Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Hemophilia A (factor VIII [factor 8] deficiency) and hemophilia B (factor IX [factor 9] deficiency) are X-linked coagulation factor disorders associated with bleeding of variable severity, from life-threatening to clinically silent. The availability of factor replacement products has dramatically improved care for individuals with these conditions. However, patients do present with acute bleeding symptoms that require rapid treatment, and planning is required for patients undergoing surgery or invasive procedures.
This topic review discusses the treatment of bleeding and perioperative management for individuals with hemophilia A and B. Our approach is consistent with the World Federation of Hemophilia Guideline updated in 2012 (available at http://www.wfh.org/en/resources/wfh-treatment-guidelines) .
The diagnosis, routine prophylaxis, obstetrical management, inhibitor eradication, and genetics of hemophilia are discussed in separate topic reviews:
●Diagnosis – (see "Clinical manifestations and diagnosis of hemophilia")
●Obstetrical issues – (see "Clinical manifestations and diagnosis of hemophilia", section on 'Obstetrical issues')
●Routine comprehensive care including factor prophylaxis – (see "Hemophilia A and B: Routine management including prophylaxis")
●Inhibitor eradication – (see "Factor VIII and factor IX inhibitors in patients with hemophilia")
●Genetics – (see "Genetics of the hemophilias")
The management of bleeding in individuals with coagulation disorders other than hemophilia A and B is also presented in detail separately. (See "Treatment of von Willebrand disease" and "Rare inherited coagulation disorders" and "Factor XI deficiency" and "Disorders of fibrinogen" and "Acquired inhibitors of coagulation".)
ACUTE THERAPY FOR BLEEDING — In patients with hemophilia with acute bleeding, the immediate goal is to raise the factor activity to a level sufficient to achieve hemostasis. The targeted factor activity level depends on the location and severity of the bleeding, and the presence of an associated injury or occurrence in a target joint, as outlined in the sections that follow.
The data to support the desired factor levels for treating acute bleeding come from extensive clinical experience and uncontrolled, observational studies [1,2]. Randomized trials comparing different target factor levels have not been conducted.
Serious, life-threatening bleeding and head trauma
Initial considerations for severe bleeding — Serious or life-threatening bleeding in a patient with hemophilia is a medical emergency that requires prompt evaluation and immediate therapy with replacement factor. For patients with potentially serious or life-threatening bleeding, it is important to initiate treatment immediately, even before the diagnostic assessment is completed. Stated another way: treat first, evaluate second, plan further therapy after weighing all relevant issues.
Serious or life-threatening bleeding includes any of the following [1,3]:
●Bleeding in the central nervous system
●Bleeding in the hip
●Deep muscle bleeding with neurovascular compromise or the potential for neurovascular complications
●Bleeding that could affect the airway (eg, into the throat or neck)
●Bleeding severe enough to result in anemia and potentially require red blood cell transfusion(s)
●Prolonged bleeding that is not adequately responding to home-based therapy
●Significant injuries such as motor vehicle accidents or falls from distances of several feet or more
An acutely hemorrhaging hemophilic patient should be transported to a facility equipped to handle the event that has the appropriate replacement products [4,5]. Guidelines from the United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) suggest that the maximum time between arrival to the hospital and clinical assessment should not exceed 15 minutes, and if treatment for bleeding is required, the maximum time to its delivery should not exceed 30 minutes [6,7]. If the patient has the appropriate replacement therapy at home, this product may be administered before leaving or on route to the facility, as long as the bleeding is not life-threatening and this does not result in delays. In life-threatening circumstances, emergency medical transport should be called and the products should be administered on-route.
As noted above, factor administration should not be delayed while awaiting imaging studies in a patient with a concerning injury or suspected central nervous system bleeding [3,8,9]. All significant head injuries must be considered nontrivial unless proven otherwise by observation and imaging (eg, with computed tomography [CT] or magnetic resonance imaging [MRI]). If there is doubt about the seriousness of bleeding, it is preferable to treat the patient as if the bleeding is serious (ie, "if in doubt, treat" ). Further, the importance of urgently giving the factor infusion outweighs considerations of the specific factor preparation (ie, "give the appropriate product that is available rather than spending time trying to obtain a different product").
Other hemostatic therapies for individuals with inhibitors or those whose bleeding is not controlled by factor infusion are presented below. (See 'Therapies other than factor replacement' below.)
Factor dosing for severe bleeding — For severe bleeding, the factor activity level should be maintained above 50 percent at all times. An immediate dose of factor should be given to raise the peak factor level to 80 to 100 percent (table 1), and additional doses should be timed to occur when a factor activity level of approximately 50 percent is achieved, so the patient's circulating factor level does not drop below 50 percent. Another option is to give a dose of factor to raise the level to 80 to 100 percent, followed by continuous infusion to maintain a consistent hemostatic level. As noted above, administration of factor should not be delayed while awaiting imaging studies. (See 'Initial considerations for severe bleeding' above.)
The following illustrates a typical calculation of factor dosing, but this should not substitute for the clinical judgement of the treating clinician, information from previous bleeding events for that patient, labeling information for specific products, consultation with the hemophilia treatment center (HTC), and/or institutional protocols that take into account local practices.
●Hemophilia A (deficiency of factor VIII [factor 8]) – Give an initial dose of factor VIII of 50 units/kg to raise the factor VIII level to 100 percent. This calculation assumes a starting factor VIII activity level close to 0 percent, a desired factor activity level of 100 percent, and a volume of distribution of approximately 0.5.
The dose equals the patient's weight (in kg) multiplied by the desired rise in factor VIII level (as a whole number, such that a desired level of 100 percent is entered as 100) multiplied by the volume of distribution (for factor VIII, this equals 0.5). As an example, for a 60 kg patient who requires an increase to 100 percent, the dose would be 60 kg x 100 x 0.5 = 3000 units of factor VIII.
The second and subsequent doses are given at intervals of approximately one half-life of the infused product for that patient, which is based on peak and trough levels as described below. A typical half-life for standard half-life factor VIII products is approximately 8 to 12 hours. Approximate half-lives for longer-lasting factor VIII products range from 10 to 20 hours. Approximate half-lives for specific products are listed in the table (table 2). These doses will be approximately half the initial dose, and will be guided by the patient's measured factor level and the desired peak level.
Another option is to give the initial factor VIII bolus followed by a continuous infusion [10-13]. A dose of approximately 4 units/kg/hour of standard half-life factor VIII concentrate will often maintain the level initially achieved by the bolus infusion. This method offers the advantage of consistent levels, less frequent monitoring, and decreased factor utilization. Factor activity levels should be checked periodically during continuous infusion, with the interval determined by the previous level, dose adjustments, and clinical bleeding. Continuous infusions should not have an attached filter, and the factor product should only be mixed with normal saline.
●Hemophilia B (deficiency of factor IX [factor 9]) – Give an initial dose of factor IX of 100 to 120 units/kg to raise the factor IX level to 100 percent. This calculation assumes a starting factor IX activity level close to 0 percent, and a desired factor activity level of 100 percent, and a volume of distribution of approximately 1.0.
The dose equals the patient's weight (in kg) multiplied by the desired rise in factor IX level (as a whole number, such that a desired factor level of 100 percent is entered as 100) multiplied by the volume of distribution (for factor IX, this equals approximately 1.0). As an example, for a 60 kg patient who requires an increase to 100 percent, the dose would be 60 kg x 100 x 1 = 6000 units of factor IX. Some factor IX products require an additional multiplier based on slightly increased or decreased volume of distribution:
•For AlphaNine, Mononine, and Ixinity, no additional calculations are needed
•For BeneFIX, multiply by 1.4 for children (ie, weight in kg x desired increase x 1.4) and 1.2 for adults
•For Rixubis, multiply by 1.4 for children and by 1.4 for adults
•For Alprolix, multiply by 1.6 (range, 1.4 to 1.67) for children; no additional calculations are needed for adults
•For Idelvion, no additional calculations are needed for children; for adults multiply by 0.77
The second and subsequent doses are given at intervals of approximately one half-life of the infused product for that patient, which is based on peak and trough levels as described below. A typical half-life for standard half-life factor IX products is approximately 18 to 24 hours. Approximate half-lives for longer-lasting factor IX products range from 54 to 104 hours. Approximately half-lives for specific products are listed in the table (table 3). These doses will be approximately half the initial dose, and will be guided by the patient's measured factor level and the desired peak level.
