Hemophilia, which means love (philia) of blood (hemo), is the most common severe hereditary hemorrhagic disorder. Both hemophilia A and B result from factor VIII and factor IX protein deficiency or dysfunction, respectively, and is characterized by prolonged and excessive bleeding after minor trauma or sometimes even spontaneously. There is Hemophilia C as well, which occurs due to deficiency of clotting factor XI but is rare. Sometimes acquired hemophilia can present related to age or childbirth and usually resolves with appropriate treatment. Hemophilia has often been called “the disease of the kings,” as is often described in the descent of Queen Victoria of England. The earliest description in ancient history dates from the second century AD in the Babylonian Talmud about a woman who had lost her first two sons from circumcision. The earliest description in modern history was documented by the American physician Dr. John Conrad Otto. Dr. Conrad described an inheritable bleeding disorder in several families where only males born from unaffected mothers were affected. He then called them the “bleeders.” Hemophilia, as a word, was first documented by Johann Lukas Schönlein on his dissertation at the University of Zurich, Switzerland. Dr. Nasse was the first to publish the genetic description of hemophilia in Nasse’s Law: which states that hemophilia is transmitted entirely by unaffected females to their sons.
Hemophilia is usually an inherited condition and is caused by the deficiency of clotting factors in the blood. It is almost always due to a defect or mutation in the gene for the clotting factor. Research has identified over 1000 mutations in the genes encoding factor VIII and IX, and around 30% are due to spontaneous mutation. The encoding genes for factors VIII and factor IX are present in the long arm of chromosome X. Both hemophilia A and B are inherited via an X-linked recessive pattern where 100% of females born from affected fathers will be carriers, and none of the males born will be affected. Female carrier mothers have a 50% chance of having affected males and a 50% chance of having carrier females. Females could also be affected if there is a complete inactivation of chromosome X through lionization, partial or complete absence of chromosome X such as in Turner Syndrome or if both parents carry the abnormal gene.
Hemophilia is equally distributed among all ethnic groups worldwide. The estimated frequency of hemophilia is around 1 in 10000 live births, and the number of people worldwide living with hemophilia is about 400000. Hemophilia A is more prevalent (80% to 85% of the total hemophilia population) than hemophilia B. It presents in 1 in 5000 live male births, whereas hemophilia B presents in 1 in 30000 live male births. Due to its autosomal recessive inheritance pattern, geographical areas with a higher frequency of consanguineous marriages like Egypt have a higher prevalence of the disease. Hemophilia C generally occurs in 1 of every 100000 people. However, Ashkenazi Jews have a higher incidence of factor XI deficiency, which is around 8%. With new advances in early diagnoses and treatment therapies, affected individuals should expect a normal life expectancy.
The process of blood clot formation involves the activation of two pathways - the extrinsic or tissue factor (TF) pathway and the intrinsic or the contact pathway. Both pathways consist of a series of cascade enzyme activation events that lead to the formation and stabilization of a blood clot by crosslinking of fibrin monomers and activation of platelets. The extrinsic pathway gets triggered by disruption of the endothelium and exposure of tissue factor (TF) in the subendothelium. Tissue factor then binds activated factor VIIa forming a complex, which then activates factors IX and X into IXa and Xa, respectively. The intrinsic pathway becomes activated when factor XII, prekallikrein, and high-molecular-weight kininogen in the blood becomes exposed to an artificial surface. Factor XII undergoes a conformational change resulting in the small generation of factor XIIa, which in turn activates PK to kallikrein with reciprocal activation of factor XII to XIIa. The resulting generation of factor XIIa activates factor XI to factor XIa, which then converts factor IX to factor IXa. Both pathways converge at the production of factor Xa. Factor Xa converts prothrombin (factor II) into thrombin (factor IIa).
Thrombin, in turn, helps release factor VIII from the von Willebrand factor and activates into factor VIIa, activates platelets by exposing phospholipids that bind IXa, and also activates factor XIII into factor XIIIa, which helps to stabilize the clot by cross-linking fibrin monomers. Factor IXa, together with factor VIIa, calcium, phospholipids form a tenase complex that recruits large quantities of factor X to activate it, and in turn, factor Xa together with the prothrombinase complex, calcium and phospholipids help convert prothrombin into thrombin. Thrombin then helps split fibrinogen into fibrin monomers. When factor VIII and factor IX are deficient or dysfunctional, the intrinsic pathway of the coagulation cascade cannot be appropriately activated, thus making the process of clot formation deficient.
Hemophilia usually presents as bleeding after minor trauma or as a spontaneous bleed. Bleeding symptoms often correlate with the degree of residual factor level, which is useful to classify hemophilia severity further. Patients with greater than 5% to 40% of factor activity of normal (mild hemophilia) often present with bleeding only after significant trauma or surgery. Spontaneous bleeding is uncommon in mild hemophilia. Typically the diagnosis is made incidentally or on routine presurgical laboratory testing. If 1% to 5% factor activity of normal is present (moderate hemophilia), bleeding usually presents after trauma, injury, dental work, or surgery. In moderate disease, recurrent joint bleed may be present in up to 25% of cases, and the diagnosis usually gets delayed. If factor activity is less than 1% of normal (severe hemophilia), bleeding often presents spontaneously. Severe hemophilia usually manifests in the first few months of life, while mild or moderate hemophilia can present later in childhood or adolescence. Recurrent frequent bleeding presents as early as in utero due to the lack of transplacental passage of both factor VIII and IX from mother to the fetus.
