1 pathophysiology of hematopoietic system disorders mehtap kaÇar koÇak m.d. phd pathophysiologist...

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PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF HEMATOPOIETIC SYSTEM HEMATOPOIETIC SYSTEM

DISORDERSDISORDERS

Mehtap KAÇAR KOÇAK M.D. PhDMehtap KAÇAR KOÇAK M.D. PhDPathophysiologistPathophysiologist

Yeditepe University, Faculty of Yeditepe University, Faculty of MedicineMedicine

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Learning objectivesLearning objectives• Alterations of erythrocyte function:Alterations of erythrocyte function:

• Anemia’s,Anemia’s,• Myeloproliferative RBC disordersMyeloproliferative RBC disorders

• Alterations of platelets and coagulation:Alterations of platelets and coagulation:• Disorders of platelets,Disorders of platelets,• Disorders of coagulation.Disorders of coagulation.

• Alterations of leukocyte function:Alterations of leukocyte function:• Infectious mononucleosis,Infectious mononucleosis,• Leukemias.Leukemias.

• Alterations of lymphoid function:Alterations of lymphoid function:• Lympadenopathy,Lympadenopathy,• Malignant Lymphomas.Malignant Lymphomas.

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ALTERATIONS OF ALTERATIONS OF ERYTHROCYTE FUNCTION:ERYTHROCYTE FUNCTION:

•AnemiasAnemias

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AnemiasAnemias• Anemia is defined as Anemia is defined as

hematocrit or hemoglobin hematocrit or hemoglobin below the lower limit of normal.below the lower limit of normal.

• For men the lower limit is a For men the lower limit is a hematocrit of less than 41% or hematocrit of less than 41% or hemoglobin less than 13.5g/dL. hemoglobin less than 13.5g/dL.

• For women the limit is a For women the limit is a hematocrit less than 36% or hematocrit less than 36% or hemoglobin less thanhemoglobin less than 12g/dL. 12g/dL.

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Classification of Classification of AnemiasAnemias

Anemias are classified in two ways, Anemias are classified in two ways, according to their etiology or according to their etiology or their morphology. their morphology.

Morphologic classification is based Morphologic classification is based on two cellular characteristics: on two cellular characteristics: size and hemoglobin content size and hemoglobin content

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Microcytic hypochromic Microcytic hypochromic anemiasanemias

• Iron Deficiency AnemiaIron Deficiency Anemia• Sideroblastic AnemiaSideroblastic Anemia• ThalassemiaThalassemia

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Iron Deficiency AnemiaIron Deficiency Anemia• Total body iron equals Total body iron equals

approximately 3800mg in adult approximately 3800mg in adult males and 2500mg in adult males and 2500mg in adult females. females.

• Iron is present in hemoglobin, a Iron is present in hemoglobin, a small amount in myoglobin and small amount in myoglobin and iron-containing enzymes, and iron-containing enzymes, and the remainder in a storage form.the remainder in a storage form.

• In normal circumstances, stored In normal circumstances, stored iron amounts to 1000mg for men iron amounts to 1000mg for men and 300mg for women. 16mg of and 300mg for women. 16mg of iron is present in the iron is present in the hemoglobin of developing hemoglobin of developing erythrocytes daily. erythrocytes daily.

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Iron pathway in the body• The following explains the pathway of iron in The following explains the pathway of iron in

the body: the body: • 1. Iron is placed in developing red blood cells 1. Iron is placed in developing red blood cells

in the bone marrow. The young blood cells in the bone marrow. The young blood cells are released into the blood stream and are released into the blood stream and circulate for 120 days; circulate for 120 days;

• 2. Old erythrocytes are removed from 2. Old erythrocytes are removed from circulation by macrophages of the spleen and circulation by macrophages of the spleen and bone marrow. Iron is liberated from the bone marrow. Iron is liberated from the hemoglobin (Hb) and stored as ferritin and hemoglobin (Hb) and stored as ferritin and hemosiderin or released to transferrin, the hemosiderin or released to transferrin, the plasma iron transporting protein; and, plasma iron transporting protein; and,

• 3. Iron bound to transferrin is carried in the 3. Iron bound to transferrin is carried in the plasma to the bone marrow for uptake by the plasma to the bone marrow for uptake by the erythroid precusors.erythroid precusors.

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Absorption of Absorption of IronIron• Iron is absorbed maximally in the duodenum and Iron is absorbed maximally in the duodenum and

jejunum. Under normal circumstances, small jejunum. Under normal circumstances, small losses of less than 1.0mg/day occur in males losses of less than 1.0mg/day occur in males mainly through desquamation of epithelial cells. mainly through desquamation of epithelial cells. Losses are higher in females of childbearing years Losses are higher in females of childbearing years secondary to menstrual blood loss, averaging secondary to menstrual blood loss, averaging approximately 1.5mg/day. approximately 1.5mg/day.

• Normally the amount of iron absorbed from the Normally the amount of iron absorbed from the diet equals the obligatory loss, and an increase in diet equals the obligatory loss, and an increase in the amount of dietary loss is associated with a the amount of dietary loss is associated with a decrease in the proportion eventually absorbed. decrease in the proportion eventually absorbed.

• Sources of iron are heme iron, contained in meat, Sources of iron are heme iron, contained in meat, fish and liver, which is more readily absorbed and fish and liver, which is more readily absorbed and non-heme iron which is contained in vegetables non-heme iron which is contained in vegetables and legumes. and legumes.

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Absorption of Absorption of IronIron• Vit C, amino acids promote absorptionVit C, amino acids promote absorption• Tea, vegTea, vegetableetable fiber increase uptake fiber increase uptake• Gastric acid helps in solubilityGastric acid helps in solubility

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Prevalans of Prevalans of Iron Iron Deficiency AnemiaDeficiency Anemia

• Iron deficiency is the most Iron deficiency is the most common nutritional deficiency common nutritional deficiency world wide. In the United world wide. In the United States, the prevalence is high States, the prevalence is high in women of childbearing age, in women of childbearing age, in infants, and adolescents in infants, and adolescents whose rapid growth require whose rapid growth require increased iron supply to increased iron supply to support an increase in red cell support an increase in red cell mass. mass.

• Iron deficiency in men or in Iron deficiency in men or in non-menstruating women is the non-menstruating women is the result of blood loss, often from result of blood loss, often from the G.I. tract. the G.I. tract.

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Iron DeficiencyIron Deficiency• Lack of body iron is divided into

two categories:

1.Iron deficiency without anemia: the storage iron is absent but the deficit in iron is not large enough to decrease the hemoglobin level to below normal.

2.Iron deficiency anemia: the deficit is so severe that stores are absent and the hemoglobin is frankly below the normal range.

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Iron Deficiency Anemia - Iron Deficiency Anemia - CausesCauses

• Inadequate dietary ironInadequate dietary iron• Blood lossBlood loss

• Generally signifies pathological loss such as Generally signifies pathological loss such as G.I. bleeding (ulcers, gastritis, IFB, tumorsG.I. bleeding (ulcers, gastritis, IFB, tumors)), , vascular malformations, hookworm vascular malformations, hookworm infestations, frequent bloodinfestations, frequent blood donationsdonations,, menorrhagia, chronic alcoholismmenorrhagia, chronic alcoholism

• ~ 50% on renal dialysis show deficiency~ 50% on renal dialysis show deficiency Most common anemia in all age groupsMost common anemia in all age groups Most common anemia in the worldMost common anemia in the world

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Iron Deficiency AnemiaIron Deficiency Anemia• Clinical featuresClinical features

• FatigueFatigue• IrritabilityIrritability• HeadachesHeadaches• ParesthesiasParesthesias• PallorPallor• Glossitis (a Glossitis (a

smooth red smooth red tongue)tongue)

• Angular cheilitis Angular cheilitis • Koilonychia Koilonychia

(spooning of the (spooning of the nails)nails)

• Pica (eating ice, Pica (eating ice, clay, dirt)clay, dirt)

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Smooth tongueSmooth tongue cheilosischeilosis

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Laboratory findingsLaboratory findings

• Laboratory findings determine if:Laboratory findings determine if:• Degree of anemia is mild to severeDegree of anemia is mild to severe• Mean corpuscular volume is decreasedMean corpuscular volume is decreased• Red cell distribution width is decreasedRed cell distribution width is decreased

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Laboratory findingsLaboratory findings• Laboratory findings determine Laboratory findings determine

if:if:• White blood cells are normalWhite blood cells are normal• Platelets are normal to increasedPlatelets are normal to increased• Serum ferritin is low (12microg/L)Serum ferritin is low (12microg/L)

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ManagementManagement

• Identify cause, correct if possibleIdentify cause, correct if possible• Oral iron therapyOral iron therapy

• Adult dose 200 mg/day elemental ironAdult dose 200 mg/day elemental iron• Pediatric dose 5mg/kg/day elementalPediatric dose 5mg/kg/day elemental

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ManagementManagement• ManagementManagement

• Duration: Anemia usually corrected in Duration: Anemia usually corrected in 4-6 wks, continue for 3-6 mo, check 4-6 wks, continue for 3-6 mo, check serum ferritin concentrationserum ferritin concentration

• Parenteral Parenteral Management Management • Iron dextran (INFeDIron dextran (INFeD®®))• Iron sucrose (FERRLECITIron sucrose (FERRLECIT®®, VENOFER, VENOFER®®

• Has less severe reaction than with iron dextranHas less severe reaction than with iron dextran

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Sideroblastic AnemiaSideroblastic Anemia (SA)(SA)

• SA are a heterogenous group of SA are a heterogenous group of disorders characterized by anemia of disorders characterized by anemia of varying severity caused by a deviation varying severity caused by a deviation in mitochondrial metabolism.in mitochondrial metabolism.

