Towards achieving a haemophilia-free mind.

Guidelines for the prophylaxis of haemophilia A and B: new horizons and ambitions.

General pediatricians are usually not familiar with the treatment and management of patients with bleeding disorders. Hemophilia is the most common severe coagulation factor deficiency. Early recognition of this condition and adequate understanding of its management are of extreme importance to prevent treatment- and condition-specific complications that lead to the development of chronic disabilities in children. Pediatricians must be aware of the role that comprehensive hemophilia treatment centers play for these patients and the need to establish a multidisciplinary model as the gold standard for hemophilia management.After completing this article, readers should be able to: Hemophilia A and B are inherited bleeding disorders characterized by the partial or complete deficiency of circulating coagulation factors VIII (FVIII) or IX (FIX), respectively. The hallmark of severe hemophilia is the presence of recurrent, spontaneous, prolonged, and abnormal bleeding episodes primarily involving soft tissues and synovial joints.Hemophilia A, or classical hemophilia, has been described since ancient times. The earliest documentation is found in the Talmud, a collection of Jewish law writings, from the fourth century. These manuscripts state that infant boys were exempt from the covenant of circumcision if 2 previous sons from the same mother had died due to severe bleeding associated with the procedure. (1) In 1803, John Conrad Otto was the first physician to report a hemorrhagic disorder, characterized by joint and muscle bleeds, that exclusively affected males in the same family. It was not until 1828 that Friedrich Hopff, a student at the University of Zurich, and his professor, Dr Schonlein, used the term haemorrhaphilia for patients presenting with this constellation of symptoms. (1)Hemophilia has often been called "the royal disease" because several members of the European royal family were affected by the condition. Queen Victoria of England, the most famous hemophilia carrier, passed the condition to several of her own children, spreading the disorder to other European royal families. The most renowned case is Tsarevich Alexei, son of the Russian Czar Nicholas II. Today, we know that this royal disease was in fact hemophilia B. Hemophilia B is also known as Christmas disease after Stephen Christmas, the first person described with the condition in 1952. (1)Hemophilia A is 4 times more common than hemophilia B, comprising 80% of all hemophilia cases. The estimated prevalence of hemophilia A is approximately 1 in 5,000 male live births (2)(3) and of hemophilia B is 1 in 30,000 male live births. Hemophilia affects all ethnic and racial groups. A recent meta-analysis estimated that there are approximately 1,125,00 males living with hemophilia worldwide, of whom approximately 418,000 have severe hemophilia. (4)(5)(6) It has also been reported that in the United States the prevalence of severe disease is approximately 50% for patients with hemophilia A compared with approximately 30% for patients with hemophilia B. (7)(8)(9)Abnormal bleeding can occur when specific components of the hemostatic system are missing or dysfunctional. Hemostasis is the sequential and self-regulated physiologic process beginning as soon as a tissue or blood vessel injury occurs. Normal hemostasis produces formation of a stable platelet-fibrin clot that stops bleeding while maintaining normal blood flow. Vasoconstriction at the site of vessel injury is the initial step. This is followed by "primary hemostasis," when an initial, but unstable, platelet clot gets formed through the adhesion, activation, and aggregation of platelets on the damaged vascular endothelium. Primary hemostasis relies on an adequate quantity of functionally normal von Willebrand factor (VWF). Stabilization of the platelet plug through the formation of a covalently cross-linked fibrin-platelet clot occurs during "secondary hemostasis." Secondary hemostasis consists of the activation of all coagulation factors in the coagulation cascade (Fig 1). Within the cascade, FVIII and FIX form an enzymatic complex with coagulation factor X (FX), producing activated FX, which ultimately induces a "thrombin burst," facilitating the formation of the fibrin-platelet clot.Regulation of the hemostatic process occurs through fibrinolysis. Fibrinolysis consists of dissolving the formed clot after the wound-healing process is completed, thereby preventing the formation of a thrombus in otherwise normal blood vessels. Components of the fibrinolytic system include antithrombin, tissue factor pathway inhibitor (TFPI), protein C, and protein S. (10)In hemophilia, a partial or complete deficiency of either FVIII or FIX will result in decreased formation of fibrin, causing a bleeding diathesis characterized by recurrent and prolonged bleeding episodes. (11) FVIII or FIX levels are expressed either as a percentage of normal activity or as international units per deciliter. The reference range for both factors fluctuates between 50% and 150% (0.50–1.50 