Hemophilia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Comprehensive care for congenital hemophilia involves:[38]

Treatment and prevention of bleeding
Rehabilitation after joint and muscle bleeds
Prevention and long-term management of joint and muscle damage, and of other sequelae of bleeding
Management and prevention of complications from treatment
Education and promotion of self-guided care
Home therapy
Management of comorbidities
Pain management
Dental care
Quality-of-life assessments and psychosocial support
Genetic counseling and diagnosis
Physical therapy and joint status-appropriate exercises for muscle strengthening, joint protection, maintenance of range of motion, and balance.

When acute bleeding occurs, treatment should be instituted early, preferably within 2 hours. Patients may have an aura (e.g., tingling sensation and tightness within the joint, preceding the appearance of clinical signs of a joint bleed), or recognize early signs before the start of a bleed. It is uncommon to have a patient present with bleeding at multiple sites, except in the setting of traumatic injury. If bleeding is particularly severe, or a life-threatening site is involved (e.g., head, neck, chest, abdomen), treatment should begin even before full assessment is complete. Patients should carry important information to aid decisions about management in an acute situation.

To assess and manage an acute bleeding episode, elicit:

Disease severity and type
Inhibitor status
Anatomical site of bleed
History of previous bleeding and type of products used in the past
Contact information of treating physician/clinic.

In patients with hemophilia B, the development of inhibitors is often heralded by anaphylaxis to factor IX products.[66][67] Thus, for the first 10-20 factor IX exposure days in hemophilia B patients, factor IX should be administered in a setting equipped for the management of anaphylaxis (unless the patient is known to have mutations deemed low risk for inhibitor development). Those who develop anaphylaxis have an increased risk of developing nephrotic syndrome upon factor IX exposure and should be monitored carefully.[36][38]

Management of acute bleeding episodes in people without factor inhibitors

Treatment options for most patients with congenital hemophilia consist of factor VIII or factor IX replacement (for hemophilia A and hemophilia B, respectively) by infusion of factor VIII or IX concentrate. Additional treatments include:

Antifibrinolytic agents (e.g., tranexamic acid, aminocaproic acid)
Pain medications
Desmopressin: patients with mild hemophilia A (with a demonstrated positive response to desmopressin) may benefit.

In patients with hemophilia A receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve hemostasis should be used for breakthrough bleeding.[38][61]

Topical hemostatic agents such as fibrin sealant and topical thrombin are used primarily in the surgical setting. Recombinant human thrombin is the preferred option to achieve topical hemostasis in this setting. Fibrin sealant, which is prepared by mixing 2 plasma-derived protein fractions (fibrinogen-rich concentrate and thrombin concentrate), has been used for local bleeding control in hemophilia.

Home infusion of clotting factor VIII or IX concentrates (for hemophilia A and hemophilia B, respectively), administered by a home healthcare nurse, trained parent, or patient, may be arranged for treatment of uncomplicated bleeding episodes or for prevention (prophylaxis).[38] Uncomplicated bleeding episodes can usually be managed as an outpatient with appropriate monitoring, follow-up, and physical therapy. Any other type of bleeding needs to be evaluated in the hospital setting.

Management of acute bleeding episodes in people with factor inhibitors

About 30% of patients with hemophilia A develop inhibitors to infused factor VIII, whereas the cumulative incidence for hemophilia B is up to 5%.[38] Genetic and environmental factors have been implicated in the development of inhibitory antibodies.[18][39][47] Risk factors for inhibitor development include:

Disease severity: more common in severe hemophilia (but may also occur in patients with mild or moderate hemophilia)
Environmental factors: treatment duration (inhibitor development is more likely during early factor concentrate treatment), treatment intensity, infection, age, type of product, ethnicity (e.g., higher incidence in black African and African-Caribbean patients)[47][48]
Genetic mutations: in particular, those that result in absence of a gene product (e.g., large deletions, nonsense mutations); immune response genes have also been implicated in inhibitor development. People with a family history of developing inhibitors to infused factor VIII and people of black African, African-Caribbean, or Hispanic descent are more likely to develop inhibitors.[47][48]

The presence of inhibitory antibodies is detected by a screening test, which is either positive or negative. If positive, further testing classifies the patient as having low responder or high-responder inhibitors, based on the amount of inhibitor present:

Low-responder inhibitors: persistently <5 Bethesda units/mL (BU/mL), despite repeated challenge with factor VIII or IX concentrate
High-responder inhibitors: ≥5 BU/mL at any given time.

