Hemophilia

Hemophilia A and hemophilia B are inherited bleeding disorders characterized by complete or partial deficiency of circulating coagulation factors VIII (FVIII) or IX (FIX), respectively. The hallmark of severe hemophilia is the presence of spontaneous, prolonged, and recurrent abnormal bleeding episodes primarily affecting soft tissues and synovial joints.

Hemophilia A, or classic hemophilia, has been described since ancient times. The oldest documentation is found in the Talmud, a collection of Jewish law writings from the 4th century. These manuscripts state that young boys were exempt from circumcision if 2 previous sons from the same mother had died from severe bleeding associated with the procedure.(1)

In 1803, John Conrad Otto was the first doctor to report a bleeding disorder, characterized by joint and muscle hemorrhages, that exclusively affected males in the same family. It was not until 1828 that Friedrich Hopff, a student at the University of Zurich, and his professor, Dr. Schonlein, used the term hemorrhaphilia for patients presenting with this constellation of symptoms.(1)

Hemophilia has often been called “the royal disease” because several members of the European royal family were affected by the condition. Queen Victoria of England, the most famous carrier of hemophilia, transmitted the condition to several of her own children, spreading the disorder to other European royal families. The best-known case is that of Tsarevich Alexei, son of the Russian Tsar Nicholas II. Today we know that this real disease was actually hemophilia B. Hemophilia B is also known as Christmas disease, after Stephen Christmas was the first person described with the condition in 1952.(1)

Hemophilia A is 4 times more common than hemophilia B, comprising 80% of all hemophilia cases.

The estimated prevalence of hemophilia A is approximately 1 in 5,000 live births (2)(3) and of hemophilia B is 1 in 30,000 live births.

Hemophilia affects all ethnicities and races. A recent meta-analysis estimated that there are approximately 1,125,000 men living with hemophilia worldwide, of whom approximately 418,000 have severe hemophilia.(4)(5)(6) It has also been reported that in the United States, the prevalence of severe disease is approximately 50% for patients with hemophilia A compared to approximately 30% for patients with hemophilia B.(7)(8)(9)

Abnormal bleeding can occur when specific components of the hemostatic system are missing or dysfunctional. Hemostasis is the sequential, self-regulated physiological process that begins as soon as an injury occurs to a tissue or blood vessel. Normal hemostasis results in the formation of a stable clot of platelets and fibrin that stops bleeding while maintaining normal blood flow.

Vasoconstriction at the site of vessel injury is the initial step. This is followed by “primary hemostasis,” in which an initial, but unstable, platelet clot forms through adhesion, activation, and aggregation of platelets on damaged vascular endothelium. Primary hemostasis depends on an adequate amount of functionally normal von Willebrand factor (VWF).

Stabilization of the platelet plug through the formation of a covalently linked fibrin-platelet clot occurs during “secondary hemostasis.” Secondary hemostasis consists of the activation of all coagulation factors in the coagulation cascade. Within the cascade, FVIII and FIX form an enzymatic complex with coagulation factor

Regulation of the hemostatic process occurs through fibrinolysis. Fibrinolysis involves the dissolution of the clot formed after the wound healing process is complete, thereby preventing the formation of thrombi in what would otherwise be normal blood vessels. Components of the fibrinolytic system include antithrombin, tissue factor pathway inhibitor (TFPI), protein C, and protein S.(10)

In hemophilia, a partial or complete deficiency of FVIII or FIX will result in decreased fibrin formation, causing a hemorrhagic diathesis characterized by recurrent and prolonged bleeding episodes.(11) FVIII or FIX levels are expressed as a percentage of normal activity or as international units per deciliter. The reference range for both factors fluctuates between 50% and 150% (0.50–1.50 IU/dl).

Hemophilia is inherited in an X-linked recessive pattern.

Men are predominantly affected because they have a single X chromosome, which expresses the defective gene . Affected men can transmit the gene that causes the disease only to their female offspring, called “obligate carriers.” Hemophilia carriers have one normal and one abnormal FVIII or FIX gene and have a 50% chance of passing the gene on to any of their children; Men who inherit the hemophilia gene express the disease and women become carriers.

