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Semin Thromb Hemost 2013; 39(07): 794-802
DOI: 10.1055/s-0033-1354424
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Emerging Issues on Comprehensive Hemophilia Care: Preventing, Identifying, and Monitoring Age-Related Comorbidities

Antonio Coppola
1   Department of Clinical Medicine, Regional Reference Centre for Coagulation Disorders, Federico II University Hospital, Naples, Italy
,
Cristina Santoro
2   Division of Hematology, Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy
,
Massimo Franchini
3   Department of Immunohematology and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy
,
Caterina Mannucci
4   Bayer Italia, Milan, Italy
,
Selene Mogavero
5   Primula Multimedia, Pisa, Italy
,
Angelo Claudio Molinari
6   Department of Experimental and Laboratory Medicine, Regional Reference Center for Hemorrhagic Diseases, Giannina Gaslini Institute, Genoa, Italy
,
Piercarla Schinco
7   Regional Reference Center for Thrombotic and Haemorrhagic Disorders, Hemophilia Center, University Hospital S. Giovanni Battista, Torino, Italy
,
Annarita Tagliaferri
8   Department of Medicine, Regional Reference Center for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
Rita Carlotta Santoro
9   Department of Oncology and Hematology, Hemophilia Center, Hemostasis and Thrombosis Unit, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
08 September 2013 (online)

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Abstract

Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease.

Keywords

hemophilia - aging - comorbidities - comprehensive-care - check-up

Note

All the authors took part in drafting this manuscript and approved its final version.


 