IU/dL).Hemophilia is inherited in an X-linked recessive pattern. Males are predominantly affected because they have only a single X chromosome, which expresses the defective gene. Affected males can transmit the disease-causing gene only to their female offspring, designated "obligate carriers." Hemophilia carriers have one normal and one abnormal FVIII or FIX gene and have a 50% chance of transmitting the gene to any child; males inheriting the hemophilia gene express the disease, and females become hemophilia carriers (Fig 2).Carrier females might or might not manifest low factor levels and symptoms. Mild hemophilia can be present in up to 25% of heterozygous female carriers. (2) Infrequently, females can manifest a severe bleeding phenotype. This occurs in the context of a compound heterozygous female born from a father with hemophilia and a hemophilia carrier mother. A female carrier can also have hemophilia because of extreme lyonization of the normal X chromosome.Since the FVIII gene was first described in 1983, different mutation variants in the FVIII and FIX genes have been identified. (7) The most frequent variants in patients with hemophilia A are the intron 22 and intron 1 inversions. The former is identified in close to 52% of patients with severe hemophilia A, whereas the latter is encountered in 1% to 5% of all patients with hemophilia A. The most common genetic variants identified in hemophilia B are missense mutations, which account for approximately 47% of all cases. (12) The "My Life, Our Future" project was established in 2012 with the goal of creating a repository of genetic information from people with hemophilia in the United States. FVIII of FIX gene sequence analysis was offered at no cost to patients with hemophilia and suspected carriers. In 2018, an interim analysis identified 700 previously unreported genetic variants and reclassified as nondeleterious several variants previously reported as causative hemophilia mutations. (13)Hemophilia is classified as mild, moderate, and severe based on the measurable factor activity level (Table 1). There is a direct correlation between FVIII or FIX levels and the severity and relative frequency of patient signs and symptoms. Patients with severe and moderate deficiencies tend to present symptoms in the first months after birth. (2)(14)(15) It has been suggested that patients with hemophilia B seem to have less severe bleeding signs and symptoms and better long-term outcomes than patients with hemophilia A. (16)Because neither FVIII nor FIX crosses the placenta, bleeding signs and symptoms in persons with hemophilia, especially those with severe forms, can present soon after birth; in some instances, bleeding can even occur in utero. In infants, intracranial hemorrhage (ICH) occurring either during birth or shortly thereafter is a significant concern. The use of forceps during delivery and vacuum extraction are considered high-risk factors for the development of ICH. The overall incidence of ICH at birth in newborns with hemophilia is estimated to be 4% to 5%, although cases of spontaneous ICH have also been reported. (17) ICH also needs to be considered in cases of head trauma, such as an infant falling from a crib or bed. When suspecting an ICH in a child with hemophilia, immediate infusion of factor concentrate before a head computed tomographic scan is indicated and should not be delayed.The hallmark of hemophilia bleeding is the occurrence of spontaneous acute hemarthrosis. Acute hemarthrosis is defined as the sudden onset of bleeding into the joint space, accompanied by joint swelling, pain, and reduced range of motion of the affected joint. Ankles, knees, and elbows are the most frequently affected joints. The clinical manifestations of joint bleeding vary depending on the patient's age and are sometimes challenging to recognize by medical providers. Infants can present with irritability and unwillingness to use the affected limb. Older children and adults can present with prodromal symptoms characterized by a warm or tingling sensation or feeling of fullness and stiffness of the affected joint before onset of the more characteristic swelling and reduced range of motion. Point-of-care musculoskeletal ultrasonography (POC-MSKUS) is becoming a preferred imaging modality for both the acute assessment and management of joint bleeds (Fig 3) and for monitoring of the development and progression of subclinical joint disease. As opposed to other imaging modalities such as magnetic resonance imaging, POC-MSKUS is less invasive, does not require sedation, is less time-consuming, and has been found to be exceptionally sensitive in detecting very low amounts of intra-articular blood. (18)(19) At the moment, multiple hemophilia-specific POC-MSKUS scoring systems have been developed and are in different stages of validation. (19)When more than 4 bleeding episodes occur in the same joint in a 6-month period, the patient is considered to have developed a "target joint." Repetitive bleeding in the joint space causes a chronic inflammatory reaction, characterized by a cytokine-mediated oxidative process and iron deposition, resulting in vascular