In cases of severe hemophilia, patients often present with internal bleeding, potentially impacting multiple organs. Joints can become painful, swollen, inflamed, warm, and have a restricted range of motion due to bleeding. The most common affected joints are knees, elbows, ankles, shoulders, wrist, and hips. Spontaneous joint bleed incidence typically increases with age reaching up to 60% by 65 years of age. Repetitive joint bleeds often lead to hemophilic arthropathies. Usually, hemarthroses become more frequent as physical activity increases. Brain bleeds, both intracranial and extracranial, are common, and patients can present with falls, confusion, lethargy, meningismus, and coma in severe cases. Intracranial hemorrhage is the earliest and most severe complication in the neonatal period (1 to 4% cases). Extracranial bleeds such as subgaleal bleed and cephalohematoma can also be part of the initial presentation.
Patients can present with occult abdominal bleed with or without trauma, and organs like the liver, spleen, and kidneys can be involved. Typical symptoms of presentation are abdominal pain, especially over the hepatic or splenic area, abdominal distension with guarding or rigidity, melena, hematemesis, hematochezia, costovertebral angle tenderness, bladder spasms, suprapubic tenderness, or hematuria. Similarly, patients can have spontaneous or traumatic thoracic bleeds, which can present with chest pain, shortness of breath, hemoptysis, and in cases of bleeding in the throat, patients can have airway compromise. Patients with spinal hematoma can present with back pain, paresthesia, or radiculopathies. Patients with ocular bleeds like vitreous hemorrhage or hemorrhage after orbital fracture can present with vision changes and restriction of eyeball movement due to ocular muscle entrapment. Other signs of bleeding like tachycardia, tachypnea, hypotension require close attention. Bleeding in the brain, abdomen, thorax, and throat can be life-threatening. Bleeding after circumcision is also typically present in the neonatal period (incidence 0.1% to 35%), and the physicians should have a high index of suspicion.
Another characteristic presentation can be unexplained bruising when an infant begins crawling or walking or musculocutaneous hemorrhage after intramuscular vaccination. Sometimes extensive soft tissue contusions or hemorrhage can be mistaken for child abuse in young patients. The hallmark clinical presentation of both hemophilia A and B is joint (hemarthroses) and muscle bleeding, which typically presents in severe disease. Around 50% of patients with severe hemophilia will have a muscle bleed or hematoma by age 6 to 8 months and can present with compartment syndrome. The most dreadful life-threatening bleeding complications are intracranial bleeding, which is the leading cause of death in patients with hemophilia, iliopsoas muscle bleeds due to significant volume loss, and risk for hypovolemic shock, retropharyngeal bleed, and airway compromise.
The diagnosis of hemophilia combines an index of suspicion due to familial history and clinical manifestation, as well as laboratory testing. Screening tests are necessary for families with an active carrier status or for those who have a family history of excessive bleeding after trauma or after surgery or known bleeding disorders in the family. Genetic testing by chorionic villous sampling or amniocentesis is available during pregnancy and is usually reserved for families with a history of hemophilia. Genetic counseling is also an option for those families who want prenatal testing for hemophilia. Pregnant females are advised to talk to their obstetricians and genetic counselors if they have one child with hemophilia and are planning to have another child. Testing for hemophilia is sometimes by obtaining a blood sample from the umbilical cord or a vein of a newborn immediately after birth, and levels of clotting factors can be checked for patients with high suspicion for hemophilia or in those patients who have a significant family history of bleeding disorders. It is important to note here that factor IX levels can be low at birth as it takes about six months in babies to reach their normal levels. Therefore umbilical cord blood samples are more accurate in finding lower levels of factor VIII, while low levels of factor IX at birth in umbilical cord blood samples do not indicate the presence of hemophilia B.
After the prenatal period, the initial laboratory work includes but is not limited to complete blood count, prothrombin time (PT), partial thromboplastin time (PTT), and bleeding time (BT). Especially those patients who have no family history of hemophilia, findings like prolonged bleeding after circumcision or delivery or after blood draw can prompt workup of hemophilia. In both hemophilia A and B, PTT will be prolonged (intrinsic pathway disruption), whereas PT and BT will be normal. The PTT could be as prolonged as 2 to 3 times the high normal range. Once PTT is found to be prolonged, it should be followed by a mixing study. In a mixing study, the PTT should normalize if factor deficiency is suspected. After the mixing study, the next step should be factor VIII and IX assay. Hemophilia is usually the diagnosis if the factor activity is less than 40% of normal factor activity. Molecular genotyping should then be offered to confirm the diagnosis and also to help predict disease severity.
Also, it is now routine in most hospitals to measure factor VIII inhibitors in patients with hemophilia as some patients develop antibodies against factor VIII, which are called "inhibitors," especially following treatment with infusions of factor VIII. This fact is important as infusions of plasma-derived or recombinant factor VIII would be ineffective in patients who have antibodies against factor VIII. Inhibitors are measurable through quantitative inhibitor assays - Bethesda assay and Nijmegen assay. Original Bethesda assay was developed to standardize the measurement of inhibitors in a factor VIII neutralization assay while in the Nijmegen assay, which is a modification of the original Bethesda method, the pH and the protein concentration of the test mixture are further standardized. This variation makes the test mixture less prone to artifactual deterioration and improves specificity. The International Society on Thrombosis and Haemostasis recommends these assays.