Inhibitor titers in patients with high-responder inhibitors may occasionally fall to <5 BU/mL, particularly when there has been no recent exposure to exogenous factor VIII or factor IX, or when patients are undergoing immune tolerance induction (ITI) therapy. Nevertheless, if a patient has had high inhibitor titers in the past, and an acute bleed occurs, they should be treated as a patient with high-responder inhibitors using bypassing agents.[38][63]

Treatment for patients with inhibitors is complex and should be managed in a specialist hemophilia center. Treatment will depend on the current and historical maximum inhibitor titer and the anatomical site of the bleed, and includes:

Specific replacement factor at a much higher dose than usual
Bypassing agents such as recombinant factor VIIa or anti-inhibitor coagulant complex (an activated prothrombin complex concentrate [aPCC]). Guidelines recommend prescribing bypassing agents for home therapy to enable bleeding episodes to be treated quickly.[68][69]

In hemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, aPCC use may be associated with thrombotic microangiopathy and thrombosis, and should be avoided for up to 6 months after emicizumab use.[70] If aPCC must be used, follow local protocols for maximum dose limits.[38][61] Consultation with a hemophilia specialist is advised.

Recombinant factor VIIa is used to promote hemostasis in hemophilia A or B patients with inhibitors. Its mechanism of action includes binding of activated factor VII to tissue factor, which activates factor X, and leads to thrombin generation. Recombinant factor VIIa, at high (supraphysiologic) concentrations, also binds the surface of activated platelets, activating factor X independent of tissue factor, and generating thrombin. The standard dose in the treatment of inhibitors is 90 to 120 micrograms/kg intravenously every 2 to 3 hours until bleeding is controlled. Subsequent doses and frequency are based on clinical judgment. Antifibrinolytic agents can be used with recombinant factor VIIa.

aPCC contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X), which generate thrombin by bypassing factor VIII/factor IX in the coagulation cascade.

The response rate for effective bleeding control is 64% to 90% for aPCC, and 80% to 95% for recombinant factor VIIa.[71][72][73]

Thrombotic events have been reported.[74]

Antifibrinolytic agents should not be given concomitantly with aPCC due to safety concerns regarding increased risk of thrombosis.[38] Some patients respond equally well to recombinant factor VIIa or aPCC, whereas others respond preferentially to one or the other, for reasons that are not known.[73]

Life-threatening bleed: no factor inhibitor

Life-threatening bleeds include those occurring in the following sites:[38]

Central nervous system/intracranial
Gastrointestinal (GI) tract
Airway (neck/throat).

Urgent treatment is necessary, even before full assessment.[75] Resuscitation and basic life-support measures (ABC) are important. The factor for the relevant disorder (factor VIII for hemophilia A, factor IX for hemophilia B) should be administered urgently. The specific factor levels need to be monitored to adjust dose and frequency. Monitoring is usually done by measuring a trough blood factor level before the first dose in the morning. The goal is to maintain peak factor VIII or factor IX levels between 80% and 100% and trough level no less than 40% to 50% for the first 10 to 14 days.

In patients receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve hemostasis should be used for breakthrough bleeding.[38][61]

Subspecialty consultation, appropriate to the anatomical site of the hemorrhage, may be necessary. Patients with intracranial hemorrhage may require anticonvulsant therapy for management of seizures.