proliferation, synovial hypertrophy, and chronic synovitis. Chronic synovitis will trigger an irreversible and destructive process known as hemophilic arthropathy.Muscle bleeding with subsequent hematoma formation is also common in persons with hemophilia. Large muscles, such as the iliopsoas or quadriceps, are most commonly affected. Patients with muscular bleeding can present with mild and nonspecific signs and symptoms: an iliopsoas bleed can manifest as vague groin pain and an inability to extend the hip. If the provider is suspicious for a psoas bleed, imaging confirmation with magnetic resonance imaging or POC-MSKUS is indicated.Extensive muscle bleeding might result in a compartment syndrome, affecting neurovascular structures. Large amounts of blood loss in muscle can lead to pseudotumor formation. Hemophilic pseudotumor is a rare complication, occurring in 1% to 2% of patients with severe hemophilia. (1) A pseudotumor is a chronic, slowly expanding, encapsulated cystic mass that evolves after recurrent hemorrhages in extra-articular musculoskeletal structures.Another bleeding site is the gastrointestinal tract. Patients with bowel hematomas can have signs and symptoms mimicking an acute abdomen. (20) Hematuria, secondary to bleeding arising from the kidneys or the bladder, is a frequent manifestation in persons with hemophilia, especially those with severe deficiencies. (21) Bleeding related to tooth eruption is rare. Dental care is extremely important in persons with hemophilia. Medical providers should promote early consistent dental hygiene practices to reduce the risk of development of periodontal disease. Preventive dental care (dental cleanings) should occur regularly. Dental extractions can require referral to an inpatient setting.Carriers or women with mild hemophilia are also at risk for abnormal reproductive uterine bleeding associated with their menstrual period and childbirth. They can also face bleeding challenges during surgery or dental extractions. (22)A complete family history exploring possible manifestations of bleeding in other family members is essential for the evaluation of a patient suspected of having hemophilia. Given the known genetic etiology of the disorder, questions about extended family members can prove enlightening. Depending on the studied population, 30% to 50% of patients with hemophilia will be found to have a sporadic de novo mutation. These patients are born to a noncarrier mother with a negative family history. For this reason, pediatricians should always consider the possible diagnosis of hemophilia in any male newborn with severe and unusual bleeding and an isolated prolonged activated partial thromboplastin time (aPTT) despite a negative family history of hemophilia. (23)When hemophilia is suspected, the initial laboratory evaluation should include a complete blood cell count, prothrombin time, aPTT, mixing studies in case of prolonged aPTT, a fibrinogen level, and a VWF antigen and activity level.Children with hemophilia present with an isolated prolonged aPTT and a normal platelet count and prothrombin time/international normalized ratio. Patients with severe hemophilia usually have an aPTT 2 or 3 times higher than the upper limit of normal. Unless the patient has an active inhibitor to FVIII or FIX, the aPTT mixing study will correct with the addition of normal plasma. Some cases of mild hemophilia can present with a normal aPTT due to poor sensitivity of the assay in the setting of mildly reduced FVIII or FIX levels. It is not possible to determine the severity of a hemophilia solely on the degree of prolongation of the aPTT. A specific assay to quantify the activity levels for FVIII or FIX will not only confirm the diagnosis but will help to differentiate other inherited bleeding disorders, such as deficiencies of coagulation factors XI or XII, which are also associated with an isolated prolonged aPTT. (24) Genetic testing is an important part of the hemophilia diagnostic evaluation. In addition to allowing accurate genetic counseling, some recognized mutations are associated with the potential risk of inhibitor development, the most common and severe complication of hemophilia treatment today.Newborn males born to a known hemophilia carrier should have their factor level quantified at the time of delivery using a cord blood sample. Cord blood testing is preferred over venipuncture because the collection of cord blood minimizes the risk of traumatic bleeding. Invasive procedures, such as circumcision, should be delayed until the diagnosis of hemophilia is confirmed or eliminated. In babies confirmed to have hemophilia whose parents request a circumcision; the procedure should be electively performed by an experienced surgeon in collaboration with the hemophilia treatment center (HTC).Patients with mild hemophilia might not be diagnosed until adolescence or early adulthood in the setting of surgical or dental procedures. Abnormal and excessive bleeding will lead to the diagnosis.Ascertaining a hemophilia carrier's baseline factor activity is important for management, but if normal, it does not rule out the carrier's status. Genetic testing is more