1、第二十一章 血液生物化学（Blood Biochemistry ）重庆医科大学生物化学教研室曾昭淳,图1 血清蛋白醋酸纤维素薄膜电泳结果,左边接负极，右边接正极。在pH8.6的巴比妥缓冲液中，蛋白质带负电荷，向正极移动。各蛋白带已注明。清蛋白染色最深，泳动的距离最长，-球蛋白的带最宽，泳动的距离最短。,血液凝固途径,血液凝固的外源性途径,外源性途径是组织因子（TF）进入血液，引起因子VII的活化并形成VII-Ca2+-TF复合物，激活因子X，凝血酶原，催化纤维蛋白原形成纤维蛋白，这是体内主要的凝血途径。,内源性凝血途径不是体内主要的凝血途径。通常是因为血管内皮损伤所引起，常常是病理现象。抽出的
2、血液也会凝固，通常是通过与玻璃管壁接触，而启动内源性凝血途径。,内源性凝血途径,凝血因子VIII膜结合结构域的结构,人类抗凝血酶III的结构,因子X肽链骨架在空间的走向,N为肽链的氨末端，C为肽链的羧末端。图中粗线部分代表EGF样结构域。,因子VIIa的蛋白酶结构域的条带结构,活性中心的底物结合口袋由H（代表193位His）、S（代表344位Ser）、D（代表338位Asp）构成。TF inhibitory peptide代表结合组织因子的区域。PNPN区域为扩大的底物结合区。E210和E220（代表210位和220位的Glu）是钙离子结合部位。,从cDNA推导的TF肽链氨基酸顺序,TF是一个
3、跨膜蛋白质，其N-末端在细胞外，1219氨基酸残基构成胞外结构域；220242氨基酸残基构成跨膜结构域；羧末端的21氨基酸残基构成胞液结构域。,含-羧基谷氨酸的蛋白质共同的结构特点,N-末端为含-羧基谷氨酸残基的区域；羧末端为丝氨酸蛋白酶结构域；EGF代表与表皮生长因子类似的结构域。酶解激活部位通常在形成二硫键的两个半胱氨酸之间某个氨基酸残基形成的肽键。,含-羧基谷氨酸酶原结构及酶解部位,图中箭头表示酶解部位，数字代表氨基酸的位置。凝血酶原第二个水解部位在二硫键外的区域，结果-羧基谷氨酸残基被切除，不再保留在凝血酶内。水解因子VII Arg152-Ile153之间的肽键而激活它。水解因子IX的
4、Arg145和Arg180 组成的肽键，释放出分子量大约11 000的肽段，而激活它。因子X含一条轻链和一条重链，二者通过二硫键连接，水解重链的Arg194-Ile195之间的肽键可激活它。蛋白C也含通过二硫键连接一条轻链和一条重链，水解重链的Arg169-Ile170之间的肽键可激活它。,凝血酶原激活示意图,凝血酶原的320位精氨酸羧基侧肽键首先被酶解，生成的两个肽段由原有的二硫键连接。随后284位精氨酸羧基侧肽键被酶解，生成由原有的二硫键连接的A肽和B肽的、有活性的-凝血酶并释放F1.2肽段。,纤维蛋白原分子结构示意图,纤维蛋白原分子由、肽链各两条组成。空间结构似两个棒形区连接三个球形区。
5、中间一个球形区内，通过二硫键将、各条肽链共价连接在一起,纤维蛋白原形成血凝块,纤维蛋白原被凝血酶水解释放出两个A肽和两个B肽，形成可溶性纤维蛋白单体。纤维蛋白单体聚集成纤维蛋白软凝块，再由XIIIa催化纤维蛋白单体之间共价交联，形成血凝块。,纤维蛋白单体之间的交联反应,血小板在凝血过程中的作用,凝血调理素的功能,凝血调理素与凝血酶形成复合物，使凝血酶水解纤维蛋白原的活性转变成酶解激活蛋白C的活性，活化的蛋白C在辅助因子蛋白S 的协助下，灭活因子VIIIa和因子XIIIa，使凝血酶的作用由促进凝血转变成抗凝血。,溶纤酶水解纤维蛋白的作用,TFPI的结构,图中有三个球形的结构域， 结构域1抑制VI
6、Ia， 结构域2抑制Xa，结构域3是胞吞TFPI、VIIa、Xa 与TF形成的复合物所必需。箭头表示每个结构域的活性部位。,假定的组织因子途径抑制机制,TFPI、Xa、VIIa与细胞膜上的TF形成复合物。抑制了Va、XIIa的活性，且Va、XIIa 随后被胞吞降解。,2,3-二磷酸甘油酸支路,2,3-二磷酸甘油酸支路是糖酵解途径的一条支路.由3-磷酸甘油变位酶催化1,3-二磷酸甘油酸生成2,3-二磷酸甘油酸,再由2,3-二磷酸甘油酸磷酸酶催化生成3-磷酸甘油酸,回到糖酵解途径.,2,3-DPG与血红蛋白的结合,2,3-DPG可以进入Hb分子4个亚基的对称中心的孔穴内，与其结合。它带的负电荷与组
7、成孔穴侧壁的2个亚基上的正电荷基团形成盐键。使Hb的构象更加稳定，降低Hb与O2的亲和力。,2,3-DPG与血红蛋白的结合,血红素的结构,-氨基-酮戊酸(ALA)的生成,胆色素原的生成,线状四吡咯的生成4分子胆色素原在尿卟啉原同合酶I的作用下,生成线状四吡咯,尿卟啉原III的生成线状四吡咯在由尿卟啉原III同合酶催化生成生成尿卟啉原III,粪卟啉原III生成尿卟啉原III在脱羧酶催化下，卟啉环上的1、3、5、8位置上的4个乙酰基脱羧转变成甲基，尿卟啉原III就转变成粪卟啉原III,原卟啉原IX生成,粪卟啉原III在酶的催化下脱氫氧化生成原卟啉原IX。原卟啉原IX与粪卟啉原III的区别在于2、4
8、两个位置上的丙酸基氧化脱羧成乙酰基。.,原卟啉IX的生成,原卟啉原IX中连接四个吡咯环的甲烯基脱氫氧化成甲炔基。四个吡咯环N原子上的氫脱掉两个。,血红素的生成,原卟啉IX与Fe 2+螯合，生成血红素。,血红素合成的全过程,高铁血红素的作用,高铁血红素抑制cAMP变构激活A激酶，抑制了eIF2激酶的磷酸化，保持在无活性状态，使 eIF2不能被磷酸化，保持持续的活性状态，促进蛋白质的合成。因而也促进血红蛋白的合成。,血红蛋白的氧饱和曲线,2,3DPG对氧饱和曲线的影响,2,3DPG在红细胞中的浓度越高，血红蛋白的氧饱和曲线越左移。达到50氧饱和度所需要的氧分压越低。在肺部，氧分压高血红蛋白与氧的结