Another option is to give the initial factor IX bolus followed by a continuous infusion [11,13-15]. A dose of approximately 6 units/kg/hour of standard half-life factor IX concentrate will often maintain the level initially achieved by bolus infusion. This method offers the advantage of consistent levels, less frequent monitoring, and decreased factor utilization. Factor activity levels should be checked periodically during continuous infusion, with the interval determined by the previous level, dose adjustments, and clinical bleeding. Continuous infusions should not have an attached filter and the factor product should only be mixed with normal saline.
As noted above, subsequent factor dosing for patients receiving bolus doses of factor should incorporate information on the patient's peak and trough factor activity levels (or steady state levels for those receiving continuous infusion) rather than a set schedule without monitoring. This is because individual pharmacokinetics vary and can significantly impact factor half-life and ultimate hemostasis. Patient characteristics such as the volume of distribution and recovery may be altered by individual handling of drugs and body fat content .
The peak factor activity level should be checked approximately 5 to 15 minutes after the first dose. For major life-threatening bleeding, the trough is checked at approximately 4 to 6 hours for factor VIII and 8 to 12 hours for factor IX. Slightly longer intervals before the first trough level may be used for less-serious bleeding.
As noted above, for patients receiving bolus doses of factor, the second and subsequent doses will be given at intervals of approximately one half-life. If the trough factor activity is lower than expected, the dosing interval may be shortened and/or the subsequent dose increased depending on peak levels. If the trough factor activity level is higher than expected, the dosing interval may be increased and/or the subsequent dose may be lowered.
The duration of factor replacement therapy for severe or potentially serious bleeding is individualized based upon a variety of issues including need for surgery, extent of bleeding, site of bleeding, presence of an injury or target joint, and response (eg, reduction in bleeding, healing) to infusion therapy. Therapy may be continued after acute intensive treatment as the patient may require physical therapy or rehabilitation and may need to use prophylactic dosing until full recovery is achieved.
For head trauma, we start treatment as soon as possible at the time of injury and often treat for at least three days, including significant trauma with negative imaging. Late bleeding following head trauma can occur up to three to four weeks following the event. Thus, individuals with head trauma or other severe bleeding should be instructed about signs of late or recurrent bleeding, plans for factor dosing should these occur, and parameters for seeking medical attention. This includes instructions about the signs and symptoms of central nervous system bleeding, so that repeat infusion, clinical and radiological assessment, and hospitalization occur at the earliest manifestation.
Considerations for hemarthroses — Bleeding into a joint (hemarthrosis) is one of the most common manifestations of hemophilia. Joint bleeds are characterized by reduced range of motion associated with pain or other unusual sensation (eg, tingling that often precedes pain), palpable swelling or warmth, or other typical findings for that patient. Bleeding into hip joints is concerning due to the greater risk of increased intra-articular pressure and osteonecrosis of the femoral head. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Joints and muscle'.)
Some patients develop a "target joint" in which repeated bleeding episodes and chronic inflammatory changes occur. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Hemophilic arthropathy'.)
The major aspects of assessment and management of joint bleeding include the following :
●Factor should be infused promptly at the first sign of joint bleeding (eg, at the onset tingling characteristic of joint bleeding rather than waiting for reduced range of motion or swelling). (See 'Factor dosing for joint bleeds' below.)
●Additional interventions to reduce bleeding, pain, and inflammation include avoidance of weight bearing or use of the affected extremity, application of ice packs, immobilization and/or splinting as recommended, and analgesics as needed (generally avoiding agents with antiplatelet activity such as nonsteroidal anti-inflammatory agents [NSAIDs], although these may be used in some circumstances such as significant joint inflammation in a patient receiving factor replacement). Selective cyclooxygenase 2 (COX2) inhibitors may be used.
●Clinical evaluation is used to distinguish an acute bleed from other conditions such as pain due to chronic arthropathy, acute fracture or sprain, or infection. In many cases, this assessment is based on the history and physical examination rather than radiography or ultrasound examinations. Arthrocentesis is not required to diagnose joint bleeding in patients with hemophilia. If arthrocentesis is deemed necessary (eg, due to concern of a septic joint or to reduce pressure from accumulated blood) it should only be performed after factor has been administered to raise the factor level to 100 percent in conjunction with a comprehensive hemophilia treatment center. Ultrasound may be useful to distinguish an acute bleed from pain associated with chronic arthropathy. (See 'Overview of surgical planning' below.)
●It may be challenging to distinguish hemarthrosis of the hip from bleeding into the iliopsoas muscle. In general, hemarthrosis of the hip results in severe pain with hip motion, whereas iliopsoas bleeding primarily causes limited hip extension. Iliopsoas bleeding may also cause reduced sensation over the ipsilateral thigh due to compression of the sacral plexus root of the femoral nerve. Ultrasonography or other radiologic evaluation may be helpful in identifying hematoma in the iliopsoas region versus the hip joint. (See 'Muscle/Soft tissue bleeding' below.)
●A decision must be made regarding whether the patient requires at-home versus in-hospital treatment. The majority of hemarthroses are managed at home. Indications for hospitalization include painful, swollen major joints; initial delay in therapy; bleeding episodes that are not responding as expected at home; associated pain that is not controlled with home oral analgesia; inability to adhere to home instructions, including children who cannot be non-weight bearing; advanced bleeding that was treated late or in association with an injury that requires more intensive treatment and intervention; suspicion of an infection; and bleeding in an individual with an inhibitor that is not responding well at home.
●Other acute management needs that may be addressed in patients whose bleeding does not rapidly respond to factor infusion and local measures at home include possible admission with use of continuous infusion, inhibitor testing to assure an inhibitor has not developed, possible joint aspiration to remove blood and relieve pressure, other hemostatic therapies, and glucocorticoids.
•Arthrocentesis may be appropriate if there is neurovascular compromise, severe pain, or other evidence of increased joint pressure that has not improved with other treatment, or there is suspicion of an infection. If joint aspiration is performed, replacement therapy should be administered to raise the factor level to 100 percent before the procedure. Inhibitor patients require use of bypassing therapy and should be treated at a comprehensive hemophilia treatment center.
•Other hemostatic therapies for individuals with inhibitors or those whose bleeding is not controlled by factor infusion are presented below. (See 'Therapies other than factor replacement' below.)
•If a target joint has undergone repeated hemorrhage, we often administer a short course of glucocorticoids as appropriate to reduce pain and swelling associated with synovial inflammation (eg, prednisone for three to five days), as long as the patient does not have an active infection. A benefit from a short course of glucocorticoids was demonstrated in a pair of trials that randomly assigned 35 children with hemophilia and a joint bleed to receive prednisone (1 mg per pound of body weight per day [equivalent to approximately 0.45 mg/kg; maximum dose, 80 mg] for three days) or placebo along with factor replacement therapy . Compared with controls, the children assigned to prednisone had similar outcomes but required less factor infusion.
●It can be challenging to determine when acute bleeding into a joint has stopped. Patient report of bleeding is most commonly used, and ultrasound may be helpful as well. Most experts continue to treat with a course of therapy designed to allow bleed resolution and prevent rebleeding based upon patient circumstances and the presence of a target joint, injury, or inhibitor. The duration of therapy depends on the joint affected, the size of the hemarthrosis, and the ability to avoid weight bearing, which affects the pace of healing. Some experts treat for approximately three to four days after bleeding has stopped; questions should be directed to the local HTC.
