Hemophilia A Treatment & Management
- Author: Robert A Zaiden, MD; Chief Editor: Steven C Dronen, MD, FAAEM more...
Approach Considerations
The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis.
Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have 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.
Dose calculations are directed toward achieving a factor VIII (FVIII) activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, 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.[9, 10] According to a review of 6 randomized controlled trials, preventative therapy started early in childhood, as compared to on-demand treatment, is able to reduce total bleeds and bleeding into joints resulting in a decrease in overall joint deterioration and an improvement in patient quality of life.[11]
In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity.[12] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, 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. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined.
Hospitalizing patients with internal bleeding, with uncontrollable bleeding, and before elective surgery or other invasive procedures is advised.
Please see the following for more information:
Prehospital Care
Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:
- Apply aggressive hemostatic techniques
- Assist patients capable of self-administered factor therapy
- Gather focused historical data if the patient is unable to communicate
Emergency Department Care
Before a patient with hemophilia is treated, the following information should be obtained:
- The type and severity of factor deficiency
- The nature of the hemorrhage or the planned procedure
- The patient's previous treatments with blood products
- Whether inhibitors are present and if so, their probable titer
- Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome.
Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.
If admission is indicated, disposition (ICU vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose attending service based on etiology of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory.
Patients whose condition and bleeding are stabilized should be transferred to a specialized center for further treatment and monitoring because a multidisciplinary approach by specialists experienced in hemophilia may be required.
Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandage). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.
If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.
Factor VIII Concentrates
Various FVIII concentrates are now available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.
Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.
Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. Third-generation products without any exposure to animal proteins are now available to further decrease this risk. 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 (ie, better stability, purity), use of continuous infusion of factors has incrementally increased. Continuous administration of antihemophilic 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.
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.
Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. Target levels by hemorrhage severity are as follows:
- Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
- Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of 50%
- Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days.
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia (Open Table in a new window)
| Indication or Site of Bleeding | Factor level Desired, % | FVIII Dose, IU/kg* | Comment |
| Severe epistaxis; mouth, lip, tongue, or dental work | 20-50 | 10-25 | Consider aminocaproic acid (Amicar), 1-2 d |
| Joint (hip or groin) | 40 | 20 | Repeat transfusion in 24-48 h |
| Soft tissue or muscle | 20-40 | 10-20 | No therapy if site small and not enlarging (transfuse if enlarging) |
| Muscle (calf and forearm) | 30-40 | 15-20 | None |
| Muscle deep (thigh, hip, iliopsoas) | 40-60 | 20-30 | Transfuse, repeat at 24 h, then as needed |
| Neck or throat | 50-80 | 25-40 | None |
| Hematuria | 40 | 20 | Transfuse to 40% then rest and hydration |
| Laceration | 40 | 20 | Transfuse until wound healed |
| GI or retroperitoneal bleeding | 60-80 | 30-40 | None |
| Head trauma (no evidence of CNS bleeding) | 50 | 25 | None |
| Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) | 100 | 50 | Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
| Trauma with bleeding, surgery† | 80-100 | 50 | 10-14 d |
Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.
Desmopressin
Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia.
DDAVP 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. Other possible mechanisms of action are noted.
A test dose should be performed. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes.
A concentrated DDAVP intranasal spray is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.
Patients should be advised to limit water intake during treatment and to avoid 3 consecutive daily doses to a prevent hyponatremia. Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed.
The major adverse effects of DDAVP include asymptomatic facial flushing and hyponatremia.
Management of Bleeding Episodes by Site
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.
Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. 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 reveal 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.
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 (epsilon-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[13]
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.
Gastrointestinal 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.
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 scanning or MRI. 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.
Treatment of Patients with Inhibitors
Inhibitors are antibodies that neutralize factor VIII and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.
Rarely, inhibitors can develop in individuals without hemophilia (eg, elderly persons, pregnant women); these occasionally are responsive to immunosuppressive therapy (eg, prednisone).
