AnemiaAnemia- General aspects- General aspects

Department of HematologyDepartment of Hematology

Rui Jin HospitalRui Jin Hospital

AnemiaAnemia

Most importantMost important Related to many diseasesRelated to many diseases Diagnosed properlyDiagnosed properly Treated properlyTreated properly

What is anemia?What is anemia?

A reduction below normal in theA reduction below normal in the

- concentration of hemoglobin- concentration of hemoglobin

- red blood cells in the blood- red blood cells in the blood

- hematocrit - hematocrit （红细胞比容）（红细胞比容） The blood hemoglobin concentration The blood hemoglobin concentration

often preferredoften preferred

- accuracy and reproducibility- accuracy and reproducibility

- value most indicative of the patho-p- value most indicative of the patho-physiologic consequences of anemiahysiologic consequences of anemia

RBCRBC

（（ ×10×101212 ／／LL ） ）

HGBHGB （（ g/g/LL ））

HemotocritHemotocrit

MM 4.0-5.5 4.0-5.5

(400-550(400-550 万／万／mmmm33) )

120-160 120-160

(12-16g/dl) (12-16g/dl) 0.4-0.5 0.4-0.5

(40-50(40-50 ％％ ) )

FF 3.5-5.0 3.5-5.0

(350-500(350-500 万／万／mmmm33) )

110-150 110-150

(11-15g/dl) (11-15g/dl) 0.37-0.45 0.37-0.45

(37-45(37-45 ％％ ))

Normal range - adultNormal range - adult

Conditions associated with a signifConditions associated with a significant disproportion between the heicant disproportion between the hematocrit and RBC?matocrit and RBC? Spurious anemia (Spurious anemia ( 假性贫血假性贫血 ))

- relative increase in plasma volume- relative increase in plasma volume

hydremia of pregnancyhydremia of pregnancy

overhydration in oliguric renal foverhydration in oliguric renal failure or congestive heart failureailure or congestive heart failure

chronic diseases and hypoalbuchronic diseases and hypoalbuminemiaminemia

congestive splenomegalycongestive splenomegaly

recumbency (recumbency ( 斜卧斜卧 ))

Normoblasts

Pronormoblast

Regulation ofRegulation of e erythropoiesisrythropoiesis

How many are producedHow many are produced?? 25 billion /24 hours25 billion /24 hours The entering cells are The entering cells are

reticulocytes which should be 1% reticulocytes which should be 1% of the total population of of the total population of circulating erythrocytescirculating erythrocytes

Erythrocytes last 120 days and Erythrocytes last 120 days and are destroyed by the spleen are destroyed by the spleen

Red cell production should equal Red cell production should equal red cell destructionred cell destruction

Anemia: EtiologiesAnemia: Etiologies

Production defectsProduction defects

Blood lossBlood loss

Blood destructionBlood destruction

RBC loss without RBC RBC loss without RBC DestructionDestruction HemorrhageHemorrhage

- Due to trauma- Due to trauma- - Due to disorders: e.g.Due to disorders: e.g. cancer, ulcers, cancer, ulcers, tuberculosis, and irritable bowel syndrome tuberculosis, and irritable bowel syndrome (including ulcerative colitis and Crohn’s (including ulcerative colitis and Crohn’s disease) disease)

Menstrual flowMenstrual flow Gynecological disorders (e.g. Gynecological disorders (e.g.

endometriosis)endometriosis) Pregnancy, especially at gestationPregnancy, especially at gestation ParasitismParasitism

- - HookwormsHookworms

RBC DestructionRBC Destruction

Intrinsic AbnormalitiesIntrinsic Abnormalities ThalassemiaThalassemia G6PDG6PD Sickle Cell AnemiaSickle Cell Anemia Hereditary SpherocytosisHereditary Spherocytosis

Extrinsic AbnormalitiesExtrinsic Abnormalities InfectionsInfections

Malaria (Malaria (PlasmodiummPlasmodiumm species) species) MycoplasmaMycoplasma ( ( 支原体）支原体）

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation Lead poisoning Lead poisoning

Conditions Associated with Anemias Due to Reduced Erythrocyte Production

Anemias due to decreased erythropoietin production

• Renal disease

• Endocrine deficiency (pituitary, adrenal, thyroid, testis)