• Its cIts can be acquired or hereditaryan be acquired or hereditary, , aacquired SA is the most commoncquired SA is the most common..

• Altered mitochondrial metabolism Altered mitochondrial metabolism causes ineffective iron uptake resulting causes ineffective iron uptake resulting in dysfunctional hemoglobin synthesis.in dysfunctional hemoglobin synthesis.

• Characterized by the presence of ringed Characterized by the presence of ringed sideroblasts in the bone marrow sideroblasts in the bone marrow :: red red cells containing iron granules that have cells containing iron granules that have not been synthesized into hemoglobin, not been synthesized into hemoglobin, but instead are arranged in a circle but instead are arranged in a circle around the nucleus.around the nucleus.

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Ringed sideroblast

The nucleated red blood cells indicated by the arrows in this bone marrow stained for iron are ringed sideroblasts. The mitochondria, which form a crown around the nucleus, contain iron. It is often asked how far must the crown extend around the nucleus for the cell to be a ringed sideroblast; it should extend at least halfway around. Ringed sideroblasts are seen in the bone marrow of patients with heavy metal intoxication, pernicious anemia, and other dyserythropoietic disorders.

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Acquired Idiopathic Acquired Idiopathic Sideroblastic AnemiaSideroblastic Anemias s

(AISA)(AISA)• The most prevalent causes of The most prevalent causes of

AISA are caused by toxins that are AISA are caused by toxins that are often associated with alcoholism, often associated with alcoholism, drugs (antituberculosis agents drugs (antituberculosis agents such as INH, pyrazinamide, and such as INH, pyrazinamide, and cycloserine; and cycloserine; and chloramphenicol), nutritional chloramphenicol), nutritional deficiences, and hypothermia. deficiences, and hypothermia.

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Acquired Idiopathic Acquired Idiopathic Sideroblastic AnemiaSideroblastic Anemias s

(AISA)(AISA)• Disruptions to the mitochondria that Disruptions to the mitochondria that

contribute to development of AISA contribute to development of AISA appear to be related to alterations in appear to be related to alterations in mitochondrial iron metabolism.mitochondrial iron metabolism.

• Mitochondrial damage causes iron not Mitochondrial damage causes iron not converted (reduced) from the ferric form converted (reduced) from the ferric form (Fe+3) to the ferrous form (Fe+2).(Fe+3) to the ferrous form (Fe+2).

• Iron is stored as ferric but requires Iron is stored as ferric but requires conversion to ferrous by ferrochelatase conversion to ferrous by ferrochelatase for use in heme synthesis. for use in heme synthesis.

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• Alcohol and drugs reduce ALA Alcohol and drugs reduce ALA (aminolevulinic acid) synthesis, thus (aminolevulinic acid) synthesis, thus decreasing heme generations.decreasing heme generations.

• Nutritional deficiencies causing AISA Nutritional deficiencies causing AISA are related to folate and copper. are related to folate and copper. Copper deficiency is thought to Copper deficiency is thought to interfere with conversion of ferric interfere with conversion of ferric iron to ferrous iron.iron to ferrous iron.

• Hypothermia may be a contributing Hypothermia may be a contributing factor because it causes diminished factor because it causes diminished heme synthesis and incorporation of heme synthesis and incorporation of iron into Hb.iron into Hb.

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Hereditary SAsHereditary SAs

• Its occur almost exclusively in Its occur almost exclusively in males, supporting a recessive males, supporting a recessive X-linked transmission (XLSA);X-linked transmission (XLSA);

• however, autosomal recessive however, autosomal recessive transmission has been transmission has been associated with genetic and associated with genetic and mitochondrial mutations and mitochondrial mutations and deficiencies of ferrochelatase in deficiencies of ferrochelatase in both genders.both genders.

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X-linked SAX-linked SA• XLSA has been linked to missense mutations XLSA has been linked to missense mutations

in the erythroid-specific ALA synthase gene.in the erythroid-specific ALA synthase gene.• ALAS is the first and rate-limiting enzyme ALAS is the first and rate-limiting enzyme

used in the heme biosynthesis pathway.used in the heme biosynthesis pathway.• ALAS uses pyridoxal phosphates as cofactors ALAS uses pyridoxal phosphates as cofactors

for the synthesis of protoporphyrin IX.for the synthesis of protoporphyrin IX.• Protoporphyrin IX is normally combined with Protoporphyrin IX is normally combined with

iron to produce heme.iron to produce heme.• Reduction in the synthesis of protoporphyrin Reduction in the synthesis of protoporphyrin

IX results in the characteristics accumulation IX results in the characteristics accumulation of iron in the erythrocyte.of iron in the erythrocyte.

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Clinical manifestationsClinical manifestations• Moderate to severe anemia (Hb Moderate to severe anemia (Hb

levels 4-10 g/dl) levels 4-10 g/dl) • Along with cardiovascular and Along with cardiovascular and

respiratory manifestations of respiratory manifestations of anemia, may also show signs of anemia, may also show signs of iron overload (iron overload (erythropoietic erythropoietic hemohemochromatoschromatosis)is)• Enlargement of spleen and liverEnlargement of spleen and liver• Bronze tint to skinBronze tint to skin• Heart rhythm disturbancesHeart rhythm disturbances• Impaired growth and development in Impaired growth and development in

young childrenyoung children

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Treatment Treatment

• Drug therapy – pyridoxineDrug therapy – pyridoxine• Iron overload requires Iron overload requires

repeated blood removal – repeated blood removal – phlebotomiesphlebotomies

• Iron chelating agents in Iron chelating agents in anemic individuals who require anemic individuals who require transfusionstransfusions

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ThalassemiaThalassemiass• Thalassemias: hereditary anemias

characterized by hypochromia, extreme microcytosis, hemolysis

• The alpha- and beta-thalassemias are inherited autosomal recessive disorders that cause an impaired rate of synthesis of one of the two chains- α or β- of adult Hb (HbA).

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ThalassemiaThalassemiass• β β -thalassemia, in which synthesis of the -thalassemia, in which synthesis of the ββ

globin chain is slowed or defective, is globin chain is slowed or defective, is prevalent among Greeks, Italians, Turkish, prevalent among Greeks, Italians, Turkish, Sephardic jews, and some Arabs. Sephardic jews, and some Arabs.

• αα- thalassemia, in which the - thalassemia, in which the αα chain is chain is affected, is most common among Chinese, affected, is most common among Chinese, Vietnamese, Cambodians, and Latoians.Vietnamese, Cambodians, and Latoians.

• β β or or αα- thalassemia can be major or minor, - thalassemia can be major or minor, depending on how many of the genes that depending on how many of the genes that control control β β or or αα chain synthesis are defective chain synthesis are defective and whether the defects are inherited and whether the defects are inherited homozygously (thalassemia major) or homozygously (thalassemia major) or heterozygously (thalassemia minor). heterozygously (thalassemia minor).

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β β -thalassemia-thalassemia• The fundamental defect is the The fundamental defect is the

uncoupling of uncoupling of αα and and ββ chain synthesis. chain synthesis. • ββ chain production is depressed – chain production is depressed –

moderately in the heterozygous form moderately in the heterozygous form ββ-thalassemia minor, and severely in -thalassemia minor, and severely in the homozygous form, the homozygous form, ββ-thalassemia -thalassemia major (also called Cooley anemia).major (also called Cooley anemia).

• Depression of Depression of ββ chain syhnthesis chain syhnthesis results in erythrocytes having a results in erythrocytes having a reduced amount of Hb and reduced amount of Hb and accumulations of free accumulations of free αα chains. chains.

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β β -thalassemia-thalassemia• The free The free αα chains are unstable and chains are unstable and

easily precipitate in the cell.easily precipitate in the cell.• Most eryhtroblasts that contain Most eryhtroblasts that contain

precipitates are destroyed by precipitates are destroyed by mononuclear phagocytes in the mononuclear phagocytes in the marrow, resulting in ineffective marrow, resulting in ineffective erythropoiesis and anemia. erythropoiesis and anemia.

