Pursuing a multivariable approach in a functionally independent older hemophiliac

INTRODUCTION

Hemophilia A is an X-linked bleeding disorder defined by a deficiency in Factor VIII in the clotting cascade. As a result, this can lead to prolonged periods of bleeding following minor trauma, injuries, and medical and dental procedures.^[1] Severe Hemophilia A is defined by plasma factor levels of <1%.^[2] Those with severe hemophilia A can have spontaneous episodes of bleeding. It is usually diagnosed by the time a child is 2 years old.^[1] Severe, untreated hemophilia can present with bleeding into major joints and internal organs as well as intracranial bleeds.^[3]

Treatment has improved within the patient’s lifetime over the past 65 years. Before the 1960s, patients with hemophilia A relied on plasma transfusions for bleeding control. These treatments did little to stop episodes of bleeding, lacked sufficient clotting factor, had a high risk of infection, poor quality of life (QOL), and led to significant joint deterioration. Then, treatment evolved with cryoprecipitate but continued to have the same issues of infection and QOL.^[4] Freeze-dried plasma helped to reduce bleeding episodes, but infections continued until the 1980s and 1990s when safety screening and treatments for HIV and Hepatitis C infections were addressed more aggressively.^[5] In the 1990s, treatment moved towards non-human plasma options, utilizing DNA technology to invent recombinant Factor VIII, which moved the field forward, decreasing infections and bleeding.^[6] Commercial examples of recombinant Factor VIII (also known as antihemophilic factor recombinant) include Recombinate, Nuwiq, Eloctate, and Altuviiio.

The current foundational treatment for hemophilia A is replacement of the deficient factor, factor VIII. The factor is administered intravenously as a prophylactic measure several times a week.^[7] In children with severe hemophilia A, primary prophylaxis with factor VIII is usually indicated before the child is 2 years old. Secondary prophylaxis can also be initiated to prevent the progression of arthropathy and other symptoms related to hemophilia.^[8]

Emicizumab, commercially known as Hemlibra^®, is a bispecific monoclonal antibody that has been employed to treat hemophilia A. Although emicizumab (Hemlibra^®) is not a factor VIII replacement therapy, it works by mimicking the actions of factor VIII and therefore eventually activating factor X.^[9] Emicizumab is administered subcutaneously and has a half-life of 27 days, which is considerably longer than that of traditional factor VIII replacement.^[9] The method of administration, as well as the significantly longer half-life, make emicizumab a more practical treatment for patients with hemophilia A.

In addition, replacing the deficient factor can lead to inhibitors against this exogenous factor VIII. In a study by Gouw et al., 32.4% of children with severe hemophilia A treated with factor VIII product developed clinically relevant inhibitor antibodies.^[10] Because emicizumab is not factor VIII replacement therapy, this medication does not carry the same risk of inhibitor development. After multiple clinical trials and studies, emicizumab was approved by the U.S. Food and Drug Administration and European Medicines Agency in 2018 to be used as a prophylactic measure in severe hemophilia A patients both with and without inhibitors against factor VIII.^[11]

Physical therapy is historically an important part of treatment for comorbidities associated with hemophilia, including maintaining health, managing pain, and enhancing function through strengthening, manual therapy, device use, and stretching. Most studies are performed on younger (<40 years old) patients with hemophilia. For example, a study by Gurcay et al. was conducted on patients 18 years old and younger because physical therapy is more effective if implemented at younger ages.^[12] Patients receiving physical therapy and rehabilitation measures typically show benefits in range of motion, strength, pain reduction, and proprioception. The studies are very heterogeneous with respect to the duration, intensity, and extent of the treatments.^[13]

CASE REPORT

A 65-year-old man with severe hemophilia A has demonstrated a high level of function despite having an excessive number of spontaneous bleeding episodes per year. Typically, a patient with severe untreated hemophilia A generally has a maximum of 20 joint bleeds per year.^[14] Another study by Ay et al. demonstrated that in a population of patients with severe hemophilia A, the median annual bleeding rate was 28.0 in patients with on-demand treatment only (i.e., no prophylaxis) and 4.9 in patients receiving prophylactic treatment.^[15] In contrast, the patient of interest in this case report had up to 250 episodes of spontaneous bleeding per year – most notably into his joints, muscles, and tongue – despite receiving prophylaxis.

