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2009 114: 750-751 doi:10.1182/blood-2009-04-217075

Is VIII worse than IX?

Michael Makris

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absolute terms, the presence of MGUS when employed with the standard electrophoretic techniques, in rst-degree relatives 80 years and older, is 13% compared with 7% in a reference population. This increase of MGUS in their investigation was found across both genders as well as in all ages of relatives 40 and older. Therefore, their ndings provide valuable evidence of a familial aggregation of MGUS and MM, and certainly answers the concept that shared genes and their environment are crucial for development of MM or MGUS among relatives. Recently in this journal, Kristinsson et al investigated genetic factors in the etiology of lymphoplasmacytic lymphoma/Waldenstroms macroglobulinimia (LPL/WM).8 They identied 2144 LPL/WM patients (1539 WM [72%] and 605 LPL [28%]) who were diagnosed in Sweden, 8379 matched controls and their linkable rst-degree relatives (n 6177 for the patient group and n 24 609 for the control group). The rst-degree relatives of LPL/WM patients were found to have 20-fold (4.1-98.4), 3.0-fold (2.04.4), 3.4-fold (1.7-6.6) and 5.0-fold (1.3-18.9) increased risk of developing LPL/WM, nonHodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and MGUS, respectively. However, there was no evidence of an increased risk of developing multiple myeloma or Hodgkin lymphoma.8 They concluded that their ndings of highly increased risk of developing LPL/WM, NHL, CLL, and MGUS support the operation of shared susceptibility genes that predispose to LPL/WM and other lymphoproliferative disorders.8 Also in this issue, Vachon and colleagues found, perhaps for the rst time, a clinically and statistically signicant increase in the prevalence of MGUS by screening rstdegree relatives of patients with MGUS or multiple myeloma when compared with a well-characterized reference population.9 First-degree family members of an MGUS- or MM-affected individual have at least a 2-fold greater risk of MGUS when compared with general population rates. These ndings support a heritable genetic predisposition for the occurrence of MGUS. We have recently published a study on an African American family prone to myeloma with an association with prostate cancer (see gure).2 Noteworthy and consistent with some of our other observations is the fact that multiple cases of MGUS and prostate cancer as
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well as a smaller number of colon and pancreas cancers occurred in the direct lineage of MMaffected family members. In a subsequent New England Journal of Medicine issue, we responded to a group from Utah that showed evidence that prostate cancer may well be integral to the spectrum of familial MM.12,13 What does this mean clinically? First, MGUS is not rare. It affects more than 3% of the general population over the age of 50 and harbors a lifelong increased risk of multiple myeloma or related malignancy. However, what kind of related malignancy might be involved? In hereditary cancer research, it is always essential to examine cancer of all anatomic sites in a family because the pattern of cancer may aid signicantly in a hereditary cancer syndrome diagnosis. Clearly, it will also indicate the need to screen and manage those cancers that constitute a particular hereditary syndrome. As mentioned, our research on multiple myeloma has disclosed differing solid tumors and hematologic malignancies, suggesting marked heterogeneity in the genetics of this disease.4 For example, we identied prostate cancer occurring in apparent excess in association with MGUS and multiple myeloma in an African American family.2 Evidence has emerged supporting the existence of a genetic predisposition that affects the incidence of monoclonal gammopathies,3,4,7,10 which is reinforced by ndings in multigenerational families wherein multiple cases of MM and MGUS favored the possibility of a shared cancer-susceptibility locus.11 These studies of MM-prone families indicate that MGUS is perhaps the single best marker of a putative hereditary family, particularly when it segregates with cancer.2,4
CLINICAL TRIALS

Conict-of-interest disclosure: The authors declare no competing nancial interests.