●Joint surgery for chronic synovitis or arthropathy may be indicated in some cases. Various procedures may be offered, including synovectomy, either isotopic or surgical, for recurrent bleeding or joint replacement for extensive joint damage. A 2016 meta-analysis of studies evaluating the role of total knee arthroplasty (TKA) in people with hemophilia reviewed outcomes of 336 procedures in 254 individuals and found an overall improvement in range of motion, although not as great as that of individuals without hemophilia . The complication rate was 32 percent; common complications included infections, bleeding, and bone abnormalities. Decisions regarding the use of invasive procedures are best made in close consultation between the patient, and an experienced multidisciplinary team including a comprehensive hemophilia treatment center hematologist (to confirm that factor replacement and other hemostatic therapies have been optimally administered) and the surgeon or interventional radiologist (to assess the feasibility of the procedure and likelihood of efficacy) .
●Following resolution of a joint bleed, it is important to initiate a rehabilitation program that involves gradual increased range of motion, weight bearing, and strength training. Attention to bone health (eg, adequate vitamin D and knowledge regarding the presence of osteopenia) is also indicated. Involvement of a physical therapist with expertise in hemophilia to design a rehabilitative program is helpful. Individuals who are not receiving routine prophylaxis should consider using a form of prophylaxis including limited short-term prophylaxis following recurrent target joint hemarthrosis, with factor administration for several weeks to months to reduce or prevent recurrent bleeding, or to use a more aggressive dosing schedule in individuals who are already receiving routine prophylaxis. Prophylaxis is discussed separately. (See "Chronic complications and age-related comorbidities in people with hemophilia", section on 'Arthropathy' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Exercise and athletic participation' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Routine factor replacement therapy (prophylaxis)'.)
Factor dosing for joint bleeds — Factor should be administered at the earliest sign of bleeding, preferably within two hours of bleed identification. This should be done at home, if possible (ie, do not wait until being evaluated at the hospital). For bleeding into the hip, iliopsoas, or a target joint; or bleeding associated with injury, higher factor levels (eg, 80 to 100 percent) are used (see 'Factor dosing for severe bleeding' above). For hemarthrosis in peripheral joints such as knees, elbows, or ankles, the factor activity level should be raised to at least 40 to 50 percent.
The following is appropriate to achieve approximately 40 to 50 percent factor activity (table 1):
●Hemophilia A – Give an initial dose of factor VIII, either based on prior experience for that patient, or, if the optimal dose for joint bleeding has not been established for that patient, give approximately 25 units/kg of factor VIII to raise the factor VIII level by 50 percent. This calculation assumes a desired factor activity level of 50 percent, and a volume of distribution of 0.5.
The dose equals the patient's weight (in kg) multiplied by the desired rise in factor VIII level (as a whole number [eg, 50]) multiplied by 0.5. As an example, for a 60 kg patient who requires a level of 50 percent, 60 kg x 50 x 0.5 = 1500 units of factor VIII.
●Hemophilia B – Give an initial dose of factor IX, either based on prior experience for that patient, or, if the dose for joint bleeding has not been established for that patient, approximately 50 to 60 units/kg of factor IX to raise the factor IX level by 50 percent. This calculation assumes a desired factor activity level of 50 percent, and a volume of distribution of at least 1.0.
The dose equals the patient's weight (in kg) multiplied by the desired rise in factor IX level (as a whole number [eg, 50]) multiplied by 1.0 (assumed volume of distribution). As an example, for a 60 kg patient who requires an increase to 50 percent, 60 kg x 50 x 1.0 = 3000 units of factor IX. Some factor IX products require an additional multiplier:
•For AlphaNine, Mononine, and Ixinity, no additional calculations are needed
•For BeneFIX, multiply by 1.4 for children (ie, weight in kg x desired increase in percent x 1.4) and 1.2 for adults
•For Rixubis, multiply by 1.4 for children and by 1.4 for adults
•For Alprolix, multiply by 1.6 (range 1.4 to 1.67) for children; no additional calculations are needed for adults
•For Idelvion, no additional calculations are needed for children; for adults multiply by 0.77
The need for additional doses and the duration of therapy are individualized according to the patient's symptoms, affected joint, concurrent issues (bleeding into the hip, iliopsoas, or a target joint; or bleeding associated with injury), and initial response. For some patients who are able to identify the early symptoms of a joint bleed and rapidly administer factor, a single dose of factor may be sufficient. However, some comprehensive treatment centers use more intensive therapy for hemarthroses for specific patients or all patients (eg, for hemophilia A, an initial factor VIII dose of 40 units/kg followed by additional doses of 20 units/kg at 24 and 72 hours after the first dose; for hemophilia B, an initial factor IX dose to provide a target level of 80 percent activity followed by additional doses to provide 40 percent activity, with the interval determined by the half-life of the factor IX product used) . At the other extreme, some individuals may require several days of factor infusion to allow bleed resolution and reduce the risk of rebleeding for a severe bleed, a bleed into a target joint, or a bleed with concurrent injury. Hip joint or acetabular hemorrhages may result in increased intra-articular pressure and osteonecrosis (aseptic necrosis) of the femoral head . Therapy designed to sustain a factor level above a minimum of 30 to 40 percent for at least three days should be given, along with enforced bed rest; often this is done in the hospital using continuous infusion.
Muscle/Soft tissue bleeding — Muscle bleeding may present with aching, pain, or swelling. In muscle groups such as the upper arm, forearm, wrist, volar hand, and anterior or posterior tibial compartment, soft tissue hemorrhage may result in development of a compartment syndrome with impingement on the neurovascular bundle. This may be associated with tingling, numbness, and in severe situations loss of distal arterial pulses.
Therapy should be initiated as soon as possible (eg, at the first sign of symptoms or immediately after injury or trauma). For severe muscle hematomas, a peak factor activity level of at least 50 percent is appropriate. This requires treatment/factor replacement therapy for individuals with any degree of factor deficiency in hemophilia A and B. For individuals with mild hemophilia A, it may be possible to raise the factor VIII level using DDAVP . (See 'DDAVP for mild hemophilia A' below.)
Severe muscle bleeds usually require more than one factor infusion. Surgical decompression is undertaken only if medical therapy fails to forestall progression, and in consultation with a comprehensive hemophilia treatment center. (See "Acute compartment syndrome of the extremities", section on 'Management'.)
Muscle bleeds can result in a significant drop in hemoglobin level, and the hemoglobin should be monitored until it is clear that bleeding has ceased.
Minor bleeding — Minor bleeding such as epistaxis or skin bleeding may be treated with local measures including ice, pressure, or elevation. Topical therapies including antifibrinolytic agents or other adjunctive local therapies may also be helpful. At times, episodes of epistaxis may be prolonged or may result in larger volume blood loss that will necessitate replacement therapy. (See 'Antifibrinolytic therapy for mucosal bleeding' below and 'Adjunctive local therapies' below.)
URGENT/EMERGENT SURGERY — Patients who require an emergency procedure should be managed with urgent infusion of factor to raise the factor activity to a level appropriate for the procedure. (See 'Major surgery' below and 'Elective surgery' below.)
Overview of surgical planning — Planning for elective surgery should include the patient/family and all relevant clinicians to ensure that best practices are followed. Collaboration with experts from a hemophilia treatment center to develop a hemostatically effective and safe care plan is strongly advised. A comprehensive plan for management before, during, and after the procedure, and excellent communication between the operative physician and the hematologist is required to assure an optimal outcome. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Hemophilia treatment centers'.)
Surgery should be performed in a setting that includes timely access to laboratory monitoring of factor activity levels and immediate availability of replacement factor (or plasma components, in resource-limited settings) and other hemostatic products, and clinicians with expertise in managing patients with hemophilia. Meticulous operative technique should be used, with local hemostatic agents as appropriate.
The preoperative assessment should include:
●General medical examination to identify associated issues including oral health prior to joint replacement, other hemostatic defects (eg, concomitant liver disease), use of medications that can affect the coagulation system, and/or cardiovascular risk factors or cardiovascular disease.
●Inhibitor screening to identify newly developed inhibitors and/or determine the inhibitor titer. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Diagnosis and screening (factor VIII inhibitors)' and "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Diagnosis (factor IX inhibitors)'.)
●DDAVP test dose for individuals with mild hemophilia A for whom this approach is being considered and has not been performed already; this should be done at least one week before planned surgery. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'DDAVP test dose for mild hemophilia A'.)