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid may be used as an adjunctive therapy in people with GI or airway bleeds. Antifibrinolytic agents work by inhibiting plasmin, a critical enzyme involved in fibrinolysis. These agents serve to control mucosal bleeding (oral, nasal, GI, uterine).

Antifibrinolytic agents are contraindicated for the treatment of hematuria, as unlysed clots will behave like stones, causing obstructive nephropathy. Antifibrinolytics should not be used for the treatment of any bleed whenever there is hematuria. Antifibrinolytics should also be avoided in patients with bleeding into the thoracic cavity (as unlysed hematoma may interfere with respiration), hence they are also contraindicated in the setting of thoracic surgery.[38]

Life-threatening bleed: with factor inhibitors

High dose of the specific factor concentrate (factor VIII for hemophilia A, factor IX for hemophilia B) is usually successful at controlling bleeding in people with a low-titer inhibitor status.[63] The approximate dose/kg of high-dose factor concentrate (for either factor VIII or factor IX) is calculated using a formula (2 × the titer in Bethesda units [BU] × % correction desired), but specialist advice is recommended.

If hemostasis is not achieved, or if the patient is known to have high titers of inhibitor, bypassing agents are indicated. Antifibrinolytics should not be given concomitantly with aPCC due to safety concerns regarding increased risk of thrombosis.[38] Additional measures are the same as for people with no inhibitors.

In hemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, aPCC use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[70] If aPCC must be used, follow local protocols for maximum dose limits.[38][61] Consultation with a hemophilia specialist is advised.

Bleed into joint, muscle, or urinary tract: no factor inhibitor

Treatment for acute hemarthrosis or bleeding into a muscle is specific factor replacement (factor VIII for hemophilia A, factor IX for hemophilia B) to control and stop the bleeding. In addition, protection, rest, ice, compression, and elevation (PRICE), and adequate pain control is beneficial.

Early factor replacement will, in most instances of acute muscular bleed, prevent the development of nerve compression and subsequent compartment syndrome. In patients receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve hemostasis should be used for breakthrough bleeding.[38][61]

Target joint bleeding: no factor inhibitor

Recurrent hemarthrosis into a single joint (named a target joint) causes chronic joint damage, with associated joint contractures and deformities.[1] Orthopedic consultation should be requested if there is recurrent hemarthrosis or when arthropathy is suspected, and a physical therapy evaluation is required.

Radioactive synovectomy (synoviorthesis) may be recommended when there are recurrent bleeds into a target joint. Orthopedic evaluation is needed prior to the procedure. In the US, the most commonly used radioisotope is phosphorus-32. Yttrium-90 has also been used successfully.[76] The majority of patients will require a single injection, although some patients may require more than one injection to the same joint at different times. The procedure can be performed in adults and children.

Synoviorthesis offers some advantages over surgical synovectomy:[77]

Less invasive
Outpatient procedure
Associated with fewer infections
Reduced risk of postoperative bleeding.

If radioactive synovectomy fails, then surgical synovectomy may be considered. A full orthopedic assessment is required to determine whether surgical synovectomy is indicated. If there is severe joint damage, a joint replacement or fusion may be indicated.

Additional measures for patients with bleed into joint, muscle, or urinary tract: no factor inhibitor

Physical therapy should be offered to every patient when joint bleeding has ceased, and not only to those who are at risk of joint contractures (due to repeated bleeds into the same [target] joint).[78] During recovery, early mobilization and weight bearing may be considered and should be carefully balanced with rest. Prolonged immobilization and joint paracentesis are is not routinely necessary.[78]

In addition to factor replacement, as described for bleeding into a joint or muscle, patients with hematuria require intravenous or oral fluid replacement at a rate of 1.5 times maintenance levels. Antifibrinolytic agents are contraindicated for the treatment of hematuria, and in the setting of thoracic surgery.[38] Antifibrinolytics should not be used for the treatment of any bleed whenever there is hematuria. Antifibrinolytics should also be avoided in patients with bleeding into the thoracic cavity.