One important bleeding disorder that often gets mixed with hemophilia is von Willebrand disease (VWD). Both hemophilia and Von Willebrand disease are bleeding disorders, but the former is caused by deficient or defective clotting factors VIII (hemophilia A) and factor IX (hemophilia B) while the latter results from deficient or defective von Willebrand factor. They are similar but have several important differences. Hemophilia is seen more in males being an X-linked disease, while von Willebrand disease equally common in males and females due to a genetic change in chromosome 12. While bleeding in hemophilia is usually musculoskeletal, bleeding in von Willebrand disease is more mucocutaneous; this is because von Willebrand factors targets skin and mucous membranes like linings of nose, mouth, vagina, uterus, intestines, etc. and that is why its deficiency primarily causes nosebleeds, gum bleeds, easy bruising, heavy menstruation or heavy peri and postpartum hemorrhage. Internal bleeding is rare in von Willebrand disease, unlike hemophilia, Von Willebrand disease is usually diagnosed by quantitative tests like checking von Willebrand factor antigen levels and factor VIII clotting activity and by qualitative tests like checking ristocetin cofactor and von Willebrand factor multimers to measure how well the von Willebrand factor works.
Healthcare providers are also often challenged when patients with hemophilia present with signs and symptoms of suspected internal bleeding. It becomes crucial for the healthcare team to evaluate them and order tests in a timely fashion to rule out life-threatening bleeds like intracranial bleeds or abdominal bleeds. When patients present with altered mental status, confusion, cognitive dysfunctions, or multiple falls, the CT scan of the head or MRI of the brain is ordered to rule out intracranial bleed. This factor is crucial, especially in neonates, infants, and during early childhood, as these patients may not be able to provide a detailed history. Sometimes adults with hemophilia may present with unusual symptoms like cognitive dysfunction due to frequent but silent cerebral microbleeds and require MRI of the brain to evaluate these microbleeds. Patients with recurrent joint bleeds can benefit from point-of-care ultrasonography of joints to monitor the progress of hemophilic arthropathies. Abdominal or thoracic bleeds can undergo evaluation with a CT scan or MRI of the chest and abdomen.
The hemophilia treatment strategy is primarily divided into two categories - management of acute bleeding and prophylaxis.
Management of acute bleeding in hemophilia
The fundamental concept of management of a diagnosed or confirmed acute bleeding in hemophilia is to achieve quick and aggressive hemostasis preferably within two hours of the onset of symptoms and correction of coagulopathy, but these measures should not be delayed even if diagnostic tests are pending or if physical symptoms are not present. Patients require hospitalization, and guidelines from the World Federation of Hemophilia should be followed for the management of acute bleed. Usually, patients can tell when a bleeding episode is about to occur by the presence of a tingling sensation or “aura,” but relevant and quick history should be obtained from available sources if patients can not communicate.
Any patient with hemophilia who presents with severe acute bleeding episode requires quick recognition of the location and severity of the bleed; this must be followed by immediate replacement with high-dose clotting factor concentrate (CFC) with factor VIII or IX. Doses of factor concentrate should be 50 IU/kg body weight factor VIII or 100 to 120 IU/kg factor IX. If factor IX concentrate is not available, then 70 to 80 IU/kg of prothrombin complex concentrate can be infused. Some patients may require urgent surgery or a procedure in cases of intracranial bleed, airway compromise from throat bleed or neck hematoma, large abdominal or thoracic bleeds or compartment syndrome with large muscle hematomas. However replacement with high-dose CFC must happen first or simultaneously with any planned surgery or procedure except when a patient requires a cardiopulmonary resuscitation (CPR) where CPR supersedes high-dose CFC replacement.
Appropriate imaging studies should be done to determine bleeding sites followed by appropriate specialty referrals based on the location and severity of the bleed. Even if the bleeding slows down or stops, high-dose CFC should still be given as required to allow healing. Frequent measurements of factor levels must be done to make sure that desired levels are maintained. Upon achieving hemostasis and once the coagulopathy is corrected, the workup for hemorrhage should begin. While performing pain management, one should avoid acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) due to their effects on platelet function and risk for increased bleeding. Acetaminophen and certain COX-2 inhibitors are safe to use. Also, intramuscular injections should be avoided if possible.
Prophylaxis in hemophilia
Apart from treating acute bleeding, another strategy of treatment in patients with hemophilia is prophylaxis. Prophylactic treatment has several advantages. It can reduce hemarthroses episodes and thereby reduce hemophilic arthropathy and the need for corrective joint surgeries. Prophylactic treatment can also reduce the frequency of cerebral and muscle bleeds and reduce the need for hospitalizations. It helps improve the quality of life for patients by allowing them to take less time off work and less frequent monitoring. Also, in a study from Bremen and Munich on low levels of prophylactic treatment, it has been suggested that the development of inhibitor risk is reducible. This study only found one low responding inhibitor in 40 children with severe hemophilia A followed up for a minimum of 40 exposures. According to the World Federation of Hemophilia guidelines, prophylaxis is further categorized as primary or secondary and continuous or intermittent. Prophylaxis is denoted as continuous if it initiates with the intent to treat for 52 weeks in a year and is accomplished for at least 45 weeks of that year.
