Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Hemophilia is a rare hereditary bleeding disorder that occurs due to the absence or deficiency of coagulation factors. It typically shows increased bleeding into the joints and muscles. Repeated bleeding into joints can lead to physical disability due to hemophilic arthritis, which restricts social participation in individuals with hemophilia. With the introduction of clotting factor concentrates, proper prophylaxis, and better comprehensive care, there has been a significant improvement in the life expectancy and quality of life of hemophilia cases.1 However, with the increase in life expectancy, patients have become more likely to suffer from chronic complications of bleeding in addition to age-related comorbidities like heart disease and cancer, and the associated treatments can escalate the bleeding risk.2
Consequences of Bleeding
The main etiologies of morbidity and mortality in both severe and non-severe hemophilia cases are intracranial hemorrhage (ICH) and joint bleeding.3 Hemorrhagic stroke is the most fatal cause of bleeding.1 ICH has a mortality rate of 19% for patients with hemophilia.4 The important risk factors for ICH are the presence of an inhibitor, previous episodes of ICH, disease severity, and reported head trauma. If provided, regular prophylaxis can prevent ICH in individuals with uncomplicated severe hemophilia.1
Internal bleeding can occur in the muscles or joints in hemophilia cases, leading to the destruction of joints and ultimately knee or hip replacement in the absence of adequate treatment.1
Prophylaxis in hemophilia was first initiated in pediatric cases, however, its uses and benefits in adult cases are now well established. Prophylaxis not only reduces the risk of joint bleeds, but of ICH as well.3
Various previous studies have documented that mortality from cardiovascular diseases (CVD) in hemophilia cases is less than that of the general population. There are many conflicting studies regarding the possible protective effects of hemophilia against CVD, but the common risk factors for CVD such as hypercholesterolemia, overweight/obese body condition, hypertension, and diabetes mellitus were also noted.5
Spontaneous venous thromboembolism (VTE) is very rarely seen in hemophilia; it is usually noted in association with additional risk factors for VTE like a postoperative setting, during clotting factor replacement, or with combined underlying thrombophilia. The estimated rate of symptomatic VTEs in hemophilic cases undergoing orthopedic surgery (without pharmacologic thromboprophylaxis) is 0.5%, which is much less than the cumulative rate of 4.3% in the general population.3
The National Health and Nutrition Examination Survey (NHANES) states the prevalence of osteoporosis in males > 65 years as 5.7%. Various cross-sectional studies involving males with hemophilia > 50 years have documented the osteoporosis prevalence to be very high in all severities of disease (39% in mild, 25% in moderate, 44% in severe).3
Osteoporosis causes reduced strength of bones because of a reduction in bone mass and disruptions in the microarchitecture. This leads to fractures and contributes to chronic pain and disability, which are already important concerns for patients with hemophilia.3
In hemophilia, there is a combination of joint bleeding and hemophilic arthropathy with reduced bone density in addition to the direct effects of factors VIII and IX. Hence, many small studies have indicated a protective effect of prophylaxis with the use of clotting factor products.6
Renal disease is an age-related medical illness that affects hemophilia cases. A 50-fold rise in mortality has been documented in hemophilia cases compared to the general population because of renal failure. Various risk factors for renal failure documented in previous literature on hemophilia include hypertension, increased age, and co-infection with human immunodeficiency virus (HIV).5
The prevalence of hepatitis B surface antigen (HBsAg) positivity in severe cases of hemophilia in developed countries is now less than 3%, however, there is still a strong potential for transmission of hepatitis B through blood and its derived products. Therefore, all cases of hemophilia must be vaccinated against hepatitis B, and immunity should be monitored on a periodic basis to deliver booster doses when required.7
The prevalence of hepatitis C virus (HCV) and HIV infections are significantly greater in hemophilia cases than in the general male population, and they are considered important causes of morbidity and mortality in patients with hemophilia. It is predicted that more than 90% of hemophilia cases that were given treatment with plasma-derived factor concentrates before 1985 acquired HCV infection, and more than 55% of these cases had a co-infection with HIV.5 HCV infection was seen in all patients who were exposed to concentrates that did not undergo viral inactivation, and in more than 80% of cases, the infection turned chronic. A retrospective study involving 863 HCV-infected hemophilia cases recorded that in cases with chronic disease, after 31 years, 13% had developed end-stage liver failure and 3% suffered from hepatocellular carcinoma. A number of new well-tolerated and highly effective oral treatments against HCV have been developed that must be administered to all patients with inherited bleeding disorders. It should also be noted that treatment of HCV does not rule out the risk of hepatocellular carcinoma in cases that suffered from advanced fibrosis or cirrhosis at the time of HCV treatment.3
- Chu WM, Ho HE, Wang JD, et al. Risk of major comorbidities among workers with hemophilia: a 14-year population-based study. Medicine (Baltimore). 2018;97(6):e9803. doi:10.1097/MD.0000000000009803
- Hoots WK, Shapiro AD. Chronic complications and age-related comorbidities in people with hemophilia. UpToDate, Accessed August 2, 2021.
- Kempton CL, Makris M, Holme PA. Management of comorbidities in haemophilia. Haemophilia. 2021;27 Suppl 3:37-45. doi:10.1111/hae.14013
- Witmer C, Presley R, Kulkarni R, Soucie JM, Manno CS, Raffini L. Associations between intracranial hemorrhage and prescribed prophylaxis in a large cohort of hemophilia patients in the United States. Br J Haematol. 2011;152(2):211-216. doi:10.1111/j.1365-2141.2010.08469.x
- Khleif AA, Rodriguez N, Brown D, Escobar MA. Multiple comorbid conditions among middle-aged and elderly hemophilia patients: prevalence estimates and implications for future care. J Aging Res. 2011;2011:985703. doi:10.4061/2011/985703
- Khawaji M, Akesson K, Berntorp E. Long-term prophylaxis in severe haemophilia seems to preserve bone mineral density. Haemophilia. 2009;15(1):261-266. doi:10.1111/j.1365-2516.2008.01912.x
- Giangrande PL. Hepatitis in haemophilia.Br J Hematol. 1998;103(1):1-9. doi:10.1046/j.1365-2141.1998.00855.x
Reviewed by Kyle Habet, MD, on 8/11/2021.