Female carriers may or may not present low levels of factors and symptoms . Mild hemophilia may be present in up to 25% of heterozygous carriers.(2) Infrequently, women may manifest a severe bleeding phenotype. This occurs in the context of a compound heterozygous woman born to a father with hemophilia and a mother who is a hemophilia carrier. A female carrier may also have hemophilia due to extreme lyonization of the normal X chromosome.

Since the FVIII gene was first described in 1983, different mutation variants have been identified in the FVIII and FIX genes.(7) The most common variants in patients with hemophilia A are inversions of intron 22 and intron 1. The former is identified in about 52% of patients with severe hemophilia A, while the latter is found in 1% to 5% of all patients with hemophilia A.

The most common genetic variants identified in hemophilia B are missense mutations, which explain approximately 47% of all cases.(12) The “My Life, Our Future” project was established in 2012 with the goal of creating a repository of genetic information of people with hemophilia in the United States.

Sequence analysis of the FVIII and FIX genes was offered free of charge to hemophilia patients and suspected carriers. In 2018, an interim analysis identified 700 previously unreported genetic variants and reclassified several variants previously reported as hemophilia-causing mutations as non-harmful.(13)

Hemophilia is classified as mild, moderate, and severe based on the level of measurable activity of the factor (Table 1). There is a direct correlation between FVIII or FIX levels and the severity and relative frequency of the patient’s signs and symptoms. Patients with severe and moderate deficiencies tend to present with symptoms in the first months after birth (2)(14)(15) It has been suggested that patients with hemophilia B appear to have less severe bleeding signs and symptoms and better long-term outcomes. term than patients with hemophilia A. (16)

Because neither FVIII nor FIX cross the placenta , signs and symptoms of bleeding in people with hemophilia, especially those with severe forms, may occur shortly after birth; In some cases, bleeding can even occur in the uterus. In infants, intracranial hemorrhage (ICH) that occurs either during birth or shortly after is a major concern. The use of forceps during delivery and vacuum extraction are considered high risk factors for the development of ICH.

The overall incidence of ICH at birth in neonates with hemophilia is estimated to be 4% to 5%, although cases of spontaneous ICH have also been reported.(17) ICH should also be considered in cases of head trauma, such as in a baby who falls out of a crib or bed. When ICH is suspected in a child with hemophilia, immediate infusion of factor concentrate prior to brain computed tomography (CT) is indicated and should not be delayed.

The hallmark of hemophilia bleeding is the occurrence of spontaneous acute hemarthrosis.

Acute hemarthrosis is defined as the sudden appearance of bleeding in the joint space, accompanied by joint edema, pain and reduced range of motion of the affected joint. Ankles, knees and elbows are the most frequently affected joints. The clinical manifestations of joint bleeding vary depending on the age of the patient and are sometimes difficult to recognize by medical professionals. Infants may present with irritability and unwillingness to use the affected limb.

Older children and adults may present with prodromal symptoms characterized by a feeling of warmth or tingling or a sensation of fullness and stiffness of the affected joint before the onset of characteristic edema and reduced range of motion. Point-of-care musculoskeletal ultrasound (POMS) is becoming the preferred imaging modality for both the acute evaluation and management of joint bleeds and for monitoring the development and progression of subclinical joint disease.

Unlike other imaging modalities such as MRI, EMEPA is less invasive, does not require sedation, takes less time, and has been found to be exceptionally sensitive in detecting very low amounts of intra-articular blood.(18) (19) To date, multiple hemophilia-specific EMEPA scoring systems have been developed and are in different stages of validation.(19)

When more than 4 bleeding episodes occur in the same joint in a 6-month period, the patient is considered to have developed a "target joint . " Repetitive bleeding into the joint space causes a chronic inflammatory reaction, characterized by a cytokine-mediated oxidative process and iron deposition, resulting in vascular proliferation, synovial hypertrophy, and chronic synovitis. Chronic synovitis will trigger an irreversible and destructive process known as hemophilic arthropathy.

Muscle bleeding with subsequent hematoma formation is also common in people with hemophilia. Long muscles, such as the iliopsoas or quadriceps, are the most commonly affected. Patients with muscle hemorrhage may present with mild, nonspecific signs and symptoms: an iliopsoas hemorrhage may present as vague pain in the groin and an inability to extend the hip. If the professional suspects psoas bleeding, confirmation with magnetic resonance imaging (MRI) or EMEPA is indicated.