Desired factor levels and duration of therapy depend on the type of procedure, as described below, with longer durations for greater bleeding risk procedures or procedures where healing requires a longer duration of coverage. DDAVP may be used in patients with mild hemophilia A who have been demonstrated to have an adequate response and in appropriate procedures (eg, dental procedures). Antifibrinolytics are often useful in dental procedures. (See 'Major surgery' below and 'Circumcision' below and 'Dental procedures' below and 'Endoscopy or tonsillectomy' below and 'Therapies other than factor replacement' below.)
For patients who require perioperative factor administration, the initial (preoperative) dose should be timed to provide maximal coverage at the time of greatest bleeding risk (typically 30 to 60 minutes before the procedure). The dose is calculated from the patient's weight, baseline factor level, desired factor level, volume of distribution, and presence of an inhibitor as described in the dosing sections above. For the first dose, we assume the baseline factor level to be 0 percent, with the exception of those with baseline factor levels >20 percent, for whom it may be appropriate to subtract the baseline factor level from the desired factor level to calculate the desired increase.
After infusion, the factor level should be checked before proceeding with the operative intervention for all procedures other than routine outpatient dental procedures. In a patient with an inhibitor who is using bypassing therapy, there is no coagulation test that reflects clinical efficacy; therefore, laboratory monitoring of factor activity levels is not used. Subsequent dosing is based on the plan of care developed, the patient's clinical status, and the measured levels, which if bolus dosing is used are typically measured at 8 to 12 hours after the previous dose for factor VIII and 12 to 24 hours after the previous dose for factor IX [23,24]. In addition, levels are often obtained in the recovery room to assure adequate hemostasis.
For the management of major surgery in which postoperative continuous infusion is planned, it is important to note that factor VIII and IX clearance is increased during surgery (ie, consumption is increased) due to expected operative bleeding. Accordingly, if an immediate factor level is not available, it is probably prudent to give an additional bolus prior to starting the continuous infusion, with an amount of factor equivalent to half the initial bolus. This is especially pertinent to orthopedic procedures.
If there is unexpected postoperative bleeding, it is important to obtain an immediate (stat) factor level and to consider the possibility that bleeding may be due to an anatomic or mechanical cause (eg, need for ligation of blood vessels) if adequate hemostatic factor levels are documented.
The efficacy and safety of long half-life factor VIII products (eg, recombinant factor VIII-Fc fusion; PEGylated recombinant factor VIII) has been demonstrated in small studies in which patients with hemophilia A were managed perioperatively for major and minor surgeries and had excellent hemostasis without serious adverse events [25,26]. Product consistency during outpatient and inpatient use is important, and if the patient uses a longer-lasting product or specific product at home, we use the same product in the hospital if possible. (See 'Patients receiving longer-lasting factor' below.)
Patients with mild hemophilia A and those who have received intensive factor replacement for the first time should be re-screened for inhibitors at the completion of therapy, and at approximately one to three months postoperatively . Patients for whom factor administration is ineffective and those requiring higher than expected doses of factor may also require earlier inhibitor screening.
Major surgery — Major surgery includes any surgery with a risk of clinically significant bleeding or penetration of a major body cavity, including orthopedic surgery. Orthopedic procedures are the most commonly performed major surgical procedures in people with hemophilia. Individuals with hemophilia can undergo any type of major surgery (eg, cancer surgery, coronary artery bypass grafting [CABG]) as long as factor replacement is given and adequate hemostasis assured. (See "Chronic complications and age-related comorbidities in people with hemophilia", section on 'Cancer' and "Chronic complications and age-related comorbidities in people with hemophilia", section on 'Cardiovascular disease'.)
The target factor activity level and duration of therapy are individualized according to the patient and procedure. Most recommendations including the 2012 World Federation of Hemophilia guideline use a desired preoperative factor level for major surgery of 80 to 100 percent for hemophilia A and 60 to 80 percent for hemophilia B, with postoperative levels gradually tapering to approximately 50 percent until the wound is healed (typically over a period of 10 to 14 days) . For wound or joint manipulation, a level of at least 50 percent is necessary.
Dosing to achieve the appropriate factor level, including calculations for bolus dosing or continuous infusion, which may provide more even factor levels and reduce factor usage, is described above. (See 'Acute therapy for bleeding' above.)
Circumcision — Circumcision is an important decision for some families and is of religious significance for certain populations such as Muslims and Jews [27,28]. Circumcision in the neonatal period is often the first bleeding challenge in an individual with hemophilia, and in some cases the first clue to the diagnosis. All individuals for whom the diagnosis of hemophilia is possible based on family history should have factor activity testing with results obtained and discussed with a hemophilia treatment center hematologist before a circumcision is performed. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Neonatal diagnosis'.)
If the diagnosis of hemophilia is confirmed and the family requests circumcision, the following is advised:
●Replacement factor should be available at the time of the procedure. Factor is generally only administered if bleeding occurs that cannot be controlled with local measures or other hemostatic products . This assessment is likely to require a longer period of observation following the procedure than used for neonates without hemophilia. If postoperative factor is needed, a single dose of factor with good local control of bleeding is often sufficient, but prolonged bleeding may require additional doses.
●Fibrin glue (also called fibrin sealant) comes as a kit made from plasma-derived clotting proteins that is applied to the external surface of a wound as a spray or patch. The products contain concentrated fibrinogen (the precursor of fibrin) and coagulation factor XIII, which crosslinks fibrin. Fibrin sealant can be used for those with hemophilia with bleeding that cannot be controlled with local measures. This product lessens the need for factor replacement and is not associated with some of the risks and expense of factor administration . Specific products and their uses are discussed in more detail separately. (See "Fibrin sealants".)
●Antifibrinolytic agents such as tranexamic acid or epsilon aminocaproic acid reduce bleeding by interfering with fibrinolysis and thus reducing clot breakdown. In our experience, these agents are less effective in circumcision; they can be used orally or intravenously. (See 'Antifibrinolytic therapy for mucosal bleeding' below.)
●The procedure should be performed so that the risk of bleeding is minimized (eg, experienced hands, use of Plastibell device). This and other techniques are discussed separately. (See "Techniques for neonatal circumcision", section on 'Techniques'.)
For the most part, practice is based on clinical experience rather than evidence from randomized trials. The variation in practice among experts is illustrated in the following:
●A 2015 survey of pediatric hematologists affiliated with hemophilia treatment centers (HTCs) in the United States documented a wide range of approaches and lack of established protocols in most cases . Major concerns included the risks of bleeding and inhibitor development after early exposure to replacement product. Of 64 respondents, 2 (3 percent) would not allow the procedure unless there was a urologic indication, 18 (28 percent) would perform the procedure at the time of another procedure that required factor administration, and 20 (31 percent) would defer the procedure until the child was older. The remaining 24 (38 percent) would perform the procedure (some reluctantly). All respondents stated they would use at least one dose of factor before the procedure; approximately one-third used two or three doses; and an additional 12 (19 percent) used more prolonged therapy. Most used a target factor level of approximately 75 percent. Approximately one-third used antifibrinolytic therapy, and smaller numbers used fibrin glue, topical thrombin, gelatin sponge, or wound seal.
●A 2009 review and survey conducted by the European Haemophilia Therapy Standardization Board (EHTSB) identified six studies involving 163 patients with hemophilia who underwent circumcision . Five of the studies used factor replacement plus local therapy (fibrin glue, antifibrinolytic agents) and one used antifibrinolytic agents alone. Target factor levels when reported were in the range of 30 to 60 percent. The survey of experts suggested a target factor activity level of 80 percent for three to four days, with adjunctive fibrin glue and/or antifibrinolytic therapy.
Additional information about risks and benefits of circumcision, methods for analgesia, and complications are presented separately. (See "Neonatal circumcision: Risks and benefits" and "Techniques for neonatal circumcision" and "Complications of circumcision".)
Dental procedures — Different dental procedures are associated with different bleeding risks. Close consultation between the dentist and hemophilia treatment center prior to the procedure is advised. A summary of recommendations from the United Kingdom Haemophilia Center Doctors' Organization (UKHCDO) in 2013 included the following recommendations, largely based on low quality evidence :
●For children and adults with hemophilia undergoing invasive dental procedures that require factor replacement, a target factor level above 50 percent for one to two days is usually sufficient; this often can be achieved with one infusion of factor plus antifibrinolytic therapy. Factor infusions should be scheduled in such a way that the number of infusions is minimized. Dosing to achieve the appropriate factor level is described above. (See 'Acute therapy for bleeding' above.)
