Anemia Blood Loss Acute Chronic IN-creased destruction (HEMOLYTIC) DE-creased production

Anemia

Blood Loss Acute Chronic

IN-creased destruction (HEMOLYTIC)

DE-creased production

Features of All Anemias

Pallor, where?

Tiredness

Weakness

Dyspnea, why?

Palpitations

Heart Failure (high output), why?

Blood Loss

Acute Trauma

Chronic Lesions of gastrointestinal tract, gynecologic

disturbances. The features of chronic blood loss anemia are the same as iron deficiency anemia, and is defined as a situation in which the production cannot keep up with the loss.

Hemolytic

Hereditary MEMBRANE disorders: e.g., spherocytosis ENZYME disorders: e.g., G6PD deficciency HGB disorders (hemoglobinopathies)

Acquired MEMBRANE disorders (PNH) ANTIBODY MEDIATED, transfusion or autoantibodies MECHANICAL TRAUMA INFECTIONS DRUGS, TOXINS HYPERSPLENISM

Impaired Production

Disturbance of proliferation and differentiation of stem cells: aplastic anemias, pure RBC aplasia, renal failure

Disturbance of proliferation and maturation of erythroblasts

Defective DNA synthesis: (Megaloblastic)

Defective heme synthesis: (Fe)

Deficient globin synthesis: (Thalassemias)

Modifiers

MCV, microcytosis, macrocytosis

MCHC, hypochromic

RDW, anisocytosis

Hemolytic Anemias

Life span LESS than 120 days

Marrow hyperplasia (M:E), EPO+

Increased catabolic products, e.g., bilirubin, serum HGB, hemosiderin

Hemolysis

INTRA-vascular (vessels)

EXTRA-vascular (spleen)

M:E Ratio normally 3:1

Sickle Cell Disease Classic hemoglobinopathy

Normal HGB is α2 β2: β-chain defects (Val->Glu)

Reduced hemoglobin “sickles” in homozygous

8% of American blacks are heterozygous

Clinical features of HGB-S disease

Severe anemia

Jaundice

PAIN (pain CRISIS)

Vaso-occlusive disease: EVEREWHERE, but clinically significant bone, spleen (autosplenectomy)

Infections: Pneumococcus, Hem. Influ., Salmonella osteomyelitis

THALASSEMIAS

A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics

Alpha or beta chains deficient synthesis involved

Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen

HEMOLYSIS is uniformly a feature, a microcytic anemia

A “crew cut” skull x-ray appearance may be seen

Paroxysmal Nocturnal Hemoglobinuria (PNH)

ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were

ACQUIRED mutations in phosphatidylinositol glycan A (PIGA)

It is “P” and “N” only 25% of the time

GlycosylphosPhatidylInositol

Immunohemolytic Anemia

All of these have the presence of antibodies and/or compliment present on RBC surfaces

NOT all are AUTOimmune, some are caused by drugs

Coombs Test

DIRECT: Patient’s CELLS are tested for surface Ab’s

INDIRECT: Patient’s SERUM is tested for Ab’s.

Direct anti-globulin test

HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA

Mechanical heart valves breaking RBC’s

MICROANGIOPATHIES:

TTP

Hemolytic Uremic Syndrome

NON-Hemolytic Anemias:i.e., DE-creased Production

“Megaloblastic” Anemias

B12 Deficiency (Pernicious Anemia)

Folate Deficiency

Iron Deficiency

Anemia of Chronic Disease

Aplastic Anemia

“Pure” Red Cell Aplasia

OTHER forms of Marrow Failure

MEGALOBLASTIC ANEMIAS

Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94)

Impaired DNA synthesis

For all practical purposes, also called the anemias of B12 and FOLATE deficiency

Often VERY hyperplastic/hypercellular marrow

Decreased intake

Inadequate diet, vegetarianism

Impaired absorption

Intrinsic factor deficiency

Pernicious anemia

Gastrectomy

Malabsorption states  

Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis

Ileal resection, ileitis  

Competitive parasitic uptake  

Fish tapeworm in

Fish tapeworm infestation    

Bacterial overgrowth in blind loops and diverticula of bowel

Increased requirement

Pregnancy, hyperthyroidism, disseminated cancer

Vit-B12 Physiology

Oral ingestion

Combines with INTRINSIC FACTOR in the gastric mucosa

Absorbed in the terminal ileum

DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia

Please remember that ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the

RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic

precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!