Extensive muscle bleeding can result in compartment syndrome, which affects neurovascular structures. Large amounts of blood loss into the muscle can lead to pseudotumor formation. Hemophilic pseudotumor is a rare complication, occurring in 1% to 2% of patients with severe hemophilia.(1) A pseudotumor is a slowly expanding, chronic encapsulated cystic mass that evolves after recurrent hemorrhages into extraneous musculoskeletal structures. -articular.

Another site of bleeding is the gastrointestinal tract.

Patients with intestinal hematomas may have signs and symptoms that mimic an acute abdomen.(20) Hematuria, secondary to bleeding arising from the kidneys or bladder, is a common manifestation in people with hemophilia, especially in those with severe deficiencies. (21) Bleeding related to tooth eruption is rare.

Dental care is extremely important for people with hemophilia. Health care professionals should promote consistent early dental hygiene practices to reduce the risk of developing periodontal disease. Preventive dental care (teeth cleaning) should be done regularly. Dental extractions may require referral to an inpatient setting.

Carriers or women with mild hemophilia are also at risk for abnormal reproductive uterine bleeding associated with their menstrual period and childbirth. They may also face bleeding challenges during surgeries or dental extractions.(22)

A complete family history exploring possible manifestations of bleeding in other family members is essential for the evaluation of a patient with suspected hemophilia. Given the known genetic etiology of the disorder, questions about extended family members can be insightful.

Depending on the population studied, 30% to 50% of patients with hemophilia will be found to have a sporadic de novo mutation.

These patients are born to a non-carrier mother with a negative family history. For this reason, pediatricians should always consider the possible diagnosis of hemophilia in any male newborn with unusual bleeding and prolonged activated partial thromboplastin time (aPTT) in isolation despite a negative family history for hemophilia.(23)

When hemophilia is suspected, initial laboratory evaluation should include a complete blood count, prothrombin time, aPTT, admixture studies in case of prolonged aPTT, fibrinogen level, VWF antigen, and activity level.

Children with hemophilia have a prolonged isolated aPTT and a normal platelet count and prothrombin time/international normalized ratio. Patients with severe hemophilia usually have an aPTT 2 or 3 times higher than the upper limit of normal. Unless the patient has an active FVIII or FIX inhibitor, the aPTT mixing study will correct with the addition of normal plasma.

Some cases of mild hemophilia may present with a normal aPTT due to the low sensitivity of the assay in the setting of mildly reduced levels of FVIII or FIX. It is not possible to determine the severity of hemophilia solely by the degree of prolongation of the aPTT. A specific assay to quantify FVIII or FIX activity levels will not only confirm the diagnosis but will help differentiate other inherited bleeding disorders, such as deficiencies of coagulation factors XI or XII, which are also associated with isolated prolonged aPTT. .(24)

Genetic testing is an important part of the diagnostic evaluation of hemophilia. In addition to allowing accurate genetic counseling, some recognized mutations are associated with the potential risk of developing inhibitors, the most common and serious complication of hemophilia treatment today.

Male neonates born to a known carrier of hemophilia should have their factor level quantified at the time of delivery using an umbilical cord blood sample.

Cord blood testing is preferable to venipuncture because cord blood collection minimizes the risk of traumatic hemorrhage. Invasive procedures, such as circumcision, should be delayed until the diagnosis of hemophilia is confirmed or eliminated. In infants with confirmed hemophilia whose parents request a circumcision, the procedure should be performed electively by an experienced surgeon in collaboration with the hemophilia treatment center (CTH).

Patients with mild hemophilia may not be diagnosed until adolescence or early adulthood in the setting of a surgery or dental procedure. Abnormal and excessive bleeding will lead to the diagnosis.

Determining the baseline factor activity of a hemophilia carrier is important for management, but if it is normal, it does not rule out the carrier state. Genetic testing is more reliable than measuring factor levels, especially in a woman with normal or borderline factor activity. Accurate identification of hemophilia carriers is important to manage current bleeding symptoms and address potential bleeding complications associated with pregnancy and childbirth.

