Text B Diagnosisand Treatmentof Anemia

Laboratory Evaluation of the Patient with Anemia

In the clinical assessment of the anemic patient，it is important to proceed in a systematic way so that the diagnosis can be established with a minimum of laboratory tests and procedures．A thorough history and careful physical examination are critical in the initial evaluation of the anemic patient．For example，a family history that reveals a dominant inheritance pattern would reinforce the tentative diagnosis of hereditary spherocytosis．The presence of fever，new heart murmur，and splenomegaly in an anemic patient suggests subacute bacterial endocarditis．In evaluating the anemic patient，the clinician must first ask whether the anemia is caused by decreased production of red cells or by loss of blood cells as a result of hemorrhage or hemolysis．Blood loss may be either the sole cause of the anemia or a significant contributor．Therefore， examination of the stool for occult blood is an indispensable part of the evaluation of all anemic patients．

The laboratory work－up of anemia includes a complete blood count，red cell indices，reticulocyte count，and microscopic examination of the blood smear．In addition，in many cases a bone marrow examination is a critical component of the initial laboratory assessment．

Complete Blood Count

Most hospitals and clinical laboratories use equipment that provides high－throughput analyses of red cell，platelet，and white cell counts and white cell differential，along with measurements of cell size．The mean red cell volume （MCV，平均红细胞容积）is normally 81 to 99 f L．These instruments also provide accurate determinations of hemoglobin concentration．The hematocrit， or fraction of packed red cells over total blood volume，is determined indirectly from the red cell count and the MCV．The mean concentration of hemoglobin within the red cell population（MCHC，平均红细胞血红蛋白浓度）is the quotient of hemoglobin divided by hematocrit．The MCV is particularly useful in classifying the anemias caused by decreased red cell production．Microcytic anemias have low MCV values and often low MCHC．Microscopic examination reveals small and often pale red cells．The MCV in the macrocytic anemias is increased，and large，oval cells（macroovalocytes）are seen．In contrast to the anemias of underproduction，the hemolytic anemias are either normocytic or slightly macrocytic owing to the preponderance of young red cells that are relatively large．Severe forms of thalassemia are an exception；there， microcytic red cells may be accompanied by brisk hemolysis．

Reticulocyte Count

This simple and cost－effective test is extremely useful for distinguishing anemias secondary to decreased red cell production from those caused by hemolysis．With the application of an appropriate supravital stain，the 1－to 2－day－old red cells in the peripheral blood reveal a network of purple strands， which are aggregates of ribosomes．The reticulocyte count in normal individuals is about 1％，consistent with a red cell lifespan of approximately 120 days．An elevated reticulocyte count reflects the release of an increased number of young cells from the bone marrow．The rate of red cell production can be assessed more quantitatively by determining the absolute reticulocyte count，the product of the percentage of reticulocytes and the red cell count．Thus，normal blood contains about 50×109／L reticulocytes．In interpreting this test，one should consider the distribution of reticulocytes between the bone marrow and the peripheral blood．When erythropoiesis is robust，marrow reticulocytes enter the circulation prematurely．These“shift reticulocytes”appear larger than average on a routine blood smear and have a lavender hue，called polychromatophilia． Because the circulation of shift reticulocytes in the peripheral blood is prolonged，the reticulocyte count should be divided by two．This correction should always be made if normoblasts are encountered in the peripheral blood because this finding indicates the premature release of newborn red cells into the circulation．1

A failure to produce red cells is reflected in an inappropriately low reticulocyte count．In contrast，a significant elevation of reticulocytes is suggestive of hemolysis．Exceptions include the following：

●The brisk reticulocyte response seen in patients with hemorrhage．

●Reticulocytosis encountered in patients recovering from impaired erythropoiesis（e．g．an individual with pernicious anemia who received an injection of cobalamin 1 week earlier）．

●Mild to moderate elevations in reticulocytes（3％to 7％）encountered in myelophthisic anemia，in which the orderly release of cells is affected by alterations of the marrow stroma owing to tumor，fibrosis or granuloma． These exceptions are generally appreciated in the initial evaluation of the patient．