• Starvation

• Hemoglobinopathy (reduced oxygen affinity)

Anemias due to inadequate marrow response to erythropoietin

• Deficiency state (iron, vitamin B12, folate)

• Anemia of chronic disease (inflammation, infection, or malignancy)

• Sideroblastic anemia

• Primary marrow disorders-pure red cell aplasia, myelodysplasia, myelofibrosis, leukemia

• metastasis to bone marrow, osteogenic sarcoma

贫血的病理生理贫血的病理生理((pathophysiology of anemiapathophysiology of anemia))

●●RBCRBC的主要功能是输送氧气的主要功能是输送氧气 ● ●正常血液一克正常血液一克 HbHb能携带能携带 1.34ml1.34ml氧氧 ● ●贫血的病理生理基础是血液携氧能力贫血的病理生理基础是血液携氧能力减低，组织缺氧减低，组织缺氧

● ●机体对缺氧进行代偿和适应机制如下机体对缺氧进行代偿和适应机制如下

贫血的病理生理贫血的病理生理

心脏搏出量增加心脏搏出量增加 贫血患者因贫血患者因 RBCRBC 减少，血液粘度减减少，血液粘度减

低和选择性的周围血管扩张，周围血低和选择性的周围血管扩张，周围血管阻力减低管阻力减低

心率加速，循环速度加快心率加速，循环速度加快 为防止对机体供氧量减少，心脏排血为防止对机体供氧量减少，心脏排血

量增加量增加

贫血的病理生理贫血的病理生理

增加组织的灌注增加组织的灌注 ： ：贫血时血液供应重新分贫血时血液供应重新分配，供血减少区域为皮肤组织和肾脏，故配，供血减少区域为皮肤组织和肾脏，故皮肤苍白，对缺氧敏感的心肌、脑和肌肉皮肤苍白，对缺氧敏感的心肌、脑和肌肉供血量增加供血量增加

肺的代偿机能肺的代偿机能 ： ：贫血时呼吸加快、加深、贫血时呼吸加快、加深、呼吸增强，但这并不能得到更多的氧，这呼吸增强，但这并不能得到更多的氧，这可能是对组织缺氧的一种反应可能是对组织缺氧的一种反应

贫血的病理生理贫血的病理生理

氧解离曲线右移氧解离曲线右移 在缓慢发生的贫血，在缓慢发生的贫血， RBCRBC 内内 22 、、 33

二磷酸甘油酸（二磷酸甘油酸（ 22 、、 33 －－ DPGDPG ））的合成增加的合成增加

22 、、 33 －－ DPGDPG 使使 HbHb 与氧的亲和与氧的亲和力减低力减低

促进促进 Hb O2Hb O2 解离曲线右移，使组解离曲线右移，使组织在氧分压降低的情况下能摄取更织在氧分压降低的情况下能摄取更多的氧多的氧

Clinical manifestationClinical manifestation

First symptomFirst symptom

- decreased work tolerance- decreased work tolerance

- shortness of breath- shortness of breath

- palpitations- palpitations

- other signs of cardiorespiratory adj- other signs of cardiorespiratory adjustments to anemiaustments to anemia

- at times, they feel fine, but their frie- at times, they feel fine, but their friends or family notes the pallornds or family notes the pallor

The manifestations depend onThe manifestations depend on

The reduction in the oxygen-carrying The reduction in the oxygen-carrying capacity of the bloodcapacity of the blood

The degree of change in total blood The degree of change in total blood volumevolume

The rate at which these two factors The rate at which these two factors developeddeveloped

The capacity of the cardiovascular The capacity of the cardiovascular and pulmonary systems to and pulmonary systems to compensate for the anemiacompensate for the anemia

The associated manifestations of the The associated manifestations of the underlying disorderunderlying disorder

Cardiorespiratory system Cardiorespiratory system

Noticeable only after exertion or excitNoticeable only after exertion or excitementement

Dyspnea and awareness of vigorous Dyspnea and awareness of vigorous or rapid heart action noted at restor rapid heart action noted at rest

Shortness of breath, tachycardia, dizShortness of breath, tachycardia, dizziness or faintness, and extreme fatiziness or faintness, and extreme fatiguegue