●Of special note, it is important to be aware of the serious risks associated with extraction of mandibular third molars (wisdom teeth) that are impacted, due to the potential for retropharyngeal bleeding and airway compromise.
●For children and adults with hemophilia undergoing inferior dental blocks, factor replacement to a level of 50 percent activity during the procedure is required. The dose of factor should be administered as close to the procedure as possible.
●For children with moderate to severe hemophilia, factor levels may also need to be raised for local anesthetic infiltration.
●For adults with moderate to severe hemophilia, certain dental procedures may not require factor infusion; examples include buccal infiltration, inter-papillary injection, endodontic (root canal) treatment, and intra-ligamentary injections. For adults undergoing dental extractions, the use of sutures and topic hemostatic gelatin matrices or cyanoacrylate tissue adhesives may minimize bleeding. (See "Overview of topical hemostatic agents and tissues adhesives", section on 'Gelatin matrix' and "Minor wound repair with tissue adhesives (cyanoacrylates)".)
●For children and adults with mild hemophilia (factor activity level above 5 percent), the majority of non-surgical dental procedures can be provided by the pediatric and adult dentists without additional interventions. Exceptions may include block injections as noted above.
Antifibrinolytic agents (eg, tranexamic acid, epsilon aminocaproic acid) are very useful for oral procedures because fibrinolysis is highly active on mucosal surfaces. These can be given orally, intravenously, or as a mouthwash; the mouthwash should be restricted to older children and adults because it may be inadvertently swallowed by younger children (see 'Antifibrinolytic therapy for mucosal bleeding' below). Antifibrinolytics can also be safely combined with factor replacement . A typical regimen is to give the first dose of the antifibrinolytic agent two hours before the procedure and continue for up to 7 to 10 days post-procedure.
Endoscopy or tonsillectomy — Factor replacement is used for individuals with moderate to severe hemophilia undergoing endoscopy or tonsillectomy. Due to the location of potential bleeding, attention to hemostasis is especially important. More than one infusion of factor may be required for endoscopy. Almost invariably, more than one infusion is required for tonsillectomy.
In particular, the risk of bleeding from tonsillectomy may be especially concerning because the bleeding may be not only oral but also retropharyngeal; the latter may be associated with airway compromise.
For those with mild hemophilia A, DDAVP may be sufficient based on the patient's factor level and response. In endoscopy, biopsies may be taken, and therefore antifibrinolytic therapy may also be given; antifibrinolytics are used with tonsillectomy. (See "Endoscopic procedures in patients with disorders of hemostasis".)
Dosing to achieve the appropriate factor level, including calculations for bolus dosing or continuous infusion, which may provide more even factor levels and reduce factor usage, is described above. (See 'Acute therapy for bleeding' above.)
Overview of patient with an inhibitor — Management of bleeding or surgery in a patient with an inhibitor (neutralizing alloantibody against infused factor) is especially challenging because inhibitors bind to the infused factor and render it ineffective. Inhibitors are much more likely to occur in individuals with hemophilia A and those with severe disease. Some patients may only become aware that they have an inhibitor in the midst of an acute bleeding episode or surgery, when factor infusions no longer raise factor activity levels to the expected range or if there is an allergic/anaphylactic reaction to the infusion. (See "Factor VIII and factor IX inhibitors in patients with hemophilia".)
Any patient with an inhibitor is best treated in consultation with a comprehensive hemophilia treatment center, especially when any decision is being made to administer the factor in which they are deficient rather than to use bypassing therapy. Protocols for managing inhibitors should be available at each institution that cares for patients with hemophilia. The local hemophilia treatment center can assist in developing general protocols and protocols for specific patients. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Hemophilia treatment centers'.)
Management of bleeding or surgery in patients with inhibitors depends on the severity of bleeding and the type and titer of the inhibitor . Inhibitors are diagnosed and classified by titer using the Bethesda assay, in which serial dilution of patient plasma is used to determine an inhibitor titer in Bethesda units (BU). Inhibitors with a titer of <5 BU despite repeated factor infusions are referred to as low responding inhibitors . Any inhibitor >5 BU/mL at any time is considered high responding, even if the titer subsequently becomes undetectable due to lack of re-exposure. Classically, high responding inhibitors rapidly increase upon re-exposure to infused factor in an amnestic response that takes four to seven days. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Diagnosis and screening (factor VIII inhibitors)' and "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Diagnosis (factor IX inhibitors)'.)
Individuals with an inhibitor titer of >5 BU and those with an unknown titer but with a known high responding inhibitor are less likely to be effectively treated with factor infusions in an emergent situation because the quantity of circulating antibody is likely too great to be overcome by factor infusion.
●For patients with a high responding inhibitor whose current titer is <5 BU, it may be possible in some circumstances to treat them with factor coverage; this decision should only be made in consultation with a comprehensive hemophilia treatment center as anamnesis is expected.
●For a patient with a titer >5 BU with a high responding inhibitor and serious bleeding with a need for major surgery, a bypassing product is used. (See 'Bypassing products (rFVIIa or FEIBA)' below.)
●In an emergency setting when a patient is receiving factor infusions and factor activity level does not increase at one hour post-infusion (or bleeding does not respond to factor infusion and a factor activity level or inhibitor titer is not available), the patient should be treated as if they have a high-titer/high responding inhibitor until inhibitor testing with a Bethesda assay can be performed. The main caveats are that the original hemophilia A or B diagnosis is correct, the correct replacement factor was given, there is no heparin contamination in the sample, and the assay is performed correctly. (See 'Bypassing products (rFVIIa or FEIBA)' below.)
Other potential hemostatic therapies are under investigation but are not yet available for clinical use. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Prophylactic therapies under development'.)
Inhibitor eradication/immune tolerance induction should be addressed once the patient is stable and the bleeding episode has resolved or at the time of inhibitor development. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Immune tolerance induction (factor VIII inhibitors)' and "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Immune tolerance induction (factor IX inhibitors)'.)
Bypassing products (rFVIIa or FEIBA) — A bypassing product is generally the first choice in a patient with hemophilia A or B who has a high-titer inhibitor and requires treatment for bleeding or surgery. These clotting factor products contain an activated form of a downstream clotting factor in the coagulation cascade. Activated factor VII (factor VIIa) can directly activate factor X, bypassing the need for factors VIII and IX. Available products include recombinant activated factor VII (rFVIIa; NovoSeven, NovoSeven RT) and activated prothrombin complex concentrates (aPCCs) such as FEIBA (factor eight inhibitor bypassing agent; the only aPCC available in most settings) (table 4).
Both rFVIIa and FEIBA contain activated clotting factors and both are effective for hemostasis in hemophilia. For hemophilia B, rFVIIa is the preferred agent because it does not contain factor IX; this is especially true in individuals with hemophilia B with an inhibitor who have experienced reactions or anaphylaxis upon exposure to factor IX. For hemophilia A, either product can be used. If the patient has had a favorable response with one of these products, it is reasonable to use the same product again.
●rFVIIa – Dosing of rFVIIa is typically 90 to 120 mcg/kg (rounded to the nearest vial size) every two to three hours until hemostasis is achieved and at three- to six-hour intervals after hemostasis has been restored .
●FEIBA – Dosing of FEIBA is typically 50 to 100 units/kg every 6 to 12 hours, not to exceed 100 units/kg/dose or 200 units/kg/day .
Dosing is adjusted based on clinical response (eg, cessation of bleeding) rather than laboratory testing . Standard interval dosing is generally continued for at least 48 to 72 hours for severe bleeding or major surgery (shorter durations for minor surgery), followed by a taper in which the dosing interval is gradually increased. In cases of severe uncontrolled bleeding, it is important to remember that therapy with one bypassing product may be effective even if the other bypassing product has failed. Also, the patient may have a surgical, traumatic, or anatomic reason for continued bleeding that may need to be addressed surgically or endoscopically. In rare cases of ongoing joint bleeding, arterial embolization has been used .