9、合不受影响，在组织氧分压低但氧合血红蛋白能释放更多的氧,pH对氧饱和曲线的影响,血液的pH增高，氧饱和曲线左移，血液的pH降低，氧饱和曲线右移。,温度对氧饱和曲线的影响,温度降低，血红蛋白氧饱和曲线左移，温度升高，血红蛋白氧饱和曲线右移。,组织细胞产生的二氧化碳进入经血液进入红细胞后的变化,第21章 血液生化选择题,1、在血凝块的形成中：,A 从纤维蛋白原形成纤维蛋白，蛋白酶解-羧基谷氨酸残基是必需的。B 通过因子XIII的转谷氨酰胺酶作用，纤维蛋白分子之间的交连稳定血凝块。C 凝血酶惟一的作用是激活因子VII。D 凝血过程开始时，因子III，即组织因子必需被灭活。E 钙离子的主要作用是结合纤
10、维蛋白分子，聚集它们形成血凝块,2、转变凝血酶原成凝血酶必需的因子Xa ，通过复合物TF-VII-Ca2+作用于因子X而形成。,A 只存在于凝血的外源性途径B 只存在于凝血的内源性途径C 既是内源性途径也是外源性途径的一部分D 只有当正常的凝血瀑布效应被抑制时，才会 发生。E 当出现纤溶时才会发生。,3、纤维蛋白凝块的溶解,A 和血凝块的形成平衡B 当溶纤酶结合于血凝块时才开始C 需要水解溶纤酶原形成轻链和重链D 蛋白酶抑制剂对溶纤酶原的作用可调节E 需要组织溶纤酶激活剂转换溶纤酶原成 溶纤酶。,4、血小板的聚集,A 在损伤部位通过转变纤维蛋白原成纤维蛋白而启动B 在未损伤的血管，由完整的内皮
11、细胞分泌PGG2而抑制。C 引起形态学的变化和释放血管舒张剂血清素D 通过释放ADP和thromboxaneA2 而被抑制E 被vWF抑制。,5 因子XIII激活后是,A蛋白水解酶 B酶的辅助因子 C蛋白酶的抑制剂 D蛋白酶的激活剂 E转谷氨酰胺酶,6 血浆清蛋白,A在生理pH条件下，带净电荷为正。B用50%硫酸铵把它从血清沉淀下来。C能结合并运输维生素A 。D维持血浆胶体渗透压，在毛细血管静 脉侧，水分从血管流入组织。 E它既能结合金属离子，也能结合有机阴离子。,7 维生素K称为凝血维生素是因为,A 促进肝合成的凝血因子 II、V、IX、X的谷氨酸残基的-羧化。 B 促进肝合成的凝血因子II
12、 、 VII 、 IX、X 的谷氨酸残基-羧化。 C 促进肝合成的凝血因子III、 VII、VIII、IX、 谷氨酸残基-羧化。 D 促进肝合成的凝血因子III、VII、IX、X、 谷氨酸残基-羧化。 E 促进肝合成的凝血因子II、VIII、IX、 XIII谷氨酸残基-羧化。,8、下列哪种蛋白运输血浆中游离的脂肪酸,A运铁蛋白 B铜蓝蛋白 C清蛋白 D结合珠蛋白 E 1-酸性糖蛋白D,9、肝功能受到损坏后受到影响较轻的是,A纤维蛋白原 B因子VIII 、V、X C 血浆清蛋白 D 凝血酶原 E 因子XIII,10、血液中运输CO2的主要形式是,A 溶解在血液中的 HCO3- B 红细胞内氨基甲
13、酸血红蛋白 C 溶解在血液中的CO2 D 与血浆蛋白结合CO2 ECaCO3,11、合成血红素的基本原料是,A 乙酰辅酶A、Fe2+B 琥珀酰辅酶A、 Fe2+C 甘氨酸、琥珀酰辅酶AD 甘氨酸、 Fe2+E 甘氨酸、琥珀酰辅酶A、Fe2+,12、血红素合成的限速酶是,AALA合酶 BALA脱水酶 C胆色素原脱氨酶 D尿卟啉原III氧化脱羧酶 E亚铁螯合酶。,13、存在于成熟红细胞的代谢有,A糖的异生 B脂肪酸合成 C磷酸戊糖途径 D 酮体合成 E 氧化磷酸化,14、ALA合成酶,A受血红素的变构抑制 B受高铁血红素的变构激活 C受血红蛋白的变构激活 D受睾丸素5-还原物的阻遏 EEPO促进其
14、活性,15 关于2，3-二磷酸甘油酸，正确地是：,A 主要是由 3- 磷酸甘油酸生成 B 分子在生理条件下带有6个负电荷C 能于血红蛋白的-亚基通过盐键结合D 血红蛋白与它结合后，氧饱和曲线向右 移。 E 平原地区生活的人红细胞的含量比在高原地区生活的人红细胞的含量高。,16 凝血酶原激活物是,AIIIa-Ca2+-Va BIXa -Ca2+-Va CVIIa -Ca2+-Va DXa -Ca2+-Va EVIIa -Ca2+- IIIa,17 血液中非蛋白N含量最多的物质是,A肌酸 B肌酐 C尿酸 D 尿素 E小分子肽,18 红细胞内最主要的抗氧化物质是,A NADH+H+ B FMNH2
15、C FADH2 D GSH E HbH2,19 凝血因子XIII,A 是一个蛋白酶，可水解因子X B 是凝血酶原激活物的辅助因子 C 抑制血浆中抗凝血因子的活性 D 催化在纤维蛋白之间形成异肽键 E 抑制血浆中溶纤酶的活性,20、既是蛋白酶的底物，激活后又作酶的辅助因子的凝血因子是,A 因子VIII B 因子VII C 因子IX D 因子XII E 因子III,21、不参与接触活化的凝血因子有,A 因子VII B 因子XII C 因子XI D 高分子激肽原 E 激肽释放酶原,1题 答案,答案A 错误答案B 正确。凝血过程中，凝血酶催化纤维蛋白原转变成纤维蛋白，因子V、VIII、XIII也对凝血
16、酶敏感。因子XIII的转谷氨酰胺酶作用，催化纤维蛋白分子之间的交连，形成稳定血凝块。因子III即组织因子是激活外源性凝血途径必需的。钙离子在凝血过程中参与凝血因子与血小板磷脂之间的搭桥作用。答案C错误答案D错误答案E错误,2题 答案,答案A正确。TF-VII-Ca2+作用于因子X生成Xa是外源性途径的一步反应，它不出现在内源性凝血途径，也不出现在内、外源途径的共同部分。更不是纤溶过程的反应。答案B 错误答案C 错误答案D 错误答案E 错误,3题 答案,答案 A 错误 答案 B 错误答案 C 错误答案 D 错误答案 E 正确 溶解纤维蛋白需要溶纤酶的作用，溶纤酶原本来就含有通过二硫键连接的一条重