Congestive heart failure, angina pectCongestive heart failure, angina pectoris, intermittent claudication oris, intermittent claudication （间歇（间歇性跛行）性跛行）

Cardiorespiratory systemCardiorespiratory system

Left ventricular hypertrophy Left ventricular hypertrophy Heart murmursHeart murmurs

- systolic in pulmonic area- systolic in pulmonic area Electrocardiographic changesElectrocardiographic changes

- depression of the ST junction- depression of the ST junction- U-shaped deformation of the - U-shaped deformation of the S-T segmentS-T segment- inverted T waves- inverted T waves

The skinThe skin

Pallor – most evident signPallor – most evident sign- dilation of the peripheral vessels- dilation of the peripheral vessels- degree and nature of the - degree and nature of the pigmentationpigmentation- nature and fluid content of the - nature and fluid content of the subcutaneous tissuessubcutaneous tissues- jaundice, cyanosis…- jaundice, cyanosis…

Detected most accurately in the Detected most accurately in the mucous membranes of the mouth mucous membranes of the mouth and pharynx, conjunctivae, lips, and and pharynx, conjunctivae, lips, and the nail beds, palms of the handsthe nail beds, palms of the hands

Tell anemia from the color of Tell anemia from the color of the skin…the skin… A waxy, dead whitenessA waxy, dead whiteness

- acute blood loss- acute blood loss A distinctly sallow A distinctly sallow （灰黄色）（灰黄色） colorcolor

- chronic anemia- chronic anemia A lemon-yellow pallorA lemon-yellow pallor

- pernicious anemia- pernicious anemia （恶性贫血）（恶性贫血） Marked pallor associated with petechMarked pallor associated with petech

iae or ecchymosesiae or ecchymoses （瘀斑）（瘀斑）- acute leukemia- acute leukemia

Neuromuscular systemNeuromuscular system

HeadacheHeadache VertigoVertigo TinnitusTinnitus 　（耳鸣）　（耳鸣） FaintnessFaintness Scotomata Scotomata （盲点）（盲点） Lack of mental concentrationLack of mental concentration DrowsinessDrowsiness RestlessnessRestlessness Muscular weaknessMuscular weakness

Gastrointestinal systemGastrointestinal system

Underlying diseases: ulcer, cancerUnderlying diseases: ulcer, cancer Glossitis and atrophy of the papillae Glossitis and atrophy of the papillae

of the tongueof the tongue Painful, ulcerative, and necrotic lesioPainful, ulcerative, and necrotic lesio

ns in the mouth and pharynx (aplastins in the mouth and pharynx (aplastic anemia, acute leukemia)c anemia, acute leukemia)

Dysphagia Dysphagia

(chronic iron-deficiency anemia)(chronic iron-deficiency anemia)

OthersOthers

Retinopathy: 20%Retinopathy: 20%- flame-shaped hemorrhages- flame-shaped hemorrhages

Slight proteinuria Slight proteinuria Fever of mild degreeFever of mild degree Hemolytic anemiaHemolytic anemia

- jaundice- jaundice- hemoglobinemia, pain in the a- hemoglobinemia, pain in the abdomen or back bdomen or back

Evaluation and diagnosisEvaluation and diagnosis

Medical HistoryMedical History Physical examinationPhysical examination Laboratory testsLaboratory tests Morphologic featuresMorphologic features

Medical historyMedical history

The duration of the symptoms aThe duration of the symptoms and their onset (insidious/acute)nd their onset (insidious/acute)

Family history of jaundice, splenFamily history of jaundice, splenectomy, bleeding disorders, and ectomy, bleeding disorders, and hemoglobin-associated abnormhemoglobin-associated abnormalitiesalities

Occupation, drugs, solvents and Occupation, drugs, solvents and other chemicalsother chemicals

OthersOthers

Stool habits: neoplasms of the colon Stool habits: neoplasms of the colon and rectum, hemorrhoidsand rectum, hemorrhoids

Women: blood lost during menstruatiWomen: blood lost during menstruationon

Child or adolescent: growth rateChild or adolescent: growth rate Dietary historyDietary history Fever: infection, lymphoma, collagen Fever: infection, lymphoma, collagen

disease, etc.disease, etc. Bruises, ecchymoses, and petechiaeBruises, ecchymoses, and petechiae