PERNICIOUS ANEMIA

MEGALOBLASTIC anemia

LEUKOPENIA and HYPERSEGS

JAUNDICE

NEUROLOGIC posterolateral spinal tracts

ACHLORHYDRIA

Can’t absorb B12

LOW serum B12

Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer

FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS

Decreased Intake: diet, etoh-ism, infancy

Impaired Absorption: intestinal disease

DRUGS: anticonvulsants, BCPs, CHEMO

Increased Loss: Hemodialysis

Increased Requirement: Pregnancy, infancy

Impaired Usage

APLASTIC ANEMIAS

ALMOST ALWAYS involve platelet and WBC suppression as well

Some are idiopathic, but MOST are related to drugs, radiation

FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired

Act at STEM CELL level, except for “pure” red cell aplasia

APLASTIC ANEMIAS

APLASTIC ANEMIAS

CHLORAMPHENICOL

OTHER ANTIBIOTICS

CHEMO

INSECTICIDES

VIRUSES EBV HEPATITIS VZ

MYELOPHTHISIC ANEMIAS

Are anemias caused by metastatic tumor cells replacing the bone marrow extensively

Fe Deficiency Anemia

Due to increased loss or decreased ingestion, almost always, in USA, nowadays, increased loss is the reason

Microcytic (low MCV), Hypochromic (low MCHC)

THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!

Fe

Transferrin

Ferritin (GREAT test)

Hemosiderin

Gut lumen

Fe +++ Fe ++ Heme Fe

Enterocyte DMT1

FerritinFe++

Fe+++

MTP1

Plasma transferrin

Enterocyteprecursor

Hepcidin

Transferrin Receptor

HFE

Regulation of iron absorption

Gastrointestinal absorption1 mg/day

Storage ironLiver, RES1 gram

Functional ironBlood, marrow, myoglobin2 grams

Plasma transferrin2 mg

Daily physiologic loss1 mg

Clinical Fe-Defic-Anemia

Adult men: GI Blood Loss

PRE menopausal women: menorrhagia

POST menopausal women: GI Blood Loss

2 BEST lab tests:

Serum Ferritin

Prussian blue hemosiderin stain of marrow (also called an “iron” stain)

Marrow iron stores

1 - 3+ 0 - 1+ 0 0

Ferritin 50 - 200 <20 <15 0

TIBC 300 - 360 >360 >380 >400

Serum iron 50 - 150 50 - 150 <50 <30

Red cells normal normal normal microcytic, hypochromic

Iron stores

Erythron iron

Serum transferrin receptor

Storage iron = 107 mg

Storage iron = 335 mg

Storage iron = 1,102 mg

Serial measurement of sTfr during phlebotomy in 3 individuals

Goodnough, Skikne, Brugnara. Blood, 2000; 96: 823 - 833

Ratio of serum transferrin receptor to ferritin as a measure of total body iron

Cook, Flowers, Skikne. Blood 2003; 101: 3359 - 64

Kaltwasser, Gottschalk. Kidney Int. 1999; 55(suppl): S49 - S56

Serum ferritin and total body iron

Treatment of iron def anemia

Oral iron is the preferred initial treatment

Recommended daily dose is 150-200mg/day of elemental iron

325 mg of ferrous sulfate contains 65 mg of elemental iron

One table three times a day

Administer iron on an empty stomach with half a glass of OJ or 250mg ascorbic acid

Serum iron after oral iron in patients with iron deficiency

WH Crosby, Arch Int Med; circa 1970

20

40

60

80

1 2 3 4

Ser

um

iron

Hours

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

Sodium ferric gluconate in sucrose (Ferrlecit)

Available in Europe > 30 years

2.7 x 106 doses/year in Germany + Italy in 1995

Iron dextran (Imferon until 1992, InFed since 1992)

3 x 106 doses/year in US in 1996

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

Reported severe adverse reactions (1976 - 1996):

SFGS 3.3 severe allergic reactions/106 doses, no fatalities

ID 8.7 severe allergic reactions/106 doses, 31 fatalities

Safety of intravenous iron

Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

Other theoretical risks:

iron overload

sepsis

acceleration of atherosclerosis

Recombinant human erythropoietin is approved only for treatment of anemia caused by renal failure or by cancer treatment and for certain hematologic malignancies.

Sodium ferric gluconate in sucrose is approved only for treatment of anemia in patients on hemodialysis and for patients who have had a severe reaction to iron dextran.

Medicare warning :(

Anemia of Chronic Disease*

CHRONIC INFECTIONS

CHRONIC IMMUNE DISORDERS

NEOPLASMS

LIVER, KIDNEY failure

* Please remember these patients may very very much look like iron deficiency anemia, BUT, they have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

Anemia of chronic disease

Typical lab findings:

Serum iron < 50

TIBC < 150

Normochromic or hypochromic red cells

Normal ferritin

Normal serum transferrin receptor

Anemia of chronic disease

Mechanisms:

blunted erythropoietin response

diminished response of erythroid precursors to erythropoietin

decreased delivery of iron from RES, increased intracellular ferritin in macrophages

decreased gastrointestinal iron absorption

Anemia of chronic disease

Mediators:

IL-1

IL-6

-interferon

TNF-

Anemia of chronic disease

Inflammation

Tissue necrosis

Infection

Neoplasia

Congestive heart failure

Acute myocardial infarction