  • References

  • 1 Tagliaferri A, Rivolta GF, Iorio A , et al; Italian Association of Hemophilia Centers. Mortality and causes of death in Italian persons with haemophilia, 1990-2007. Haemophilia 2010; 16 (3) 437-446
    PubMedSearch in Google Scholar
  • 2 Coppola A, Tagliaferri A, Franchini M. The management of cardiovascular diseases in patients with hemophilia. Semin Thromb Hemost 2010; 36 (1) 91-102
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Dolan G. The challenge of an ageing haemophilic population. Haemophilia 2010; 16 (Suppl. 05) 11-16
    CrossrefPubMedSearch in Google Scholar
  • 4 Dunn AL. Malignancy in patients with haemophilia: a review of the literature. Haemophilia 2010; 16 (3) 427-436
    PubMedSearch in Google Scholar
  • 5 Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol 2010; 148 (4) 522-533
    CrossrefPubMedSearch in Google Scholar
  • 6 Mannucci PM, Schutgens RE, Santagostino E, Mauser-Bunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114 (26) 5256-5263
    CrossrefPubMedSearch in Google Scholar
  • 7 Tagliaferri A, Di Perna C, Santoro C , et al; Italian Association of Hemophilia Centers. Cancers in patients with hemophilia: a retrospective study from the Italian Association of Hemophilia Centers. J Thromb Haemost 2012; 10 (1) 90-95
    CrossrefPubMedSearch in Google Scholar
  • 8 Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC, Biesma DH, Schutgens RE. Cardiovascular disease in patients with hemophilia. J Thromb Haemost 2009; 7 (2) 247-254
    CrossrefPubMedSearch in Google Scholar
  • 9 Biere-Rafi S, Zwiers M, Peters M , et al. The effect of haemophilia and von Willebrand disease on arterial thrombosis: a systematic review. Neth J Med 2010; 68 (5) 207-214
    PubMedSearch in Google Scholar
  • 10 Fabri DR, de Paula EV, Costa DS, Annichino-Bizzacchi JM, Arruda VR. Novel insights into the development of atherosclerosis in hemophilia A mouse models. J Thromb Haemost 2011; 9 (8) 1556-1561
    CrossrefPubMedSearch in Google Scholar
  • 11 Foley CJ, Nichols L, Jeong K, Moore CG, Ragni MV. Coronary atherosclerosis and cardiovascular mortality in hemophilia. J Thromb Haemost 2010; 8 (1) 208-211
    CrossrefPubMedSearch in Google Scholar
  • 12 Khallou-Laschet J, Caligiuri G, Tupin E , et al. Role of the intrinsic coagulation pathway in atherogenesis assessed in hemophilic apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2005; 25 (8) e123-e126
    CrossrefPubMedSearch in Google Scholar
  • 13 Zwiers M, Lefrandt JD, Mulder DJ , et al. Coronary artery calcification score and carotid intima–media thickness in patients with hemophilia. J Thromb Haemost 2012; 10 (1) 23-29
    CrossrefPubMedSearch in Google Scholar
  • 14 Fransen van de Putte DE, Fischer K, Makris M , et al. History of non-fatal cardiovascular disease in a cohort of Dutch and British patients with haemophilia. Eur J Haematol 2012; 89 (4) 336-339
    CrossrefPubMedSearch in Google Scholar
  • 15 Biere-Rafi S, Baarslag MA, Peters M , et al. Cardiovascular risk assessment in haemophilia patients. Thromb Haemost 2011; 105 (2) 274-278
    PubMedSearch in Google Scholar
  • 16 Fransen van de Putte DE, Fischer K, Makris M , et al. Increased prevalence of hypertension in haemophilia patients. Thromb Haemost 2012; 108 (4) 750-755
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Kulkarni R, Soucie JM, Evatt BL. Hemophilia Surveillance System Project Investigators. Prevalence and risk factors for heart disease among males with hemophilia. Am J Hematol 2005; 79 (1) 36-42
    CrossrefPubMedSearch in Google Scholar
  • 18 Lim MY, Pruthi RK. Cardiovascular disease risk factors: prevalence and management in adult hemophilia patients. Blood Coagul Fibrinolysis 2011; 22 (5) 402-406
    CrossrefPubMedSearch in Google Scholar
  • 19 Ragni MV, Moore CG. Atherosclerotic heart disease: prevalence and risk factors in hospitalized men with haemophilia A. Haemophilia 2011; 17 (6) 867-871
    CrossrefPubMedSearch in Google Scholar
  • 20 Rosendaal FR, Varekamp I, Smit C , et al. Mortality and causes of death in Dutch haemophiliacs, 1973-86. Br J Haematol 1989; 71 (1) 71-76
    CrossrefPubMedSearch in Google Scholar
  • 21 Sharathkumar AA, Soucie JM, Trawinski B, Greist A, Shapiro AD. Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US). Haemophilia 2011; 17 (4) 597-604
    CrossrefPubMedSearch in Google Scholar
  • 22 Siboni SM, Mannucci PM, Gringeri A , et al; Italian Association of Haemophilia Centres (AICE). Health status and quality of life of elderly persons with severe hemophilia born before the advent of modern replacement therapy. J Thromb Haemost 2009; 7 (5) 780-786