Physical examinationPhysical examination

Icterus Icterus 黄疸 黄疸 (hemolytic)(hemolytic) Sternal tenderness (leukemia)Sternal tenderness (leukemia) Lymph nodes enlargements (infLymph nodes enlargements (inf

ection, lymphoma, leukemia, meection, lymphoma, leukemia, metastatic carcinoma)tastatic carcinoma)

Cardiac murmurs (bacterial endCardiac murmurs (bacterial endocarditis)ocarditis)

Liver, spleen, and kidneysLiver, spleen, and kidneys

Morphologic featureMorphologic feature

Blood smearBlood smear

Bone marrow examinationBone marrow examination

ClassificationClassification

Impaired erythrocyte productionImpaired erythrocyte production- hypoproliferative- hypoproliferative

iron-deficient erythropoiesisiron-deficient erythropoiesiserythropoietic deficiencyerythropoietic deficiencyhypoplastic anemiahypoplastic anemiainfiltrationinfiltration

- ineffective- ineffectivemegaloblasticmegaloblasticmicrocyticmicrocytic

Increased erythrocyte productionIncreased erythrocyte production- hemolytic anemia- hemolytic anemia

Anemia?

Production? SurvivalDestruction?

The key test is the …..

The reticulocyte countThe reticulocyte count

Increased reticulocytes (greater than Increased reticulocytes (greater than 2-3% or 100,000/mm2-3% or 100,000/mm33 total) are seen total) are seen in blood loss and hemolytic processein blood loss and hemolytic processes, although up to 25% of hemolytic as, although up to 25% of hemolytic anemias will present with a normal retinemias will present with a normal reticulocyte count due to immune destruculocyte count due to immune destruction of red cell precursors. ction of red cell precursors.

Retic counts are most helpful if extreRetic counts are most helpful if extremely low (<0.1%) or greater than 3% mely low (<0.1%) or greater than 3% (100,000/mm(100,000/mm33 total). total).

Another step of diagnosisAnother step of diagnosis

AnemiaAnemia

Erythrocyte indicesErythrocyte indices

blood smearblood smear

MCV>100MCV>100 MCV 80-100 MCV 80-100 MCV<80MCV<80

MacrocyticMacrocytic Normocytic Normocytic MicrocyticMicrocytic

(( 大细胞性大细胞性 )) ( ( 正常细胞性正常细胞性 )) (( 小细胞小细胞性性 ))

Macrocytic anemiasMacrocytic anemias

Vitamin B12 or folate deficiencyVitamin B12 or folate deficiency Accelerated erythropoiesisAccelerated erythropoiesis

- hemolytic anemia - hemolytic anemia Erythroleukemia (Erythroleukemia ( 红白血病红白血病 )) Increased membrane surfaceIncreased membrane surface

- hepatic disease, obstructive jaundic- hepatic disease, obstructive jaundicee

Refractory anemiasRefractory anemias- myelodysplastic anemias- myelodysplastic anemias

Normal, RBC's. They have a zone of central Normal, RBC's. They have a zone of central pallor about 1/3 the size of the RBC.). A few pallor about 1/3 the size of the RBC.). A few small fuzzy blue platelets are seen. In the small fuzzy blue platelets are seen. In the center of the field are a band neutrophil on the center of the field are a band neutrophil on the left and a segmented neutrophil on the right.left and a segmented neutrophil on the right.

Note the hypersegmented neurotrophil and also that the RBC are almost as large as the lymphocyte. Finally, note that there are fewer RBCs.