• Some of the precipitate-carrying cells Some of the precipitate-carrying cells do mature and enter the bloodstream, do mature and enter the bloodstream, but they are destroyed prematurely in but they are destroyed prematurely in the spleen, resulting in mild hemolytic the spleen, resulting in mild hemolytic anemia.anemia.

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ββ-Thalassemia-Thalassemia• Cooley Anemia

• Thalassemia minor or Thalassemia trait - mild microcytic anemia – no treatment necessary

• Thalassemia intermedia – severe anemia• Thalassemia major – severe anemia

requires transfusions

• The patients have a selective advantage to malaria.

• Severe anemia - cardiac failure and death in early childhood without transfusion support

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Clinical manifestations of Clinical manifestations of β β --ThalassemiaThalassemia

• β β -Thalassemia-Thalassemia minor causes:Mild to moderate microcytic-hypochromic

anemia,Mild splenomegaly,Bronze coloring of the skin,Slight elevation in serum iron and indirect

bilirubin levels,And hyperplasia of the bone marrow. • The degree of reticulocytosis depends on the

severity of the anemia, resulting in skeletal changes.

• Overabundance of erythrocytes formed by bone marrow leads to bone marrow expansion.

• Patients are usually asymptomatic.

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Clinical manifestations of Clinical manifestations of β β --ThalassemiaThalassemia

• β β -Thalassemia-Thalassemia major causes:Severe anemia which results in high-

output congestive heart failure,Liver enlargement due to progressive

hemosiderosis,Spleen enlargement due to

extramedullary hematopoiesis and increased destruction of RBC,

And hyperplasia of the bone marrow. Its causes a characteristic deformity

of the facial bones, as the nasal bridge, mandible, and maxilla widen.

4343With permission from Dr. Cappellini.

characteristic deformity of the facial bones

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--ThalassemiaThalassemia• In Alpha-Thalassemia the production of In Alpha-Thalassemia the production of αα-globin is -globin is

decreased due to a gene deletion or inactivation.decreased due to a gene deletion or inactivation.• There are four forms of There are four forms of --ThalassemiaThalassemia::• 1- 1- trait (carrier state), in which a single trait (carrier state), in which a single chain- chain-

forming gene is defective.forming gene is defective.• 2- 2- -thalessemia minor, in which two genes are -thalessemia minor, in which two genes are

defective.defective.• 3- Hemoglobin H disease, in which three genes 3- Hemoglobin H disease, in which three genes

are defective.are defective.• 4- 4- -thalassemia major, (hydrops fetalis) a fatal -thalassemia major, (hydrops fetalis) a fatal

condition in which all four condition in which all four -forming genes are -forming genes are defective; death is inevitable because defective; death is inevitable because chains is chains is absent and oxygen cannot be released to the absent and oxygen cannot be released to the tissues.tissues.

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-Thalassemia-Thalassemia• α-trait thalassemia patients

usually are symptom free, having, at most, mild microcytosis.

• α-thalassemia minor causes:Mild microcytic-hypochromic

reticulocytosis,Bone marrow hyperplasia,Increased serum iron levels,Moderate splenomegaly.

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-Thalassemia-Thalassemia• Hemoglobin H diseaseHemoglobin H disease::• With Hemoglobin H disease, With Hemoglobin H disease,

Hemoglobin H (B4) stains with cresyl Hemoglobin H (B4) stains with cresyl blue and is visualized by Hb blue and is visualized by Hb electrophoresis. electrophoresis.

• 20-40% Hb Barts is found in newborns 20-40% Hb Barts is found in newborns and 5-40% Hb H is found in adultsand 5-40% Hb H is found in adults. .

• HHemoglobin H disease emoglobin H disease causes vcauses variable ariable hemolytic anemiahemolytic anemia,, splenomegaly splenomegaly, , hepatomegaly, ihepatomegaly, ineffective neffective erythropoiesis, erythropoiesis, and and iron-loading iron-loading

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-Thalassemia-Thalassemia

• -Thalassemia-Thalassemia major causes:Hydrops fetalis and fulminant

intrauterine congestive heart failure.In addition to edema and massive

ascites, the fetus has a grossly enlarged heart and liver.

• Both -Thalassemia-Thalassemia major and β β --ThalassemiaThalassemia major are life threatening.

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Pathophysiologic Sequelae of Untreated Pathophysiologic Sequelae of Untreated Thalassaemia and Corresponding Clinical Thalassaemia and Corresponding Clinical

ManifestationsManifestations

HaemolysisIneffective

erythropoiesis

Membranebinding ofIgG and C3

AnaemiaIncreased

erythropoietinsynthesis

Skeletaldeformities,osteopaenia

Erythroidmarrow

expansionIron overload

Splenomegaly

Excess free -globin chains Denaturation

Degradation

Formation of haeme and haemichromes

Iron-mediated toxicity

Removal ofdamaged red cells

Increased

Iron absorption

Reduced tissue

oxygenation

Olivieri NF. N Engl J Med. 1999;341:99.

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Others Others Clinical Clinical ManifestationsManifestations• ~6 month old (fetal Hg is

exhausted)• Pale, FTT, hepatosplenomegaly, severe

anemia• Frequent epistaxis• Osteoporosis, growth delay,

fractures• Chronic CHF, murmurs• Hepatic and pancreatic insufficiency• Delayed sexual maturation• Usually fatal, in adolescence or

young adulthood generated cardiac failure

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Diagnosis & LabDiagnosis & Lab• Severe anemia – Hgb <6 g/dl

(>10 nl)• Hemoglobin electrophoresis

• Decreased hemoglobin chain production

• Hypochromic, microcytic erythrocytes

• Folic acid deficiency• Heritage, pedigree

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ManagementManagement• Supportive• Goal - maintain nl hemoglobin levels

above 10g/dl• Blood transfusions (~1/month)

• side effect=iron overload (iron-chelating drug - deferozamine SQ/IV)

• given with vit C PO - will help with Fe excretion by kidneys

• Bone marrow transplantation• Genetic counseling• Splenectomy - prophylactic

antibiotics• Immunizations!

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Macrocytic-Macrocytic-normochromic anemiasnormochromic anemias

(Megaloblastic Anemias)(Megaloblastic Anemias)

• Pernicious AnemiaPernicious Anemia• Folate deficiency AnemiaFolate deficiency Anemia

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Megaloblastic AnemiasMegaloblastic Anemias

• Megaloblastic anemia is an important cause Megaloblastic anemia is an important cause of macrocytic anemia.of macrocytic anemia.

• The cause is impaired DNA (deoxyribonucleic The cause is impaired DNA (deoxyribonucleic acid) synthesis. Cell division is impaired acid) synthesis. Cell division is impaired which causes the cells to become enlarged. which causes the cells to become enlarged.

• The most common causes of megaloblastic The most common causes of megaloblastic anemia are Vitamin B12 and folic acid anemia are Vitamin B12 and folic acid deficiency. deficiency.

• In the anemias of cobalamin (B12), and In the anemias of cobalamin (B12), and folate deficiency, the bone marrow reveals folate deficiency, the bone marrow reveals cells of the myeloid series to be cells of the myeloid series to be exceptionally large. exceptionally large.

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• The polymorphonuclear The polymorphonuclear leukocytes (PMNs) in peripheral leukocytes (PMNs) in peripheral blood are larger than normal and blood are larger than normal and usually have an increased number usually have an increased number of nuclear lobes. of nuclear lobes.

• The morphologic changes in the The morphologic changes in the bone marrow and peripheral blood bone marrow and peripheral blood resulting from lack of cobalamin resulting from lack of cobalamin (B12) and/or folate are identical, (B12) and/or folate are identical, but only cobalamin deficiency but only cobalamin deficiency gives rise to neurologic problems.gives rise to neurologic problems.

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• Folate and Vitamin B12 are Folate and Vitamin B12 are both critical for a specific both critical for a specific enzymatic step in the synthesis enzymatic step in the synthesis of DNA. of DNA.

• Retarded replication of DNA is Retarded replication of DNA is responsible for the responsible for the megaloblastic anemia that megaloblastic anemia that occurs with deficiency of either occurs with deficiency of either of these vitamins.of these vitamins.