17、链和一条轻链。溶纤酶原在组织溶纤酶激活剂或尿激酶的作用下，暴露或形成酶的活性中心，转变成溶纤酶。,4题 答案,答案A 错误答案 B 错误答案 C 正确血小板的积聚，引起血小板形态上的改变，释放血清素， ADP、某些类型的磷脂和蛋白质，有助于血液的凝固和损伤组织的修复。 答案 D 错误答案 E 错误,5题 答案,答案 A 错误 答案 B 错误答案 C 错误答案 D 错误答案 E 正确因子XIII 是转谷氨酰胺酶原，激活后成谷氨酰氨酶，催化可溶性纤维蛋白形成异肽键相连。形成纤维蛋白网。,6题 答案,答案 A 错误答案 B 错误答案 C 错误答案 D 错误答案 E 正确 前清蛋白可以结合游离脂肪酸，
18、胆红素等小分子有机化合物，也能结合钙离子。,7题 答案,答案 A 错误答案 B 正确 因子II、VII、IX、X肽链合成后，其谷氨酸残基需要进行-羧化修饰，才具有凝血活性，维生素K是谷氨酸-羧化酶的辅助因子。答案 C 错误答案 D 错误答案 E 错误,8题 答案,答案 A 错误答案 B 错误答案 C 正确血浆中的游离脂肪酸是与血浆中的清蛋白结合而运输。答案 D 错误答案 E 错误,9题 答案,答案 A 错误。答案 B 错误。答案 C 错误。答案 D 错误。答案 E 正确。纤维蛋白原、因子VIII 、V、X、 血浆清蛋、凝血酶原均在肝合成，故肝功能受到损坏后受到的影响较大。因子XIII不在肝合成
19、肝功能受到损坏后受到影响较轻。,10题 答案,答案 A正确: 溶解在血液中的 HCO3- ,溶解在血液中的 HCO3- ，占血液运输CO2的88%，是血液运输CO2主要形式。答案 B 错误答案 C 错误答案 D 错误答案 E 错误,11题 答案,答案A 错误。答案B 错误。答案C 错误。答案D 错误。答案E 正确。合成血红素的基本原料是甘氨酸、琥珀酰辅酶A、Fe2+。,12题 答案,答案 A 正确。血红素合成的限速酶是ALA合酶。该酶催化琥珀酰辅酶A和甘氨酸反应生成ALA。答案 B 错误。答案 C 错误。答案 D 错误。答案 E 错误。,13题 答案,答案 A 错误。答案 B 错误。答案 C
20、正确。酮体合成和氧化磷酸化是在限粒体内进行，成熟的红细胞没有线粒体，故不能进行酮体合成和氧化磷酸化。成熟的红细胞不能从头合成脂肪酸，也不能合成糖原，但可以进行糖酵解和磷酸戊糖途径。答案 D 错误。答案 E 错误。,14题 答案,答案 A 正确。血红素合成可受多种因素的调节，但ALA合酶是血红素合成的限速酶,主要受血红素的反馈抑制。答案 B 错误答案 C错误答案 D错误答案 E 错误,15题 答案,答案 A 错误 答案 B 错误答案 C 错误答案 D 正确2,3DPG由1,3DPG生成，在生理条件下分子带5个负电荷，可进入血红蛋白中心孔隙，与亚基带的正电荷生成盐键，它与血红蛋白结合后，使血红蛋白
21、的氧饱和曲线向右移，氧合血红蛋白释放更多的氧。高原地区生活的人，红细胞的 2,3DPG含量比平原地区生活的人高。答案 C 错误,16题 答案,答案 A 错误 答案 B 错误。答案 C 错误。答案 D 正确。无论凝血的内源性或外源性途径，都需要形成Xa -Ca2+-Va，即凝血酶原激活物，激活凝血酶原，生成凝血酶。答案 E 错误。,17题 答案,答案 A 错误 答案 B 错误。答案 C 错误。答案 D 正确。血液中的非蛋白类含氮化合物主要有尿素、肌酸、肌苷、尿酸、胆红素和氨等，它们含的氮总称非蛋白氮，其中血尿素氮约占NPN的1/2。答案E正确。,18题 答案,答案 A 错误 答案 B 错误。答案
22、 C 错误。答案 D 正确。GSH是红细胞内最主要的抗氧化物质，它被氧化后生成GSSG，GSSG可由NADPH提供H，在谷胱甘肽还原酶的催化下，还原成GSH。GSH的氧化可以保护红细胞内的蛋白质、酶、膜脂质免受氧化损伤。答案E正确。,19题 答案,答案 A 错误 答案 B 错误。答案 C 错误。答案 D 正确。因子XIII是一个酶原，被酶解激活后，是生成转谷氨酰胺酶，催化在纤维蛋白之间形成异肽键，即谷氨酰胺残基与赖氨酸的氨基之间生成异肽键。 答案 E 正确。,20题 答案,答案 A 正确。因子VIII被酶解激活后，生成VIIIa，与因子IXa生成1:1的复合物，作为IXa的辅助因子,激活因子X
23、。答案B错误。答案C错误。答案D错误。答案E错误。,21题 答案,答案 A 正确。接触活化途径即内源性途径。因子VII参与外源性途径凝血过程，但又不参与两条途径的共同部分。答案B 错误。答案C 错误。答案D 错误。答案E 错误。,Hans Fischer BiographyKarl Landsteiner Biography,Hans Fischer was born in July 27, 1881 at Hoechst, on the river Main, in Germany. His father was Dr. Eugen Fischer, Director of the firm
24、 of Kalle his mother was Anna Herdegen. He went to a primary school in Stuttgart, and later to the humanistische Gymnasium (grammar school with emphasis on the classics) in Wiesbaden,matriculating in 1899. He read chemistry and medicine simultaneously, first at the University of Lausanne and then at
25、 Marburg. He obtained his chemistry degree under T. Zincke at Marburg in 1904; two years later, in 1906, a licence for medicine was conferred on him at Munich. In 1908 he qualified for his M.D. under F. von Mller, also at Munich.,Fischer spent his first working years at the Second Medical Clinic in
