct gene sequencing is performed

      5. FVIII/IX concentrates should be given prior to the procedure to raise factor level to ≥50%

   2. Amniocentesis

2. Noninvasive methods^1,2

   1. Modern ultrasound assessment in the second and third trimesters can accurately determine fetal sex

   2. The use of quantitative real-time polymerase chain reaction (RT-PCR) to assess free fetal DNA in the maternal circulation for the presence or absence of Y-chromosome specific DNA sequences

   3. Knowledge of fetal gender precludes a need for invasive testing in pregnancy

Antenatal management

1. Check FVIII/IX levels at 28 and 34 weeks of gestation, especially in carriers with low pre-pregnancy levels <50%^1,2

2. Treatment with factor concentrates usually is not necessary during pregnancy because of the significant rise of the FVIII level. Hemophilia B carriers with a low level of factor IX are more likely to require factor concentrate for delivery, as factor IX does not significantly rise in pregnancy^1,2,5

3. The use of desmopressin (DDAVP) to increase FVIII during pregnancy is controversial because of the theoretical risk of placental insufficiency associated with arterial vasoconstriction. This may result in a miscarriage or preterm labor. However, several studies have indicated its safety during pregnancy^1,6

Labor/delivery

1. There is no contraindication for an epidural block if the APTT and platelet count are normal, and factor VIII/IX is raised to ≥50%

2. The risk of serious bleeding during a normal vaginal delivery is small and is considered standard of care. However, vacuum extraction, midcavity forceps, scalp sampling, and prolonged labor should be avoided. If a difficult delivery is anticipated then an early recourse to caesarian section should be considered^1,7

3. Arrange for cord blood sampling at delivery. Cord blood should be collected from all male offspring of hemophilia carriers to assess clotting factor levels for identification and early management of newborns at risk

4. Avoid intramuscular vitamin K administration and circumcision until results of cord blood sampling are known

5. Factor levels should be monitored postdelivery and maintained >50% for at least 3 days (or 5 days if a C-section was performed)

COMPLICATIONS OF HEMOPHILIA

Factor VIII Inhibitors

Epidemiology (Van Helden PMW et al. Br J Haematol 2008;142:644–652)

1. FVIII inhibitors are IgG antibodies, predominantly of the IgG₄ subclass which interfere with the interaction of FVIII with its cofactors and activators

2. An estimated 22–52% of patients with severe hemophilia A and 3–13% of patients with moderate or mild hemophilia develop inhibitors

Risk factors for inhibitor development

1. Genetic risk factors (Astermark J et al. Haemophilia 2008;14[Suppl 3]:36–42)

   1. Hemophilia severity

   2. FVIII mutations, for example, nonsense mutations, intron 22/intron 1 inversions

   3. Major histocompatibility complex (MHC)

   4. Polymorphisms of cytokine genes (tumor necrosis factor-alpha [TNF-α], interleukin-10 [IL-10], cytotoxic T-lymphocyte associated protein-4 [CTLA-4])

   5. Family history of inhibitors

   6. Race/ethnicity (African American and Latino descent)

2. Environmental risk factors (Oldenburg J et al. Semin Hematol 2004;41[1 Suppl 1]:82–88)

   1. Intensive FVIII exposure (particularly during the first 50 exposure days)

   2. Immunologic/inflammatory/or infectious events, for example, vaccination, surgery, illness

   3. Some studies have suggested a higher incidence of inhibitor with the use for recombinant products. However, the role of product type in the occurrence of an inhibitor is unresolved

Laboratory Diagnosis (Hay CRM et al. Br J Haematol 2006;133:591–605)

1. When an inhibitor is suspected, the Bethesda assay is performed to both confirm and quantify the anti-FVIII antibody. In this assay, normal pooled plasma is incubated with undiluted patient plasma for 2 hours at 37°C (98.6°F) and then assayed for residual FVIII

2. Bethesda unit = log[% residual FVIII in test mixture]

3. One Bethesda unit (1 BU) = amount of inhibitor needed to inactivate 50% of FVIII in pooled normal plasma after incubation

4. Typical sensitivity of Bethesda assay = 0.5–0.6 BU

5. Nijmegen modification of the above assay

   1. May better allow the detection of very-low-titer inhibitors

      (1) The Bethesda assay may result in false positives at very-low-titer inhibitors (<1 BU)