Intermittent prophylaxis regimen does not exceed more than 45 weeks in a year. On-demand or episodic treatment is indicated at the time of clinically evident bleeding. Continuous prophylaxis can further subdivide into (1) primary if the treatment initiates before the onset of osteochondral joint disease, before 3 years of age and before the two clinically evident large joint bleeds, (2) secondary if the treatment starts after two or more major bleeds into a large joint and before the onset of osteochondral joint disease and (3) tertiary if the treatment starts after the onset of documented osteochondral joint disease. The optimal regimen remains to be defined, but two prophylactic protocols currently used are the Malmo protocol and the Utrecht protocol. A frequent practice is to initiate prophylactic treatment once or twice per week and increase the frequency until a full primary prophylactic dose is reached, before the onset of joint bleeding or other serious bleeds at 12-18 months of age.
Factor VIII dosing calculations, schedules, and target levels
Ideally, the goal of dosing is to maintain the factor levels above 1% to 2%, but dosing schedules vary and are dependent on factor deficiency and the patient, their bleeding rate, and ease of IV access. In hemophilia A, factor VIII infusion of 25 to 40 units/kg of body weight three times per weak per Malmo protocol or 15 to 30 units/kg three times per week per Utrecht protocol, can be used. In hemophilia B, factor IX infusion of 25 to 40 units/kg of body weight two times per week per Malmo protocol or 15 to 30 units/kg two times per week per Utrecht protocol, can be used. The dose of factor VIII is calculated by body weight in kilograms and multiplying it with the desired increase in factor VIII and 0.5 units/kg. Factor levels are usually measured 15 minutes after the infusion to verify the calculated dose. Typically, 1 unit/kg factor VIII infusion increases plasma levels of factor VIII by 2% with a half-life of about 8 to 12 hours, and hence, the infusion dose is calculated accordingly. Infusion is done slowly at a rate of less than 3 ml/minute in adults and less than 100 units/minute in young children. Factor VIII target levels are dependent on the location and severity of bleeding. In mild hemorrhages, levels are maintained at 30%, in moderate hemorrhages, levels are maintained at 50% and in severe life-threatening hemorrhages, levels are maintained at 80% to 90%, and after stabilizing the bleeding, levels are maintained at 40% to 50% at least for 7 to 10 days. Due to its half-life of 8 to 12 hours, the second dose of factor VIII is given 8 to 12 hours after the first dose and is usually half of the first calculated dose. Mild hemorrhages require 1 to 3 doses, while severe hemorrhages require many more doses with the goal of maintaining levels at 40% to 50% for 7 to 10 days at least. Occasionally continuous infusions are also required for very severe hemorrhage or major surgery. The decision to stop prophylaxis is dependent on patients, their symptoms, and their concerns. Some patients may want to switch to less frequent dosing schedules or may want to go off prophylaxis and monitor symptoms.
Plasma-derived versus recombinant factor VIII
In the 1950s, fresh frozen plasma was first used as a replacement factor in patients with hemophilia, followed by cryoprecipitates in the 1960s. In the 1970s, lyophilized factor VIII was derived from plasma and brought a huge change in the treatment of patients allowing them to gets home infusion therapy. However, in the 1980s, many patients with hemophilia were affected by contaminated factor concentrates, and 60% to 70% of patients got infected with HIV. Almost 100% of patients got infected with hepatitis C. This tragedy prompted more research to make plasma-derived factor concentrate safer. Eventually, cloning of the gene for factor VIII occurred in 1984, and recombinant factor VIII concentrate became available in 1992.
The availability of recombinant factor VIII, along with viral inactivation and better screening technology, made factor products safer and revolutionized the treatment of hemophilia. Despite the availability of plasma-derived factor concentrates, about 75% of patients with hemophilia worldwide receive recombinant factor VIII products since they are much safer. Today, many different recombinant factor VIII products are available, including first, second, third, and fourth-generation with and without extended half-life. In developed countries, third-generation recombinant factor VIII products are now most commonly used as their production does not contain any animal or human products. Also, the focus is now shifting towards third-generation recombinant products with extended half-life.
Extended half-life products have made it possible to have fewer scheduled infusions, with research underway to produce factor VIII products with PEGylation and fusing factor VIII with Fc receptor, which has led to products with longer half-lives. FDA has recently approved PEGYlated factor VIII and Fc-factor VIII fusion product with the later having a half-life of 19.7 hours, the longest among all the currently available products. Even a modest increase in the half-life of factor VIII can reduce the frequency of infusions and can significantly improve the quality of life for the patients. More and more research is now being done to improve the half-lives to decrease the frequency of infusions and decrease the immunogenicity of the factor products to lessen the prevalence of the development of inhibitors. 
Other pharmacological options
Apart from plasma-derived and recombinant coagulation factor concentrates, other agents are also useful in the treatment of hemophilia. They are desmopressin, tranexamic acid, and epsilon aminocaproic acid.