This patient was diagnosed with hemophilia A at birth via testing of the umbilical cord blood due to a known family history of the disease. Although his maternal uncle had moderate hemophilia, this patient has severe hemophilia, meaning his factor VIII levels are <1%.^[2] Although hemophilia is only one variable in this patient’s life, it has caused considerable burden for most of his life.

The patient has tried many treatments throughout his lifetime. The first attempted treatment was a blood-product-based medication in the mid-1960s. This medication had a short half-life of only a couple of hours. Because this was a blood-based product, there was a constant risk of infection, especially because of the time of its invention. In 1990, the patient then switched to Recombinate, which he was on for almost 30 years. This treatment had a very short half-life but no cellular blood components, decreasing the risk of infection. Other attempted treatments include Nuwiq – which was adequate for a septoplasty but failed during a rhinoplasty – and Eloctate. With Eloctate, the patient would have to receive daily infusions via a midline, and a nurse would come to his home every week to change the dressing. Recombinate, Nuwiq, and Eloctate are all antihemophilic factor recombinant, which were used as prophylactic treatment.

Despite these treatments and careful preventative measures to avoid bleeds, the patient continued to have a severe phenotype beyond the typical upper limit of “severe hemophilia”. The excessive number of spontaneous bleeding episodes had a significant negative impact on the patient’s life. For example, the patient, via a natural language interview, reported that if he had a spontaneous bleeding episode while out grocery shopping, he would have to go to his car and take his medication intravenously in the parking lot. The patient reported that this would cause him undue biopsychosocial stress as he feared this scene could appear to be something less socially acceptable to others who were passing by and attract unwanted attention. These bleeds were spontaneous. The patient had no way to predict when they would occur because there were no apparent precipitating factors. As these episodes could occur anywhere under any circumstance, stress also came from the constant worry that a bleed could happen at any inconvenient moment. The patient had to carry his medication wherever he went, and in the event of a bleed, find a place to privately administer his medication. A private place was not always easily accessible. These factors have all affected the patient not only physically but socially, emotionally, and mentally. His QOL has been significantly affected by these episodes or the fear of these episodes throughout his lifetime.

Despite the severe phenotype of this disease, this patient has demonstrated a high level of function and improvements in his symptoms with physical therapy, helping to facilitate strong resilience. Severe hemophilia A and the subsequent complications of these numerous bleeds have led to significant chronic myofascial pain and mobility issues in his neck, shoulders, elbows, and hips. As one can imagine, this chronic pain and limited mobility previously caused the patient to struggle with regular daily activities, such as pouring tea from a kettle, retrieving mail from his mailbox, caring for his cats, independently washing himself, toileting, and brushing his teeth. To address the issue of chronic pain, this patient regularly received physical therapy for many years. His physical therapy regimen currently includes manual treatment to prevent joint loss, Graston Technique to improve tendinopathy, cupping, dry needling (recently discharged from as he has improved in functionality and symptomatology), and blood flow restriction (BFR), for which he now is independent with and has a unit at home. The patient had and has been able to achieve significant gains in function, strength, and increased range of motion. These have given him more independence, such as being able to pour tea from a kettle without pain, care for his cats, open French doors without assistance, and drive independently. These have all improved his overall QOL and confidence.

This patient has demonstrated remarkable reported improvements in his QOL after taking emicizumab (Hemlibra^®). He started Hemlibra^® in April 2023 as a maintenance treatment for his hemophilia. The patient takes 2 mL of Hemlibra^® every other week via a subcutaneous injection, rotating between four different positions in his thighs. This treatment has essentially eliminated his spontaneous bleeding and minimized his breakthrough bleeds, reducing the up to 250 annual bleeds to about 1–2 breakthrough bleeds per year, i.e., when he bites his tongue. The patient also started taking 3 mL of Altuviiio intravenously as needed in August 2023. He only takes Altuviiio as needed for minor trauma and procedures (e.g., cosmetic, dental). With these two medications, the patient has been able to control his hemophilia and is able to partake in more aggressive physical therapy treatment to address his chronic pain.

Hemlibra^® has allowed the patient to receive more aggressive physical therapy to address the symptoms that come with hemophilia, including arthropathy. Addressing the patient’s chronic pain has provided significant improvements to his life. Previously, the patient was taking very high doses of opioids and ketamine to adequately control his levels of pain. The patient is now taking little to no pain medications, which occurred even before the addition of Hemlibra^®. The patient was able to undergo myofascial release before taking Hemlibra^® but not as aggressively as after. All these current physical therapy treatments were approved by the patient’s hematologist and medical team.