      (2) In contrast, the Nijmegen modified assay would result zero inhibition levels

   2. The control consists of normal plasma incubated with immunodepleted FVIII-deficient plasma

   3. The normal plasma used in the incubation mixture is buffered to a pH of 7.4 with 0.1 M imidazole buffer

Classification of inhibitors (White GC II et al. Thromb Haemost 2001;85:560)

1. Low-titer inhibitor: Inhibitor levels ≤5 BU

2. Low-responding inhibitor: An inhibitor titer that never increases to >5 BU despite immunologic challenge with FVIII; may be transient

3. High-titer inhibitor: Inhibitor levels >5 BU

4. High-responding inhibitor: Inhibitor that increases markedly in response to FVIII concentrate within a few days (anamnesis); the inhibitor titer may become low titer over time

TREATMENT OF ACUTE BLEEDING EPISODES IN PATIENTS WITH FVIII INHIBITORS

Treatment of acute bleeding in a patient with a factor VIII inhibitor depends on

1. Whether the patient has a high-response or low-response inhibitor

2. The current inhibitor titer

3. The severity of a bleeding episode

Both recombinant and plasma-derived factor VIII products can be used in treatment

DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

Lloyd Jones M et al. Haemophilia 2003:9:464–520

Bleeding in a patient with a low-response and/or low-titer inhibitor

Suggested therapy: Attaining a therapeutic plasma level ≥50% is recommended

1. Loading dose

   Factor VIII 100 units/kg; prepare according to the manufacturer's instructions and administer intravenously over <5 minutes (maximum infusion rate = 10 mL/min)

2. Maintenance dose

   Factor VIII 50–100 units/kg prepare according to the manufacturer's instructions and administer intravenously over ≤5 minutes (maximum infusion rate = 10 mL/min) every 8–12 hours for 5 days

3. Continuous infusion

   Factor VIII 10 units/kg per hour administered intravenously in 0.9% sodium chloride injection for 5 days

   Note: Factor VIII doses should be great enough to saturate the inhibitor and increase the plasma factor VIII activity to hemostatic levels. With an inhibitor expressed in BU (Bethesda units), the dose needed to saturate the inhibitor can be calculated according to the following formula:

    

   

    

4. In addition to factor VIII bolus or infusion regimens for the management of a low-response inhibitor, aminocaproic acid 50 mg/kg per dose can be administered orally every 6 hours for 3–10 days for patients with oral mucosal dental bleeding

5. If a patient is known to respond to desmopressin acetate (mild hemophilia A), one may give desmopressin acetate 300 mcg intranasally (150 mcg for patients <50 kg) for minor bleeding

Metijan A, Konkle BA. Inhibitors in hemophilia A and B. In: Hoffman R, Benz EJ Jr, Shattil SJ et al., eds. Hematology: Basic Principles and Practice, 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2009

Bleeding in a patient with a high-response and/or high-titer inhibitor

Suggested therapy

1. Factor VIIa bolus dose protocol

    Bolus dose^✫: Coagulation factor VIIa (recombinant) (NovoSeven RT; Novo Nordisk, Inc.) 90 mcg/kg per dose, prepared according to the manufacturer's instructions and administered by slow intravenous injection over 2–5 minutes

    Additional bolus doses^†: Coagulation factor VIIa (recombinant) (NovoSeven RT) 90 mcg/kg per dose, prepared according to the manufacturer's instructions, and administered by slow intravenous injection over 2–5 minutes every 2–3 hours for at least 3–4 doses or more if bleeding continues

    Recent evidence from a number of studies supports the administration of single doses of 270 mcg/kg and has shown the dose is both effective and safe

    

2. Factor VIIa bolus dose followed by continuous infusion protocol

    Bolus dose^✫: Coagulation factor VIIa (recombinant) (NovoSeven RT) 90–150 mcg/kg; prepared according to the manufacturer's instructions, and administered by slow intravenous injection over >2–5 minutes

    Continuous infusion: Coagulation factor VIIa (recombinant) (NovoSeven RT); prepared according to the manufacturer's instructions and administered by continuous infusion at a rate of 20–50 mcg/kg per hour

Note: NovoSeven RT is labeled to be used within 3 hours after preparation. Continuous administration for longer periods will require additional preparation steps to replace expired drug supplies

NovoSeven RT Coagulation factor VIIa (Recombinant) Room Temperature Stable product labeling, May 9, 2008. Novo Nordisk Inc., Princeton, NJ

