11 Comorbidities in the ageing patients with hemophilia
1 Introduction
Improved treatment has extended life expectancy for PWH during the last three to four decades making them susceptible not only to complications of hemophilia, but also to age related co-morbidities same as in the general population [1–5].
Apart from the initial devastating effects on morbidity and mortality associated with the transmission of viral pathogens during the 1980’s and early 1990’s, the availability of factor concentrates, and improved treatment regimens have had a favorable influence on longevity and quality of life of PWH.
At present with only scarce evidence-based data available, little is known about how to manage these “new” concomitant illnesses in a scientific manner, apart from hemophilic arthropathy and chronic infections with HIV (human immunodeficiency virus) and HCV (hepatitis C virus).
Comorbidities like metabolic syndrome, cardiovascular and renal disease, along with infection related issues and cancer represent a series of challenges to physicians treating PWH.
Comorbidities should be managed appropriately as they may emphasize problems associated with hemophilia and impact the patient’s quality of life. Thus, expertise from specialists in e.g. cardiology, neurology, oncology, nephrology, and urology, as well as collaboration with patients’ primary care physician need to be included in the multidisciplinary team of physicians treating elderly PWH in comprehensive hemophilia care centers [6,7].
2 Current status and recommendations / managing suggestions
2.1 Joint disease
The most prominent co-morbidity in middle-aged and older PWH is irreversible joint arthropathy [1,2,8].
Recurrent hemarthroses result in initial synovial hypertrophy and neoangiogenesis further increasing the risk of bleeding and later result in degenerative changes of the joint.
This leads to limited use of the affected, often weight-bearing joint, causes pain, muscle atrophy, anchylosis (reduces range of motion), contractures and osteoporosis, the latter express by a reduced bone mineral density (BMD) or impaired bone structure.
The goal of treatment is to try to improve joint function, relieve pain and assist the patient in resuming to normal activities of daily living.
Physiotherapy is an important treatment modality to improve or maintain muscle function and joint motion, may reduce the risk of falls, and encourage an interest for an active lifestyle.
Appropriate pain management including suitable medication needs to be carried out to prevent further deterioration, but also needs to be monitored closely for side effects [9].
Lifestyle changes e.g. weight loss and regular exercise, is beneficial for joint health.
The use of secondary prophylaxis (regular treatment with factor concentrate after onset of arthropathy) reduces bleeding frequency and facilitates rehabilitation but does not alter established degenerative changes that worsen with age.
Despite adequate treatment and even in the absence of an inhibitor, target joint bleeds might require procedures, such as radiosynovectomy to control synovial hypertrophy or at times angiographic embolization to stop joint bleeding from arterial origin [9,10].
To reduce severe pain and disability arthroscopy, arthrodesis or arthroplasty are efficient interventions.
Consultations services and multidisciplinary programs with rehabilitation medicine, orthopedics and pain clinics should be an integral part of the hemophilia care team [7].
2.2 RECOMMENDATION
- To protect and improve joint function and relieve pain the use of factor prophylaxis, physiotherapy, regular exercise and when appropriate, weight loss, pain management, and orthopedic procedures are recommended.
2.3 Osteoporosis
Osteoporosis is frequently occurring in PWH [11] .
There are many predisposing factors for patients with hemophilia, such as prolonged periods of immobility, reduced weightbearing and co‐morbidities associated with bone loss [12].
Osteopenia can be prevented or reduced through a supplement of calcium, vitamin D and weight bearing exercise, while osteoporosis necessitates specialist treatment with one or several drugs including bisphosphonates, estrogens, calcitonins and monoclonal antibodies [13].
Assessment of BMD by imaging studies (DEXA scan) and laboratory evaluation are recommended as part of comprehensive hemophilia care in patients with high risk or multiple risk factors.
2.4 RECOMMENDATION
- Assessment of BMD status by imaging studies (DEXA scan) and laboratory evaluation are recommended as part of comprehensive hemophilia care.
2.5 RECOMMENDATION
- Osteopenia can be prevented or reduced by supplement of calcium, vitamin D and exercise, while osteoporosis necessitates specialist treatment with bisphosphonates, estrogens, calcitonins or monoclonal antibodies.