Although FEIBA and/or rFVIIa may be lifesaving in individuals with severe hemophilic bleeding for whom factor replacement is ineffective, these products are prothrombotic and thus attention to the occurrence of this potential complication should be maintained .
Randomized trials comparing FEIBA and rFVIIa in patients with inhibitors and severe bleeding or major surgery are challenging to perform. In the FENOC (FEIBA NovoSeven Comparative) trial, 66 patients with hemophilia A (age range, 8 to 55 years; median inhibitor titer, 8.6 BU/mL) and a joint bleed were randomly assigned to receive one dose of FEIBA (85 units/kg) or two doses of rFVIIa (105 mcg/kg, twice); patients were then instructed to use the other product for their next joint bleed . Participants were instructed to initiate the treatment within four hours of bleeding symptoms and to record the hemostatic efficacy at several time points. At six hours post-bleeding, the overall efficacy of FEIBA and rFVIIa were similar (81 and 79 percent, respectively); other time points and efficacy measures did not show one product to be clearly superior. However, some individual patients derived greater efficacy from one product or the other, especially during the first 12 hours. Additional smaller randomized trials have also found comparable efficacy of FEIBA and rFVIIa in treating bleeding [40-42]. Perioperative use of bypassing agents has also been reported to show comparable efficacy of FEIBA and rFVIIa, although there is a greater body of experience with rFVIIa in surgical patients .
aPCCs may be associated with reactions due to activation of the complement and bradykinin systems when infused rapidly, as well as prothrombotic complications including venous thromboembolism, myocardial infarction, and disseminated intravascular coagulation . These risks appear to be greater with aPCCs or in settings of trauma, large repeated doses, or prolonged administration. As noted above, individuals with hemophilia B and an inhibitor can have anaphylactic reactions to factor IX, which is present in all PCCs and aPCCs. rFVIIa and aPCC have been used together in some patients, but this should only be done in the hospital by experienced clinicians at a hemophilia treatment center [43,44].
Recombinant porcine factor VIII (hemophilia A) — Another option for a patient with hemophilia A and a high-titer inhibitor is recombinant porcine (pig) factor VIII (Obizur), which was initially developed for treating patients with autoantibodies to endogenous factor VIII (ie, acquired factor VIII deficiency [acquired hemophilia A]). Use in inherited hemophilia A is off-label in the United States. Recombinant porcine factor VIII has no role in hemophilia B.
This product has the theoretical advantage of achieving hemostasis with decreased cross reactivity to the neutralizing antibodies against human factor VIII and has been used effectively in individuals with hemophilia A and an inhibitor. However, cross-reacting antibodies to recombinant porcine factor VIII have been described.
We reserve porcine factor VIII for patients with hemophilia A and life-threatening or limb-threatening bleeding that cannot be controlled with a bypassing agent. When used, the product is dosed according to the weight of the patient and the standard dosing guidelines for acquired hemophilia A until a titer of anti-porcine factor VIII antibodies is available; subsequent dosing is guided by standard factor VIII activity levels. Monitoring factor VIII levels is essential.
A plasma-derived porcine factor VIII (Hyate-C) is no longer available; it was removed from the market due to the presence of porcine parvovirus and porcine endogenous retroviruses in the product despite no documentation of human transmission of either. This product was previously used to treat patients with hemophilia A who had life-threatening bleeding complicated by high titer inhibitors to human factor VIII, most commonly when titers against porcine factor VIII were below 10 BU [45-47]. The product was associated with hypersensitivity reactions in approximately 1 to 2 percent of patients, more commonly observed in individuals treated with higher doses . Obizur does not appear to be associated with an increased risk of allergic reactions.
Plasmapheresis — Plasmapheresis may be useful in patients with a high titer inhibitor to acutely lower the inhibitor titer and allow transient use of replacement factor. This approach is generally reserved for an individual with life-threatening or limb-threatening bleeding and an inhibitor titer >5 BU for whom bypassing therapy is not effective or recombinant porcine factor VIII is not available.
High-dose factor infusion — A final option for an individual with bleeding and an inhibitor is to provide high-dose factor infusion. This approach may be effective for patients with hemophilia A or B and a low titer (<5 BU) or a low responding inhibitor, as long as the patient does not have an infusion reaction to the replacement factor (reactions are more commonly seen with factor IX). High-dose factor also may be useful for patients with high responding inhibitors currently at a low titer or a titer lowered by plasmapheresis, with the understanding that this is only likely to be effective for a limited time period (four to seven days) and is likely to induce anamnesis .
Dosing in this setting has not been established from prospective trials. One approach is to administer the full replacement dose as described for a patient without an inhibitor above, plus an additional 50 percent more factor for every BU of inhibitor. As an example, for a 60 kg patient with factor VIII deficiency and an inhibitor of 2 BU who requires correction to 100 percent factor activity, the patient would be given the usual replacement dose (60 kg x 100 x 0.5 = 3000 units of factor VIII) plus an additional (2 BU x 60 kg x 50 x 0.5 = 3000 units of factor VIII) for a total of 6000 units of factor VIII.
This may be followed by bolus dosing, based on factor activity level measured 10 to 15 minutes after the infusion is completed, or by continuous infusion, at a starting rate adequate to compensate for altered pharmacokinetics based on the presence of an inhibitor, with dose adjustments based on factor activity levels.
Patients receiving longer-lasting factor — Some patients use a longer-lasting factor for routine prophylaxis or acute bleeding and thus may have a longer-lasting product in their system or available for use. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer lasting recombinant factor VIII' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer lasting recombinant factor IX'.)
Management of bleeding is the same as for other patients, with factor infusion to maintain the factor level above the threshold determined necessary for the location and severity of bleeding. The calculations for dosing generally assume that the patient is at their baseline level (ie, calculations should be the same as for any other patients). (See 'Acute therapy for bleeding' above.)
For elective surgery, it is best to use the same longer-lasting factor that the patient uses at home, as this simplifies care and potentially simplifies issues of adverse events and the difficulty in determining how to ascribe these if changing products. Issues related to the use of longer-lasting products for surgical procedures are essentially the same as for standard half-life products and include use of appropriate monitoring assays for levels and assurance of adequate hemostatic levels. Use of longer-lasting products may reduce the number of infusions needed during and after procedures, depending on the product, the patient, and the individual half-life. It is important to use an assay for factor activity that is tailored to the specific factor being used.
Patient with mild hemophilia — Individuals with mild hemophilia (factor level between 5 and 40 percent) may require factor replacement therapy for acute bleeding, surgery, or invasive procedures; it is important to remember that patients with mild hemophilia are also at risk of inhibitor development and should be followed closely during times of intensive replacement therapy. Thus, they should be managed by experts and a care team knowledgeable about hemophilia at a facility with access to factor should it be needed, similar to those with more severe deficiency.
●Severe bleeding – Patients with mild hemophilia A or B who have serious bleeding or require major surgery should be treated similarly to those with severe or moderate deficiency. (See 'Acute therapy for bleeding' above and 'Major surgery' above.)
●Mild hemophilia A, minor bleeding – Patients with mild hemophilia A may have a sufficient increase in factor VIII activity level upon administration of DDAVP (desmopressin; a synthetic analog of vasopressin/antidiuretic hormone that lacks pressor activity), which promotes release of endogenous factor VIII. A DDAVP test dose should be performed before use in an invasive procedure to assure an adequate hemostatic response, as discussed separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'DDAVP test dose for mild hemophilia A'.)
DDAVP administration and adverse events are discussed below. (See 'DDAVP for mild hemophilia A' below.)
●Mild hemophilia B, minor bleeding – Mild hemophilia B cannot be treated with DDAVP because factor IX is not stored or released. Patients with mild hemophilia B are treated with factor IX or other hemostatic therapies such as antifibrinolytic agents and/or topical therapies. (See 'Antifibrinolytic therapy for mucosal bleeding' below and 'Adjunctive local therapies' below.)