Ludlam CA et al. Br J Haematol 2003;120:808–813

Santagostino E et al. Thromb Haemost 2001;86:954–958

Antiinhibitor Coagulant Complex (AICC)

Antiinhibitor Coagulant Complex (Activated prothrombin complex concentrate; Feiba NF or Feiba VH, Baxter Healthcare Corporation) 50–100 units/kg of body weight; prepare according to the manufacturer's instructions, and administer intravenously every 12 hours for 3–4 doses as needed, or longer if there is continued bleeding. AICC should be infused slowly, at a rate not greater than 2 mL/kg of body weight per minute

Note: If headache, flushing, changes in pulse rate, or changes in blood pressure appear to be infusion-related, the rate should be decreased. In such instances, it is advisable to initially stop the infusion until the symptoms disappear, then to resume at a slower rate

Hay CRM et al. Br J Haematol 2006;133:591–605

General rules for treating acute bleeding in patients with inhibitors

(Dargaud Y et al. Haemophilia 2008;14(Suppl 4):20–27)

The choice of bypassing agent (FVIIa or AICC) used as first-line treatment is left up to treating physicians. A recent randomized study comparing AICC and rFVIIa in hemophilia with inhibitors showed these 2 products appeared to exhibit a similar beneficial effect on joint bleeds (Astermark J et al. Blood 2007;109:546–551)

Some favor the use of rFVIIa in “plasma-naïve patients, especially children.” The use of rFVIIa does not usually induce an anamnestic response, a beneficial attribute in the context of immune tolerance

If the hemostatic response is unsatisfactory with the first bypassing agent, one could increase the administration frequency of the product used in treatment. If still no improvement results in spite of increasing the dose or administration frequency, consider using the alternative product (rFVIIa or AICC)

If hemorrhage still persists under monotherapy with either class of bypassing agents, one may consider sequential therapy with both types of bypassing agents. However, the clinical benefit of this approach requires confirmation. The optimal time period between sequential administration of each product has not been identified

Antifibrinolytic agents (eg, aminocaproic acid) may be used concomitantly with either of the bypassing agents for oral or muscle bleeds. Antifibrinolytics ideally should not be given within 12 hours of AICC administration because of a potential risk of thrombosis. Patients who receive sequential therapy with rFVIIa and AICC should not receive antifibrinolytic therapy

Neither bypassing agent is able to effect hemostasis in all patients or in all bleeds. Product effectiveness should be assessed early after administration and products switched or doses increased promptly when a patient shows signs of insufficient or lacking response to treatment. A consensus guideline recommends re-evaluating treatment response every 8–12 hours for 1 day, and every 24 hours thereafter for limb bleeding, and every 2–4 hours for life-threatening bleeds

Aledort LM. Management of inhibitors in patients with hemophilia A (monograph). December 2008

Astermark J et al. Blood 2007;109:546–551

Berntorp E. Haemophilia 2009;15:3–10

Teitel J et al. Haemophilia 2007;13:256–263

SURGERY IN A PATIENT WITH A HIGH-RESPONSE INHIBITOR

CONSENSUS RECOMMENDATIONS FOR IMMUNE TOLERANCE INDUCTION (ITI)

DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

Recommendations for when to start ITI

1. Postpone initiating ITI until the inhibitor titer has decreased to at least <10 Bethesda units (BU) although an inhibitor titer substantially <10 BU may correlate with a better response

   • a. The waiting time is usually short, and most children are young at the start of ITI

   • b. Closely monitor inhibitor levels during the waiting period to ensure ITI is promptly started

   • c. Avoid FVIII exposure during a waiting period

2. Consider starting ITI regardless of the inhibitor titer if:

   • d. The inhibitor titer does not decrease to <10 BU during a 1–2-year period of close observation

   • e. Severe life- or limb-threatening bleeding occurs

Recommendations for ITI dosing

1. Among good-risk patients (ie, peak historical inhibitor titers <200 BU, pre-ITI titer <10 BU, <5 years since diagnosis), no dosing regimen has been shown superior to another. These patients may be eligible to participate in the I-ITI study (International Immune Tolerance Induction Study). This study is an evaluation of the effect of FVIII dose on the overall ITI success rate and time to success by randomly assigning 150 patients with severe hemophilia A to receive FVIII doses of either 200 IU/kg daily or 50 IU/kg 3 times weekly for up to 33 months