REFERENCES
1. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined signicance. N Engl J Med. 2006;354:1362-1369. 2. Lynch HT, Ferrara K, Barlogie B, et al. Familial myeloma. N Engl J Med. 2008;359:152-157. 3. Lynch HT, Sanger WG, Pirruccello S, et al. Familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst. 2001;93:1479-1483. 4. Lynch HT, Watson P, Tarantolo S, et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol. 2005;23:685-693. 5. Landgren O, Kristinsson SY, Goldin LR, et al. Risk of plasma cell and lymphoproliferative disorders among 14 621 rst-degree relatives of 4458 patients with monoclonal gammopathy of undetermined signicance in Sweden. Blood. 2009;114:791-795. 6. Bizzaro N, Pasini P. Familial occurrence of multiple myeloma and monoclonal gammopathy of undetermined signicance in 5 siblings. Haematologica. 1990;75:58-63. 7. Sandstrom H, Wahlin A, Eriksson M, Bergstrom I, Wickramasinghe SN. Intravascular haemolysis and increased prevalence of myeloma and monoclonal gammopathy in congenital dyserythropoietic anaemia, type III. Eur J Haematol. 1994;52:42-46. 8. Kristinsson SY, Bjorkholm M, Goldin LR, et al. Risk of lymphoproliferative disorders among rst-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood. 2008;112:3052-3056. 9. Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in rst-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined signicance. Blood. 2009;114:785-790. 10. Axelsson U, Bachmann R, Hallen J. Frequency of pathological proteins (M-components) om 6,995 sera from an adult population. Acta Med Scand. 1966;179:235-247. 11. Turesson I, Linet MS, Bjorkholm M, et al. Ascertainment and diagnostic accuracy for hematopoietic lymphoproliferative malignancies in Sweden 1964 2003. Int J Cancer. 2007;121:2260-2266. 12. Lynch HT, Thome S. Familial myeloma. N Engl J Med. 2008;359:1735. 13. Camp NJ, Werner TL, Cannon-Albright LA. Familial myeloma. N Engl J Med. 2008;359:1734-1735.

Comment on Tagariello et al, page 779

Is VIII worse than IX? ---------------------------------------------------------------------------------------------------------------Michael Makris

UNIVERSITY OF SHEFFIELD

In this issue of Blood, Tagariello and colleagues report that patients with severe hemophilia A are more likely to undergo hip or knee arthroplasty than those with severe hemophilia B and suggest that there is a difference in the severity of the 2 hemophilias.

raditional teaching has been that the clinical manifestations of hemophilia A and B are identical and cannot be differentiated without measurement of the specic FVIII

and IX clotting factor activities. However, the possibility that hemophilia B is a milder disease was proposed 50 years ago by Quick, who based his opinion on his personal experience
23 JULY 2009 I VOLUME 114, NUMBER 4

blood

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with 24 hemophilia B patients diagnosed in his department at a time prior to the availability of clotting factor concentrates.1 Quicks suggestion has been supported by some more recent data. In a preliminary Canadian report, adult severe hemophilia B patients were found to have had 35% fewer bleeds than severe hemophilia A patients,2 while a second Canadian study, on virtually the whole of the Canadian hemophilia population, reported that signicantly more severe hemophilia A patients used prophylaxis (69%) compared with severe hemophilia B patients (32%). The effect was most pronounced in those under 2 years of age but was noted at every age group, including those over the age of 50.3 A higher bleed frequency for hemophilia A and subsequently hemophilia severity score was also observed by Schulman and colleagues in Sweden, but the number of severe patients in the derivation cohort was relatively small at 43 individuals.4 The study by Tagariello et al in this issue describes a 3-fold higher frequency of joint arthroplasty in patients with hemophilia A compared with hemophilia B of the same severity, dened as a coagulation factor level of 1 U/dL. This difference was not due to confounders such as age, HIV or hepatitis C infections, or the presence of an inhibitor.5 The data reported were retrospective but covered the whole of the Italian hemophilic population, a major strength of the study. The authors also performed a systematic review of published hemophilia arthroplasty series and found that in the 7 other series, 147 (91.3%) of the 161 patients with hemophilia undergoing joint arthroplasty had hemophilia A. Although these other series did not report the total number of patients registered in their centers, this proportion is signicantly higher than expected from the proportion of hemophilia A patients in the large comprehensive registries (84% in Canada, the United Kingdom, and Italy).5 A potential criticism of this study is that joint arthroplasty is an end-stage event and a surrogate of severity. The frequency of bleeds would have been a better variable to compare in the 2 hemophilias, but this information was not available. Heterogeneity in the treatment of bleeds or referral for arthroplasty could have inuenced the results, but it is not obvious why these would have varied by hemophilia type. Furthermore, it is not known if the lack of FVIII (compared with IX) results in more bleeds, if the bleeds respond less well to