2.7 RECOMMENDATION
- HAART may increase the risk of metabolic syndrome, diabetes, renal insufficiency and atherosclerotic cardiovascular disease and frequency and severity of hemarthrosis, thus close laboratory monitoring and follow-up is recommended.
2.8 Metabolic syndrome
The term describes a complex of signs that increase the risk for type 2 diabetes, stroke, and coronary artery disease.
Effective prevention strategies throughout life are most important, as management of thrombotic complications in PWH is a special challenge.
Diagnostic criteria include increased body mass index (BMI) >30 kg/m2, hypertension, dyslipidemia, and hyperinsulinemia.
Middle-aged PWH have an increased risk of becoming obese and inactive due to severe arthropathy. On the other hand, high BMI has been associated with a significant limitation in range of motion, increased arthropathic pain and increased risk of developing target joints.
Lipid profile should be measured in ageing hemophilia patients at risk of CVD and treatment initiated according to the general guidelines.
Glucose levels should be checked annually, especially in those patients who are overweight.
HAART can result in hypertension, ischemic heart disease and dyslipidemia.
Patients need appropriate treatment management, regular clinical and laboratory follow-up, which should also be coordinated with the primary care physician, with consultation services from internal medicine and endocrinology as needed [15].
2.9 RECOMMENDATION
- Effective prevention strategies are necessary throughout life.
2.10 RECOMMENDATION
- Lipid profile should be measured in ageing hemophilia patients at risk of cardiovascular disease and treatment initiated according to the general guidelines. Glucose levels should be checked annually, especially in overweight patients.
2.11 Cardiovascular disease
Conflicting data exist on whether hemophilia protects against development of atherosclerosis and cardiovascular events [10,13,16,17], but there is evidence that PWH develop atherosclerosis at similar rates to those in the general population [18].
The same risk factors that affect the general population also seem to have impact on ageing PWH.
Increasing age, obesity, smoking, arterial hypertension, diabetes and dyslipidemia and inflammation contribute to cardiovascular disease.
A Clinical Practice Guidance document on antithrombotic treatment in PWH was developed by the European Hematology Association - International Society on Thrombosis and Haemostasis - European Association for Hemophilia and Allied Disorders - European Stroke Organization (EHA-ISTH-EAHAD-ESO) [19,20]. Treatment strategy should be tailored to the individual. However, a minimum trough FVIII/IX level must be maintained to allow for necessary treatment:
For single antiplatelet therapy (SAPT [aspirin or clopidogrel]) a minimum trough factor level of 1-5IU/dL is recommended.
For dual antiplatelet therapy (DAPT) or oral anticoagulation (vitamin K antagonist [VKA] with INR levels 2-3 or full dose direct oral anticoagulant [DOAC]) a minimum trough factor level of 20 IU/dL is recommended.
For triple therapy (oral anticoagulation and DAPT) a minimum trough factor level of 80 IU/dL is recommended.
Antithrombotic treatment recommendations in PWH [20] Recommended NOT recommended To individually consider therapy initiation with a baseline trough clotting factor or coagulation factor above 20 IU/dL Any thrombotic therapy in: DOACs over VKAs for oral anticoagulation given their effectiveness, safety and ease of administration for:
non-valvular atrial fibrillation
venous thromboembolism
PWH without clotting factor prophylaxis or emicizumab use
PWHA (severe and non-severe) with inhibitors not using emicizumab
PWHB with inhibitors
To actively manage anemia in association with antithrombotic treatment Empiric proton pump inhibition in all PWH on antiplatelet therapy Systemic thrombolysis is considered to be relatively contraindicated in all PWH.
Also, DDAVP (desmopressin) should be avoided as a hemostatic due to non-specific thrombogenic effects.
In PWH with acute coronary syndrome (ACS) where percutaneous cardiac intervention (PCI) is indicated:
Clotting factor supplementation with a target FVIII/FIX peak level of 80–100 IU/dL before the procedure is recommended and then 50 IU/dL for the first 24-48 hours.
Radial artery access site is preferred over femoral, to minimize retroperitoneal or groin bleeds.
Heparin can be administered according to standard cardiologic treatment protocols. Glycoprotein IIb/IIIa inhibitors used in PCI with stenting can be administered.