26、Munich and at the First Berlin Chemical Institute under Emil Fischer. He returned to Munich in 1911 and qualified as lecturer on internal medicine one year later. In 1913 he was appointed E.F. Weinlands successor at the Physiological Institute (O. Frank) in Munich, where he became a lecturer on phys
27、iology. In 1916 Fischer followed the invitation of the University of Innsbruck to succeed Windaus as Professor of Medical Chemistry; from there he went to the University of Vienna in 1918.,From April 1, 1921 until his death he held the position of Professor of Organic Chemistry at the Technische Hoc
28、hschule (Technical University) in Munich, as successor to Wieland.,Fischers scientific work was mostly concerned with the investigation of the constitutive properties of the pigments in blood, bile, and also leaves, as well as with the chemistry of pyrrole. The main reason for the latter investigati
29、on was the synthesis of these natural pyrrole pigments. Of special importance was his synthesis of bilirubin. His numerous papers were mostly published in Liebigs Annalen der Chemie and Hoppe-Seylers Zeitschrift fr physiologische Chemie.,In recognition of his work in these fields, the title of a Geh
30、eimer Regierungsrat (Privy Councillor) was conferred upon Hans Fischer in 1925; in 1929 he was awarded the Liebig Memorial Medal; Harvard University bestowed the title of honorary doctor on him in 1936; he received the Davy Medal in 1937. Fischer received the greatest honour of all, the Nobel Prize
31、for 1930, for his work on the chemistry of pyrrole and the synthesis of haemin. In 1935, Professor Fischer married Wiltrud Haufe. He died on March 31, 1945 in Munich.,Karl Landsteiner Biography,Karl Landsteiner was born in Vienna on June 14, 1868. His father, Leopold Landsteiner, a doctor of law, wa
32、s a well-known journalist and newspaper publisher, who died when Karl was six years old. Karl was brought up by his mother, Fanny Hess, to whom he was so devoted that a death mask of her hung on his wall until he died. After leaving school, Landsteiner studied medicine at the Univerisity of Vienna,
33、graduating in 1891.,Even while he was a student he had begun to do biochemical research end in 1891 he published a paper on the influence of diet on the composition of blood ash. To gain further knowledge of chemistry he spent the next five years in the laboratories of Hantzsch at Zurich, Emil Fisch