reliable than measurement of factor levels, especially in a woman with normal or borderline normal factor activity. Accurate identification of hemophilia carriers is important for managing current bleeding symptoms and troubleshooting potential bleeding complications associated with pregnancy and delivery. Knowledge of carrier status allows appropriate recommendations for testing offspring. (2) Women with suspected hemophilia should also be tested for von Willebrand disease (VWD), as VWD variants or severe type 3 VWD can have a bleeding phenotype similar to that of hemophilia.Traditionally, clotting factor replacement has been the standard of care for hemophilia. (25)(26) However, hemostatic adjuvant therapies are also helpful in controlling acute bleeding episodes.Treatment of hemophilia has evolved significantly (Fig 4). In the 1950s and 1960s, bleeding events were treated with whole blood, fresh frozen plasma, or cryoprecipitate. Individuals with severe hemophilia experienced prolonged hospitalizations with bleeding events and developed significant joint morbidity. The 1970s brought the development of plasma-derived factor concentrates. In the 1980s through the early 1990s, contamination of these products with human immunodeficiency virus as well as hepatitis B and C devastated the hemophilia community. During that era, in the United States most individuals with hemophilia would treat bleeding events only on demand due to difficulties with an adequate supply of factor concentrates and concerns about factor concentrate safety. (27) In response to the human immunodeficiency virus and hepatitis epidemics, factor concentrate purity and safety became the therapeutic focus. Purification strategies for plasma-derived concentrates incorporated the development of enhanced blood donor screening and the development of techniques for viral removal and inactivation: pasteurization, solvent or detergent treatment, dry heating, immunoaffinity chromatography, and, more recently, nanofiltration. These techniques have into no of viral in patients using plasma-derived factor concentrates since the Today, factor concentrates are of the human FVIII or FIX gene in cell the and human of concentrates based on either the or of human or plasma-derived are concentrates are commonly used in the United States. These concentrates neither human nor plasma-derived in their cell the development of the treatment in hemophilia to from bleeding episodes to the use of of factor concentrate to prevent bleeding is defined as or (Table early in has been to compared with Early has been to result in a more than in joint bleeding and significant in joint disease, hemophilic and on standard concentrates FVIII at to per 2 to 3 for patients with hemophilia A and FIX at to for patients with hemophilia B. to prevent bleeding episodes is to the needs of the can be used for bleeding factor levels of 80% to or for management of bleeds, and iliopsoas It is that factor levels than 50% to are depending on the specific procedure (Table hemostasis should be by an coagulation in with the patient's for acute bleeding episodes is by the patient's by the percentage of FVIII this is by of in patients with hemophilia A. For patients with hemophilia B, the will the patient's by the percentage of FIX level, by 1 of should be to children with hemophilia at The of Hemophilia these than should be to the site of for at after and should be to the site for at It is not to factor concentrate before the of For circumcision, it is to the circulating factor VIII or IX levels to 80% to before the procedure. The also the use of as an management of hemophilia has become some patients have to adequate treatment due to with and time This has to the development of extended factor concentrates on treatment through the of for There have been recent extended FVIII concentrates developed with different protein and and that a prolongation of FVIII The approximately allows as opposed to 3 times per or other This is due in part to the of factor VIII with its carrier protein in the There might soon be a of FVIII concentrates that extend the FVIII to or even less frequent to extended FIX concentrates have been more in using or These have to or current hemophilia treatment has on the specific clotting factor to promote normal are therapies to either the of the factor or the of coagulation the is a developed to activated FIX and on the mimicking the FVIII (Fig is has a of 4 to and is for in individuals with hemophilia A with and to its of has the potential to severe events such as and These events have been reported in individuals with hemophilia A and are and activated prothrombin complex concentrate for bleeding episodes. Acute or surgical bleeding in hemophilia A must be with of FVIII concentrate because is only for first for hemophilia A is a in patient for that the aPTT and FVIII activity will not be accurate in the patient because the require activation of Accurate FVIII activity the use of a factor VIII assay should a patient require of FVIII therapies in development are based on the that some individuals with hemophilia and such as deficiency or factor have a bleeding phenotype. is