    CrossrefPubMedSearch in Google Scholar
  • 23 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285 (19) 2486-2497
    CrossrefPubMedSearch in Google Scholar
  • 24 Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States. Natl Health Stat Report 2009; 13: 1-7
    PubMedSearch in Google Scholar
  • 25 Girolami A, Ruzzon E, Fabris F, Varvarikis C, Sartori R, Girolami B. Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature. Acta Haematol 2006; 116 (2) 120-125
    CrossrefPubMedSearch in Google Scholar
  • 26 Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18 (3) e173-e187
    CrossrefPubMedSearch in Google Scholar
  • 27 Sklar P, Masur H. HIV infection and cardiovascular disease-is there really a link?. N Engl J Med 2003; 349 (21) 2065-2067
    CrossrefPubMedSearch in Google Scholar
  • 28 Lim MY, Pruthi RK. Impact of lifestyle modification on symptomatic coronary artery disease in a haemophilia patient with inhibitors. Haemophilia 2011; 17 (6) e1006-e1007
    CrossrefPubMedSearch in Google Scholar
  • 29 Conroy RM, Pyörälä K, Fitzgerald AP , et al; SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24 (11) 987-1003
    CrossrefPubMedSearch in Google Scholar
  • 30 D'Agostino Sr RB, Vasan RS, Pencina MJ , et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117 (6) 743-753
    CrossrefPubMedSearch in Google Scholar
  • 31 Heald CL, Fowkes FG, Murray GD, Price JF. Ankle Brachial Index Collaboration. Risk of mortality and cardiovascular disease associated with the ankle-brachial index: systematic review. Atherosclerosis 2006; 189 (1) 61-69
    CrossrefPubMedSearch in Google Scholar
  • 32 Simon A, Megnien JL, Chironi G. The value of carotid intima-media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol 2010; 30 (2) 182-185
    CrossrefPubMedSearch in Google Scholar
  • 33 Mauser-Bunschoten EP, Fransen Van De Putte DE, Schutgens RE. Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy. Haemophilia 2009; 15 (4) 853-863
    CrossrefPubMedSearch in Google Scholar
  • 34 Soucie JM, Nuss R, Evatt B , et al; The Hemophilia Surveillance System Project Investigators. Mortality among males with hemophilia: relations with source of medical care. Blood 2000; 96 (2) 437-442
    PubMedSearch in Google Scholar
  • 35 Kulkarni R, Soucie JM, Evatt B. Hemophilia Surveillance System Project Investigators. Renal disease among males with haemophilia. Haemophilia 2003; 9 (6) 703-710
    CrossrefPubMedSearch in Google Scholar
  • 36 Prentice CR, Lindsay RM, Barr RD , et al. Renal complications in haemophilia and Christmas disease. Q J Med 1971; 40 (157) 47-61
    PubMedSearch in Google Scholar
  • 37 Walsh M, Macgregor D, Stuckless S, Barrett B, Kawaja M, Scully MF. Health-related quality of life in a cohort of adult patients with mild hemophilia A. J Thromb Haemost 2008; 6 (5) 755-761
    CrossrefPubMedSearch in Google Scholar
  • 38 Ewenstein BM, Takemoto C, Warrier I , et al. Nephrotic syndrome as a complication of immune tolerance in hemophilia B. Blood 1997; 89 (3) 1115-1116
    PubMedSearch in Google Scholar
  • 39 Lambing A, Kuriakose P, Lanzon J, Kachalsky E. Dialysis in the haemophilia patient: a practical approach to care. Haemophilia 2009; 15 (1) 33-42
    CrossrefPubMedSearch in Google Scholar
  • 40 Solak Y, Turkmen K, Atalay H, Turk S. Successful peritoneal dialysis in a hemophilia A patient with factor VIII inhibitor. Perit Dial Int 2010; 30 (1) 114-116
    CrossrefPubMedSearch in Google Scholar
  • 41 Araujo AB, Wittert GA. Endocrinology of the aging male. Best Pract Res Clin Endocrinol Metab 2011; 25 (2) 303-319
    CrossrefPubMedSearch in Google Scholar
  • 42 Gianotten WL, Heijnen L. Haemophilia, aging and sexuality. Haemophilia 2009; 15 (1) 55-62
    CrossrefPubMedSearch in Google Scholar
  • 43 Bar-Chama N, Snyder S, Aledort L. Sexual evaluation and treatment of ageing males with haemophilia. Haemophilia 2011; 17 (6) 875-883
    CrossrefPubMedSearch in Google Scholar
  • 44 Annon JS. The PLISSIT model: a proposed conceptual scheme for the behavioral treatment of sexual problems. J Sex Educ Ther 1976; 2: 1-15
    PubMedSearch in Google Scholar
  • 45 Dune T. Sexual expression, fulfilment and haemophilia: reflections from the 16th Australian and New Zealand Haemophilia Conference. Haemophilia 2012; 18 (3) e138-e139
    CrossrefPubMedSearch in Google Scholar
  • 46 Parish KL. Sexuality and haemophilia: connections across the life-span. Haemophilia 2002; 8 (3) 353-359