Analgesics such as acetaminophen, opioids, or cylo-oxygenase-2 (COX-2) inhibitors may be used. These may be combined, depending on the level of analgesia required.

Bleed into joint, muscle, or urinary tract: with factor inhibitors

First-line treatment in people with low-titer (<5 BU) factor inhibitor (and no high responder history) presenting with bleeding into a joint, muscle, or urinary tract is high-dose factor concentrate.

High-dose factor VIII is required for people with hemophilia A; high-dose factor IX is required for people with hemophilia B. If this fails to control the bleeding, bypassing agents such as recombinant factor VIIa or aPCC are used. People with high-titer inhibitor (5 BU or more) or a high responder history are generally treated first-line with bypassing agents.

Additional measures for bleeding into a joint or muscle, such as analgesics, PRICE, and orthopedic and physical therapy evaluation, are the same as for patients with no inhibitors. Management of recurrent hemarthrosis with radioactive synovectomy or surgery is the same as in patients without inhibitors.

People with inhibitors presenting with hematuria require oral or intravenous fluid replacement.

Antifibrinolytic agents are contraindicated for the treatment of hematuria, and in the setting of thoracic surgery.[38] Antifibrinolytics should not be used for the treatment of any bleed whenever there is hematuria. Antifibrinolytics should also be avoided in patients with bleeding into the thoracic cavity.

Nasal or oral bleeding with mild hemophilia A (factor levels >5%): no factor inhibitor

Desmopressin can be used in individuals (with a demonstrated positive response to desmopressin) with mild hemophilia A (factor levels >5%) with nasal or oral bleeding.[70] Its mechanism of action is multifactorial, including:

An increase in plasma levels of factor VIII and von Willebrand factor
Stimulation of platelet adhesion and platelet procoagulant activity.

Desmopressin is not effective for the treatment of patients with hemophilia B, as factor IX levels are not influenced by desmopressin. The indications for desmopressin in mild hemophilia A are determined by:

The type of bleeding episode
Baseline and desired level of factor VIII.

A desmopressin test dose should be given in the doctor's office or clinic, which should produce a 2- to 4-fold rise in the levels of factor VIII or a peak level sufficient for management of the type/severity of bleeding or surgical procedure. In the outpatient setting, desmopressin may be administered intranasally (150 micrograms in patients <50 kg, 300 micrograms in patients >50 kg; lower concentration intranasal preparations for enuresis will not be effective) or subcutaneously prior to dental procedures or for the management of oral/nasal mucosal bleeding. If bleeding is controlled, venipuncture is avoided.

Peak desmopressin levels tend to be higher and achieved faster following intravenous administration, which is typically used in the inpatient setting.

During desmopressin use, patients should be advised to limit water intake in order to reduce the risk of excessive fluid retention and the risk of developing hyponatremia and seizures. A practical guide is to limit fluid intake to ≤1.5 L for 24 hours after desmopressin administration. Serum sodium concentration should be monitored when repeated doses of desmopressin are given. Avoid more than 3 consecutive daily doses of desmopressin to reduce the risk of tachyphylaxis. Desmopressin should not be used in children <2 years of age.

Antifibrinolytics (e.g., tranexamic acid and aminocaproic acid) may be used as adjunctive therapy to control oral and nasal bleeding, and are usually well tolerated. The most common adverse effect is GI discomfort. Antifibrinolytics should not be given in the presence of hematuria, or concomitantly with aPCC due to safety concerns regarding increased risk of thrombosis.[38]

If initial treatment is unsuccessful or there is severe bleeding, factor VIII concentrate is given on-demand every 12 to 24 hours until symptoms have resolved. This can be done on an outpatient basis. Supportive care includes general observation, red blood cell transfusion if needed (e.g., for significant blood loss and symptomatic anemia), and iron supplementation (for less severe iron deficiency).