34、er at Wurzburg, and E. Bamberger at Munich.,Returning to Vienna, Landsteiner resumed his medical studies at the Vienna General Hospital. In 1896 he became an assistant under Max von Gruber in the Hygiene Institute at Vienna. Even at this time he was interested in the mechanisms of immunity and in th
35、e nature of antibodies. From 1898 till 1908 he held the post of assistant in the University Department of Pathological Anatomy in Vienna, the Head of which was Professor A. Weichselbaum, who had discovered the bacterial cause of meningitis, and with Fraenckel had discovered the pneumococcus.,Here La
36、ndsteiner worked on morbid physiology rather than on morbid anatomy. In this he was encouraged by Weichselbaum, in spite of the criticism of others in this Institute. In 1908 Weichselbaum secured his appointment as Prosector in the Wilhelminaspital in Vienna, where he remained until 1919. In 1911 he
37、 became Professor of Pathological Anatomy in the University of Vienna, but without the corresponding salary.,Up to the year 1919, after twenty years of work on pathological anatomy, Landsteiner with a number of collaborators had published many papers on his findings in morbid anatomy and on immunolo
38、gy. He discovered new facts about the immunology of syphilis, added to the knowledge of the Wassermann reaction, and discovered the immunological factors which he named haptens (it then became clear that the active substances in the extracts of normal organs used in this reaction were, in fact, hapt
39、ens). He made fundamental contributions to our knowledge of paroxysmal haemoglobinuria.,He also showed that the cause of poliomyelitis could be transmitted to monkeys by injecting into them material prepared by grinding up the spinal cords of children who had died from this disease, and, lacking in
40、Vienna monkeys for further experiments, he went to the Pasteur Institute in Paris, where monkeys were available. His work there, together with that independently done by Flexner and Lewis, laid the foundations of our knowledge of the cause and immunology of poliomyelitis.,Landsteiner made numerous c
41、ontributions to both pathological anatomy, histology and immunology, all of which showed, not only his meticulous care in observation and description, but also his biological understanding. But his name will no doubt always be honoured for his discovery in 1901 of, and outstanding work on, the blood