Knowing carrier status allows appropriate recommendations to be made for evaluating offspring. (2) Women with suspected hemophilia should also be tested for von Willebrand disease (VWD), as VWD variants or severe VWD type 3 may have a hemorrhagic phenotype similar to that of hemophilia.

Traditionally, clotting factor replacement has been the standard of care for hemophilia.(25)(26) However, adjuvant hemostatic therapies are also useful in controlling acute bleeding episodes.

The treatment of hemophilia has evolved significantly. In the 1950s and 1960s, hemorrhagic events were treated with whole blood, fresh frozen plasma, or cryoprecipitate. Individuals with severe hemophilia experienced prolonged hospitalizations for bleeding events and developed significant joint morbidity. The 1970s brought the development of plasma-derived factor concentrates.

In the 1980s and early 1990s, contamination of these products with human immunodeficiency virus (HIV) as well as hepatitis B and C devastated the hemophilia community. During that time, in the United States, most people with hemophilia treated bleeding events only as needed due to difficulties with adequate supply of factor concentrates and concerns about factor safety.(27) In response to concerns HIV and hepatitis epidemics, the purity and safety of factor concentrate became the therapeutic focus.

Purification strategies for plasma-derived concentrates incorporated the development of improved blood donor screening and techniques for viral removal and inactivation: pasteurization, treatment with solvents or detergents, dry heating, immunoaffinity chromatography and, more recently, nanofiltration .(28)(29)(30) These purification techniques have not resulted in additional reports of viral transmission in patients using plasma-derived factor concentrates since the mid-1990s.(31)

Nowadays, safer recombinant factor concentrates are produced through transfection of the human FVIII or FIX gene into various cell lines, including Chinese hamster ovary, baby hamster kidney, and human embryonic kidney.(31)(32) )(33)(34)(35) Multiple generations of recombinant concentrates are available based on the inclusion or exclusion of proteins derived from human or animal plasma. Standard half-life third-generation recombinant concentrates are commonly used in the United States. These concentrates contain proteins derived from human or animal plasma in their cell culture media.

With the development of safer products, the treatment paradigm in hemophilia shifted from treating bleeding episodes primarily on demand to the use of prophylactic therapy: regularly scheduled administrations of factor concentrate to prevent bleeding events. Prophylaxis is defined as primary, secondary, or tertiary (Table 2).(26) Prophylaxis initiated early in life has been shown to provide superior benefits compared to on-demand episodic therapy.

Early prophylaxis results in a greater than 90% reduction in joint bleeding rates and in significant reductions in degenerative joint disease, hemophilic arthropathy, and life-threatening bleeding.(36)(37) Preferred prophylactic regimens based on standard half-life infuse FVIII at 25 to 40 IU/kg per dose every 2 to 3 days for patients with hemophilia A and FIX at 40 to 60 IU/kg twice weekly for patients with hemophilia B. An individualized regimen to prevent bleeding episodes adapts to the individual needs of the patient.(26)(38)

Similar doses can be used for breakthrough bleeding events, targeting factor levels of 80% to 100% or higher for the management of critical hemorrhages, including intracranial, gastrointestinal, and iliopsoas bleeds.(26) Achieving factor levels is recommended. preoperative values ​​greater than 50% to 100% depending on the specific procedure (Table 3).(26) Surgical hemostasis should be guided by a hematologist expert in coagulation in coordination with the patient’s local physician.

The factor dose for acute bleeding episodes is calculated by multiplying the patient’s weight (in kilograms) by the desired percentage of FVIII level; this total is then multiplied by 0.5 (volume of distribution) in patients with hemophilia A. For patients with hemophilia B, the total dose will be equal to the patient’s weight (in kilograms) multiplied by the desired percentage of the FIX level, multiplied times 1 (volume of distribution).

Routine vaccines should be administered to children with hemophilia at age-appropriate intervals.