Examination of the Blood Smear

In the evaluation of any patient with unexplained anemia，the physician should take the time to examine a well－stained peripheral blood film．Many subtleties escape the attention of the technologist，whose primary aim is to confirm or refine the white cell differential count provided by automated cell counters．The clinician approaches the specimen with a prepared mind and can scrutinize it for specific abnormalities．Examination of the blood film can confirm the size and color of red cells estimated by red blood cell indices．In contrast to the mean statistical values provided by automated cell counters， microscopic examination can reveal variations in red cell size（anisocytosis）or shape（poikilocytosis），abnormalities that are helpful in diagnosing specific anemias．2 Examination of the blood smear is particularly important in a patient with hemolysis．Many types of hemolytic anemia have characteristic abnormalities in red cell morphology．The presence of abnormal white cells may be the first clue to a lymphoproliferative or primary bone marrow disorder．

Bone Marrow Examination

A microscopic examination of the bone marrow is often useful and may be critical in the work－up of any unexplained anemia．Study of the bone marrow is informative in diagnosis of anemias of underproduction，particularly those accompanied by abnormalities in white cells and／or platelets，suggesting disordered hematopoiesis．The more severe the anemia，the more likely it is that the procedure will be informative．An assessment of the quantity and quality of red cell precursors may identify a defect in cell production due to either hypoplasia or ineffective erythropoiesis．A marrow biopsy is required for estimating overall cellularity．The ratio of myeloid（M）to erythroid（E） precursors is normally about 2∶1，but it may be artifactually increased by the inclusion of circulating leukocytes．The ratio is increased in patients with infection，a leukemoid reaction，or neoplastic proliferation of myeloid cells． Rarely，a high M／E ratio is due to seletive aplasia of the red cell precursors．A decreased M／E ratio indicates erythroid hyperplasia．Erythroid maturation is normal in hemolysis and hemorrhage，but it is disordered when erythropoiesis is ineffective，such as in megaloblastic and sideroblastic anemias and inβ－thalassemia major or intermedia．The bone marrow examination is also important in demonstrating the presence of cellular infiltrates such as those found in leukemia，lymphoma，or multiple myeloma．The demonstration of tumor，fibrosis，or granuloma usually requires a bone marrow biopsy，not just a bone marrow aspiration．A portion of the marrow specimen should be stained with Prussian blue．In addition to providing an assessment of iron stores，this iron stain is required for the identification of erythroid sideroblasts．

Approach to the Treatment of Anemia

As in other disorders，the effective treatment of anemia is based on a thorough diagnostic evaluation．Hematinics such as iron，cobalamin，or folic acid should not be administered unless a specific deficiency has been demonstrated or is anticipated．Although indiscriminate treatment with cobalamin is not harmful per se，it lulls both the patient and the physician into a false sense of security． In contrast，the inappropriate use of iron preparations over a prolonged period can be directly harmful，leading to a state of iron overload．

Many kinds of anemias can be corrected if a precipitating cause can be uncovered and reversed．If a drug or toxin is responsible，its withdrawal may allow full recovery．Correction of anemia secondary to a chronic disease usually depends on whether the underlying condition can be reversed．One of the most dramatic dividends of successful renal transplantation is the rapid correction of the anemia of uremia．

Erythropoietin Therapy

The administration of recombinant human erythropoietin（r Hu EPO，重组人促红细胞生成素）is remarkably effective in certain circumstances．In addition to those with anemia of chronic renal failure，selected patients with other types of anemia may benefit from r Hu EPO．Treatment can lower transfusion requirements in patients with cancer or HIV infection in whom anemia has been aggravated by chemotherapy．In comparison to patients with renal failure，higher doses are required for those with cancer or AIDS to achieve the same increases in red cell mass．Treatment with r Hu EPO has also been effective in some patients with primary bone marrow disorders， particularly myelodysplasia．Transfusion requirements in surgical patients，both perioperatively and postoperatively，may be reduced by prior short－term administration of r Hu EPO．Treatment may also benefit rare patients who are unable to receive blood transfusions because of either antigen incompatibility or religious convictions．

A note of caution has emerged from a number of large studies suggesting that high doses of r Hu EPO that drive the hemoglobin level above 120 g／L are associated with a slight but significant increase in the risk of thrombosis and cardiovascular mortality．3 A meta－analysis of randomized controlled clinical trials of chronic kidney disease patients treated with r Hu EPO showed that targeting higher levels of hemoglobin was associated with an increased risk of all－cause mortality and arteriovenous access thrombosis．Administration of the erythropoiesis－stimulating agents erythropoietin and darbepoetin to patients with cancer has been associated with an increased risk of venous thromboembolism and mortality．The possibility of increasing risk of tumor progression may be mediated by erythropoietin receptors on malignant cells．