treatment, or if the bleeds are more severe or more destructive. An important issue that could potentially explain the results is that severe hemophilia A and B are currently dened on the basis of a clotting factor level of 1 U/dL6 and not on the phenotype. The accuracy of the commonly used clotting assays at these low levels has been questioned.7 It is also well recognized that patients with severe disease with clotting factors of 1 U/dL show heterogeneity in the phenotype in terms of bleed frequency as well as in their thrombin-generating capacity.8 It is likely that the group of 1 U/dL patients contains individuals with truly no VIII/IX activity, as well as some with low but detectable activity. If the proportion of these was different for the 2 hemophilias, it could have inuenced the results. Tagariello et al tried to address this issue by comparing the patient groups with genetic defects likely to result in absent clotting factor and those with less disrupting defects but found no difference in the arthroplasty rate. At present, it is reasonable to conclude that when dening the 2 severe hemophilias in the same way as 1 U/dL level, there appears to be a difference in the bleeding phenotype. The Tagariello study does not give us the denitive answer but does suggest that the observation is true. This will undoubtedly be the start of a new avenue to rstly reproduce and conrm these ndings in other cohorts and to try to
IMMUNOBIOLOGY

explain the pathophysiology of this observation. Conict-of-interest disclosure: The author declares no competing nancial interests.

REFERENCES
1. Quick AJ, Hussey CV. Hemophilia B (PTC deciency, or Christmas disease). AMA Arch Intern Med. 1959;103: 762-775. 2. Pai KM, Walker I, Almonte T, et al. Comparing bleed frequency and factor concentrate use between haemophilia A and haemophilia B [abstract]. J Thromb Haemost. 2005; 3(suppl 1). Abstract P0807. 3. Biss TT, Chan AK, Blanchette VS, et al for the association of hemophilia clinic directors of Canada (AHCDC) and the Canadian association of nurses in hemophilia care (CANHC). The use of prophylaxis in 2663 children and adults with haemophilia: results of the 2006 Canadian national haemophilia prophylaxis survey. Haemophilia. 2008;14:923-930. 4. Schulman S, Eelde A, Holmstrom M, et al. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost. 2008;6:1113-1121. 5. Tagariello G, Iorio A, Santagostino E, et al. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deciency: an index of different clinical severity of the 2 coagulation disorders. Blood. 2009;114: 779-784. 6. White GC, Rosendaal F, Aledort LM, et al. Denitions in hemophilia. Recommendation of the scientic and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001; 85:560. 7. Preston FE, Kitchen S, Jennings I, Woods TA, Makris M. SSC/ISTH classication of hemophilia A: can hemophilia center laboratories achieve the new criteria? J Thromb Haemost. 2004;2:271-274. 8. Dargaud Y, Beguin S, Lienhardt A, et al. Evaluation of thrombin generation capacity in plasma from patients with haemophilia A and B. Thromb Haemost. 2005;93:475-480.

Comment on Beq et al, page 816

Where have all the T cells gone? ---------------------------------------------------------------------------------------------------------------Irini Sereti

NATIONAL INSTITUTES OF HEALTH

In this issue of Blood, Beq and colleagues describe the massive yet transient exodus of T cells from peripheral blood to lymph nodes, skin, and gut lymphoid tissue after in vivo IL-7 administration to healthy Rhesus macaques.1 This dramatic brief T-cell lymphopenia has previously been described in both cancer and HIV clinical trials of rhIL-7.2,3 Tissue redistribution of T lymphocytes had been invoked to explain this unusual occurrence but there was no data supporting this hypothesis until now.

eq et al follow healthy Rhesus macaques after administration of recombinant simian (rs) interleukin (IL)7 with repeat sampling of peripheral blood and tissues, measuring apoptosis, expression of chemokine receptors in CD4 and CD8 T-cell subsets, and

chemokine levels in tissues and plasma. Their results show lack of increased apoptosis after rsIL-7 administration but signicant upregulation of homing chemokine receptors on T cells including CXCR4, CCR6, and CCR9 coupled with increased chemokine levels in
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blood 2 3 J U L Y 2 0 0 9 I V O L U M E 1 1 4 , N U M B E R 4