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Vitamin B12 DeficiencyVitamin B12 Deficiency• What is normalWhat is normal

• 1-10mg total body Vitamin B121-10mg total body Vitamin B12• Daily dietary requirement 2 Daily dietary requirement 2

microgramsmicrograms

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Vitamin B12 DeficiencyVitamin B12 Deficiency• Causes of deficiencyCauses of deficiency

• Pernicious anemia, GastrectomyPernicious anemia, Gastrectomy• Pancreatic insufficiencyPancreatic insufficiency• GI bleeding, Vitamin B12 GI bleeding, Vitamin B12

malabsorptionmalabsorption• Exposure to nitrous oxideExposure to nitrous oxide• Neurological findingsNeurological findings

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Vitamin B12 DeficiencyVitamin B12 Deficiency

• DiagnosisDiagnosis• Check B12 levels. If borderline, Check B12 levels. If borderline,

then check >serum or urine then check >serum or urine methylmalonic acidmethylmalonic acid

• LDH-1 isoenzyme > LDH-2 LDH-1 isoenzyme > LDH-2 • Elevated indirect bilirubin, serum Elevated indirect bilirubin, serum

iron, <haptoglobiniron, <haptoglobin

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Pernicious AnemiaPernicious Anemia• Clinical Features:Clinical Features:

• Megaloblastic anemiaMegaloblastic anemia• Serum B-12 defSerum B-12 deficiencyiciency• Chronic atrophic gastritisChronic atrophic gastritis• Neurologic manifistationsNeurologic manifistations::paresthesias, numbness, weakness, memory paresthesias, numbness, weakness, memory

loss, personality changes, ataxia, loss of loss, personality changes, ataxia, loss of vibration and position sense, psychosis vibration and position sense, psychosis “megaloblastic madness”“megaloblastic madness”..

• Atrophic glossitisAtrophic glossitis• Achlorhydria (lack of HCl in gastric juice)Achlorhydria (lack of HCl in gastric juice)• Elevated serum bilirubin and LDH reflective Elevated serum bilirubin and LDH reflective

of increased RBC breakdown due to of increased RBC breakdown due to ineffective erythropiesis.ineffective erythropiesis.

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Pathophysiology Pathophysiology of the of the Pernicious AnemiaPernicious Anemia

• Autoantibody to IFAutoantibody to IF•Two types: Two types:

•Type I blocks attachment of B-Type I blocks attachment of B-12 to IF12 to IF

•Type II blocks B-12-IF complex Type II blocks B-12-IF complex to ileal receptorto ileal receptor

•Present in up to 70% of patients Present in up to 70% of patients with P.A. with P.A.

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Pathophysiology Pathophysiology of the of the Pernicious AnemiaPernicious Anemia

• Autoantibody to gastric parietal cellsAutoantibody to gastric parietal cells•Directed against the H/K-ATPase on Directed against the H/K-ATPase on cell membranecell membrane

•Leads to decline in # of parietal Leads to decline in # of parietal cells and IF productioncells and IF production

•Leads to chronic atrophic gastritis Leads to chronic atrophic gastritis and gastric atrophy.and gastric atrophy.

•Found in 90% of patients with Found in 90% of patients with pernicious anemia.pernicious anemia.

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Pernicious AnemiaPernicious Anemia• Chronic Atrophic Gastritis

• Type A (autoimmune):• The type involved in P.A. (due to autoantibodies)• Involves the fundus and body which contain

acid-secreting parietal cells and spares the antrum which contains gastrin-producing cells. This leads to achlorhydria and high serum gastrin levels.

• Type B:• Involves fundus, body, and antrum• Usually associated with H.pylori infection.

• The progression of Type A chronic atrophic gastritis to gastric atrophy and clinical anemia is likely to span 20 – 30 years.

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Pernicious AnemiaPernicious Anemia

• Schilling TestSchilling Test• Stage IStage I

• Give 1mcg of radiolabeled B-12 orally, Give 1mcg of radiolabeled B-12 orally, followed by 1000 mcg of B-12 IM one followed by 1000 mcg of B-12 IM one hour later to “flush” any absorbed hour later to “flush” any absorbed radiolabeled B-12 from tissues. A 24-hr radiolabeled B-12 from tissues. A 24-hr urine is collected to determined how urine is collected to determined how much radiolabeled B-12 is excreted. much radiolabeled B-12 is excreted. Normal is 8-35%.Normal is 8-35%.

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• Schilling TestSchilling Test• Stage IIStage II

• Done only if Stage I is abnormal. Done only if Stage I is abnormal. • Repeat Stage I, except with the addition Repeat Stage I, except with the addition

of added oral IF which should normalize of added oral IF which should normalize B-12 absorption in P.A., but not intestinal B-12 absorption in P.A., but not intestinal malabsorption. malabsorption.

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• Schilling TestSchilling Test• Many false pos and neg resultsMany false pos and neg results• Not commonly usedNot commonly used• Not readily available in many placesNot readily available in many places• Less sensitive test checking HC and Less sensitive test checking HC and

MMA to detect B-12 def.MMA to detect B-12 def.• Only recommended when anti-IF Only recommended when anti-IF

antibodies are normal. antibodies are normal.

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• TreatmentTreatment• IM B-12 at 1000 mcg daily for one IM B-12 at 1000 mcg daily for one

week, then 1000 mcg weekly for one week, then 1000 mcg weekly for one month, then 1000 mcg every month month, then 1000 mcg every month for one year – indefinitely.for one year – indefinitely.

• No harm in “overtreatment.” No harm in “overtreatment.” Inexpensive, non-toxic and excess is Inexpensive, non-toxic and excess is excreted in urine. excreted in urine.

7070

Total Body Folate Total Body Folate DeficiencyDeficiency

• Can cause megaloblastic anemiaCan cause megaloblastic anemia• Adult has 5-10mg total body folateAdult has 5-10mg total body folate• Usually accompanies Vitamin B12 Usually accompanies Vitamin B12

deficiencydeficiency•TreatmentTreatment

• Folic acid therapy: oral 0.5-1.0mg/dayFolic acid therapy: oral 0.5-1.0mg/day• Give B12 alsoGive B12 also

7171

Normocytic-Normocytic-Normochromic AnemiasNormochromic Anemias

• Aplastic Anemia• Hemolytic Anemia• Anemia of Chronic Disease• Sickle Cell Anemia

7272

Aplastic AnemiaAplastic Anemia

• Caused by decrease in or damage to Caused by decrease in or damage to marrow stem cells & replacement of marrow stem cells & replacement of marrow with fatmarrow with fat

(reduced hematopoiesis)(reduced hematopoiesis)• Precise etiology unknownPrecise etiology unknown• Can be congenital or acquired, but Can be congenital or acquired, but

most cases are idiopathicmost cases are idiopathic• Rx includes; BMT, PBSCT, Rx includes; BMT, PBSCT,

immunosuppresive therapyimmunosuppresive therapy

7373

Aplastic Anemia - Aplastic Anemia - SymptomsSymptoms

• Bleeding in skin/mucous membranesBleeding in skin/mucous membranes• Fatigue, fever, infectionFatigue, fever, infection• Mortality secondary to infectionMortality secondary to infection• PancytopeniaPancytopenia

7474

Aplastic Anemia - Aplastic Anemia - EtiologiesEtiologies• Idiopathic in 50%Idiopathic in 50%

• ChemicalsChemicals• ChemotherapyChemotherapy• Ionizing radiationIonizing radiation• Viral infectionViral infection• LeukemiaLeukemia• Medications: Chloramphenicol, sulfaMedications: Chloramphenicol, sulfa• Auto-immune disordersAuto-immune disorders

7575

Aplastic AnemiaAplastic Anemia

• DiagnosisDiagnosis• Bone marrow biopsyBone marrow biopsy

• EpidemiologyEpidemiology• 2 / million worldwide2 / million worldwide• Prevalent in OrientPrevalent in Orient• Peaks in late adolescence/early Peaks in late adolescence/early

adulthoodadulthood

7676

Aplastic AnemiaAplastic Anemia• PathogenesisPathogenesis

• <Hematopoiesis<Hematopoiesis• AutoimmunityAutoimmunity

• TherapyTherapy• Supportive: blood product transfusions, Supportive: blood product transfusions,

antibioticsantibiotics• Bone marrow transplant, Bone marrow transplant,

immunosuppressionimmunosuppression• If severe: ATG + cyclosporineIf severe: ATG + cyclosporine

7777

Hemolytic AnemiaHemolytic Anemia

• Premature, accelerated destruction of Premature, accelerated destruction of erythrocytes, either episodically or erythrocytes, either episodically or continuous, is a clinical manifestation of continuous, is a clinical manifestation of many disease states and is the many disease states and is the predominant event in hemolytic anemias.predominant event in hemolytic anemias.

• These anemias are divided two forms: These anemias are divided two forms: inherited or acquiredinherited or acquired

• Inherited forms are caused by intrinsic Inherited forms are caused by intrinsic abnormalities, typically of the abnormalities, typically of the erythrocyte’s plasma membrane or erythrocyte’s plasma membrane or cytoplasmic contents and hemoglobin cytoplasmic contents and hemoglobin structure and synthesis. structure and synthesis.

7878

• Inherited forms are caused by Inherited forms are caused by intrinsic abnormalities, typically intrinsic abnormalities, typically of the erythrocyte’s plasma of the erythrocyte’s plasma membrane or cytoplasmic membrane or cytoplasmic contents and hemoglobin contents and hemoglobin structure and synthesis. structure and synthesis.

• Acquired forms are caused by Acquired forms are caused by extrinsic defects such as extrinsic defects such as infection, chemical agents infection, chemical agents (drugs, toxins, venom), trauma, (drugs, toxins, venom), trauma, physical agents and abnormal physical agents and abnormal immune response.immune response.

