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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EBiomarkers are important diagnostic tools that help physicians determine a patient\u0027s risk for developing a disease and can guide clinical decisions. However, at times, it is critical to understand if a specific biomarker causes disease or is merely reflective of the disease process. This distinction is important mainly if the biomarker is intended to be a therapeutic target (ie, lowering a biomarker with a drug with the hopes of lowering risk for disease). In humans, randomized controlled clinical trials and human genetics are two approaches to understand causal factors. This article discusses a human genetics approach\u2014Mendelian randomization\u2014to distinguish causal from noncausal biomarkers.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EBiomarkers are important diagnostic tools that help physicians determine a patient\u0027s risk for developing a disease and can guide clinical decisions. However, at times, it is critical to understand if a specific biomarker causes disease or is merely reflective of the disease process. This distinction is important mainly if the biomarker is intended to be a therapeutic target (ie, lowering a biomarker with a drug with the hopes of lowering risk for disease). In humans, randomized controlled clinical trials and human genetics are two approaches to understand causal factors. Sekar Kathiresan, MD, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, discussed a human genetics approach\u2014Mendelian randomization\u2014to distinguish causal from noncausal biomarkers and presented the question, \u201cWhich lipid pathways have a causal relationship for myocardial infarction?\u201d\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe leading cause of death in the world, myocardial infarction (MI), is a heritable condition [Roger VL. \u003Cem\u003ECirculation\u003C\/em\u003E 2012]. In the United States, 610,000 new MIs occur each year. Observational epidemiology studies provided the initial clues behind the mechanisms that cause MI. In the original Framingham Study that was published in 1961, increasing serum cholesterol levels were associated with increasing incidence rate per 1000 individuals [Kannel WB et al. \u003Cem\u003EAnn Int Med\u003C\/em\u003E 1961]. Since then, research has advanced the understanding of the structure and function of lipoproteins, including the presence of high-density lipoproteins (HDL), low-density lipoproteins (LDL), and the lowest density lipoproteins\u2014very LDL and chylomicrons.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIn a more recent study, the mean serum levels of LDL, HDL, and triglyceride serum levels were plotted against the hazard ratio (HR) for risk of coronary heart disease (CHD) [The Emerging Risk Factors Collaboration. \u003Cem\u003EJAMA\u003C\/em\u003E 2009]. Increasing levels of LDL were associated with an increased HR, whereas increasing HDL levels were associated with decreased HR (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Although increasing triglyceride levels appear to be associated with increased HR, when the data were adjusted for other risk factors, the relationship disappeared. Dr. Kathiresan stated that based on the information about LDL, HDL, and triglycerides, HDL was viewed as the \u201ckey protective factor\u201d in CHD, while the role of triglycerides is less clear.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Lipoprotein Association With Risk of CHD\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-697009775\u0022 data-figure-caption=\u0022Lipoprotein Association With Risk of CHD\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13671\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003ELipoprotein Association With Risk of CHD\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced from The Emerging Risk Factors Collaboration. Major Lipids, Apolipoproteins, and Risk of Vascular Disease. \u003Cem\u003EJ JAMA\u003C\/em\u003E 2009;302(18):1993\u20132000. With permission from the American Medical Association.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EDr. Kathiresan said that a causal relationship is difficult to establish based on observational epidemiology. For example, a soluble biomarker such as HDL may be demonstrated in the literature to be associated with a disease, such as MI. However, the same relationship could be demonstrated if reverse causation\u2014the disease process itself increases the soluble biomarker\u2014were true, or if a confounder was present. Epidemiological studies are not able to distinguish between causation, reverse causation, and confounders. One way to demonstrate true causality is by a randomized, controlled trial; however, it would be time consuming and expensive to do this for every potential biomarker.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EA second potential way to demonstrate causality is by human genetics through Mendelian randomization (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Hingorani A, Humphries S. \u003Cem\u003ELancet\u003C\/em\u003E 2005]. The theory behind Mendelian randomization is that the random allocation of alleles during meiosis is similar to the randomization performed in a randomized, controlled trial. Several advantages of Mendelian randomization are that genotypes are not modified by disease, thereby minimizing reverse causation, and genotypes are randomly assigned during meiosis, which minimizes confounding factors.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Comparison of a Randomized, Controlled Trial to Mendelian Randomization\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-697009775\u0022 data-figure-caption=\u0022Comparison of a Randomized, Controlled Trial to Mendelian Randomization\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13672\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EComparison of a Randomized, Controlled Trial to Mendelian Randomization\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003ECV=cardiovascular.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EReproduced from Hingorani A, Humphries S. Nature\u0027s randomised trials. \u003Cem\u003ELancet\u003C\/em\u003E 2005;366(9501):1906\u20131908. With permission from Elsevier.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003ETo evaluate a potential biomarker using Mendelian randomization, the gene variants, called \u201cinstruments,\u201d that code for the biomarker of interest are used to develop a theoretically predicted risk estimate, which is based on the amount of change in the biomarker from baseline and how that extent of biomarker change is expected to affect disease risk in a population. As a result, a disease risk can be estimated. Then, the variant can be directly associated with disease in the population and this observed risk estimate can be compared with that theoretically predicted. If the observed risk estimate matches that theoretically predicted, this would lend support to the idea that the biomarker is causal for the disease.