Newer generation drug-eluting stent (DES) is recommended as these allow the shortest DAPT time (1 month) without an increase in the risk of stent thrombosis.
When treating valvular heart disease, a material should be chosen that does not necessitate anticoagulation.
Emphasis should be made on not to “overtreat” during replacement therapy especially with bypassing agents to avoid thrombotic events. A way to avoid hazardous peak levels during substitution therapy can be achieved by administering the needed coagulation factor by continuous infusion instead of bolus injections.
Virtually no data are available for defining treatment strategies for cerebrovascular and peripheral artery disease [17].
Some recommendations are available based on case series regarding non-valvular atrial fibrillation and venous thromboembolism [21].
For atrial fibrillation, no anticoagulation, DOAC or warfarin are considered depending on basal factor levels and stroke risk.
Erectile dysfunction can be seen as the first manifestation of vascular disease and endothelial dysfunction. It can accompany the metabolic syndrome or be caused by age-related changes in hormonal, neurological and psychological function [22].
2.12 RECOMMENDATION
- PWH with cardiovascular disease should receive routine care adapted to the individual situation, in discussion with a cardiologist.
2.13 RECOMMENDATION
- Anticoagulation and antiplatelet therapies are possible with replacement therapy.
2.14 Renal disease
In young PWH, hematuria often is a benign, transient, usually idiopathic event.
In older patients this bleeding symptom can be caused by several different conditions and etiology should be evaluated [23].
In chronic renal disease uremia and anemia via platelet dysfunction increase the risk for kidney bleeding [23,24]. So does hypertension that can be caused by chronic renal disease and at the same time represents a risk factor for development of cardiovascular disease as well as cerebral hemorrhage.
HIV-associated nephropathy and immune complex glomerulonephritis, nephrotoxicity of HAART and co-infection with HCV make up a large proportion of causes for renal insufficiency.
If dialysis is needed, peritoneal dialysis could be the preferred choice since no anticoagulation is needed. This however could contain the risk for infection and peritoneal hemorrhage especially in patients co-infected with HIV and HCV [10,16,25].
For hemodialysis patients prophylactic factor dosing needs to be carefully tailored for access surgery and to allow the required anticoagulation.
2.15 RECOMMENDATION
- Etiology for recurrent hematuria should be evaluated especially in older patients.
2.16 RECOMMENDATION
- Peritoneal dialysis could be the preferred choice since no anticoagulation is needed.
2.17 Cancer
If malignancies that are a consequence of viral infection are excluded only a few clinical studies have addressed the issue of cancer in the ageing hemophilia population.
It is uncertain whether the incidence of cancer in PWH differs from that observed in the general middle-aged population [9,25].
Persons with severe hemophilia tend to have a higher rate of virus-related cancers whereas milder forms present an overweight of non-virus-related cancer types.
Attention must be drawn to the importance of prompt evaluation if a middle-aged PWH experiences new, aggravated, or recurring bleeding episodes due to a second peak of inhibitor incidence at the age of 60 and above.
Despite the increased risk of bleeding investigation and procedures should not be delayed or avoided in PWH [26]. Relevant hemostatic treatment must be given to prevent bleeds both in the setting of diagnostic interventions and later as well prior to surgical, chemo, or radiotherapeutic treatment.
One specific cancer type need mentioning since it is one of the most frequent cancers in men, with increasing frequency up to the age of 70: prostate cancer [27]. Prostate specific antigen (PSA) screening has reduced the percentage of disseminated disease at diagnosis more then 20-fold.
Despite hemostatic treatment bleeding occurs but is often mild to moderate and self-limiting.
Antifibrinolytics should be used with caution and close observation for thrombus formation in the bladder and in the upper urinary tract with the risk of developing hydronephrosis.
2.18 RECOMMENDATION
- New, aggravated or recurring bleeding episodes should be promptly investigated, and relevant hemostatic treatment must be given to prevent bleeds in the setting of diagnostic interventions and prior to surgical, chemo, or radiotherapeutic treatment.
2.19 RECOMMENDATION
- For prostate cancer diagnostics and treatment, antifibrinolytics should be used with caution.