8080

• Hemolysis occurs within blood vessels Hemolysis occurs within blood vessels (intravascular) or lymphoid tissues (intravascular) or lymphoid tissues (extravascular) that filter blood that is (extravascular) that filter blood that is spleen and liver.spleen and liver.

• Intravascular hemolysis is the least Intravascular hemolysis is the least common and typically is caused by common and typically is caused by physical destruction of RBCs or physical destruction of RBCs or complement-mediated lysis facilitated by complement-mediated lysis facilitated by antibodies acting as a lysin, opsonin, or antibodies acting as a lysin, opsonin, or agglutinin.agglutinin.

• Extravascular hemolysis, occuring within Extravascular hemolysis, occuring within lymphoid tissues is most common and is lymphoid tissues is most common and is caused by macrophage destruction and/or caused by macrophage destruction and/or digestion by the mononuclear phagocyte digestion by the mononuclear phagocyte system (MPS). system (MPS).

8181

Autoimmune hemolytic Autoimmune hemolytic anemiasanemias

• These are acquired disorders These are acquired disorders caused by extravascular caused by extravascular hemolysis and are most often hemolysis and are most often associated with autoimmune associated with autoimmune mechanisms.mechanisms.

• Classification:Classification:• 1- warm antibody type,1- warm antibody type,• 2- cold agglutinin type,2- cold agglutinin type,• 3- cold hemolysins type.3- cold hemolysins type.

8282

warm antibody typewarm antibody type• The most common form, The most common form, • Females > age of 40 Females > age of 40 • IgG is the mediating antibody specific for IgG is the mediating antibody specific for

erythrocyte antigens and has a maximum erythrocyte antigens and has a maximum binding capacity to the surface of the binding capacity to the surface of the erythrocyte at body temperature (37erythrocyte at body temperature (37°°C). C).

• IgG coated RBCs bind to the Fc receptors IgG coated RBCs bind to the Fc receptors on monocytes and splenic macrophages.on monocytes and splenic macrophages.

• Attempted phagocytosis of the IgG coated Attempted phagocytosis of the IgG coated cells results in partial loss of the cell cells results in partial loss of the cell membrane causing erythrocytes to membrane causing erythrocytes to undergo spheroidal transformation.undergo spheroidal transformation.

• These RBCs are sequestered in the spleen These RBCs are sequestered in the spleen removing them from the circulation.removing them from the circulation.

8383

• Drug-induced hemolytic anemiaDrug-induced hemolytic anemia is is classified as warm antibody type classified as warm antibody type according to three mechanisms of according to three mechanisms of action:action:

• The autoantibody model, (The autoantibody model, (αα--methyldopa),methyldopa),

• The hapten model, (penicillin, The hapten model, (penicillin, cephalosporins)cephalosporins)

• The immune complex formation The immune complex formation (quinidine).(quinidine).

8585

cold agglutinin typecold agglutinin type• It is mediated by IgM and occurs less It is mediated by IgM and occurs less

often than warm antibody hemolysis, often than warm antibody hemolysis, affecting mostly older females.affecting mostly older females.

• Cold antibodies have a RBC binding Cold antibodies have a RBC binding capacity that occurs at colder capacity that occurs at colder temperatures (lower than 31temperatures (lower than 31°°C) with C) with maximal binding capacity at 0 maximal binding capacity at 0 °°C to -4 C to -4 °°C.C.

• HIV, infectious mononucleosis, HIV, infectious mononucleosis, mycoplasma pneumonia, mycoplasma pneumonia, cytomegalovirus, influenza virus, cytomegalovirus, influenza virus, lymphoid neoplasms….lymphoid neoplasms….

8686

• IgM binding agglutinates RBCs and IgM binding agglutinates RBCs and rapidly fixes complement on their rapidly fixes complement on their surface.surface.

• IgM is rapidly released when the IgM is rapidly released when the blood recirculates and warms, blood recirculates and warms, usually before complement-mediated usually before complement-mediated hemolysis can occur.hemolysis can occur.

• However the temporary interaction However the temporary interaction with IgM allows the deposition of C3b with IgM allows the deposition of C3b on the RBC surface, which results in on the RBC surface, which results in rapid phagocytosis by mononuclear rapid phagocytosis by mononuclear phagocytes in the liver and spleen. phagocytes in the liver and spleen.

8787

cold hemolysins typecold hemolysins type• It is rare disorder involving IgG It is rare disorder involving IgG

autoantibodies and is associated with autoantibodies and is associated with paroxysmal cold hemoglobinuria.paroxysmal cold hemoglobinuria.

• The involvedThe involved antibody also calledantibody also called Donath-Landsteiner antibodyDonath-Landsteiner antibody, , was first was first recognized with chronic syphilis recognized with chronic syphilis infection.infection.

• This anemia involves acute intermittent This anemia involves acute intermittent but massive intravascular hemolysis and but massive intravascular hemolysis and often hemoglobinuria after exposure to often hemoglobinuria after exposure to cold temperatures.cold temperatures.

• Destruction or lysis is clearly Destruction or lysis is clearly complement-dependent.complement-dependent.

• This anemia associated with Measles, This anemia associated with Measles, mumps, mycoplasma pneumonia, flu….mumps, mycoplasma pneumonia, flu….

8888

Anemia of chronic disease Anemia of chronic disease (ACD)(ACD)

• ACD is mild to moderate anemia in ACD is mild to moderate anemia in individuals with chronic conditions that individuals with chronic conditions that include AIDS, RA, SLE, CRF, CHF, include AIDS, RA, SLE, CRF, CHF, hepatitis…hepatitis…

• Three pathologic mechanisms Three pathologic mechanisms associated with ACD include:associated with ACD include:

• 1- decreased erythrocyte life span,1- decreased erythrocyte life span,• 2- ineffective bone marrow response to 2- ineffective bone marrow response to

erythropoetin,erythropoetin,• 3- altered iron metabolism.3- altered iron metabolism.

9090

NEW????NEW????Hepcidin and iron Hepcidin and iron

regulation regulation • The recent discovery of hepcidin, a liver-The recent discovery of hepcidin, a liver-

derived antimicrobial protein, has provided derived antimicrobial protein, has provided new insights into iron regulation, maternal-new insights into iron regulation, maternal-fetal iron transport across the placenta, and fetal iron transport across the placenta, and its role in ACD.its role in ACD.

• Hepcidin inhibits iron uptake in the Hepcidin inhibits iron uptake in the duodenum, modifies intestinal iron duodenum, modifies intestinal iron absorption, and inhibits iron release from absorption, and inhibits iron release from macrophages.macrophages.

• Thus an increase in hepcidin would explain Thus an increase in hepcidin would explain iron deficiency and inadequate iron deficiency and inadequate erythropoiesis resulting in anemia.erythropoiesis resulting in anemia.

• Inflammation and IL-6 are strong stimuli for Inflammation and IL-6 are strong stimuli for hepcidin production.hepcidin production.

9191

Sickle Cell AnemiaSickle Cell Anemia• Sickle cell anemiaSickle cell anemia

occurs in people occurs in people homozygoushomozygous (receives 2 abnormal (receives 2 abnormal genes) genes)

• Sickle cell trait : Sickle cell trait : heterozygousheterozygous (receives only 1 (receives only 1 defective gene): no defective gene): no symptoms, but can symptoms, but can pass onto children.pass onto children.

• Although defect is Although defect is inherited, sickling inherited, sickling phenomenon is not phenomenon is not apparent until later in apparent until later in infancy (10-12 weeks)infancy (10-12 weeks)

9292

Sickle Cell Anemia: Sickle Cell Anemia: PathophysiologyPathophysiology• Defective hemoglobin Defective hemoglobin

molecule: molecule: Hemoglobin S (HbS) Hemoglobin S (HbS) causes RBC to stiffen causes RBC to stiffen & elongate when & elongate when exposed to exposed to low low oxygen levelsoxygen levels precipitated by:precipitated by:• Viral or bacterial Viral or bacterial

infectioninfection• High altitudeHigh altitude• Stress. Surgery, Stress. Surgery,

blood lossblood loss

9393

Sickle Cell Anemia: Sickle Cell Anemia: PathophysiologyPathophysiology

• Sickle Cell Crisis is a severe, painful, acute exacerbation of RBC sickling causing vascular occlusion.

• As blood flow is impaired, vasospasm occurs hypoxia further sickling

• Sickled cells are broken down by the spleen anemia

• Tissue necrosis occurs from hypoxia chronic leg ulcers.