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003ETo illustrate Mendelian randomization in MI, Dr. Kathiresan used the example of LDL cholesterol as a causal biomarker for MI. A variant of the gene PCSK9 was found in 3.2% of individuals, which resulted in a 15% decrease in serum LDL levels and a 45% decrease in CHD risk compared with individuals with wild-type PCSK9 [Cohen JC et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2006]. The gene variant is PCSK9, the biomarker is circulating LDL cholesterol levels, and the disease is CHD risk. The observed risk is the relative risk for CHD in individuals who are carriers for the PCSK9 variant compared with individuals with wild-type PCSK9 (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E). Based on the fact that the PCSK9 variant led to a 21-mg\/dL decrease in serum LDL cholesterol, one would expect carriers of this mutation to be protected from risk for CHD by 20% (theoretically predicted risk estimate OR 0.80 (range, 0.78 to 0.83). When the PCSK9 variant was directly tested for association with CHD in the population, the observed risk estimate was 28% decrease in risk for CHD. Here, as the observed risk estimate matched the theoretically predicted, Dr. Kathiresan stated these data indicate that LDL is a causal factor of CHD and suggested that inhibition of PCSK9 could lower CHD risk.\u003C\/p\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Schematic of Mendelian Randomization for the LDL Biomarker\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-697009775\u0022 data-figure-caption=\u0022Schematic of Mendelian Randomization for the LDL Biomarker\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13673\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ESchematic of Mendelian Randomization for the LDL Biomarker\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003ECHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; MI=myocardial infarction.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EReproduced with permission from S Kathiresan, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003ESeveral companies have begun development of PCSK9 inhibitors, primarily through monoclonal antibodies. In Phase 2 trials, PCSK9 monoclonal antibody injections in combination with statins result in about a 50% decrease in serum LDL cholesterol levels [Stein EA et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012; Dias CS et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2012]. Phase 3 trials evaluating the efficacy of PCSK9 inhibitors on CHD risk are currently underway.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EFor HDL cholesterol as a biomarker for CHD, a recent case-control trial evaluated a variant of LIPG, which causes serum HDL cholesterol levels to be elevated in carriers [Voight BF et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012]. The variant is present in \u22123% of individuals and results in a 6-mg\/dL increase in serum HDL cholesterol. Therefore, it would be expected that carriers of the LIPG variant would have a relative risk ratio of 0.87 (range, 0.84 to 0.91) for CHD. However, in this study of 116,320 individuals, carriers of the LIPG variant did not have a lower risk for CHD. In this study, the relative risk was 0.99 (range, 0.88 to 1.11; p=0.80). In addition, individuals with a combination of single nucleotide polymorphisms (SNPs) that raise serum HDL cholesterol also did not demonstrate a decrease in MI risk [Voight BF et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012]. Dr. Kathiresan suggested that an intervention that raises serum HDL level cannot be assumed to lead to a lower risk for MI.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EA randomized, controlled trial evaluated dalcetrapib in about 16,000 patients was halted early for futility. Although dalcetrapib raised serum HDL cholesterol by \u221230%, it did not result in a decreased risk for MI [dal-OUTCOMES; Schwartz GG et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012]. Dr. Kathiresan suggested that the reason low serum HDL cholesterol level is associated with increased MI risk is because low HDL tracks with multiple other confounding factors that are also associated with MI.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EMendelian randomization for serum triglyceride levels is more challenging than LDL and HDL, because a gene variant that affects serum triglyceride levels also affects other traits that may be important in MI. Using a novel analytical method, Dr. Kathiresan\u0027s research group has generated data that suggest that triglyceride-rich lipoproteins most likely are causal factors in CAD. He went onto describe three specific genes that alter plasma triglycerides and affect risk for CAD\u2014lipoprotein lipase, apolipoprotein A5, and apolipoprotein C3.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EAlthough traditional epidemiology can provide clues about factors that may have a causal link to a disease process, it cannot provide a definitive answer. Although randomized, controlled trials are the gold standard to establish causation, it is a challenging approach in the identification of biomarkers. Instead, Mendelian randomization appears to be a promising new approach that can accurately identify biomarkers that have a causal relationship in a disease process.\u003C\/p\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022                MANY THANKS The editors would like to thank the many members of the XXIV Congress of the ISTH presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-697009775\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;                \u0026amp;lt;strong\u0026amp;gt;MANY THANKS\u0026amp;lt;\/strong\u0026amp;gt; The editors would like to thank the many members of the XXIV Congress of the ISTH presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure4\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F4.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure4\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/6\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13674\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n            \u003Cp id=\u0022p-17\u0022 class=\u0022first-child\u0022\u003E\n               \u003Cstrong\u003EMANY THANKS\u003C\/strong\u003E The editors would like to thank the many members of the XXIV Congress of the ISTH presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/13\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznoxe\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznoxe\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}