Resource-poor settings (no access to purified factor) — Purified factor products (virally inactivated plasma-derived concentrates or recombinant products) should be used whenever possible, to avoid potential transfusion-transmitted infection and transfusion reactions. However, individuals in resource-poor settings may not have access to these products. For such individuals, options include Fresh Frozen Plasma (FFP), or, for those with hemophilia A, Cryoprecipitate. Dosing is based on the factor concentration in the product, patient weight, and the desired factor level. One bag of Cryoprecipitate is made from approximately 250 mL of FFP and contains approximately 70 to 80 units of factor VIII in a volume of 30 to 40 mL (concentration of factor VIII in Cryoprecipitate, approximately 3 to 5 units/mL) . One mL of FFP contains one unit of factor activity. A dose of 15 to 20 mL/kg will raise the factor VIII level by approximately 30 to 40 percent and the factor IX level by approximately 15 to 20 percent (different increases are due to different volumes of distribution of factors VIII and IX). (See "Clinical use of plasma components", section on 'Plasma products' and "Clinical use of Cryoprecipitate".)
THERAPIES OTHER THAN FACTOR REPLACEMENT
Antifibrinolytic therapy for mucosal bleeding — Antifibrinolytic agents include tranexamic acid (TXA) and epsilon aminocaproic acid (EACA). These may be used in combination with factor replacement therapy for individuals with a mucosal source of bleeding, or as single agents in settings with mucosal bleeding that is less severe (eg, dental procedures). Topical administration to skin sites has also been reported .
These agents are most useful for stabilizing clots in areas of increased fibrinolysis such as the oral or nasal cavity (eg, dental bleeding, epistaxis) or for menorrhagia in women with bleeding disorders [33,49]. Their mechanism of action is to inhibit fibrinolysis by inhibiting plasminogen activation in the fibrin clot, thereby enhancing clot stability. The decision between these agents is based on local preference; they have not been directly compared in patients with hemophilia and have appeared to have comparable efficacy in other settings.
●TXA – The usual dose is 25 mg/kg per dose every six to eight hours.
●EACA – The usual dose is 75 to 100 mg/kg per dose every six hours (maximum single dose 3 to 4 g).
These drugs can be administered orally or intravenously. When given orally, they must be given three or four times over a 24-hour period because of their short half-lives. Dosing is often continued for several days, depending on the degree of injury and bleeding.
Neither TXA nor EACA should be given simultaneously with an activated prothrombin complex concentrate (aPCC), as this will increase the risk of thromboembolism. If an antifibrinolytic agent and a PCC are used, they should be separated by at least 12 hours . There is some experience using TXA and recombinant factor VIIa (rFVIIa) together in the surgical setting; consultation with a hemophilia treatment center is advised. (See 'Bypassing products (rFVIIa or FEIBA)' above.)
Adjunctive local therapies — Other adjunctive hemostatic therapies include microfibrillar collagen, especially for bleeding in the oral cavity, and fibrin glue, which has been used following circumcision . (See "Fibrin sealants".)
DDAVP for mild hemophilia A — DDAVP (desmopressin) is a synthetic analog of vasopressin (antidiuretic hormone]) that lacks pressor activity and may be effective for minor bleeding or certain elective procedures in patients with mild hemophilia A (typically those with factor VIII activity in the higher range, closer to 40 percent) who have had a documented response to a test dose [22,50-54].
The test dose is generally performed as part of routine comprehensive care. If not done previously it should be performed at least one week prior to use for hemostasis, to allow review of the results, surgical planning, and communication among treating clinicians. Details of the test dose are described separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'DDAVP test dose for mild hemophilia A'.)
For those who respond, a typical dose is 0.3 mcg/kg (maximum dose, 20 mcg), administered intravenously or subcutaneously; or as a nasal spray (Stimate), one puff (150 mcg) in one nostril in patients weighing <50 kg and two puffs (150 mcg in both nostrils) in patients weighing ≥50 kg. A repeat dose may be given at 12 hours, and subsequent doses are often administered once daily. When using the nasal spray it is important to use the spray intended for hemostasis and not the spray for enuresis, which has a lower concentration.
DDAVP can increase the factor VIII level two- to fourfold. A patient with a baseline factor activity of 25 percent who has an increase to 50 percent may have adequate hemostasis with DDAVP in the setting of minor bleeding or procedures and thus avoid factor infusion. Tachyphylaxis may occur; the administration should be timed to provide the maximal response at the time of greatest bleeding risk, while limiting the number of doses.
The following caveats apply to DDAVP use:
●DDAVP is not effective for patients with severe hemophilia A (factor VIII activity <1 percent) because factor activity level cannot be increased sufficiently, and usually is not used in individuals with moderate hemophilia A (factor VIII activity from 1 to 5 percent) for the same reason.
●DDAVP should only be used for mild bleeding for which a 30- to 60-minute delay is acceptable and a two- to fourfold factor VIII increase are likely to be sufficient for hemostasis. For more serious bleeding, factor VIII infusion should be used.
●DDAVP is not effective for patients with hemophilia B because factor IX is not stored in platelets or endothelial cells.
●DDAVP generally is not used in children under two years of age due to an increased risk of water retention that may result in a syndrome of inappropriate ADH (SIADH)-like picture and potentially cerebral edema and seizures . If used in this age group, it should be done under hematologist supervision.
●DDAVP has antidiuretic activity and can cause hyponatremia, especially with prolonged use or excess free water intake. As a result, doses often are limited to once daily for three consecutive days, and water intake is restricted. The serum sodium concentration is monitored in hospitalized individuals, especially those receiving more than one or two doses of DDAVP.
●Additional adverse effects include facial flushing, headache, nausea, and tingling sensations. These can often be controlled by decreasing the rate of the infusion when administering the medication intravenously . Cases of thrombosis have been reported, although a causal relationship is difficult to establish. Hypotension and hypertension have been reported but are not common and usually are mild. Approaches other than DDAVP may be preferable in older patients with underlying cardiovascular disease.
In rare patients with mild hemophilia A who have mild bleeding and wish to avoid factor infusion but have not been tested for DDAVP response, it may be reasonable to use DDAVP, especially if a post-dose factor VIII level is obtained; however, evidence to support this practice is lacking. Effective therapy should not be delayed in a bleeding patient, which may occur if the response to DDAVP is not documented.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia, von Willebrand disease, and other coagulation disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hemophilia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●For a patient with hemophilia who has serious life-threatening bleeding including any intracranial bleeding or head trauma, factor concentrate should be infused as urgently as possible to target a factor activity level of 80 to 100 percent (table 1).
•For hemophilia A, give 50 units/kg of factor VIII (factor 8)
•For hemophilia B, give 100 to 120 units/kg of factor IX (factor 9)
Subsequent factor dosing should be administered at intervals based upon measured peak and trough factor levels. (See 'Serious, life-threatening bleeding and head trauma' above.)
●Factor should also be infused promptly (within two hours of bleed identification) at the first sign of joint bleeding, with a target factor activity level of approximately 50 percent (for hemophilia A, give 25 units/kg of factor VIII; for hemophilia B, give 50 to 60 units/kg of factor IX). Additional considerations for joint bleeding include need for higher target levels in specific circumstances such as trauma, the need for repeated factor infusions to assure adequate resolution, decisions regarding hospitalization, distinction from other conditions (eg, infection, muscle bleeding), the need for arthrocentesis or a surgical procedure, appropriate rehabilitation, and optimal prophylactic therapy. (See 'Hemarthroses' above.)
●For patients with hemophilia undergoing elective surgery, coordination among the patient/family and all relevant clinicians is essential. This should involve inhibitor screening, determination of desired factor activity levels, and planning for factor activity monitoring and administration. Certain sites of potential bleeding may be especially serious due to their location and possibility of causing airway compromise (eg, retropharyngeal bleeding from tonsillectomy or impacted mandibular wisdom tooth extraction). (See 'Elective surgery' above.)