42、 groups, for which he was given the Nobel Prize for Physiology or Medicine in 1930.,In 1875 Landois had reported that, when man is given transfusions of the blood of other animals, these foreign blood corpuscles are clumped and broken up in the blood vessels of man with the liberation of haemoglobin
43、. In 1901-1903 Landsteiner pointed out that a similar reaction may occur when the blood of one human individual is transfused, not with the blood of another animal, but with that of another human being, and that this might be the cause of shock, jaundice, and haemoglobinuria that had followed some e
44、arlier attempts at blood transfusions.,His suggestions, however, received little attention until, in 1909, he classified the bloods of human beings into the now well-known A, B, AB, and O groups and showed that transfusions between individuals of groups A or B do not result in the destruction of new
45、 blood cells and that this catastrophe occurs only when a person is transfused with the blood of a person belonging to a different group. Earlier, in 1901-1903, Landsteiner had suggested that, because the characteristics which determine the blood groups are inherited, the blood groups may be used to
46、 decide instances of doubtful paternity.,Much of the subsequent work that Landsteiner and his pupils did on blood groups and the immunological uses they made of them was done, not in Vienna, but in New York. For in 1919 conditions in Vienna were such that laboratory work was very difficult and, seei
47、ng no future for Austria, Landsteiner obtained the appointment of Prosector to a small Roman Catholic Hospital at The Hague. Here he published, from 1919-1922, twelve papers on new haptens that he had discovered, on conjugates with proteins which were capable of inducing anaphylaxis and on related p
48、roblems, and also on the serological specificity of the haemoglobins of different species of animals.,His work in Holland came to an end when he was offered a post in the Rockefeller Institute for Medical Research in New York and he moved there together with his family. It was here that he did, in c
49、ollaboration with Levine and Wiener, the further work on the blood groups which greatly extended the number of these groups, and here in collaboration with Wiener studied bleeding in the new-born, leading to the discovery of the Rh-factor in blood, which relates the human blood to the blood of the rhesus monkey.,