The World Federation of Hemophilia (WFH) guidelines recommend giving these vaccines subcutaneously rather than intramuscularly. Ice should be applied to the injection site for at least 5 minutes after vaccination, and pressure should be applied to the injection site. the site for at least 10 minutes.(26)

It is not recommended to administer factor concentrate before the administration of vaccines. For infants undergoing circumcision, it is recommended to increase circulating levels of factor VIII or IX to 80% to 100% before the procedure. The WFH guidelines also suggest the use of a fibrin sealant as adjuvant therapy.

As home prophylactic treatment of hemophilia has become routine, some patients have struggled to maintain adequate adherence to treatment due to difficulties with venous access and time constraints.(39)(40)(41)(42) )(43) This has led to the development of long half-life factor concentrates focused on reducing the burden of treatment by decreasing the number of infusions required for prophylactic therapy. Long half-life FVIII concentrates have recently been developed with different protein structures and manufacturing processes, including Fc fusion and PEGylation, which demonstrate a modest prolongation of the half-life of FVIII.(44)(45)(46)(47)

The extension of the half-life by approximately 1.5 times(48) allows prophylactic dosing twice a week as opposed to infusions 3 times a week or every other day. This is due in part to the close interaction of factor VIII with VWF, its chaperone transporter protein in the circulation.(49) There may soon be a new class of FVIII concentrates that could further extend the half-life of FVIII, leading to weekly or even less frequent dosing. (fifty)

Techniques to produce extended half-life FIX concentrates have been most successful in extending half-life using Fc fusion, PEGylation, or albumin fusion technologies. (51)(52)(53) These modifications have allowed prophylactic dosing every 7 to 14 days or more.(54)

The current paradigm of hemophilia treatment has focused on replacement of the specific deficient coagulation factor to promote normal hemostasis.

Several groups are investigating new non-factorial therapies to replicate the function of the deficient cofactor or modify the balance of coagulation proteins towards pro-hemostatic ones.

Emicizumab is a humanized monoclonal bispecific antibody developed to bind activated FIX and FX to the phospholipid membrane mimicking the functionality of the FVIII cofactor.(55)(56) Emicizumab is administered via subcutaneous injection, has a half-life of 4 to 5 weeks, and is approved for prophylaxis in people with hemophilia A with and without inhibitors.(56)(57)(58)(59)

Due to its mechanism of action, emicizumab has the potential to induce severe adverse events such as thrombosis and thrombotic microangiopathy. (60) These adverse events have been reported particularly in individuals with hemophilia A and inhibitors who are concomitantly receiving emicizumab concentrate and prothrombin complex. activated by intercurrent bleeding episodes.(60) Acute traumatic or surgical bleeding in hemophilia A without inhibitors should be managed with infusions of FVIII concentrate because emicizumab is used only for prophylaxis.

This first factor-free subcutaneous therapy for hemophilia A is a major advance in patient convenience for prophylaxis. It should be noted that phase 1 aPTT and FVIII activity assays will not be accurate in the patient taking emicizumab because traditional assays require FVIII activation. Precise FVIII activity requires the use of a bovine reactive factor VIII chromogenic assay in case a patient taking emicizumab requires simultaneous administration of FVIII concentrate.

Other non-factor therapies currently in development are based on the finding that some people with hemophilia and concurrent prothrombotic features, such as antithrombin or factor V Leiden deficiency, have a milder bleeding phenotype.(61)(62) Fitusiran is a investigational drug, a small interfering RNA designed to suppress antithrombin through post-transcriptional gene silencing in hepatocytes, increasing the amount of thrombin generation.(63) This mechanism of action, however, creates a potential risk for the development of thrombotic events.(64)

Interim analysis of a phase 1 clinical trial reported one patient death associated with fitusiran that involved the development of cerebral sinus thrombosis after concurrent administration of FVIII concentrates.(65) The clinical trial was resumed and recently reported data long-term efficacy and safety positives for phase 2 extension study (66)

TFPI is a Kunitz-type serine protease inhibitor that physiologically regulates excessive thrombin generation by inhibiting the interaction of tissue factor with activated factor VII (FVII) and activated FX in the coagulation cascade.(67) Concizumab is an investigational humanized monoclonal antibody that blocks the physiological regulatory action of TFPI, subsequently increasing thrombin generation in patients with hemophilia and healthy individuals. This therapy is currently under clinical trial. (68)(69)(70) These studies were temporarily suspended due to some reports of non-fatal thrombosis, but have since been resumed.(71)