    CrossrefPubMedSearch in Google Scholar
  • 47 Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 2010; 19 (8) 1893-1907
    CrossrefPubMedSearch in Google Scholar
  • 48 UK Statistics Authority. UK national statistics. Office for National Statistics. Available at: http://www.statisticsauthority.gov.uk/ . Accessed March 12, 2013
    PubMed
  • 49 Miesbach W, Alesci S, Krekeler S, Seifried E. Comorbidities and bleeding pattern in elderly haemophilia A patients. Haemophilia 2009; 15 (4) 894-899
    CrossrefPubMedSearch in Google Scholar
  • 50 Darby SC, Kan SW, Spooner RJ , et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110 (3) 815-825
    CrossrefPubMedSearch in Google Scholar
  • 51 Franchini M, Lippi G, Montagnana M , et al. Hemophilia and cancer: a new challenge for hemophilia centers. Cancer Treat Rev 2009; 35 (4) 374-377
    CrossrefPubMedSearch in Google Scholar
  • 52 Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995; 123 (11) 823-827
    CrossrefPubMedSearch in Google Scholar
  • 53 Walker IR, Julian JA. Association of Hemophilia Clinic Directors of Canada. Causes of death in Canadians with haemophilia 1980-1995. Haemophilia 1998; 4 (5) 714-720
    CrossrefPubMedSearch in Google Scholar
  • 54 Marcucci F, Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2011; 117 (6) 1792-1798
    CrossrefPubMedSearch in Google Scholar
  • 55 Rabkin CS, Hilgartner MW, Hedberg KW , et al. Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia. JAMA 1992; 267 (8) 1090-1094
    CrossrefPubMedSearch in Google Scholar
  • 56 Ragni MV, Belle SH, Jaffe RA , et al. Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas and other malignancies in patients with hemophilia. Blood 1993; 81 (7) 1889-1897
    PubMedSearch in Google Scholar
  • 57 Philipp C. The aging patient with hemophilia: complications, comorbidities, and management issues. Hematology (Am Soc Hematol Educ Program) 2010; 2010: 191-196
    CrossrefPubMedSearch in Google Scholar
  • 58 Miesbach W, Seifried E. Does haemophilia influence cancer-related mortality in HIV-negative patients?. Haemophilia 2011; 17 (1) 55-60
    CrossrefPubMedSearch in Google Scholar
  • 59 Tradati F, Colombo M, Mannucci PM , et al; The Study Group of the Association of Italian Hemophilia Centers. A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. Blood 1998; 91 (4) 1173-1177
    PubMedSearch in Google Scholar
  • 60 Park JS, Saraf N, Dieterich DT. HBV plus HCV, HCV plus HIV, HBV plus HIV. Curr Gastroenterol Rep 2006; 8 (1) 67-74
    CrossrefPubMedSearch in Google Scholar
  • 61 Konkle BA, Kessler C, Aledort L , et al. Emerging clinical concerns in the ageing haemophilia patient. Haemophilia 2009; 15 (6) 1197-1209
    CrossrefPubMedSearch in Google Scholar
  • 62 Noda I, Kitamoto M, Nakahara H , et al. Regular surveillance by imaging for early detection and better prognosis of hepatocellular carcinoma in patients infected with hepatitis C virus. J Gastroenterol 2010; 45 (1) 105-112
    CrossrefPubMedSearch in Google Scholar
  • 63 Santagostino E, Colombo M, Rivi M , et al; Study Group of the Association of Italian Hemophilia Centers. A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus. Blood 2003; 102 (1) 78-82
    CrossrefPubMedSearch in Google Scholar
  • 64 Hoffman RM. Clinical practice. Screening for prostate cancer. N Engl J Med 2011; 365 (21) 2013-2019
    CrossrefPubMedSearch in Google Scholar
  • 65 Bretthauer M. Colorectal cancer screening. J Intern Med 2011; 270 (2) 87-98
    CrossrefPubMedSearch in Google Scholar
  • 66 Cummings LC, Cooper GS. Colorectal cancer screening: update for 2011. Semin Oncol 2011; 38 (4) 483-489
    CrossrefPubMedSearch in Google Scholar
  • 67 Babjuk M, Oosterlinck W, Sylvester R , et al; European Association of Urology (EAU). EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011; 59 (6) 997-1008
    CrossrefPubMedSearch in Google Scholar
  • 68 Rodeghiero F, Stasi R, Gernsheimer T , et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113 (11) 2386-2393
    CrossrefPubMedSearch in Google Scholar
  • 69 Stasi R. How to approach thrombocytopenia. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 191-197
    PubMedSearch in Google Scholar
  • 70 Provan D, Stasi R, Newland AC , et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (2) 168-186
    CrossrefPubMedSearch in Google Scholar
  • 71 Neunert C, Lim W, Crowther M, Cohen A, Solberg Jr L, Crowther MA. American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117 (16) 4190-4207