Nasal or oral bleeding with hemophilia B or moderate-severe hemophilia A: no factor inhibitor

On-demand (as needed) factor concentrate is used as a first-line approach. Antifibrinolytic agents are used as adjuvant therapy in individuals with moderate-severe hemophilia A or hemophilia B (of any severity).

Nasal or oral bleeding: with factor inhibitors

High dose of the specific factor concentrate (factor VIII for hemophilia A, factor IX for hemophilia B) is usually successful at controlling bleeding in people with a low-titer inhibitor status.[63] The approximate dose/kg of high-dose factor concentrate (for either factor VIII or factor IX) is calculated using a formula (2 × the titer in BU × % correction desired), but specialist advice is recommended. Antifibrinolytic agents can be used in addition to specific factor concentrate.

Bypassing agents are used first-line in people with high-titer inhibitors (≥5 BU). Antifibrinolytic agents may be used with recombinant factor VIIa. However, patients receiving aPCC should not be treated with antifibrinolytic agents because of the increased risk of thrombosis. Supportive care includes general observation, red blood cell transfusion if needed (e.g., for significant blood loss and symptomatic anemia), and iron supplementation (for less severe iron deficiency).

Acquired hemophilia

Treatment of acquired hemophilia involves the use of bypassing agents, (such as aPCC, recombinant activated factor VIIa) or recombinant porcine factor VIII to control acute bleeding episodes.[65][79][80] Recombinant activated factor VIIa is indicated for use in patients with acquired hemophilia A due to inhibitors.[70] Recombinant porcine factor VIII is less likely to be affected by antibodies against human factor VIII that are present in people with acquired hemophilia A.

Immunosuppression with prednisone plus cyclophosphamide is usually effective at reducing inhibitor production and bringing about a sustained rise in the factor VIII level. Rituximab, usually in combination with prednisone, may be an alternative immunosuppressive agent.[81][82]

Prophylaxis

Prophylaxis is defined as the regular, continuous administration of a hemostatic agent/agents with the goal of preventing bleeding in people with hemophilia while allowing them to lead active lives and achieve quality of life comparable to non-hemophilia individuals.[38] Prophylaxis should be considered standard of care therapy for individuals with severe hemophilia A or B (factor VIII or factor IX <1%), including those with inhibitors.[69] Prophylactic therapy may also be considered for people with moderate and mild hemophilia with a severe phenotype. Prophylactic therapy should be instituted early (prior to the onset of frequent bleeding).[69]

Primary prophylaxis refers to therapy initiated in young patients (under the age of 3 years) with hemophilia, prior to clinically detectable joint damage (preventive therapy) and before the second major joint bleed.[83] Secondary prophylaxis refers to therapy initiated after 2 or more bleeds into large joints, and before the onset of joint disease.[1][83] Tertiary prophylaxis refers to therapy initiated after development of joint disease.[83]

For hemophilia A, the typical infusion schedule is 2 to 3 times weekly with standard recombinant or plasma-derived factor VIII, or once every 5 to 7 days for extended half-life (long-acting) factor VIII. Standard recombinant or plasma-derived factor IX is usually administered twice weekly for hemophilia B; however, extended half-life (long-acting) factor IX molecules are generally administered once every 7 to 14 days to maintain trough levels of 3% to 5% or higher.[38]

Observational studies suggest that prophylaxis is superior to episodic treatment in delaying or preventing joint arthropathy, even in patients with severe hemophilia.[84][85][86][87]

Individualized prophylaxis protocols using target trough levels and pharmacokinetic-guided profiling (taking into account considerations such as joint status, physical activity and lifestyle, availability of clotting factors, patient ability to undertake self-guided care, and acceptability of various regimens) are intended to optimize patient outcome.[88][89] Extended half-life factor concentrates, when infused at dosing schedules comparable to those of standard factor concentrates, may increase the trough levels and facilitate a more active lifestyle.[90][91]

Prophylaxis is recommended following the initial treatment of intracranial bleeding.[83] In this scenario, different treatment regimens have been suggested, ranging from infusions every-other-day to weekly infusions.