Additional less developed factor-free therapies, including inhibition of protein S or activated protein C, are currently under investigation. Recently, a serpin (serine protease inhibitor) was designed to specifically inhibit the anticoagulant activities of activated protein C while preserving its other functions, restoring hemostasis in mouse models of hemophilia.(72)(73)

Another potential mechanism of inhibition of activated protein C is through inhibitory monoclonal antibodies.(74) A small interfering RNA has also been developed in mouse models of hemophilia to “silence” the production of protein S, which can rebalance the coagulation.(75) These therapies without factors under investigation may be additional avenues for future management.

The definitive cure for hemophilia has long been the dream of patients with this disorder. (76) Hemophilia B saw the first success in the early 2010s with gene transfer mediated by adenovirus-associated vectors, followed a few years later by hemophilia A. (77)(78)(79) The material Genetics for the FVIII or FIX gene are packaged into a recombinant adenovirus capsid and then infused intravenously.

The viral vector with genetic material is then delivered to hepatocytes that transfect it and produce the deficient clotting factor. Through gene therapy, FVIII and FIX activities have been increased in patients with severe hemophilia to levels consistent with those found in mild hemophilia, or even normal hemostatic levels.

The slight increase in transaminase levels that occurs with gene transfection is usually transient. Patients are usually treated with a course of corticosteroids. Additional long-term safety encompasses the possible integration of the adenoviral vector genome into the liver, although this occurs significantly less than with other viruses. (76)(80) Questions about gene therapy include long-term safety, efficacy, durability of response, and appropriate therapeutic window.(76)(81)(82)

Desmopressin, a synthetic analogue of vasopressin, transiently increases levels of FVIII and VWF, and can be used to control minor bleeding in patients with hemophilia A who have a documented response to this medication. Response is defined as a 2- to 3-fold increase above baseline FVIII levels, with a peak at 30 to 60 minutes after administration.

Desmopressin is not effective in patients with severe hemophilia A and is not indicated in patients with hemophilia B. The response to desmopressin decreases with repeated administration (tachyphylaxis), and it is usually contraindicated in children younger than 2 years due to the potential risk of Dilutional hyponatremia and seizures.

Antifibrinolytic agents such as tranexamic acid and epsilon aminocaproic acid are useful in controlling bleeding in areas with increased fibrinolytic activity, such as the oral mucosa and nasal cavity. They can be used in combination with factor replacement therapy to prevent bleeding associated with surgical procedures. These agents have also been shown to be effective in controlling menorrhagia in women with mild hemophilia.

The main classic long-term complications of hemophilia are chronic hemarthroses with concomitant hemophilic arthropathy and the development of antibodies against infused clotting factor concentrates (inhibitors).

As people with hemophilia live longer, they are also developing age-related comorbidities. Studies have shown a high incidence of obesity, cardiovascular disease (83), and chronic kidney disease. (21) The increased risk of bleeding in hemophilia and the lack of robust evidence-based guidelines for the management of these comorbidities create a greater risk of medical complications.

The development of inhibitors is the most serious complication of hemophilia treatment today. It remains a significant and costly clinical challenge for the healthcare professional. Inhibitors are specific immunoglobulin G-type antibodies directed against FVIII or FIX that normally neutralize the activity of the infused factor. Inhibitors develop in approximately 35% of patients with severe hemophilia A and 5% of patients with severe hemophilia B.

Inhibitors tend to develop within the first 50 days of exposure, although most inhibitors will develop within the first 20 days of exposure, which corresponds to a mean age of 1 to 2 years at onset.(15) Patients with moderate and mild hemophilia can develop inhibitors, but as young or older adults.