1. Desmopressin (DDAVP) - Desmopressin is a synthetic vasopressin analog. It works by increasing endogenous factor VIII plasma concentrations by 3 to 5 times by inducing the release of von Willebrand factor (VWF). It has utility in the treatment of patients with mild or moderate hemophilia A instead of using a factor concentrate and thereby reducing the expense and decreasing the risk of development of inhibitors. It is mainly useful in the prevention or treatment of bleeding in patients who are carriers of hemophilia. It has no value in hemophilia B as it does not affect levels of factor IX. Desmopressin is much cheaper than factor concentrates, and it carries no risk of viral infection transmission. It can be used subcutaneously, which is the most common route of administration but can also be given intravenously and intranasally. It should be avoided in pre-eclampsia and eclampsia as those patients already have high levels of von Willebrand factor. Also, due to its antidiuretic property, hyponatremia and water retention can occur. Therefore its use is contraindicated in children less than two years of age who can be at risk of developing seizures due to cerebral edema secondary to water retention and should also be used carefully in adults with a history of congestive heart failure or cardiovascular disease.
2. Tranexamic acid and epsilon aminocaproic acid - Both tranexamic acid and epsilon aminocaproic acid are antifibrinolytic agents and promote clot stability. Epsilon aminocaproic acid is less commonly used as it is more toxic, has a shorter half-life, and is less potent. They cannot be used as a standalone treatment for musculoskeletal bleeding but are useful in preventing mucocutaneous bleeds like epistaxis, heavy menstruation, or in the setting of dental surgery except in patients with hematuria as it may prevent the dissolution of clots in the urine and may cause obstructive uropathy. Also, in patients undergoing thoracic surgery, it may result in the development of insoluble hematomas and should not be used.
Novel therapies in hemophilia
1) Gene therapy
Cloning of the gene not only allowed the production of recombinant factor but also promoted gene therapy efforts to cure the disease. Due to the monogenic nature of inheritance and because even a small amount of increase in clotting factor activity can significantly reduce bleeding incidences and improve quality of life, hemophilia remains an optimal target for gene therapy, and early phase I and II trials have shown success. The biggest issue right now is that gene therapy has still certain limitations when used in patients with liver disease, pediatric populations, and patients who have pre-existing antibodies to factor, and further research and trials are underway to make it more broadly applicable.
2) Monoclonal antibodies
Apart from gene therapy, the development and application of monoclonal antibodies, like emicizumab and concizumab, for the treatment of hemophilia have generated a lot of excitement. Emicizumab is a monoclonal antibody that mimics the function of activated factor VIII molecule but does not structurally or immunologically resemble factor VIII and, therefore, are not affected by inhibitors. Also, it has excellent safety and tolerability, can be administered subcutaneously, has a longer half-life of 4 to 5 weeks, and has led to significantly decreased annualized bleeding rate with the administration of a higher dose. Also, no anti-drug antibodies were detected during the studies. Still, more studies are ongoing to study potential side effects and the impact of treatment in patients suspected of having poor outcomes. Monoclonal antibodies have the potential to revolutionize the treatment of hemophilia, and therefore, emicizumab received breakthrough treatment designation.
Management of joint bleeding in hemophilia
The most common complication of hemophilia is joint bleed, which can cause significant morbidity and requires early prevention and treatment before chronic degenerative changes set in. Management of joint bleeds requires a comprehensive strategy with the primary focus being the prevention of bleed, and prophylaxis is the recommended first-choice treatment by the World Health Organization and World Federation of Hemophilia. Primary prophylaxis is given to patients with severe hemophilia before the joint bleed, while secondary prophylaxis is given after the first joint bleed but before the onset of joint damage. Prophylaxis is usually started at an early age to prevent and reduce the risk of joint bleed and development of hemophilic arthropathy. Dosing is individualized and changed according to the severity of the bleed. In acute bleeding episodes, it is important to achieve hemostasis quickly by giving on-demand factor infusion as early as possible. Patients who have chronic synovitis and recurring joint bleeds can benefit from short term treatment courses of secondary prophylaxis for about 6 to 8 weeks.
Apart from on-demand and prophylactic treatment, pain management remains the most important aspect to control the patient's symptoms. ASA and NSAIDs should be avoided, and milder opioids or acetaminophen are options for pain control. Occasionally for chronic synovitis, intraarticular steroid injections can be given. Rest, ice application, compression, and elevation are therapeutic choices for patients with minor joint bleeds. Immobilization of painful joints should occur only for the necessary duration as prolonged immobilization can lead to muscle atrophy and limitation of range of motion. Early initiation of physical therapy and exercise program are critical for reducing swelling and pain, maintaining strength and range of motion, and prevent further injury by gait training patients. It also plays a huge part in preventing bleeding and also rehabilitating patients after surgery or those who have severe joint damage. In some cases, joint aspiration may be necessary following failed response to factor replacement after 48 to 72 hours or where bleeding is in a major joint like hip where the pain is uncontrollable, but in general, it is not a recommended treatment. If aspirating a joint, then factor replacement should be done simultaneously, and the utmost precautions should be taken to avoid the incidence of septic arthritis.
Surgery is usually reserved for refractory cases where conservative management has failed, or irreversible joint destruction has occurred. Different modalities like synovectomy, joint debridement, joint arthroplasty, and joint fusion, known as arthrodesis, can be employed on a case by case basis. Despite the availability of many treatment modalities, hemophilic arthropathy remains the single most common complication in patients affecting their quality of life.