Emicizumab prophylaxis in patients with hemophilia A

Emicizumab, a humanized monoclonal antibody that mimics the function of factor VIII without being affected by factor VIII inhibitors, is approved by the Food and Drug Administration and the European Medicines Agency for prophylaxis in hemophilia A patients with and without inhibitors.[70][92][93]

Emicizumab is administered subcutaneously and can be given weekly, biweekly, or at 4-week intervals. Emicizumab has a long half-life and its plasma level remains constant (without peaks and troughs as in clotting factor prophylaxis) once a steady-state is reached after loading doses over the initial 4 weeks.

In patients with hemophilia A with or without inhibitors, emicizumab is associated with substantial and meaningful improvements in health-related outcomes.[94] Emicizumab cannot be used to treat acute bleeds or to cover surgical procedures, and cannot be used for hemophilia B prophylaxis.

Emicizumab will interfere with the activated partial thromboplastin time assay, one-stage based assay for clotting factor activity, and factor VIII inhibitor titer. When using emicizumab, a chromogenic assay using bovine reagents should be used for quantitation of endogenous or infused factor VIII levels, and a chromogenic Bethesda assay using bovine reagents should be used for quantitation of factor VIII inhibitor.[61][95] In hemophilia A patients who are receiving emicizumab prophylaxis, aPCC use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[70]

Ongoing management of people with factor inhibitors

The ultimate goal in patients with factor inhibitors is to eliminate the inhibitor with the use of ITI.[96] With this approach, patients receive high doses of factor VIII or IX concentrate for months to years, usually given once a day, although some patients may be treated 3 times/week. Scheduled factor VIII or IX infusions (prophylaxis) 2 or 3 times per week are recommended after successful ITI.

The international multicenter trial (International Immune Tolerance Study) demonstrated that high-dose (200 U/kg/day) and low-dose (50 U/kg 3 times per week) factor VIII regimens achieved a comparable success rate of about 70% in patients with hemophilia A factor inhibitors.[97] However, the low-dose approach was slower to achieve the tolerization end point, and was associated with more bleeding events during ITI.[97][98] The success rate of ITI is lower in patients with hemophilia B factor inhibitors.[38] Furthermore, hemophilia B patients with factor inhibitors and a history of anaphylaxis to factor IX should be monitored carefully for the development of nephrotic syndrome and recurrent severe allergic reactions during ITI with factor IX concentrates.[36][38]

Rituximab may be effective in the eradication of inhibitors in nonsevere hemophilia A patients.[99]

Bypassing agents

While the factor inhibitor remains present, the patient continues to be at risk of bleeding. Bypassing agents such as recombinant factor VIIa or aPCC are used to treat bleeding events in patients with inhibitors with variable effectiveness. There is no significant difference in hemostatic effectiveness between recombinant factor VIIa and aPCC.[73]

Prophylaxis with bypassing agents may be used to decrease bleeding rates in patients with factor inhibitors.[69] This may be done during ITI (although bleeding rates tend to decrease once ITI is initiated), if unable to initiate ITI, or if ITI fails to clear the inhibitor. Although overall and joint bleeding rates are reduced in prophylaxis with bypassing agents compared with on-demand treatment, there is no significant improvement in health-related quality of life (contrary to prophylaxis with regular factor concentrates in noninhibitor hemophilia patients).[100]

If bypassing agents are indicated, guidelines recommend prescribing them for home therapy, which can improve adherence and enable bleeding episodes to be treated quickly. Patients and family members should be given advice on preparing and administering bypassing agents, and who to contact in an emergency.[68][69]

In hemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, recombinant factor VIIa can be used for breakthrough bleeding.

In hemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, aPCC use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[70] If aPCC must be used, follow local protocols for maximum dose limits. Consultation with a hemophilia specialist is advised.

In hemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor level monitoring should be by chromogenic assay using bovine reagents.

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