• Shock is possible caused by decreased cardiac output

9494

SCA: PathophysiologySCA: Pathophysiology• Changes in oxygen tension precipitate crisis

(infection usually)• Decreased blood flow – local hypoxia

• Stasis of blood with enlargement of organs & abdomen• Abdominal enlargement with jaundice & pooling

of blood in liver, spleen & other organs• Edema of extremities (Hand & Foot Syndrome)

• Infarction with ischemia & destruction• Joint & back pain

• Replacement with scar tissue (fibrous tissue)• Complications: multisystem failure, MI,

hemorrhage, retinal damage. Osteoporosis, pulmonary hypertension

9595

Sickle Cell Disease: Sickle Cell Disease: S&SS&S

• Other complicationsOther complications• Acute chest syndromeAcute chest syndrome

– most common – most common complicationcomplication• Sickling RBCs block Sickling RBCs block

blood vessels in the blood vessels in the lunglung

• Similar to pneumoniaSimilar to pneumonia• Chest pain – cough – Chest pain – cough –

tachypnea – wheezing - tachypnea – wheezing - hypoxiahypoxia

• CVA, StrokeCVA, Stroke• Sickled cells block Sickled cells block

major blood vessels in major blood vessels in the brainthe brain

• Neurologic impairmentNeurologic impairment

9696

Sickle Cell Disease: Sickle Cell Disease: DiagnosisDiagnosis

• LabsLabs• Hgb/Hct lowHgb/Hct low• Hgb: 80% Hg-S & not Hg-AHgb: 80% Hg-S & not Hg-A• RBC indices normalRBC indices normal• Reticulocytes high Reticulocytes high • Serum iron levels normalSerum iron levels normal• Sickled cells may be seenSickled cells may be seen• Bilirubin levels may be Bilirubin levels may be

elevated r/t hemolysis of elevated r/t hemolysis of RBCsRBCs

• WBC elevated if infectionWBC elevated if infection

9797

Sickle Cell AnemiaSickle Cell Anemia

• Four Primary Treatment Four Primary Treatment ModalitiesModalities

1.1.BMTBMT

2.2.HydroxyureaHydroxyurea

3.3.ArginineArginine

4.4.Long-term RBC TransfusionLong-term RBC Transfusion

Supportive TherapySupportive TherapyPain ManagementPain Management

9898

HemophiliaHemophilia• Hemophilia A (classic hemophilia)

• Deficiency of factor VIII• 80% of hemophiliacs• 1:5000-10,000 live, white male births• Sex-linked recessive trait

• Hemophilia B (Christmas disease)• Deficiency of factor IX• 15% of hemophiliacs• Sex-linked recessive trait

• Hemophilia C• Deficiency of factor XI – mild

symptoms• Autosomal recessive trait

100100

X-linked Recessive X-linked Recessive TransmissionTransmission

• ~20% are a new mutation (80% of all cases are heredity)

• Classified as mild, moderate or severe. Severity determined by % of active clotting factor in blood (nl 50-150%) Severe hemophilia <1% of needed factor.

101101

Clinical ManifestationsClinical Manifestations• First symptoms start ~ 6 months of

age, but often not diagnosed until child is active

• Spontaneous bleeding, easy – spontaneous bruising, hemarthrosis (esp knees, ankles, elbows), deep tissue hemorrhage, bleeding after circumcision, nosebleeds, hematuria, excessive bleeding from minor trauma, GI bleeding

• Pain or paralysis resulting from the pressure of hematomas on nerves

102102

ManagementManagement• Diagnosis and genetic testing early

• chorionic villus sampling, amniocentesis

• family member testing for carriers• low levels of factor VIII or IX, prolonged

activated partial prothrombin time• Control bleeding and replacement

&/or transfusion of missing factor at home

• Mild-moderate disease can live nl lifespan

• Mild• Desmopressin acetate (DDAVP)• 2-4x increase in factor VIII activity

103103

Von Willebrand DiseaseVon Willebrand Disease• Most common hereditary bleeding

disorder• Reduced platelet adhesion• Deficiency of von Willebrand factor

• Component of factor VIII• Defective clot formation

• Autosomal dominant trait• Frequently a new mutation• Males and females equally affected

• Easy bruising, epistaxis, gingival bleeding, increased bleeding with laceration and with surgery, increased menstrual bleeding

104104

DiagnosisDiagnosis

• Serum clotting values• Decreased von Willebrand factor• Decreased von Willebrand factor

antigen• Decreased factor VIII activity• Decreased platelet agglutination• Prolonged bleeding time (PT)• Normal or prolonged activated

partial thromboplastin time (APPT)

105105

ManagementManagement• Mild cases

• DDAVP (desmopressin acetate – stimulates release of factor VIII & Von Willebrand’s factor and vasoconstricts) for bleeding or before surgery

• No aspirin or ibuprofen• Normal life expectancy• Severe cases (Type III)

• Infusion of von Willebrand protein concentrate and factor VIII

106106

Myeloproliferative RBC Myeloproliferative RBC disorders: disorders:

- primary polycythemia - primary polycythemia - polycythemia verapolycythemia vera

107107

Myeloproliferative Myeloproliferative DisordersDisorders

• The opposite of anemias – here we have too The opposite of anemias – here we have too many RBC’s.many RBC’s.

• Polycythemia – excessive production of RBC’sPolycythemia – excessive production of RBC’s• Primary polycythemia – cause is unknown, Primary polycythemia – cause is unknown,

but is in effect, a benign tumor of the but is in effect, a benign tumor of the marrow, leading to increased numbers of marrow, leading to increased numbers of stem cells and therefore RBC’s, and stem cells and therefore RBC’s, and splenomegally.splenomegally.

• Polycythemia veraPolycythemia vera – rare, mostly – rare, mostly Northern European Jewish males between 60 Northern European Jewish males between 60 – 80 yrs.– 80 yrs.

108108

Secondary PolycythemiaSecondary Polycythemia• Due to the overproduction of Due to the overproduction of

erythropoietin caused by hypoxia. erythropoietin caused by hypoxia. This is more common.This is more common.

• Seen in:Seen in:• Persons living at high altitudesPersons living at high altitudes• SmokersSmokers• COPD patientsCOPD patients• Congestive heart failure patientsCongestive heart failure patients

109109

• Polcythemia leads to :Polcythemia leads to :• Increased blood volume and Increased blood volume and

viscosityviscosity• Congestion of liver and spleenCongestion of liver and spleen• ClottingClotting• Thrombus formationThrombus formation• (last two may be due increased (last two may be due increased

numbers of platelets along with the numbers of platelets along with the increase in RBC’s due to bone increase in RBC’s due to bone marrow dysfunction.)marrow dysfunction.)

110110

Clinical manifestation of Clinical manifestation of PolycythemiaPolycythemia

• HeadacheHeadache• DizzinessDizziness• Weakness Weakness • Increased blood pressureIncreased blood pressure• Itching / sweatingItching / sweating

111111

Treatment of Treatment of polycythemiapolycythemia

• Reduce blood volume by Reduce blood volume by phlebotomy – 300-500 ml. phlebotomy – 300-500 ml.

• Treat underlying condition - Stop Treat underlying condition - Stop smokingsmoking

• Radioactive phosphorus injectionsRadioactive phosphorus injections• Prevent thrombosisPrevent thrombosis

112112

Alterations of platelets Alterations of platelets

• Thrombocytopenia (immune Thrombocytopenia (immune thrombocytopenic purpurathrombocytopenic purpura- ITP),ITP),

• Thrombocythemia (essential Thrombocythemia (essential thrombocythemia – ET) thrombocythemia – ET)

113113

Immune Immune Thrombocytopenic Thrombocytopenic

Purpura: EpidemiologyPurpura: Epidemiology• ITP is an autoimmune diseaseITP is an autoimmune disease• The number of individuals in the United States The number of individuals in the United States

with ITP has been estimated to be approximately with ITP has been estimated to be approximately 200,000200,000• In adults, about 3 times more women have In adults, about 3 times more women have

the disease than men; however, the ratio the disease than men; however, the ratio equalizes with increasing ageequalizes with increasing age

• In children, the ratio is about evenIn children, the ratio is about even• It affects all age and ethnic groupsIt affects all age and ethnic groups

• ITP is a disease characterized by low platelet ITP is a disease characterized by low platelet counts and mucocutaneous bleedingcounts and mucocutaneous bleeding

114114


Purpura: Purpura: IncidenceIncidence• There are about 100 new cases of ITP per million There are about 100 new cases of ITP per million

people per yearpeople per year11

• Approximately half of the new cases are in Approximately half of the new cases are in childrenchildren

• In adults, ITP presents most commonly between In adults, ITP presents most commonly between the ages of 18 and 40the ages of 18 and 4011

• In a recent study of 221 adults with ITP, at the In a recent study of 221 adults with ITP, at the timetimeof diagnosisof diagnosis22

• ~ 45% had a platelet count < 10 x 10~ 45% had a platelet count < 10 x 1099/L/L• ~ 85% had a platelet count < 50 x 10~ 85% had a platelet count < 50 x 1099/L/L

115115

Immune Thrombocytopenic Purpura: Immune Thrombocytopenic Purpura: A Chronic Disease With A Chronic Disease With

Potentially Serious ConsequencesPotentially Serious ConsequencesSevere cutaneous Severe cutaneous

bleedingbleeding

MenorrhagiaMenorrhagia

Gingival bleedingGingival bleeding

Intracranial hemorrhageIntracranial hemorrhage1 1

2

1. Cines DB, Blanchette VS. N Engl J Med. 2002;346:995-1008.2. eMedicine. Intracranial Hemorrhage. Available at: http://www.emedicine.com/neuro/topic177.htm. Accessed Dec 21, 2006.