Several risk factors have been identified associated with an increased risk of developing inhibitors. severe hemophilia; specific genetic mutations, including large deletions and missense mutations; family history of inhibitors; and African American and Hispanic ethnicity are non-modifiable, patient-specific risk factors for the development of inhibitors.(83)

Environmental risk factors for the development of inhibitors include young age at first exposure to treatment, type of concentrate (plasma-derived vs. recombinant) used in treatment, dose intensity, and use of prophylaxis vs. treatment on demand. Recently, the SIPPET study was the first large prospective randomized study to investigate differences in the risk of inhibitor development between plasma-derived and recombinant factor concentrates in previously untreated children with hemophilia A.(84)

The study results suggest that patients receiving recombinant concentrates are more likely to develop inhibitors than those receiving plasma-derived products. However, the study population was largely outside the United States, and participants had a higher number of mutations associated with a higher risk of inhibitor development. These results sparked a debate about the appropriate prophylactic regimen to initiate in children newly diagnosed with hemophilia.

It is also important to consider that not all recombinant concentrates were included in the study, raising the question of whether these results could be generalized to all recombinant FVIII products, including the standard and newer extended half-life concentrates.

The main therapeutic objective of patients with inhibitors is the complete eradication of antibodies. Immune tolerance induction (ITI) remains the most effective strategy for inhibitor eradication. It involves the use of high and frequent doses of factor concentrates so that the patient’s immune system tolerates the factor and, subsequently, the production of antibodies is reduced.

Currently, indications for ITI are individualized and depend on the patient’s clinical characteristics and preferences. Emicizumab has recently become another option for patients with hemophilia A and inhibitors. Clinical studies have shown high efficacy in preventing bleeding events when patients with hemophilia A with inhibitors receive prophylaxis with emicizumab instead of ITI, although these patients will still require a bypass agent or high doses of FVIII concentrates to treat episodes. acute hemorrhagic.

It is crucial that the clinician know the patient’s inhibitor status and how to manage severe acute bleeding episodes in patients with positive inhibitors, including the use of bypass agents such as activated recombinant FVII concentrate and activated prothrombin complex concentrates or need for higher doses of FVIII concentrates (patients with hemophilia A) or FIX (patients with hemophilia B).

The 2020 WFH guidelines for the management of hemophilia state that a comprehensive multidisciplinary care model should be established in the care of people with hemophilia.

Comprehensive hemophilia treatment centers (HTCs) have been organized around the world. This treatment strategy ensures that people with hemophilia have access to a full range of clinical specialties and laboratory services appropriate for the proper management of their condition and associated complications.(26)

In 1973, the National Hemophilia Foundation launched a 2-year campaign to establish the creation of a national network of hemophilia diagnosis and treatment centers in the United States. To date, there are more than 140 CTHs across the country.

The establishment of this comprehensive approach over the past 40 years has greatly improved the quality of life not only for people with hemophilia but also for all people with bleeding disorders, allowing them to live more independent and productive lives.

A study of 3,000 people with hemophilia showed that people treated at a HTC were 40% less likely to die from a hemophilia-related complication compared to those who did not receive care at a HTC.(8) Similarly, People with hemophilia who were cared for in a treatment center were 40% less likely to be hospitalized for bleeding complications.(8)

Table 1. Severity of hemophilia

Table 2. Types of hemophilia prophylaxis regimens.

Table 3. Recommended treatment regimens for acute bleeding episodes (26)

Hemophilia A and hemophilia B are inherited bleeding disorders characterized by complete or partial deficiency of FVIII or FIX, respectively. They are inherited in an X-linked recessive pattern, so males are predominantly affected.

A complete family history exploring bleeding manifestations in other family members is essential for the evaluation of a patient with suspected hemophilia although, depending on the population, 30% to 50% of patients will have a de novo sporadic mutation. This diagnosis should be considered in any male neonate with unusual bleeding and prolonged aPTT.

Patients with mild hemophilia may not be diagnosed until adolescence or early adulthood in the setting of a surgery or dental procedure. Abnormal and excessive bleeding will lead to the diagnosis. Severe cases are characterized by spontaneous, prolonged and recurrent bleeding episodes that mainly affect soft tissues and synovial joints.

Clotting factor replacement has traditionally been the standard of care for hemophilia; however, adjuvant hemostatic therapies are also useful in controlling acute bleeding episodes.

The main complications are chronic hemarthrosis with arthropathy and the development of antibodies against the infused coagulation factor concentrates (inhibitors). Knowing these complications and their management, as well as carrying out a comprehensive approach to the patient with hemophilia, will help control the symptoms and improve the quality of life of people who suffer from this disorder.