Pain management in hemophilia
Pain in patients with hemophilia can be acute or chronic. It could be pain from joint or muscle bleeds, from repeated attempts at venous access, from hemophilic arthropathy due to chronic degenerative joint disease or after surgery/procedure. It is important to know the cause of pain to decide the management. Usually, for pain caused by repeated attempts at venous access, no pain medications are necessary, especially in adults, but in children, the application of local anesthetic spray or cream can help at the site of IV access. For acute joint or muscle bleeds, rest, compression, elevation, cold packs, immobilization, crutches, splints, braces, or wheelchairs can be useful as adjunctive therapies. Intramuscular injections of pain medications or steroids should be avoided. Ideally, the first-choice drug for pain control is acetaminophen or paracetamol. If those are not effective, then COX-2 inhibitors such as celecoxib, meloxicam, etc. can be used. If COX-2 inhibitors are not preferred, then the combination of acetaminophen or paracetamol with low dose opioids such as codeine, tramadol, hydrocodone, or morphine can be used. These medications can be given 3 to 4 times per day, along with other adjunctive therapies to control the pain. Products containing ASA or NSAIDs should be avoided. Sometimes, persistent pain may require corrective surgery or referral to a pain management team.
Importance of physical activity in hemophilia
Physical activity is of utmost importance in patients with hemophilia to ensure physical fitness, muscle strengthening, maintaining healthy body weight, bone density, and proper muscle development. Preventive physical therapy and therapy after a joint bleed or surgery are extremely crucial. The choice of physical activity is usually determined by the patient's ability, interests, and available resources. Contact sports like soccer, rugby, boxing, etc. should be avoided. High-velocity sports like racing, skiing should be avoided too. Noncontact sports such as swimming, golf, badminton, cycling, table tennis, walking, etc. should be encouraged. Organized sports activities are the recommended option, as they can have appropriate supervision, and protective gear and equipment are available. Also, before indulging in any physical activity, patient should talk to a therapist or a professional to discuss what kind of protective gear they should wear to protect the problem joints, to know whether they require any additional physical training before doing the activity and also to discuss whether they need any prophylactic treatment to get their factor levels higher and prevent bleeding.
Hemophilia treatment cost
With the improved life expectancy due to the availability of early diagnosis and improved treatment options for acute bleeding and prophylaxis both, children born with hemophilia today are now expected to have a normal life expectancy in developed countries. But this has also increased the cost significantly as patients with hemophilia are not only living longer, but they also require more frequent infusions due to low half-lives of factor products and development of inhibitors in about 25% to 30% of patients. The average cost of treatment per year in the US is about $150000 to $300000, while in Europe, it is close to 77000 euros to 112000 euros, and those patients who have inhibitors can have 3.3 times the cost compared to patients who do not have inhibitors. Also, apart from treatment, there are additional costs for hospitalizations, laboratory tests, office visits, and indirect costs for decreased productivity and missing work or school. Plus, the disease takes a heavy emotional and physical toll on patients and their caregivers by reducing their quality of life, causing them pain and suffering, and increasing their intangible costs. The disease that was formerly fatal has now become a chronic well-managed problem. Still, there is a tremendous need for understanding the proper utilization of healthcare resources and the education of patients regarding their clinical condition and compliance with treatment.
Other conditions can also present similarly with bleeding after minor trauma or spontaneous bleeds and require exclusion before confirming the diagnosis of hemophilia. Some of these conditions include von Willebrand disease, scurvy, diseases of platelet dysfunction, deficiency of other coagulation factors like V, VII, X or fibrinogen, Ehlers-Danlos syndrome, Fabry disease, disseminated intravascular coagulation, and child abuse. In von Willebrand disease, bleeding symptoms can be similar to mild hemophilia, but patients with von Willebrand disease have more mucosal bleeding compared to musculoskeletal bleeding seen in hemophilia. Von Willebrand disease is diagnosed by checking for von Willebrand factor antigen or von Willebrand factor multimers. Similarly, in scurvy, Ehlers-Danlos syndrome, and Fabry disease; also, the bleeding is usually mucosal, unlike hemophilia, where it is musculoskeletal. In scurvy, there is a deficiency of vitamin C. In Ehlers-Danlos syndrome, the skin is hyperextensible, and joints are hypermobile. The diagnosis is usually through clinical features, genetic testing, and tissue biopsy. Similarly, in Fabry disease, patients may also have other organs being affected, including kidneys and heart and have skin lesions called angiokeratomas. They also have pain in extremities. Fabry disease is usually diagnosed with clinical findings and genetic testing. In cases of platelet dysfunction disorders, bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. In the deficiency of other coagulation factors, musculoskeletal bleeding is uncommon, and in fact, sometimes thrombosis can occur, especially in patients with factor VII or fibrinogen deficiency or in patients with combined factor V and VIII deficiency. Specific coagulation factor assays usually confirm the diagnosis. Disseminated intravascular coagulation (DIC) that mimics hemophilia is hard to differentiate, but usually, there is an underlying condition in DIC, for example, acute promyelocytic leukemia. Diagnosis is usually carried out by blood tests that show decreased platelet count and absence of factor VIII autoantibodies. Child abuse can sometimes be misidentified and confused with hemophilia, and it is essential to find the inconsistencies in the history of how trauma has occurred. Other signs of malnourishment require vigilance and x-rays may reveal evidence of fractures of different ages.