2. Among poor-risk patients (ie, peak historical titer >200 BU, pre-ITI titer >10 BU, >5 years since inhibitor diagnosis) evidence suggests a higher success rate with the use of high-dose FVIII regimens. These patients may be eligible to participate in the Resist Study (Rescue Immune Tolerance Study), which randomly assigned patients to receive high-dose FVIII (200 units/kg per day) with either recombinant FVIII or a plasma-derived FVIII concentrate containing von Willebrand factor (VWF)

Recommendations in favor of using FVIII products

1. ITI is successful using FVIII products with or without VWF

2. No data supports the superiority of any FVIII product

3. There is no evidence to support switching from one FVIII product to another for de novo ITI

4. There is no role for immunoabsorption as a first-line treatment for ITI

Recommendations for prophylaxis during ITI

1. Prophylaxis should be considered if patients continue to bleed frequently while awaiting or receiving ITI

2. Recombinant FVIIa (NovoSeven RT) 90–270 mcg/kg daily is preferred for prophylaxis when ITI is delayed to allow time for inhibitor titers to decline to <10 BU

3. Prophylaxis with AICC (Feiba NF) 50–200 units/kg daily or twice weekly, or recombinant FVIIa 90–270 mcg/kg daily may be considered for patients undergoing ITI who experience early joint bleeding or intracranial hemorrhage

   Note: The total daily AICC dosage should not exceed 200 units/kg

4. Monitor FVIII recovery when the inhibitor titer drops to 10 BU

5. Discontinue bypassing therapy at any level of FVIII recovery

Recommendations for central venous access devices (CVAD)

1. Use peripheral venous access whenever possible

2. Subcutaneously implanted vascular access ports (infusion ports) are preferable to external catheters because of their significantly lower risk of infection

3. Follow published guidelines for catheter care and infection prevention

   1. A CVAD with the smallest possible catheter diameter should be used; the tip of the catheter should be positioned in the lower third of the superior vena cava (SVC)

   2. Refrain from using a CVAD in the first week after surgery to prevent the introduction of bacteria through the surgical wound

   3. Remove the residual lipid of anesthetic creams from the skin by scrubbing with soap and water before accessing an implanted port

   4. Use of topical antiseptics to reduce infection is encouraged (eg, chlorhexidine)

4. Instruct families on techniques for accessing and caring for CVADs before starting ITI

5. If a CVAD-related deep venous thrombosis (DVT) occurs, discontinue bypassing prophylaxis (if used) and review infusion techniques with the family in addition to the following:

   1. Consider removing the catheter and switch to a peripheral vascular access device

   2. Consider modifying the ITI regimen and future bypass therapy regimens

   3. Monitor closely for clot resolution

   4. If a severe clot fails to resolve or progresses, consider catheter-directed thrombolysis or a short-term course of anticoagulation

    

   Valentino LA et al. Haemophilia 2004;10:134–146

    

6. An AV fistula (AVF) is an option for venous access in children ≥1 year of age who have experienced CVAD failure

   1. Long-term follow-up of an AVF with ultrasound (duplex) is important

   2. Dismantle an AVF as soon as peripheral veins provide adequate vascular access

   3. If an AVF-related thrombosis occurs, ITI can continue but stop prophylactic bypassing therapy access

DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

Santagostino E et al. Br J Haematol 2003;123:502–506

Recommendations for managing incomplete or lack of response to ITI

1. Continue initial ITI regimen particularly if a low-dose regimen is being used for reasons of preferential use of peripheral vascular access

2. Maximize the ITI dose if a low-dose regimen is being used and adequate venous access exists

3. Consider switching to a FVIII/VWF product if ITI was initiated with a recombinant product

    

   Gringeri A et al. J Thromb Haemost 2005;3(Suppl 1):A207

    

4. Consider adding rituximab or another immunomodulating drug to the current regimen (rituximab dosage: 375 mg/m² weekly for 4 consecutive weeks)

Franchini M et al. Haemophilia 2008;14:903–912

Recommendations for defining ITI outcome

1. Pharmacokinetic parameters of success

   1. Disappearance of the inhibitor (ie, undetectable using Bethesda assay)

   2. Normal FVIII recovery (≥66% of predicted)

   3. Normal FVIII half-life (≥6 hours after a 72-hour FVIII washout period)

   4. Absence of anamnesis upon further FVIII exposure

    

   DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

    

2. Pharmacokinetic parameters of partial success

   1. An inhibitor titer of <5 BU

   2. FVIII recovery <66% of predicted

   3. FVIII half-life <6 hours after a 72-hour FVIII washout period

   4. Clinical response to FVIII

   5. No increase in the inhibitor titer >5 BU over a 6-month period of on-demand therapy or a 12-month period of prophylaxis

    

   DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

    

3. Pharmacokinetic parameters of failure

   1. Failure to fulfill criteria for full or partial success within 33 months

   2. Less than a 20% reduction in the inhibitor titer for any 6-month period during ITI after the first 3 months of treatment which implies:

      • 9 months is the minimum period for an ITI

      • 33 months is the maximum duration of ITI, although the decision may be made to continue immune tolerance

    

   DiMichele DM et al. Haemophilia 2007;13(Suppl 1):1–22

    

4. If the criteria for success are met

   1. Treatment can be terminated by tapering the FVIII dose by 10–50% each month

   2. If there is no inhibitor, subsequent interventions include prophylaxis (eg, AICC 20–40 units/kg 3 times weekly) or on-demand treatment

   3. Participation in prospective randomized national or international trials if available

HEMOPHILIC ARTHROPATHY

Monitoring by radiographic imaging:

1. A plain x-ray is a well-tested and reliable technique to image bones and soft tissues, but it cannot directly visualize the cartilage that is lost early in hemophilia arthropathy

2. Ultrasound can visualize cartilage synovium blood and fluid but does not visualize bone

    

   Klukowska A et al. Haemophilia 2001;7:286–292

    

3. Magnetic resonance imaging (MRI) has been shown to detect early signs of arthropathy such as synovial hypertrophy or early cartilage damage that is not identified on x-rays

    

   Yu W et al. Haemophilia 2009;15:1090–1096

    

Management of chronic hemophilic arthropathy:

1. Primary or secondary prophylaxis to prevent recurrent bleeds

2. Radiosynovectomy (synoviorthesis)

   1. Developed as a simple, noninvasive alternative to arthroscopic or open surgical synovectomy

   2. The radioisotopes utilized are pure β-emitting radioisotopes that avoid whole-body irradiation: they are large enough to avoid leakage from the joint space and have a short half-life

       

       Bossard D et al. Haemophilia 2008;14(Suppl 4):11–19

       

   3. Are used as a colloidal suspension allowing homogenous distribution into the joint space Bossard D et al. Haemophilia 2008;14(Suppl 4): 11–19

   4. Radioactive phosphorus (³²P) single agent licensed in the United States

       (1) Indication: Chronic/progressive arthropathy with recurrent bleeding and synovial hypertrophy of a “target” joint with few cartilage and bone lesions

       (2) Safety issues: Little cartilage or bone toxicity, two cases of acute lymphoblastic leukemia reported in pediatric patients

       

       Dunn AL et al. J Thromb Haemost 2005;3:1541–1542

       

       (3) No standard guidelines for the use of this procedure

Surgical procedures:

1. Open surgical synovectomy

   1. Effective for removing hypertrophied synovium and thus decrease recurrence of hemarthroses

   2. The procedure can be complicated by a reduction in range of motion and cannot stop progressive joint damage

       

       Montane I et al. J Bone Joint Surg Am 1986;68:210–216

       

   3. Above rarely performed and may be indicated when there is limited access to the synovial hypertrophia under arthroscopy or when bone surgery is necessary

       

       Bossard D et al. Haemophilia 2008;14(Suppl 4):11–19

       

2. Arthroscopic synovectomy

   1. Most frequent procedure for decreasing pain and improving range of motion

   2. Indicated for knee arthropathy but increasing experience is being gained within ankles, elbows, and shoulders

       

       Pasta G et al. Haemophilia 2008;14(Suppl 3):170–176

       Wiedel JD. Haemophilia 2002;8:372–374

       

3. Joint replacement and prosthesis

   1. Orthopedic surgery is higher risk surgery for hemophiliacs than for nonhemophiliacs because of

      • The increased wear or loosening of a prosthesis since implantation is often done in patients younger than those undergoing surgery for osteoarthritis

      • The necessity for a revision of the prosthesis 10–20 years after initial implantation