116116

PetechiaPetechiaee

Pinpoint hemorrhages

117117

PurpuraPurpura

118118


PurpuraPurpuraProduction and Regulation of Production and Regulation of

ThrombopoietinThrombopoietin

119119

Thrombopoietin (TPO)Thrombopoietin (TPO)• eTPO is the endogenous eTPO is the endogenous

cytokine for cytokine for megakaryocyte growth megakaryocyte growth and platelet formationand platelet formation

• eTPO binds specifically to eTPO binds specifically to the TPO receptor (TPO-R)the TPO receptor (TPO-R)

• eTPO also plays a central eTPO also plays a central role in the survival and role in the survival and proliferation of proliferation of hematopoietic progenitor hematopoietic progenitor cellscells

TPO structure adapted from: Feese MD, et al. Proc Natl Acad Sci USA. 2004;101:1816-1821. Deutsch VR, Tomer A. Br J Haematol. 2006;134:453-466.

120120

Thrombopoietin Thrombopoietin Production Is ConstantProduction Is Constant

Liver

TPO

TPO structure adapted from: Feese MD, et al. Proc Natl Acad Sci USA. 2004;101:1816-1821.

2007 Amgen. All rights reserved.

121121

Thrombopoietin Binds to Thrombopoietin Binds to Hematopoietic CellsHematopoietic Cells

TPO TPO-R


122122

Surfacereceptor

TPO

TPO-R

Transcription signaling pathway

Transmembranereceptor

JAK2, STAT5

Thrombopoietin: Thrombopoietin: Thrombopoietin Thrombopoietin

Receptor BindingReceptor Binding


123123

Signaling Pathways Signaling Pathways Activated Activated

by Thrombopoietinby Thrombopoietin

0 5 30

TPO (20 ng/mL)

BaF3 cells expressing murine Mpl were incubated with 20 ng/mL TPO for 0, 5, or 30 minutes at 37°C. Mpl, JAK2, or STAT5 were immunoprecipitated (IP) and analyzed by immunoblotting (IB) with an antiphosphotyrosine antibody (anti-PY).Modified from: Broudy VC, Lin NL. Cytokine. 2004;25:52-60.

IPIP IBIB

Anti-MplAnti-Mpl Anti-PYAnti-PY

Anti-MplAnti-Mpl

Anti-JAK2Anti-JAK2 Anti-PYAnti-PY

Anti-JAK2Anti-JAK2

Anti-Anti-STAT5STAT5 Anti-PYAnti-PY

Anti-Anti-STAT5STAT5

Time (Minutes)

124124

Thrombopoietin Level Thrombopoietin Level Drives Drives

Platelet ProductionPlatelet ProductionMaintenance of normal

platelet numberGeneral

thrombocytopenia

Blue arrow represents amount of free or unbound TPO in the system.Adapted from: Kuter DJ, et al. Thrombopoiesis and Thrombopoietins; 1997.

Liver


125125

Normal Physiology of Normal Physiology of Platelet TurnoverPlatelet Turnover

Aging platelet

Macrophage

Spleen

TPO-bound platelets


126126


PurpuraPurpuraMechanism of DiseaseMechanism of Disease

127127

Traditional Concept of Traditional Concept of ThrombocytopeniaThrombocytopenia

Impaired production:CIT and aplastic anemia

Destruction:ITP

Spleen

Antiplatelet antibody

TPO

CIT = chemotherapy-induced thrombocytopenia.


128128

Immune Thrombocytopenic Purpura Immune Thrombocytopenic Purpura Pathophysiology: Accelerated Pathophysiology: Accelerated

Platelet DestructionPlatelet DestructionTPO- bound platelets

Macrophage

SpleenAutoantibodies bind to

healthy platelet

Gamma receptor

B cell


129129

Immune Thrombocytopenic Purpura Immune Thrombocytopenic Purpura Pathophysiology: Pathophysiology:

A Disease of Accelerated Platelet Destruction A Disease of Accelerated Platelet Destruction and Suboptimal Platelet Productionand Suboptimal Platelet Production

Blue arrow represents amount of free or unbound TPO in the system.

Spleen

Liver


130130

Antiplatelet Antibodies Impact Antiplatelet Antibodies Impact Platelet Production in Immune Platelet Production in Immune

Thrombocytopenic PurpuraThrombocytopenic PurpuraTPO TPO-R

PGP

Antibody

PGP = platelet glycoprotein.

131131

Thrombopoietin: Thrombopoietin Thrombopoietin: Thrombopoietin Regulation Regulation

in Immune Thrombocytopenic Purpurain Immune Thrombocytopenic Purpura

General thrombocytopenia

ITP

Blue arrow represents amount of free or unbound TPO in the system.

Spleen

Liver


132132

Immune Thrombocytopenic Purpura: Immune Thrombocytopenic Purpura: A Disease of Suboptimal Platelet A Disease of Suboptimal Platelet

ProductionProductionand Increased Destructionand Increased Destruction

• Autoantibodies result in accelerated platelet Autoantibodies result in accelerated platelet destructiondestruction11

• Platelet production may not be maximal in patients Platelet production may not be maximal in patients with ITPwith ITP• Autoantibodies inhibit megakaryocyte growth Autoantibodies inhibit megakaryocyte growth

in vitro and promote apoptosis resulting in in vitro and promote apoptosis resulting in impaired thrombopoiesisimpaired thrombopoiesis2,32,3

• Platelet production is reduced or normal in two Platelet production is reduced or normal in two thirds thirds of patientsof patients4-64-6

• TPO levels are normal in 75% of thrombocytopenic TPO levels are normal in 75% of thrombocytopenic (< 30 x 10(< 30 x 1099/L) patients with ITP, rather than /L) patients with ITP, rather than increased increased

• Current medical and surgical options decrease platelet Current medical and surgical options decrease platelet destruction and do not affect platelet productiondestruction and do not affect platelet production

133133

EEssential ssential TThrombocythemiahrombocythemia: : PathophysiologyPathophysiology

• Platelet production increased more than 5-Platelet production increased more than 5-foldfold• 237 million (normal 43 million) per day237 million (normal 43 million) per day

• Platelet survival normalPlatelet survival normal• Megakaryocyte mass increased almost 4-foldMegakaryocyte mass increased almost 4-fold

• Number increasedNumber increased• Volume increasedVolume increased• Diameter increased (reflects increased ploidy)Diameter increased (reflects increased ploidy)

• Megakaryocyte ploidy increasedMegakaryocyte ploidy increased• 64N and 128N cells relatively common64N and 128N cells relatively common

134134

Clinical Features of ETClinical Features of ET

• Median age at diagnosis = 60 yearsMedian age at diagnosis = 60 years• Between 25 and 50 years, more common in Between 25 and 50 years, more common in

women; young women in childbearing age women; young women in childbearing age are a subgroup with special problemsare a subgroup with special problems

• Microvascular symptoms are common; Microvascular symptoms are common; thrombotic complications exceed bleeding thrombotic complications exceed bleeding complicationscomplications

• < 5% incidence of transformation into < 5% incidence of transformation into myelofibrosis with myeloid metaplasia or myelofibrosis with myeloid metaplasia or acute leukemiaacute leukemia

HS Gilbert

135135

Thrombosis in ETThrombosis in ET

• Increased incidence of thrombotic Increased incidence of thrombotic complications in treated patients complications in treated patients with inadequately controlled with inadequately controlled platelet countsplatelet counts• Current data suggest that thrombotic Current data suggest that thrombotic

complications can and do occur at complications can and do occur at relatively low platelet levels and relatively low platelet levels and recommend reduction of platelets to recommend reduction of platelets to <400,000/<400,000/LL

136136

Reactive Reactive ThrombocytosisThrombocytosis

• Acute or chronic inflammatory diseaseAcute or chronic inflammatory disease• Acute or chronic bleedingAcute or chronic bleeding• Iron deficiencyIron deficiency• Chronic marrow stimulation, e.g. Chronic marrow stimulation, e.g.

hemolysishemolysis• Post-thrombocytopenic reboundPost-thrombocytopenic rebound• Disseminated malignancyDisseminated malignancy• Absence of spleen (surgical, congenital, Absence of spleen (surgical, congenital,

functional)functional)• Intense exertion, parturition, trauma, Intense exertion, parturition, trauma,

epinephrineepinephrine

137137

Disorders of Disorders of coagulationcoagulation

• Disseminated Intravascular Disseminated Intravascular Coagulation (DIC)Coagulation (DIC)