The life expectancy of people who had severe hemophilia in the 1950s and 1960s before the development of factor concentrates was only 11 years. Most people who had severe hemophilia died in early childhood or adolescence from intracranial bleeds or bleeding inside the vital organs. In 1964, Judith Pool found the fraction cryoprecipitate from the plasma, which had large quantities of factor VIII concentrate, and that improved treatment for hemophilia significantly. Before that, patients with hemophilia could only have treatment with whole blood or fresh plasma, which lacked sufficient quantities of factor VIII or IX proteins. In the 1970s, lyophilized plasma concentrates of coagulation factors became available, and this improved treatment significantly.
Primary prophylaxis began in Sweden before being adopted by other countries, which ended up preventing major bleeding episodes and complications of arthropathies. In 1977, researchers discovered desmopressin. With that, patients were able to get a better, safer, and relatively inexpensive option for treatment, and risks of blood-borne infections from repeated use of plasma-derived products were minimized. After patients with severe hemophilia got infected with HIV and hepatitis C from contaminated coagulation factors in the 1980s, methods to screen and inactivate viruses in blood were developed, and this improved the safety of plasma-derived products significantly. Eventually, the advancement in DNA technology allowed industrial production of recombinant factor VIII and IX.
With the widespread availability of replacement therapy to prevent and treat active bleeding, advancement in viral inactivation techniques, management of blood-borne infections through surveillance, and availability of newer treatment options for hepatitis C and HIV treatment have significantly improved the life-style of patients with hemophilia. Today, life expectancy for patients is almost the same as the general population in developed countries, provided those patients respond well to the treatment and do not have other health conditions. But in developing countries, where healthcare access and treatment resources are scarce, the mortality rate remains almost twice that of the general population.
Development of inhibitors and the role of immune tolerance induction and monoclonal antibodies
The major complication of therapy in patients with hemophilia is the development of inhibitors. Inhibitors are alloantibodies (IgG) directed against factor VIII and IX that neutralizes its action. It is the most severe treatment-related complication of hemophilia. The presence of inhibitors should be suspected if bleeding fails to stop after infusion of clotting factors in a patient who was responsive in the past. Inhibitors make the half-life of infused factor concentrate even shorter and thereby decrease their efficiency. Inhibitors are more frequent in hemophilia A than hemophilia B, as well as in severe hemophilia with an incidence of 20% to 30% compared to mild hemophilia with an incidence of 5% to 10%. The median age of inhibitor development is three years or less in severe hemophilia while it is closer to 30 years in mild or moderate hemophilia. Inhibitors in mild or moderate hemophilia predominantly cause bleeding from mucocutaneous sites. Confirmation of the presence of an inhibitor is via the Nijmegen-modified Bethesda assay.
Children and adults should receive frequent screening for the development of inhibitors. For children, there should be screening once every five exposure days until 20 exposure days, every ten exposure days between 21 and 50 exposure days, at least two times a year until 150 exposure days, before surgery or when switching to a new factor concentrate. They should be measured in all patients who have received intensive treatment lasting more than five days and within four weeks of the last infusion. If post-operative bleeding occurs and response to on-demand therapy is not optimal, then the presence of inhibitors should be assessed. Inhibitors are further sub-classified as low responding and high responding. High responding inhibitors usually persist in time. If not treated for an extended period, the levels may fall or become undetectable, but when infusing the factor concentrate again, they will become active and may render the infusion ineffective. Titers might decrease, but when the patient is exposed again to factor products, titers may rise within 3 to 5 days of the exposure. Low responding titer inhibitors are usually transient, disappear by six months, and would not reappear after the patient is re-exposed to factor products.
Treatment of acute bleeding episodes in patients with the presence of inhibitors starts with a consultation with the hemophilia center as soon as possible. Some treatment modalities include but are not limited to a higher dose of factor, porcine factor VIII, recombinant factor VII activated, and prothrombin factor complex concentrates. Eradication of inhibitors in a patient with hemophilia A is also possible by immune tolerance induction. So far, immune-tolerance induction has been found to be a proven therapy to eradicate inhibitors. This protocol involves repeated and frequent infusion of factor VIII. Patients who are getting immune-tolerance therapy typically get daily doses of factor concentrate over weeks or even years in some cases. Some patients may also be given immunosuppressive medications while on treatment, which can make them more prone to infections. The goal of this therapy is to ensure that the body tolerates the factor infusions and does not mount an immune response by downregulating already established antibody response. Immune-tolerance induction can remove inhibitors in about 70% of patients with hemophilia A and 30% of patients with hemophilia B. Another promising therapy is monoclonal antibodies, which are now being studied and have shown a lot of promise in the treatment of patients with inhibitors. This potential benefit is because monoclonal antibodies like emicizumab mimic the function of activated factor VIII molecule but do not structurally or immunologically resemble factor VIII and, therefore, are not affected by inhibitors.