This multivariable approach to this patient’s care has led to not only decreased bleeding but also increased overall function. The patient is now able to function at a much higher level than previously thought possible, even at increased life stress levels. He can comfortably perform daily activities, such as caring for his cats and pouring tea from a kettle, to more ambitious activities such as taking 12-hour road trips to Florida, his first flight in 15 years, and undergoing elective surgical procedures without incident and with faster recovery. Given the patient’s age, severe hemophilia, and subsequent chronic pain, the patient is performing at a very high functional level, and it is uncommon to have a patient with severe hemophilia doing this well at this point in his life.

DISCUSSION

Although there is abundant literature on the clinical presentation of a patient with severe hemophilia, the literature often fails to include the complete picture of the patient beyond the physical aspects of the disease and is often not inclusive of those in this age demographic. Though the physical aspects of the disease – such as spontaneous bleeds, arthropathy, and chronic pain – are important, the implications these have on the patient’s overall QOL should also be addressed and recorded through natural language processing and other patient-reported outcomes to better understand the impact and for furthering improvements in future treatment options. When a patient is unable to perform regular activities of daily living independently due to severe hemophilia, such as toileting and brushing his teeth, his confidence can be greatly affected. Many people struggle with a lack of autonomy and independence. This could lead to psychological symptoms of depression, anxiety, fear, and stress. Anxiety can also come from the unpredictable spontaneous bleeds, especially since this patient had far beyond the average number of annual spontaneous bleeds. There is the necessity to always be prepared in the event of a bleed and the worry of how administering intravenous prescription drugs may appear to other people due to the potentially negative perceptions and social connotations. It can be significant to address these psychological symptoms while also addressing the underlying cause.

There is a significant financial burden that comes with severe hemophilia. Though many patients have insurance to pay for treatment, this insurance comes with a notorious administrative and emotional symptom burden. Fear of coverage changes, network limitations, and claim denials is a constant concern. The medication and nursing staff to come regularly to administer certain prophylactic medications for severe hemophilia is costly and cumbersome. Patients may choose to receive physical therapy and other rehabilitative measures to address the chronic pain that comes with the disease but often do so at personal, financial, and administrative costs due to the necessity of prolonged care requirements. Due to all these expenses and burdens, insurance is usually required and comes with stressors.

Because the disease is multifaceted, the approach should also be multifaceted, addressing physical, mental, emotional, and relational aspects. In patients with severe hemophilia, it is important to see each individual patient as a whole person and not simply as a physical manifestation of the disease.

Through it all, it is imperative to foster patient resilience throughout their disease presentations. Though this specific patient has gone through many hardships due to this disease, he often emphasized that this is only one part of who he is. The patient has demonstrated admirable resilience in not letting the disease be the sole defining factor of his life. Though it has impacted his life greatly, he has been able to achieve significant personal and professional goals outside of health care. This patient paints a unique picture of a severe hemophilia case and continues to gain progressively higher achievements when it comes to function, range of motion, and QOL. He is open to trying new and cutting-edge treatments and press the envelope of what is possible for his life.

Given the small number and specificity in this population, there are limitations and room for future studies. Future studies should continue to consider the whole person and the specific biopsychosocial variables of impact for the individual; the characteristics of the individuals concerning age, weight, the joints affected, the degree of joint impairment, and the assessment; and the treatments’ characteristics. Future research should consider patients as knowledgeable colleagues and employ techniques such as natural language interviews to capture their insights into the disease and impact. There is little uniformity and high variability in the research concerning the assessment and treatment of patients with hemophilia. This study was no different as it had multiple variables to consider and, considering the small “n” of one, a network analysis or logistic regression to assess was obviously not possible. There is no rigorous evidence on assessment and the effects of the treatments in this population. Methodological quality of studies is low in general for this population, especially given the patient’s age, so present a unique opportunity for exploration. There are no studies that we know of to date that consider Hemlibra^®, a whole-person biopsychosocial natural language processing approach, innovative treatment (e.g., BFR, dry needling), or QOL in a person 65 years of age or older.

CONCLUSION

It is possible for a patient with an extremely severe phenotype of hemophilia A to have continuous improvements in QOL. This case underlines the importance of a multivariable approach to the disease.