an for of gene in thereby the of This of a potential risk for development of analysis from a 1 clinical reported a patient associated with involving the development of after FVIII concentrate The clinical and reported long-term and safety for the 2 is a inhibitor that excessive by the tissue factor with activated coagulation factor and activated in the coagulation is an that the physiologic of in patients with hemophilia and This is clinical These studies were due to a of but clinical have since less developed of activated protein C or protein are a was to the of activated protein C while its other hemostasis in hemophilia potential of activated protein C is A has also been developed in hemophilia to of protein which can These therapies can be for for hemophilia has been the of patients with hemophilia. Hemophilia B the first in the early with gene followed a by hemophilia A. The genetic for the FVIII or FIX gene is into a and is The viral with genetic is to that become and the clotting gene FVIII and FIX have been in patients with severe hemophilia to levels consistent with those found in mild hemophilia, or even normal hemostatic levels. A mild in levels occurring with gene is Patients are usually treated with a of long-term safety potential into the although this occurs significantly less than with other for gene include long-term of and the appropriate therapeutic a of the levels of FVIII and and it can be used to bleeding in patients with mild hemophilia A have a response to this is defined as a to baseline FVIII levels, with a to after is not in patients with severe hemophilia A and is not indicated in patients with hemophilia B. response with and it is usually in children than 2 due to its potential risk of and such as and are helpful in controlling bleeding in with fibrinolytic such as the and They can be used in with factor replacement to prevent bleeding associated with surgical procedures. These have also to be in controlling in women with mild long-term complications of hemophilia are chronic with hemophilic and the development of to coagulation factor concentrates people with hemophilia are living persons with hemophilia are as have a incidence of disease, and chronic disease. (21) The bleeding risk in hemophilia and the of for managing these a higher risk of medical development of is the most severe complication of hemophilia treatment It a and important clinical for the medical are specific FVIII or FIX that the activity of the are reported to occur in approximately of patients with severe hemophilia A and 5% of patients with severe hemophilia B. tend to the first although most will the first to a age of 1 to 2 at Patients with moderate and mild hemophilia can but as adults or risk factors associated with an risk of inhibitor development have been identified. specific genetic mutations, and a family history of and and are known to be and risk factors for inhibitor risk factors for inhibitor development include early age at first treatment type of concentrate used in treatment, and the use of the study was the first and the in risk of inhibitor development between plasma-derived and factor concentrates in previously children with hemophilia A. suggested that patients concentrates are more to than those plasma-derived However, the study was the United and study had an of mutations associated with higher risk of inhibitor These a about the appropriate to in diagnosed children with hemophilia. It is also important to that not all concentrates were in the the of these be to all FVIII standard and extended therapeutic goal for patients with is complete of the the most for inhibitor It using and frequent of factor concentrates to the patient's system to the factor and the of the for are and on both the patient's clinical and has become for patients with hemophilia A and studies have in preventing bleeding episodes when patients with hemophilia A with are on of on although these patients will require a or of FVIII concentrates to treat acute bleeding episodes. It is for the medical provider to know the patient's inhibitor status and to acute bleeding episodes in the use of such as activated concentrate and activated prothrombin complex concentrates or the need for higher of FVIII with hemophilia or FIX with hemophilia for the management of hemophilia state that a multidisciplinary comprehensive care model should be established when for individuals with hemophilia. have been established the This treatment that persons with hemophilia have to a range of clinical and appropriate laboratory for the adequate management of their condition and associated In the Hemophilia a to establish the of a of hemophilia diagnostic and treatment centers in the United States. there are more than the The of this comprehensive during the has the of not only for persons with hemophilia but also for all people with bleeding disorders, allowing to live more and A study of persons with hemophilia that individuals treated at an were less to of a complication compared with those not care at an persons with hemophilia used a treatment center were less to be for bleeding Dr A. at the University of Hemophilia for her to the

Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel

The majority of patients receiving plasma-derived clotting factor concentrates between 1970s and the mid-1980s are now hepatitis C positive. The progression of hepatitis C is extremely variable and there is frequently a poor correlation among liver biochemistry, viral load and the stage of liver disease. Liver biopsy remains the only definitive way of staging fibrosis and grading necroinflammatory activity. Concerns have been expressed about the safety of the procedure; however, with modern regimes for the correction of coagulopathy in patients with inherited bleeding disorders, normal haemostasis may be maintained during the peribiopsy period. We performed 21 liver biopsies between 1984 and 1997 on patients with factor VIII (FVIII) or IX (FIX) deficiency and von Willebrand's Disease (VWD). Four had concomitant human immunodeficiency virus (HIV) infection, five were thrombocytopenic and one had a prolonged prothrombin time (PT). Haemostasis was achieved using an intermittent bolus of factor concentrate or continuous infusion regimens. One patient with VWD received Desmopressin (DDAVP). There were no bleeding episodes associated with biopsy. We suggest that liver biopsy is a safe procedure in patients with inherited bleeding disorders when the coagulopathy is fully corrected. It is the only definitive method of staging the extent of fibrosis associated with hepatitis C infection, and it is this that defines prognosis.

Phenotypic Correction of Hemophilia A by Ectopic Expression of Activated Factor VII in Platelets

DDAVP-Induced Increase of Factor VIII Activity in Blood Is Likely Due To Release of Factor VIII That Is Synthesized by Endothelial Cells.

Successful treatment of canine hemophilia by continuous expression of canine FVIIa

Pharmacokinetics of Subcutaneously Administered Simoctocog Alfa with Von Willebrand Factor Fragment Candidates in a Minipig Model

Target of prophylaxis in severe haemophilia: more than factor levels.

Intracellular Co-Localization of Factor VIII and Von Willebrand Factor Is Necessary for In Vivo FVIII Secretion.

Ancestral Sequence Reconstruction of Von Willebrand Factor Reveals Highly Conserved Structure/Function

"Outgrowing" the Laboratory Diagnosis of Type 1 Von Willebrand's Disease: A Two Decade Study

Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

VWF-FVIII Interactions Influence Hemostatic Thrombus Stability in Murine Models of Hemophilia Α and Type 2N VWD

BackgroundABO blood group is a hereditary factor of plasma levels of coagulation factor VIII (FVIII) and von Willebrand factor (VWF). Age and gender have been shown to influence FVIII, VWF, fibrinogen (Fbg), and ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 motif, 13). We investigated the effects of ABO type, age, and gender on plasma levels of FVIII, Fbg, VWF, and ADAMTS13 in a Chinese population.MethodsA total of 290 healthy volunteers were eligible for this study. ABO blood group was determined by indirect technique. FVIII:C and Fbg were measured by clotting assays. VWF antigen (VWF:Ag), collagen-binding activity (VWF:CBA), and ADAMTS13 antigen were assessed by ELISA, whereas VWF ristocetin cofactor activity (VWF:Rcof) was performed by agglutination of platelets with ristocetin.ResultsMean FVIII:C and VWF levels (VWF:Ag, VWF:CBA, and VWF:Rcof) were significantly higher in non-O than in O type subjects (p < 0.05 for all comparison). ADAMTS13 antigen decreased with increasing age, whereas the other parameters increased. Other than ADAMTS13 (p < 0.01), no gender-related variations were observed in the other parameters. Moreover, FVIII:C, Fbg, VWF:Ag, VWF:CBA, and VWF:Rcof showed significant and positive relationships with age (r = 0.421, 0.445, 0.410, 0.401, and 0.589, resp.; all p < 0.001), whereas a negative relationship was observed for ADAMTS13 antigen (r = 0.306; p = 0.006). Furthermore, FVIII:C were strongly correlated with VWF:Ag, VWF:CBA, and VWF:Rcof (r = 0.746, r = 0.746, and r = 0.576, resp.; p < 0.0001). VWF parameters were also strongly correlated with each other (r = 0.0.847 for VWF:Ag and VWF:CBA; r = 0.722 for VWF:Ag and VWF:Rcof; p < 0.0001).ConclusionsABO blood group, age, and gender showed different effects on plasma levels of FVIII:C, Fbg, VWF:Ag, VWF:CBA, VWF:Rcof, and ADAMTS13 antigen. These new data on a Chinese population are quite helpful to compare with other ethnic groups.