      • The difficulty in performing surgery in persons with hemophilia as a result of stiffness and potentially severe joint deformities

      • Increased postoperative complications such as sepsis or bleeding

         

         Beeton K et al. Haemophilia 2000;6:474–481

         Bossard D et al. Haemophilia 2008;14(Suppl 4):11–19

         

4. Total knee replacement (TKR): TKR is the most frequent surgery performed in patients with advanced hemophilic arthropathy of the knee. In general, surgical outcomes are less than those achieved in nonhemophiliac persons with respect to mobility

   1. TKR surgery in hemophiliac patients with inhibitors is feasible, especially with the use of recombinant factor VIIa (NovoSeven RT) and antiinhibitor coagulant complex (activated prothrombin complex concentrate; Feiba NF)

      • The EUREKA (European Register on Knee Arthroplasty) Study is ongoing in order to provide additional information, including long-term outcome data on TKR surgery in hemophiliacs with inhibitors receiving first line or FVIIa

         

         Laurain YD et al. J Thromb Haemost 2007;5(Suppl 2):abstract PM 140

         

   2. With respect to hip surgery, synovectomy in hemophiliacs is limited a result of difficult anatomic access. Total hip replacement (THR) is the best option, provided it is performed in a center in which hematologists and orthopedic surgeons work together frequently

   3. Mann et al. described a relatively noninvasive technique for ankle arthropathy; that is, medial malleolar osteotomy bone graft and compression with staples

       

       Mann HA et al. Haemophilia 2009;15:458–463

       

5. Orthotics: A foot-supporting device or insole, or a more complex device to control joint motion

   1. Can serve as an interim measure before definitive reconstructive surgery

   2. Ankle guards and arch supports useful in patients with ankle arthropathy and can assist in maintaining and improving gait and weight bearing

   3. Shoe lifts can equalize the lengths of lower extremities and improve gait

   4. Orthotics often applied to knees and occasionally elbows

CARDIOVASCULAR DISEASE (CVD) RISK MANAGEMENT

Data are often lacking on the risk of cardiovascular disease in persons with hemophilia largely because of the early death of the previous generations of patients. However, the number of hemophiliacs with cardiovascular disease, although lower than the general population, appears to be increasing

Strategies for optimally managing hemophiliacs with CVD

1. Emphasize the importance of exercise

2. Despite the cardiovascular concerns that lead to the recall of the COX-2 inhibitors, many healthcare providers who treat patients with hemophilia believe that the benefits of this class of nonsteroidal antiinflammatory drugs (NSAIDs) outweigh the risks. NSAIDs may be effective in relieving the pain of hemophilic arthropathy, and, consequently assisting older hemophiliac patients maintain an active lifestyle

3. Although hemophilia is associated with increased morbidity from bleeding, it has been found to have a protective effect on cardiovascular disease. It is unclear whether long-term prophylaxis mitigates this benefit. Also, it may argue for lower prophylactic doses in hemophilia patients with CVD risk factors, particularly those that adversely affect cardiovascular health

    Highly active antiretroviral therapy (HAART) increases the risk of hyperepidemia, whereas active HCV is associated with early atherosclerosis

4. Cardiovascular risk factors such as hypertension, diabetes, and renal disease, should be managed as aggressively as for individuals without hemophilia (opinion, not evidence based)

5. Anecdotal studies of cardiac surgery in patients with hemophilia have demonstrated surgery can safely be performed with pre- and postoperative factor VIII or IX replacement, use of antifibrinolytic agents, and postoperative thromboprophylaxis (if required)

    

    Tang M et al. Haemophilia 2009;15:101–107

    

6. Although drug-eluting stents appear superior to bare-metal stents in preventing reocclusion, antiplatelet therapy with aspirin and clopidogrel is recommended for 12 months after placement of a drug-eluting stent compared with up to 4 weeks after insertion of a bare-metal stent

    

    Dolan G et al. Haemophilia 2009;15(Suppl 1):20–27

    Schutgens REG et al. Haemophilia 2009:15:952–958

    Smolka G et al. Haemophilia 2007;13:428–431

    Tuinenburg A et al. J Thromb Haemost 2009;7:247–254

    

    Thus, a bare metal stent is more appropriate for hemophiliacs, particularly since the longer duration of antiplatelet therapy increases the risk of bleeding

    

    Dolan G et al. Haemophilia 2009;15(Suppl 1):20–27

    