Another critical complication of hemophilia is hemophilic arthropathies from repeated musculoskeletal bleeding. About 90% of patients with severe hemophilia who have had repeated musculoskeletal bleeds end up having chronic degenerative changes in major joints like ankles, knees, and elbows in their 20s and 30s. The only way to prevent these arthropathies is to prevent spontaneous intraarticular hemorrhage by providing prophylactic treatment; however, subclinical hemorrhages can still occur despite prophylactic treatment. Management of joint bleeds has been discussed extensively in the treatment section.
Pseudotumor is a life, and limb-threatening condition due to inadequately treated soft tissue bleeds, usually in muscles adjacent to the bones. It is most commonly seen in long bones or pelvis. If not treated timely and adequately, pseudotumors can rapidly enlarge and lead to neurovascular compromise by pressure on adjacent structures. It can also cause pathologic fractures and create fistulas through the skin. Clinical examination and imaging studies are essential in diagnosis. Small pseudotumors can be monitored while larger ones can receive aspiration or surgical ablation. Factor concentrate infusion is necessary and should occur for at least six weeks, followed by repeat imaging to document a decrease in the size. Large pseudotumors that have failed conservative management and those that are rapidly expanding may require limb amputations. Abdominal pseudotumors require surgery as soon as possible.
Fractures can occur in patients with hemophilic arthropathy. Immediate treatment of a fracture is replacement with factor concentrate to raise the levels to almost 50% and maintain them at that level for at least 3 to 5 days. Surgical management depends on the location and severity of the fracture, and splints or external fixators may be necessary. Immobilization for a necessary duration with early initiation of physical therapy is crucial.
Blood-borne infection-related complications
In the 1980s, factor concentrates got contaminated with viruses like HIV and HCV, and patients who received those got infected with HIV and hepatitis C. This resulted in high mortality rates in patients with hemophilia in the 1980s and early 1990s. Today, many studies show that HIV and HCV transmission through factor concentrate has been almost eliminated due to careful selection of donors, screening techniques, viral elimination process during manufacturing, and advancement in diagnostic procedures to detect these viruses early. Higher usage of recombinant factors has dramatically decreased the risk of infection. However, the new challenges from non-lipid enveloped viruses and prion diseases are emerging. Also, currently available anti-HIV medications are all safe for use in patients, with no contraindications. For patients with hepatitis C and hemophilia, pegylated interferon, and ribavirin are the treatment.
The patient should be treated in a comprehensive treatment center where an interprofessional approach between doctors (chronic pain specialist, geneticist, hematologist, immunologist, etc.), nurses, musculoskeletal experts, laboratory specialists, pharmacists, and psychology experts is available at all times to the patients and their families.
Patient education is vital in improving the long term prognosis of patients, reducing mortality rate, and improving their lifestyles. Ideally, early detection, adequate follow-up, and timely treatment all play a significant part in improving patients' prognosis. Any patient with hemophilia should receive a hematology referral and require close follow-up by a specialized hemophilia center or service. Education should be provided to the patients to monitor their symptoms and seek early treatment.
Children with hemophilia should be vaccinated, even with intramuscularly administered vaccines. The vaccination is best with a 23 gauge needle with prior ice pack application to the area for 5 minutes, and soon after. Factor replacement is given but not on the same day. Appropriate dental care should be encouraged for all children with at least two times per day dental cleaning with flossing and a medium texture bristles toothbrush and age-appropriate toothpaste with fluoride. Some dental procedures might require the prophylactic application of factor concentrates or other prophylactic modalities. Suggestions are that any major dental surgeries should occur within a hemophilia treatment center. Physical activity is a recommendation in all children with hemophilia. The activity of choice should reflect patients' interests. Non-contact sports (swimming, walking, golf, badminton, archery, cycling, etc.) are always encouraged. Contact sports (soccer, rugby, boxing, etc.) and high-velocity sports are permissible if the patient is on good prophylaxis to cover these sports. With an increase in the complexity of hemophilia treatment, a shared decision-making approach should be taken involving patients in their care, and all the tools should be provided to the patients to facilitate informed decision-making. 
It is also crucial to make sure that patients are compliant with prophylactic treatment schedules to reduce the incidence of joint bleeds and improve the quality of life. There were studies to measure adherence to prophylaxis in children and adults, and some of the studies found that although the rate of adherence is improving with better patient education and more awareness among the patients, about 40% of patients still find it difficult in adhering to prophylactic treatments over a long period. Adherence is usually quantifiable by the number of doses of medications given compared with the number of doses prescribed. The target goal of adherence should be at least 75% to 80% of medication doses. The pharmacist should carefully examine the patient's medication profile frequently and collaborate with the treating clinicians regarding any necessary changes to either agents or dose regimens. The healthcare team should try to discover the factors that could be affecting adherence to prophylaxis for patients and try to address them comprehensively to improve compliance and reduce long-term complications and improve physical activity in patients.
Patients should be followed up for at least every six months by all core team members to coordinate care and supervise at-home treatment regimens. Nursing staff can verify therapeutic compliance, serve as an entry point to the healthcare team, and answer patient questions, reporting any concerns to the rest of the team. Home therapies should be established promptly after diagnoses and as soon as families have the required education and training, and feel comfortable with hemophilia management since it provides the most immediate access to early treatment and decreases overall pain, dysfunction, disability, and hospital admissions.
Hemophilia requires a complete interprofessional effort at an even higher level than most other conditions; when executed properly, this approach can lead to a higher quality of life and life expectancy. [Level 5]
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