Vitamin B12 deficiencyVitamin B12 deficiency

Dietary deficiency (rare)Dietary deficiency (rare) Lack of intrinsic factorLack of intrinsic factor

- pernicious anemia- pernicious anemia- gastric surgery- gastric surgery

Functionally abnormal intrinsic factorFunctionally abnormal intrinsic factor Biologic competitionBiologic competition

- small-bowel bacterial overgrowth- small-bowel bacterial overgrowth Drug-induced vitamin B12 malabsorptionDrug-induced vitamin B12 malabsorption Chronic disease of the pancreasChronic disease of the pancreas Zollinger-Ellision syndromeZollinger-Ellision syndrome HemodialysisHemodialysis

Folate deficiencyFolate deficiency

Dietary deficiencyDietary deficiency Increased requirementsIncreased requirements

- alcoholism and cirrhosis- alcoholism and cirrhosis

- pregnancy- pregnancy

- infancy- infancy Congenital folate deficiencyCongenital folate deficiency Extensive intestinal resectionExtensive intestinal resection

DiagnosisDiagnosis

SmearSmear

- Macrocytic (High MCV) RBCs, +/- h- Macrocytic (High MCV) RBCs, +/- hypersegmented neutrophils, +/- modypersegmented neutrophils, +/- modest neutropeniaest neutropenia

B12B12

- Low serum B12 level- Low serum B12 level FolateFolate

- Serum folate level -- can normalize - Serum folate level -- can normalize with a single good mealwith a single good meal

Neurological presentation of B12 deficiency Paresthesias of fingers & toes Reduced vibration sense (256-Hz) Ataxia 共计失调 (Combined system

disease) Perversion of taste & smell Optic atrophy Dementia ( 痴呆 ), Memory Loss & D

epression “Megaloblastic Madness” – Paranoid

Schizophrenia Specific MRI abnormalities

TreatmentTreatment

B12 deficiencyB12 deficiency

- B12 1 mg/month IM, or 1-2 mg/day - B12 1 mg/month IM, or 1-2 mg/day popo

Folate deficiencyFolate deficiency

- Improved diet, - Improved diet, 5mg tablets5mg tablets Monitor for a response to therapyMonitor for a response to therapy Pernicious Anemia – monitor for GI cPernicious Anemia – monitor for GI c

ancersancers

FoodFood

B12 deficiencyB12 deficiency MeatMeat EggsEggs

Folate deficiencyFolate deficiency Green vegebablesGreen vegebables NutsNuts CerealCereal FruitFruit YeastYeast

Microcytic anemiasMicrocytic anemias

Disorders of iron metabolismDisorders of iron metabolism

- iron-deficiency anemia- iron-deficiency anemia

- anemia of chronic disorders- anemia of chronic disorders Disorders of globin synthesisDisorders of globin synthesis

- thalassemias- thalassemias

- hemoglobin E and C disease- hemoglobin E and C disease Sideroblastic anemiaSideroblastic anemia

The RBC's here are smaller than normal and have The RBC's here are smaller than normal and have an increased zone of central pallor. This is an increased zone of central pallor. This is indicative of a hypochromic (less hemoglobin in indicative of a hypochromic (less hemoglobin in each RBC) microcytic (smaller size of each RBC) each RBC) microcytic (smaller size of each RBC) anemia. There is also increased anisocytosis anemia. There is also increased anisocytosis (variation in size) and poikilocytosis (variation in (variation in size) and poikilocytosis (variation in shape).shape).

Iron Deficiency Anemia vs. Iron Deficiency Anemia vs. anemia of chronic disorders anemia of chronic disorders

SmearSmear- hypochromic and microcytic (low MCV) R- hypochromic and microcytic (low MCV) RBCs, usually not seen unless Hct BCs, usually not seen unless Hct 30% 30%- platelet count is often elevated- platelet count is often elevated

Ferritin: a measure of total body iron stores,Ferritin: a measure of total body iron stores, but also an acute phase reactant but also an acute phase reactant- <15- <15g/l = Fe deficiencyg/l = Fe deficiency- - 150 150 g/l = Not Fe deficiency g/l = Not Fe deficiency - 15-150 - 15-150 g/l = Not conclusiveg/l = Not conclusive

Bone marrowBone marrow- absent Fe stores Gold standard for IDA- absent Fe stores Gold standard for IDA

ThalassemiasThalassemias

Genetic defect in hemoglobin synthesisGenetic defect in hemoglobin synthesis- - synthesis of one of the 2 globin chains synthesis of one of the 2 globin chains (( or or ))- Imbalance of globin chain synthesis leads - Imbalance of globin chain synthesis leads to depression of hemoglobin production anto depression of hemoglobin production and precipitation of excess globin (toxic)d precipitation of excess globin (toxic)- “Ineffective erythropoiesis”- “Ineffective erythropoiesis”- Ranges in severity from asymptomatic to i- Ranges in severity from asymptomatic to incompatible with life (hydrops fetalis)ncompatible with life (hydrops fetalis)- Found in people of African, Asian, and Me- Found in people of African, Asian, and Mediterranean heritagediterranean heritage