Primary bone marrow disorders pose a formidable therapeutic challenge when considering r Hu EPO therapy．Aplastic anemia can be cured by both immunosuppressive therapy and stem cell transplantation．Long－lasting remissions can be achieved in an increasing fraction of patients with acute leukemias by chemotherapy，often coupled with stem cell transplantation．Other primary bone marrow disorders that are unresponsive to these interventions are treated with supportive measures such as transfusions of red cells and platelets．4

Red Cell Transfusion

The decision whether to transfuse an anemic patient is often challenging． Patients with chronic or long－standing anemia are able to compensate in several ways．A considerable reduction in red cell mass can be surprisingly well tolerated，especially if the patient is young or sedentary．Transfusion is seldom indicated in a patient with chronic anemia whose hemoglobin is 90 g／L or greater．Those who are expected to respond to the administration of a specific agent such as iron，folic acid or vitamin B12can usually be spared transfusions． However，if the anemia is severe and accompanied by myocardial or cerebral ischemia or by congestive heart failure，prompt but slow administration of packed red cells is indicated．Whole blood should be given only if the patient is hypovolemic．

Splenectomy

Splenectomy is indicated in the treatment of certain hemolytic anemias． The efficacy of splenectomy correlates with the degree to which the abnormal or defective red cells are destroyed or sequestered in the spleen．5 Splenectomy is curative in nearly all patients with hereditary spherocytosis．The operation may be also beneficial in selected patients with immunohemolytic anemia， congestive splenomegaly，spur cell anemia and certain hemoglobinopathies and enzymopathies．The operative morbidity and mortality from elective splenectomy are very low．The procedure can often be done via mini－laparotomy．Occasional patients develop postoperative left subphrenic abscess．Following splenectomy， young children are at risk of developing overwhelming septicemia．This complication can be partially circumvented by vaccination against pneumococcus and meningococcus．Post－splenectomy sepsis occurs rarely in adults．The risk of sepsis can be circumvented by partial splenectomy．Thrombocytosis generally develops promptly following splenectomy．However，in most cases it is transient．In patients with continued hemolysis or with a myeloproliferative disorder，the thrombocytosis usually persists and may occasionally be associated with thromboembolic complications．