    CrossrefPubMedSearch in Google Scholar
  • 72 Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011; 9 (9) 1713-1723
    CrossrefPubMedSearch in Google Scholar
  • 73 Tripodi A. Hemostasis abnormalities in liver cirrhosis: myth or reality?. Pol Arch Med Wewn 2008; 118 (7-8) 445-448
    PubMedSearch in Google Scholar
  • 74 Riordan MF, Hill FG. Atypical bleeding due to idiopathic thrombocytopenia in association with low factor VIII levels. Arch Dis Child 2002; 87 (3) 227-228
    CrossrefPubMedSearch in Google Scholar
  • 75 Siboni SM, Zanon E, Sottilotta G , et al. Central nervous system bleeding in patients with rare bleeding disorders. Haemophilia 2012; 18 (1) 34-38
    PubMedSearch in Google Scholar
  • 76 Zanon E, Iorio A, Rocino A , et al; Italian Association of Hemophilia Centers. Intracranial haemorrhage in the Italian population of haemophilia patients with and without inhibitors. Haemophilia 2012; 18 (1) 39-45
    PubMedSearch in Google Scholar
  • 77 Witmer CM, Raffini LJ, Manno CS. Utility of computed tomography of the head following head trauma in boys with haemophilia. Haemophilia 2007; 13 (5) 560-566
    CrossrefPubMedSearch in Google Scholar
  • 78 Klinge J, Auberger K, Auerswald G, Brackmann HH, Mauz-Körholz C, Kreuz W. Prevalence and outcome of intracranial haemorrhage in haemophiliacs—a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr 1999; 158 (Suppl. 03) S162-S165
    CrossrefPubMedSearch in Google Scholar
  • 79 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
    PubMedSearch in Google Scholar
  • 80 Iannone M, Pennick L, Tom A , et al. Prevalence of depression in adults with haemophilia. Haemophilia 2012; 18 (6) 868-874
    CrossrefPubMedSearch in Google Scholar
  • 81 Copeland JR, Beekman AT, Braam AW , et al. Depression among older people in Europe: the EURODEP studies. World Psychiatry 2004; 3 (1) 45-49
    PubMedSearch in Google Scholar
  • 82 Dalle Carbonare L, Maggi S, Noale M , et al; ILSA Working Group; The Italian Longitudinal Study on Aging (ILSA). Physical disability and depressive symptomatology in an elderly population: a complex relationship. Am J Geriatr Psychiatry 2009; 17 (2) 144-154
    CrossrefPubMedSearch in Google Scholar
  • 83 Minicuci N, Maggi S, Pavan M, Enzi G, Crepaldi G. Prevalence rate and correlates of depressive symptoms in older individuals: the Veneto Study. J Gerontol A Biol Sci Med Sci 2002; 57 (3) M155-M161
    CrossrefPubMedSearch in Google Scholar
  • 84 Clifford DB. HIV-associated neurocognitive disease continues in the antiretroviral era. Top HIV Med 2008; 16 (2) 94-98
    PubMedSearch in Google Scholar
  • 85 Purohit V, Rapaka R, Shurtleff D. Drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. Mol Neurobiol 2011; 44 (1) 102-110
    CrossrefPubMedSearch in Google Scholar
  • 86 Gannon P, Khan MZ, Kolson DL. Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol 2011; 24 (3) 275-283
    CrossrefPubMedSearch in Google Scholar
  • 87 Spudich SS, Ances BM. Central nervous system complications of HIV infection. Top Antivir Med 2011; 19 (2) 48-57
    PubMedSearch in Google Scholar
  • 88 Yesavage JA, Brink TL, Rose TL , et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982– 1983; 17 (1) 37-49
    PubMedSearch in Google Scholar
  • 89 Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12 (3) 189-198
    CrossrefPubMedSearch in Google Scholar
  • 90 von Mackensen S, Bullinger M. Haemo-QoL Group. Development and testing of an instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL). Haemophilia 2004; 10 (Suppl. 01) 17-25
    PubMedSearch in Google Scholar
  • 91 von Mackensen S, Gringeri A, Siboni SM, Mannucci PM. Italian Association Of Haemophilia Centres (AICE). Health-related quality of life and psychological well-being in elderly patients with haemophilia. Haemophilia 2012; 18 (3) 345-352
    CrossrefPubMedSearch in Google Scholar
  • 92 Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16 (9) 606-613
    CrossrefPubMedSearch in Google Scholar
  • 93 Lambing A, Kuriakose P, Kachalsky E. Liver transplantation in the haemophilia patient. Haemophilia 2012; 18 (2) 300-303
    CrossrefPubMedSearch in Google Scholar
  • 94 Hay CR, Palmer B, Chalmers E , et al; United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO). Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood 2011; 117 (23) 6367-6370
    CrossrefPubMedSearch in Google Scholar
  • 95 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38 (1) 79-94
    Thieme ConnectPubMedSearch in Google Scholar