    However, there are no randomized trials to confirm the best approach

DIALYSIS IN PATIENTS WITH HEMOPHILIA

In a meta-analysis of medical records of 3422 patients with hemophilia, 52% were documented to have chronic renal disease

Most common causes of renal disease in hemophiliacs

1. HIV infection

2. Hypertension

3. Diabetes

4. Chronic hepatitis B and C, which may cause membranous nephropathy and membranoproliferative glomerulonephritis

5. Nephrotic syndrome in patients with hemophilia B undergoing immune tolerance therapy for inhibitors

Types of dialysis:

1. Small studies have suggested peritoneal dialysis (PD) is safer because it minimizes bleeding risk of bad IV access for dialysis treatment. However, patients with coexisting hepatitis C with liver involvement may not be the best candidates for PD, because complications of liver disease such as ascites may impair PD clearance

2. Patients with HIV may be at risk of peritonitis. If a peritoneal dialysis catheter is to be placed, factor VIII or IX infusion (≥50% level) should be given preoperatively and for 2–3 days postoperatively

3. Hemodialysis

   1. During the decision process for permanent access, an external catheter or Vas-Cath is placed as a temporary measure. Factor correction to 100% for 24–48 hours after catheter placement is recommended

   2. An AV fistula is recommended for more permanent access

   3. There are no standard recommendations for the factor replacement target level in an undialyzed patient or for the use of heparin. The target factor level prior to dialysis should be the lowest amount of factor replacement required to reduce the bleeding risk without increasing the dialysis machine clotting risk. The clearance of FVIII is not affected by dialysis

   4. Several studies suggest that low-dose FVIII infusions of 1000 units before dialysis (to maintain FVIII level between 10% and 20%) and through the arterial dialysis line at the end of dialysis is sufficient to minimize bleeding, but not great enough to exacerbate clot formation in the extracorporeal dialysis circuit without heparin

 Lambing A et al. Haemophilia 2009;15:33–42

Epidemiology

Hemophilia B is a congenital X-linked, recessive bleeding disorder, characterized by deficient or defective factor IX or coagulation factor IX

Work-up

1. Elevated aPTT: This is corrected by the addition of an equal volume of normal plasma. If the APTT remains prolonged after the addition of an equal volume of normal plasma, consider the presence of an inhibitor to factor IX

2. Prothrombin time is usually normal but may be prolonged in some patients if ox-brain thromboplastin is used

3. A specific assay of factor IX levels is necessary for diagnosis

Treatment Options

1. Factor IX concentrates

2. Coagulation factor VIIa (recombinant)

Regimen for Factor IX Replacement

Low-purity plasma-derived human antihemophilic factor IX complex concentrates (Feiba NF, Bebulin VH, Profilnine D, and Proplex T)

Very-High Purity Plasma-Derived Factor IX (AlphaNine SD or Mononine) Recombinant Ultrapure Coagulation factor IX (BeneFIX)

Cohen AJ, Kessler CM. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia, PA: WB Saunders; 2002:43

Kasper CK. Haemophilia 2000;6(Suppl 1):13–27

Kasper CK. Hemophilia of Georgia, USA. Haemophilia 2000;6(Suppl 1):84–93

National Hemophilia Foundation, MASAC (Medical and Scientific Advisory Council) recommendation concerning the treatment of hemophilia and other bleeding disorders. 2003; No. 141

Srivastava A. Br J Haematol 2004;127:12–25

Toxicity

INHIBITORS IN HEMOPHILIA B

Epidemiology:

1. 1.5–3% of all patients with hemophilia B

2. 9–23% of severe hemophilia B

3. High-affinity neutralizing IgG antibody

4. Possible hypotheses explain the lower incidence of inhibitors in factor IX compared to FVIII deficiency

   1. Lower proportion of severe phenotype (<1%) in hemophilia B compared to hemophilia A (30–40% to 60%, respectively, in the United States)

   2. More patients with factor IX than FVIII deficiency are cross-reactive material (CRM) positive (ie, have a detectable factor IX antigen)

   3. Higher prevalence of masseuse Mutations (thus less-severe disease) in patients with factor IX than FVIII deficiency

5. A strong association between absent endogenous factor IX protein as a result of gross or complete gene mutations and inhibitor development

Risk factors for factor IX inhibitor development:

1. Positive family history

2. African ethnicity

3. Hemophilia B genotype (large deletion)

Clinical manifestations:

1. Allergic, anaphylactic reaction prior or concomitant with antibody development occurs characteristically in conjunction with inhibitor development

   1. Factor IX (55,000 kDa) accounts for its extracellular distribution and thus the potential for mast-cell activation and IgE-mediated hypersensitivity response

2. Antibody development occurs in all ethnic groups and in response to therapy with both plasma-derived and recombinant factor IX concentrates

Laboratory detection:

1. Factor IX inhibitors are IgG antibodies, predominately of the IgG₄ subclass (κ light chain) that interfere with the interaction of factor IX with its cofactors and activators. Most of these inhibitors can be detected when the PTT is prolonged on a mixture of normal and patient's plasma. In contrast to inhibitors in hemophilia A, antibodies to factor IX are neither time-dependent nor temperature-dependent; thus, it is not necessary to incubate the mixture for 2 hours at 37°C (98.6°F). Inhibitors to factor IX can be quantified by modifying the Bethesda method for detecting factor VIII inhibitors

2. There is no international consensus on the definition of a negative antibody titer, by either Bethesda or Nijmegen assay

Treatment/prevention of hemorrhage:

1. Few retrospective or prospective studies of treatment or prevention of bleeding in inhibitor patients have involved those with factor IX inhibitors. Thus, current standards of care for the treatment of hemorrhage in patients with factor IX inhibitors derive from those of FVIII inhibitor patients

2. Treatment of hemorrhage in patients with low titer (<5 BU) or low responder inhibitors

   1. High-dose factor IX therapy (eg, twice the dose as in standard therapy) bolus or continuous infusion of factor IX. Frequent monitoring of factor IX levels is crucial for accurately estimating a patient's daily factor IX requirement

   2. If there is a poor therapeutic response, the factor IX dose can be increased based on measured plasma IX activity, or, alternatively, bypass therapy (AICC or recombinant VIIIa)

3. Treatment of hemorrhage in patients with a high titer (≥5 BU)

   1. Antiinhibitor coagulant complex (AICC; activated prothrombin complex concentrates)

       (1) Feiba (Baxter Healthcare Corporation, Westlake, CA, USA) is the only currently licensed product within this class of bypass agents

       (2) Dose: 50–100 units/kg and subsequent infusions as needed to a maximum of 200 units/kg per day

   2. Recombinant activated factor VII (rFVIIa; NovoSeven)

       (1) Dose: 90 mcg/kg every 2–3 hours until bleeding stops. Several studies have indicated that a single dose of 270 mcg/kg can be used safely and can rapidly relieve pain (especially in hemarthrosis)

   3. Recombinant FVIIa is the treatment of choice in those with a history of anaphylaxis to factor IX concentrate

Bypass therapy bleeding prophylaxis:

1. There have been no controlled trials to assess optimal dosing or treatment efficacy/safety

2. Feiba: 50–100 units/kg twice daily or 3–4 times/week

3. rFVIIa: 90-mcg/kg or 270-mcg/kg regimens have been used

4. Whenever possible, patients with factor IX inhibitors should be enrolled in prospective, randomized, well-designed national or international studies

5. Use of plasmapheresis or protein A Sepharose column immunoabsorption can result in a rapid and efficient reduction of inhibitor titer if bypass agents fail to control hemostasis or if there is life- or limb-threatening bleeding. It can be used also for the initiation of immune tolerance for a high-titer inhibitor

6. Immune tolerance induction (ITI)

   1. Experience with factor IX inhibitors is quite limited

   2. ITI therapy associated with frequent development of allergic reactions or nephrotic syndrome

   3. Less successful than in patients with factor VIII inhibitors

DiMichele D. Br J Haematol 2007;138:305–315

Roth DA et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates [see comment]. Blood 2001;98:3600–3606. Comment in: Blood 2002;100:4242–4243

Indications

For control and prevention of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency) including control and prevention of bleeding in surgical settings

Efficacy

More than 90% of success in controlling bleeding on an on demand basis or for prevention of bleeding including soft tissue or muscle bleed and hemarthroses

Notes

1. Previously untreated and minimally treated patients should receive the recombinant product (BeneFIX). If the recombinant product is not available, then a very-high-purity plasma-derived product can be used

2. Factor IX concentrates can also be given by continuous infusion in a similar manner as that described for factor VIII for those undergoing major surgery