138138

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation

• Not a disease but a sign of an underlying Not a disease but a sign of an underlying disorderdisorder

• Severity is variable; may be life-threatening Severity is variable; may be life-threatening

• Triggers may include sepsis, trauma, shock, Triggers may include sepsis, trauma, shock, cancer abruptio placentae, toxins, and allergic cancer abruptio placentae, toxins, and allergic reactionsreactions

• Altered hemostasis mechanism causes massive Altered hemostasis mechanism causes massive clotting in microcirculation; as clotting factors clotting in microcirculation; as clotting factors are consumed, bleeding occurs; symptoms are are consumed, bleeding occurs; symptoms are related to tissue ischemia and bleedingrelated to tissue ischemia and bleeding

• Treatment: treat underlying cause, correct Treatment: treat underlying cause, correct tissue ischemia, replace fluids and electrolytes, tissue ischemia, replace fluids and electrolytes, maintain blood pressure, replace coagulation maintain blood pressure, replace coagulation factors, and use heparin factors, and use heparin

139139

140140

• Alterations of Leukocyte Alterations of Leukocyte Function:Function:

•LeukemiasLeukemias•MyelomaMyeloma

141141

Leukemia Leukemia • Hematopoietic malignancy with Hematopoietic malignancy with

unregulated proliferation of leukocytesunregulated proliferation of leukocytes

• Types:Types:

• Acute myeloid leukemiaAcute myeloid leukemia

• Chronic myeloid leukemiaChronic myeloid leukemia

• Acute lymphocytic leukemiaAcute lymphocytic leukemia

• Chronic lymphocytic leukemiaChronic lymphocytic leukemia

142142

Acute Myeloid Leukemia Acute Myeloid Leukemia (AML)(AML)

• Defect in the stem cells that differentiate into Defect in the stem cells that differentiate into all myeloid cells: monocytes, granulocytes, all myeloid cells: monocytes, granulocytes, erythrocytes, and plateletserythrocytes, and platelets

• Most common nonlymphocytic leukemiaMost common nonlymphocytic leukemia• Affects all ages with peak incidence at age 60Affects all ages with peak incidence at age 60• Prognosis is variablePrognosis is variable• Manifestations: fever and infection, weakness Manifestations: fever and infection, weakness

and fatigue, bleeding tendencies, pain from and fatigue, bleeding tendencies, pain from enlarged liver or spleen, hyperplasia of gums, enlarged liver or spleen, hyperplasia of gums, and bone painand bone pain

• Treatment is aggressive chemotherapy: Treatment is aggressive chemotherapy: induction therapy, BMT, and PBSCT induction therapy, BMT, and PBSCT

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Chronic Myeloid Leukemia Chronic Myeloid Leukemia (CML)(CML)

• Mutation in myeloid stem cell with uncontrolled Mutation in myeloid stem cell with uncontrolled proliferation of cells: Philadelphia chromosomeproliferation of cells: Philadelphia chromosome

• Stages: chronic phase, transformational phase, Stages: chronic phase, transformational phase, blast crisis blast crisis

• Uncommon in people under 20; incidence Uncommon in people under 20; incidence increases with age; mean age is 55 to 60 yearsincreases with age; mean age is 55 to 60 years

• Life expectancy is 3 to 5 yearsLife expectancy is 3 to 5 years• Manifestations (initially may be asymptomatic): Manifestations (initially may be asymptomatic):

malaise; anorexia; weight loss; confusion or malaise; anorexia; weight loss; confusion or shortness of breath due to leukostasis; shortness of breath due to leukostasis; enlarged, tender spleen; enlarged liverenlarged, tender spleen; enlarged liver

• Treatment: imatinib mesylate (Gleevec) blocks Treatment: imatinib mesylate (Gleevec) blocks signals in leukemic cells that express BCR-ABL signals in leukemic cells that express BCR-ABL protein; chemotherapy, BMT, and PBSCTprotein; chemotherapy, BMT, and PBSCT

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Acute Lymphocytic Acute Lymphocytic LeukemiaLeukemia

• Uncontrolled proliferation of immature Uncontrolled proliferation of immature cells from lymphoid stem cellcells from lymphoid stem cell

• Most common in young children, boys Most common in young children, boys more often than girlsmore often than girls

• Prognosis is good for children; 80% event-Prognosis is good for children; 80% event-free after 5 years, but survival drops with free after 5 years, but survival drops with increased ageincreased age

• Manifestations: leukemic cell infiltration Manifestations: leukemic cell infiltration is more common with this leukemia with is more common with this leukemia with symptoms of meningeal involvement and symptoms of meningeal involvement and liver, spleen, and bone marrow painliver, spleen, and bone marrow pain

• Treatment: chemotherapy, imatinib Treatment: chemotherapy, imatinib mesylate (if Philadelphia chromosome mesylate (if Philadelphia chromosome positive), BMT or PBSCT, and monoclonal positive), BMT or PBSCT, and monoclonal antibody therapy antibody therapy

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Chronic Lymphocytic Chronic Lymphocytic LeukemiaLeukemia

• Malignant B lymphocytes, most of which are Malignant B lymphocytes, most of which are mature, may escape apoptosis, resulting in mature, may escape apoptosis, resulting in excessive accumulation of cellsexcessive accumulation of cells

• Most common form of leukemiaMost common form of leukemia• More common in older adults and affects men More common in older adults and affects men

more oftenmore often• Survival varies from 2 to 14 years depending Survival varies from 2 to 14 years depending

upon stageupon stage

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Chronic Lymphocytic Chronic Lymphocytic Leukemia Leukemia

• Manifestations: lymphadenopathy, Manifestations: lymphadenopathy, hepatomegaly, splenomegaly; in later hepatomegaly, splenomegaly; in later stages, anemias and thrombocytopenia; stages, anemias and thrombocytopenia; autoimmune complications with RES autoimmune complications with RES destroying RBCs and platelets may occur; destroying RBCs and platelets may occur; B symptoms include fever, sweats, and B symptoms include fever, sweats, and weight loss weight loss

• Treatment: early stage may require no Treatment: early stage may require no treatment, chemotherapy, or monoclonal treatment, chemotherapy, or monoclonal antibody therapyantibody therapy

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Multiple MyelomaMultiple Myeloma

• Malignant disease of plasma cells in the bone Malignant disease of plasma cells in the bone marrow with destruction of bonemarrow with destruction of bone

• M protein and Bence-Jones proteinM protein and Bence-Jones protein• Median survival is 3 to 5 years; there is no cureMedian survival is 3 to 5 years; there is no cure• Manifestations: bone pain, osteoporosis, Manifestations: bone pain, osteoporosis,

fractures, elevated serum protein fractures, elevated serum protein hypocalcemia, renal damage, renal failure, hypocalcemia, renal damage, renal failure, symptoms of anemia, fatigue, weakness, symptoms of anemia, fatigue, weakness, increased serum viscosity, and increased risk increased serum viscosity, and increased risk for bleeding and infectionfor bleeding and infection

• Treatment may include chemotherapy, Treatment may include chemotherapy, corticosteroids, radiation therapy, and corticosteroids, radiation therapy, and biphosphonatesbiphosphonates

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Alterations of Lymphoid Function:Alterations of Lymphoid Function:Malignant lymphomas:Malignant lymphomas:

• Hodgkin’s lymphomaHodgkin’s lymphoma

• Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma

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Hodgkin’s DiseaseHodgkin’s Disease• Unicentric originUnicentric origin

• Reed–Sternberg cell Reed–Sternberg cell

• Suspected viral etiology; familial pattern; incidence Suspected viral etiology; familial pattern; incidence occurs in early 20s and again after age 50occurs in early 20s and again after age 50

• Excellent cure rate with treatmentExcellent cure rate with treatment

• Manifestations: painless lymph node enlargement; Manifestations: painless lymph node enlargement; pruritus; B symptoms such as fever, sweats, and pruritus; B symptoms such as fever, sweats, and weight lossweight loss

• Treatment is determined by stage of the disease Treatment is determined by stage of the disease and may include chemotherapy and/or radiation and may include chemotherapy and/or radiation therapytherapy

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Non-Hodgkin's Lymphoma Non-Hodgkin's Lymphoma (NHL)(NHL)

• Lymphoid tissues become infiltrated with Lymphoid tissues become infiltrated with malignant cells that spread unpredictably; malignant cells that spread unpredictably; localized disease is rarelocalized disease is rare

• Incidence increases with age; the average age of Incidence increases with age; the average age of onset is 50 to 60onset is 50 to 60

• Prognosis varies with the type of NHLPrognosis varies with the type of NHL• Treatment is determined by type and stage of Treatment is determined by type and stage of

disease and may include interferon, disease and may include interferon, chemotherapy, and/or radiation therapychemotherapy, and/or radiation therapy

1 pathophysiology of hematopoietic system disorders mehtap kaÇar koÇak m.d. phd pathophysiologist...

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