●Management of bleeding and surgery in patients with hemophilia with an inhibitor (neutralizing antibodies against infused factor) is especially challenging. For a patient with a high titer and high responding inhibitor (eg, 5 to 10 Bethesda units or greater) who has serious bleeding or requires major surgery, a bypassing product (eg, FEIBA or recombinant factor VIIa) is used. For patients with a low responding inhibitor, options include factor concentrates or other hemostatic agents. Inhibitor eradication/immune tolerance induction should be addressed. (See 'Inhibitors' above and 'Therapies other than factor replacement' above.)
●Antifibrinolytic therapy is a useful adjunct for stabilizing clots in areas of increased fibrinolysis (eg, oral cavity, nasal bleeding). (See 'Antifibrinolytic therapy for mucosal bleeding' above.)
●DDAVP (desmopressin) may be effective for elective procedures in patients with mild hemophilia A (factor VIII activity between 5 and 40 percent) who have had a documented response to a test dose. DDAVP can be administered intravenously, subcutaneously, or intranasally. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'DDAVP test dose for mild hemophilia A' and 'DDAVP for mild hemophilia A' above.)
●Our approach is overall consistent with the World Federation of Hemophilia Guideline updated in 2012 (available at http://www.wfh.org/en/resources/wfh-treatment-guidelines).
●Separate topic reviews discuss hemophilia A and B diagnosis, routine comprehensive care, factor prophylaxis, inhibitor eradication, and genetics. (See "Clinical manifestations and diagnosis of hemophilia" and "Hemophilia A and B: Routine management including prophylaxis" and "Factor VIII and factor IX inhibitors in patients with hemophilia" and "Genetics of the hemophilias".)
- Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19:e1.
- Vanderhave KL, Caird MS, Hake M, et al. Musculoskeletal care of the hemophiliac patient. J Am Acad Orthop Surg 2012; 20:553.
- Hoots KW. Emergency management of hemophilia. In: Textbook of Hemophilia, 3rd ed, Lee CA, Berntorp EE, Hoots WK (Eds), John Wiley & Sons, Ltd, 2014. p.463.
- Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379:1447.
- Ljung RC, Knobe K. How to manage invasive procedures in children with haemophilia. Br J Haematol 2012; 157:519.
- Fowler H, Lacey R, Keaney J, et al. Emergency and out of hours care of patients with inherited bleeding disorders. Haemophilia 2012; 18:e126.
- http://www.ukhcdo.org/wp-content/uploads/2015/12/EmergencyCareStandardsFinalVersionJune2009-For-Website.pdf (Accessed on August 16, 2016).
- Hoots WK. Emergency management in hemophilia. In: Textbook of Hemophilia, 2nd ed, Lee CA, Berntorp EE, Hoots WK (Eds), Wiley-Blackwell, Oxford, UK 2010. p.394.
- Gilchrist GS, Piepgras DG, Roskos RR. Neurologic Complications in Hemophilia. In: Hemophilia in the Child and Adult, Hilgartner MW, Pochedly C (Eds), Raven Press, New York 1989. p.45.
- Schulman S, Varon D, Keller N, et al. Monoclonal purified F VIII for continuous infusion: stability, microbiological safety and clinical experience. Thromb Haemost 1994; 72:403.
- Martinowitz UP, Schulman S. Continuous infusion of factor concentrates: review of use in hemophilia A and demonstration of safety and efficacy in hemophilia B. Acta Haematol 1995; 94 Suppl 1:35.
- Hay CR, Doughty HI, Savidge GF. Continuous infusion of factor VIII for surgery and major bleeding. Blood Coagul Fibrinolysis 1996; 7 Suppl 1:S15.
- Holme PA, Tjønnfjord GE, Batorova A. Continuous infusion of coagulation factor concentrates during intensive treatment. Haemophilia 2017.
- Schulman S, Wallensten R, White B, Smith OP. Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery. Haemophilia 1999; 5:96.
- Yamamoto M, Nakadate H, Iguchi U, et al. [Successful management of neurosurgical procedures with continuous infusion of recombinant factor IX in a child with hemophilia B]. Rinsho Ketsueki 2013; 54:300.
- Henrard S, Speybroeck N, Hermans C. Body weight and fat mass index as strong predictors of factor VIII in vivo recovery in adults with hemophilia A. J Thromb Haemost 2011; 9:1784.
- Simpson ML, Valentino LA. Management of joint bleeding in hemophilia. Expert Rev Hematol 2012; 5:459.
- Kisker CT, Burke C. Double-blind studies on the use of steroids in the treatment of acute hemarthrosis in patients with hemophilia. N Engl J Med 1970; 282:639.
- Moore MF, Tobase P, Allen DD. Meta-analysis: outcomes of total knee arthroplasty in the haemophilia population. Haemophilia 2016; 22:e275.
- Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357:535.
- Paton RW, Evans DI. Silent avascular necrosis of the femoral head in haemophilia. J Bone Joint Surg Br 1988; 70:737.
- Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8:421.
- Poon MC, Aledort LM, Anderle K, et al. Comparison of the recovery and half-life of a high-purity factor IX concentrate with those of a factor IX complex concentrate. Factor IX Study Group. Transfusion 1995; 35:319.
- Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369:2313.
- Brand B, Gruppo R, Wynn TT, et al. Efficacy and safety of pegylated full-length recombinant factor VIII with extended half-life for perioperative haemostasis in haemophilia A patients. Haemophilia 2016; 22:e251.
- Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123:317.
- Kavakli K, Kurugöl Z, Göksen D, Nisli G. Should hemophiliac patients be circumcised? Pediatr Hematol Oncol 2000; 17:149.
- Rosner F. Hemophilia in the Talmud and rabbinic writings. Ann Intern Med 1969; 70:833.
- Hermans C, Altisent C, Batorova A, et al. Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations. Haemophilia 2009; 15:639.
- Martinowitz U, Varon D, Jonas P, et al. Circumcision in hemophilia: the use of fibrin glue for local hemostasis. J Urol 1992; 148:855.
- Kearney S, Sharathkumar A, Rodriguez V, et al. Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers. Haemophilia 2015; 21:52.
- Anderson JA, Brewer A, Creagh D, et al. Guidance on the dental management of patients with haemophilia and congenital bleeding disorders. Br Dent J 2013; 215:497.
- Djulbegovic B, Marasa M, Pesto A, et al. Safety and efficacy of purified factor IX concentrate and antifibrinolytic agents for dental extractions in hemophilia B. Am J Hematol 1996; 51:168.
- Kempton CL, White GC 2nd. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009; 113:11.
- Mauser-Bunschoten EP, Zijl JA, Mali W, et al. Successful treatment of severe bleeding in hemophilic target joints by selective angiographic embolization. Blood 2005; 105:2654.
- Lusher JM. Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors--benefits and limitations. Semin Hematol 1994; 31:49.
- Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109:546.
- Young G, Shafer FE, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia 2008; 14:287.
- Santagostino E, Mancuso ME, Rocino A, et al. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost 2006; 4:367.
- Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95:600.
- Schneiderman J, Rubin E, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience. Haemophilia 2007; 13:244.
- Gringeri A, Fischer K, Karafoulidou A, et al. Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors. Haemophilia 2011; 17:630.
- Hay C, Lozier JN. Porcine factor VIII therapy in patients with factor VIII inhibitors. Adv Exp Med Biol 1995; 386:143.
- Hay CR, Lozier JN, Lee CA, et al. Safety profile of porcine factor VIII and its use as hospital and home-therapy for patients with haemophilia-A and inhibitors: the results of an international survey. Thromb Haemost 1996; 75:25.
- Brettler DB, Forsberg AD, Levine PH, et al. The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience. Arch Intern Med 1989; 149:1381.
- Noble S, Chitnis J. Case report: use of topical tranexamic acid to stop localised bleeding. Emerg Med J 2013; 30:509.
- Stajcić Z. The combined local/systemic use of antifibrinolytics in hemophiliacs undergoing dental extractions. Int J Oral Surg 1985; 14:339.
- Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada. CMAJ 1995; 153:147.
- Revel-Vilk S, Blanchette VS, Sparling C, et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J Haematol 2002; 117:947.
- Rose EH, Aledort LM. Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 1991; 114:563.
- Nolan B, White B, Smith J, et al. Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders. Br J Haematol 2000; 109:865.
- Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1:869.
- Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia 2000; 6:11.