ThalassemiasThalassemias

DiagnosisDiagnosis- Smear: microcytic/hypochromic- Smear: microcytic/hypochromic- - -thal will have an abnormal Hgb -thal will have an abnormal Hgb electrophoresis (electrophoresis (HbAHbA22,, HbF)HbF)- The more severe - The more severe -thal syndromes ca-thal syndromes can have HbH inclusions in RBCsn have HbH inclusions in RBCs- Fe stores are usually elevated- Fe stores are usually elevated

TreatmentTreatment- Mild: None- Mild: None- Severe: RBC transfusions + Fe ch- Severe: RBC transfusions + Fe chelation, Stem cell transplantselation, Stem cell transplants

Sideroblastic AnemiasSideroblastic Anemias

Heterogenous grouping of anemias defined Heterogenous grouping of anemias defined by presence of ringed sideroblasts in the Bby presence of ringed sideroblasts in the BMM

EtiologiesEtiologies- Hereditary (rare)- Hereditary (rare)- Myelodysplasia- Myelodysplasia- EtOH- EtOH- Drugs (INH, Chloramphenicol - Drugs (INH, Chloramphenicol 氯霉素氯霉素 ))

TreatmentTreatment- Trial of pyridoxine for hereditary or INH in- Trial of pyridoxine for hereditary or INH induced sideroblastic anemiaduced sideroblastic anemia

Normocytic anemiasNormocytic anemias

Associated with appropriately increased eryAssociated with appropriately increased erythrocyte productionthrocyte production- posthemorrhagic anemia- posthemorrhagic anemia- hemolytic anemia- hemolytic anemia

Associated with impaired marrow responseAssociated with impaired marrow response- intrinsic bone marrow disease- intrinsic bone marrow disease

hypoplasiahypoplasiainfiltration of the bone marrowinfiltration of the bone marrow

- decreased erythropoietin secretion- decreased erythropoietin secretionrenalrenal

TherapyTherapy

EtiologyEtiology 急、慢性失血而致的贫血：相应

的治疗措施 药物诱发的溶血性贫血或血型不

合输血引起的溶血反应所致的贫血：停用药物或停止输血

对营养不良性贫血：补充铁剂、叶酸或维生素 B12 ，针对原因进行纠正或治疗

TherapyTherapy

Drug treatmentDrug treatment

1.Iron ：亚铁制剂仅对缺铁性贫血有效对非缺铁性贫血长期应用是有害的。

2.Folic acid and VitaminB12 ：仅对缺乏这两种维生素的巨幼细胞贫血有效。溶血性贫血可补充叶酸。

TherapyTherapy

3. Vitamin B6 ： 100mg 2 ～ 3 次 /d 部分铁粒幼细胞贫血有效。4.Glucocorticoid( 糖皮质激素 ) ： 自身免疫性溶血性贫血 再生障碍性贫血或阵发性睡眠性血红蛋白尿 发作期，尤其有出血倾向时。5. Androgen( 雄激素 ) ： 长期（＞ 3 ～ 6 月）应用于再生障碍性贫血。 一些慢性疾病伴发的贫血有一定疗效。6. Epoetin （ EPO ）：可纠正肾性贫血。

TherapyTherapy

Transfusion support ：急性大量失血时：恢复血容量及纠正贫血。慢性贫血有明显缺氧症状者：减轻症状。长期多次输血：负荷过重或继发性血色病。

TherapyTherapy

Splenectomy ： 红细胞破坏的主要场所，与抗体的产生有关。 可使遗传性球形细胞增多症及脾功能亢进患者的红细胞破坏减少，减轻贫血。 用糖皮质激素难以维持疗效的自身免疫性溶血性贫血，有一定疗效。

TherapyTherapy

Marrow transplantation ：- 重型再生障碍性贫血- 部分重型珠蛋白生成障碍性贫血- 骨髓增生异常综合征