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New Words and Phrases

spherocytosis［,sfɪrəʊsaɪ'təʊsɪs］n． 球形红细胞增多症

splenomegaly［,spliːnəʊ'meɡəlɪ］n． 脾（肿）大

reticulocyte［rɪ'tɪkjʊləsaɪt］n． 网状细胞，网织红细胞

smear［smɪə］n． 涂片v． 涂抹，弄脏

quotient［'kwəʊʃənt］n． 商数；系数

preponderance［prɪ'pɒndərəns］n． 优势，优越

thalassemia［,θælə'siːmɪə］n． 地中海贫血，珠蛋白生成障碍性贫血

supravital［,sjuːprə'vaɪtəl］a． 体外活体的

ribosome［'raɪbəsəʊm］n． 核糖体

lavender［'lævəndə］n． 熏衣草；淡紫色

hue［hjuː］n． 色彩；色调；形式

polychromatophilia［,pɒlɪ,krəʊmətə'fɪlɪjə］n． 多染（色）性；嗜多染性

normoblast［'nɔːməʊblæst］n． 正成红细胞，幼红细胞

pernicious［pə'nɪʃəs］a． 有毒的；恶性的；致命的

cobalamin［kəʊ'bæləmɪn］n． 钴胺素，维生素B12

myelophthisic［maɪələʊ'tɪzɪk］a． 骨髓抑制的

stroma［'strəʊmə］n． 基质

granuloma［ɡrænjʊ'ləʊmə］n． 肉芽肿，肉芽瘤

subtlety［'sʌtltɪ］n． 微妙，精明

scrutinize［'skruːtɪnaɪz］v． 详细检查

poikilocytosis［,pɒɪkɪləʊsaɪ'təʊsɪs］n． 异形红细胞症

morphology［mɔː'fɒlədʒɪ］n． 形态学

precursor［,priː'kзːsə］n． 前体，先质

hypoplasia［,haɪpəʊ'pleɪzjə］n． 发育不全；细胞减生

myeloid［'maɪəlɒɪd］a． 骨髓的；髓细胞样的；脊髓的

leukemoid［ljuː'kiːmɒɪd］a． 白血病样的

aplasia［ə'pleɪzɪə］n． 发育不全

megaloblastic［,meɡələʊ'blæstɪk］a． 巨成红细胞的

aspiration［,æspə'reɪʃən］n． 渴望，抱负

hematinic［hiːmə'tɪnɪk］n． 补血药

precipitating［prɪ'sɪpɪteɪtɪŋ］a． 促成的，使发生的

dividend［'dɪvɪdend］n． 益处，回报

myelodysplasia［,maɪələʊdɪs'pleɪʒə］n． 脊髓发育不良

thromboembolism［,θrɒmbəʊ'embəlɪzm］n． 血栓栓塞

remission［rɪ'mɪʃən］n． 宽恕；减轻；缓解

leukemia［ljuː'kiːmɪə］n． 白血病

intervention［ɪntə'venʃən］n． 介入，干预；调解

spar［spɑː］v． 辩论

hemoglobinopathy［'hiːməʊ,ɡləʊbɪ'nɒpəθɪ］n． 血红蛋白病

enzymopathy［,enzaɪ'mɔːpəθɪ］n． 酶（不全）病

circumvent［,sзːkəm'vent］v． 预防，防止

Notes

1．This correction should always be made if normoblasts are encountered in the peripheral blood because this finding indicates the premature release of newborn red cells into the circulation．

参考译文：如果在外周血中见到幼红细胞，就应采取这种修正计算方法，因为这一现象表明有新生红细胞在成熟前释放进入血液循环。

This correction指上文提到的the reticulocyte count should be divided by two（网织红细胞计数结果除以2）。this finding指normoblasts are encountered in the peripheral blood（在外周血中见到幼红细胞）。

2．In contrast to the mean statistical values provided by automated cell counters，microscopic examination can reveal variations in red cell size （anisocytosis）or shape（poikilocytosis）abnormalities that are helpful in diagnosing specific anemias．

参考译文：与细胞自动计数器记录的平均统计数值相比，显微镜检查可揭示红细胞大小的变化和形态异常，这有助于对特定贫血患者作出诊断。

provided．．．为过去分词短语，修饰values；that为关系代词，引导限定定语从句，修饰variations和abnormalities。

3．A note of caution has emerged from a number of large studies suggesting that high doses of r Hu EPO that drive the hemoglobin level above 120 g／L are associated with a slight but significant increase in the risk of thrombosis and cardiovascular mortality．

参考译文：一些重要研究的结果提示，可使血红蛋白水平升高至120 g／L以上的r Hu EPO（重组人促红细胞生成素）的大剂量用药与血栓形成和心血管病死亡风险的轻度但有意义的增加具有相关性。

句中 suggesting that high doses of r Hu EPO that drive．．．and cardiovascular mortality是分词短语做定语，修饰studies；第一个that引导的从句作suggesting的宾语，high doses of r Hu EPO是从句的主语，are associated with是谓语；第二个that引导限定性定语从句，修饰high doses of r Hu EPO。

4．Other primary bone marrow disorders that are unresponsive to these interventions are treated with supportive measures such as transfusions of red cells and platelets．

参考译文：对这些干预治疗无效的其他原发性骨髓病可采用红细胞和血小板输入之类的支持疗法。

that are unresponsive to these interventions为限定性定语从句，修饰disorders；are treated是主句的谓语。

5．The efficacy of splenectomy correlates with the degree to which the abnormal or defective red cells are destroyed or sequestered in the spleen．参考译文：脾切除效果与异常红细胞或受损红细胞在脾中的破坏程度或分离程度有关。

句中to which引导限定性定语从句，修饰the degree，意为“在……程度上”。e．g．Newspapers vary in the degree to which they emphasize propaganda rather than information．

Exercises

Ⅰ．Answer the following questions．

1．What does the laboratory work－up of anemia include？

2．Why is the riticulocyte count test extremely useful？

3．What is the effective treatment of anemia based on？

4．How can aplastic anemia be cured？

5．What can the microscopic examination reveal in contrast to the mean statistical values provided by automated cell counters？

Ⅱ．Decide whether the following statements are True or False．

1．Blood lose may be either the sole cause of the anemia or a significant contributor．

2．A microscopic examination of the bone marrow is often useful and may be critical in the work－up of any explained anemia．

3．Following splenectomy，both young children and adults are at risk of developing overwhelming septicemia．

4．Correction of anemia secondary to a chronic disease usually depends on whether the underlying condition can be reversed．

5．Thorough history and careful physical examination are critical in the initial evaluation of the anemic patient．