The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[14] There is no established treatment for bleeding episodes in patients with high-titer inhibitors. A study of 26 patients over 2 years of age with severe hemophilia A tested the prophylactic use of anti-inhibitor coagulant complex (AICC) for preventing bleeding. Results show treatment 3 times per week on nonconsecutive days for 6 months led to a 62% reduction in all bleeding episodes as compared with on-demand therapy. Other bleeding events including hemarthroses and target-joint bleeding were also reduced; 61% and 72%, respectively.[15]
Other approaches to treating patients with FVIII inhibitors include the following:
- Porcine FVIII, which has low cross-reactivity with human factor VIII antibody
- Activated prothrombin complex concentrate (PCC)
- Activated FVII
- Desensitization
- Immune tolerance induction (ITI)
Recombinant activated FVIIa
Recombinant activated FVIIa (Eptacog Alfa or Novo Seven) has become the first choice of bypassing agents.[16] Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[17] It is manufactured by using DNA biotechnology.
Intravenous recombinant FVIIa has been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis.[16] Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.
To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with inhibitors for FVIII; when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding.
Desensitization
Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FVIII along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy.
Immune tolerance induction
In immune tolerance induction (ITI), a person is rendered tolerant to FVIII by means of daily exposure to FVIII over several months to years.[14, 18] The overall likelihood of success with ITI is 70% ± 10%.
First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia.
Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in ITI.[19] Reports describe durable complete responses with a brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.[20] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[21, 22]
Attenuation of B-cells essential to the development of an acquired immune response, or autoimmunization seen in patients with refractory FVIII inhibitors, with a 4-week course of weekly rituximab has shown durable and complete responses in several small trials. The addition of prednisone with or without cyclophosphamide has increased response rates.
An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high-dose ITI. For information, please see the study Web site Immune Tolerance Induction Study.
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 regimens of factor concentrate infusions that are administered at home, usually by a parent.
The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method.
Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance 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.
Assessing adherence to prophylaxis
The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries).[23]
Pain Management
Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.
Hemophilic chronic arthropathy is associated with pain. Narcotic agents have been used, but frequent use of these drugs may result in addiction. Nonsteroidal anti-inflammatory drugs may be used instead because their effects on platelet function are reversible and because these drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its irreversible effect on platelet function.
Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.
Complications
HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.
Allergic reactions are occasionally reported with the use of cryoprecipitate, fresh-frozen plasma (FFP), and factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.
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 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.
In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[24] This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.
Carrier testing
Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.
Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages.
Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[25, 26, 27] The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination.
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.
Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.
Gene Therapy
With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived. Substantial progress has been made in the development of gene therapy for hemophilia A and hemophilia B.[28] This advancement reflects technical improvements of existing vector systems and the development of new delivery methods.
Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. The induction of neutralizing antibodies often precludes stable phenotypic correction.
Certain promoters are prone to transcriptional inactivation in vivo, resulting in failure of long-term FVIII expression. Several phase I trials of gene therapy are ongoing in patients with severe hemophilia. Some individuals report fewer bleeding episodes than before, and low levels of clotting factor activity are occasionally detected.
Consultations
Consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.
A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.
Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.
Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.
Management should be provided in coordination with a comprehensive hemophilia care center.
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| Classification | Factor Activity, % | Cause of Hemorrhage |
| Mild | >5-40 | Major trauma or surgery |
| Moderate | 1-5 | Mild-to-moderate trauma |
| Severe | < 1 | Spontaneous, hemarthrosis |
| Indication or Site of Bleeding | Factor level Desired, % | FVIII Dose, IU/kg* | Comment |
| Severe epistaxis; mouth, lip, tongue, or dental work | 20-50 | 10-25 | Consider aminocaproic acid (Amicar), 1-2 d |
| Joint (hip or groin) | 40 | 20 | Repeat transfusion in 24-48 h |
| Soft tissue or muscle | 20-40 | 10-20 | No therapy if site small and not enlarging (transfuse if enlarging) |
| Muscle (calf and forearm) | 30-40 | 15-20 | None |
| Muscle deep (thigh, hip, iliopsoas) | 40-60 | 20-30 | Transfuse, repeat at 24 h, then as needed |
| Neck or throat | 50-80 | 25-40 | None |
| Hematuria | 40 | 20 | Transfuse to 40% then rest and hydration |
| Laceration | 40 | 20 | Transfuse until wound healed |
| GI or retroperitoneal bleeding | 60-80 | 30-40 | None |
| Head trauma (no evidence of CNS bleeding) | 50 | 25 | None |
| Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) | 100 | 50 | Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
| Trauma with bleeding, surgery† | 80-100 | 50 | 10-14 d |

