Formation of blood cells

provides the cellular elements (RBCs and leukocytes) of the peripheral blood

takes place in the bone marrow

delivery of oxygen to the tissues and host cell defense

replaces 0.5 X 10^12 cell/day

Give rise to progenitor cells of all lineages

highest proliferative potential of any hematopoietic cell type

can't be identified morphologically

Impotant role in maintenance and differentiation of hematopoietic cells

examples: adipocytes, fibroblastoid cells and reticuloendothelial cells

stem cells/primitive precursors bind firmly

maturing precursor cells are nonadherent

differential expression of cell adhesion molecules regulates the binding activity

Drive specific cell differentiation pathways

progenitor cell cytokines act on immature cells

end-stage cytokines act on more differentiated cell types to induce lineage-specific differentiation

Released by macrophages at inflammatory sites

circulates to bone marrow to cause the production and release of neutrophils

makes granulocytes in the bone marrow

produced/released by peritubular interstitial cells (kidney) in response to hypoxia

circulates to bone marrow to cause the production/release of RBCs

elevated oxygen pressure inhibits production of EPO

inhibitory cytokine

downregulation of stem cell growth/differentiation

Bone marrow active in hematopoeisis

the formation or production of RBCs

starts: primitive RBCs in the embryonic yolk sac

continues: extramedullary organs (liver, spleen)

predominates in the red marrow during late fetal development

Production of cells in the granulocytic lineage, including neutrophils, eosinophils and basophils

after release, circulate for a few hours then die

Splenic macrophages remove dead granulocytes from circulation

increased % of band forms in the blood termed "shift to the left" = infection

macrophages develop from monocytes and are distributed throughout the body

monocytes circulate for approximately 8 hours, then enter the tissues to differentiate into macrophages

macrophage lifespan - months to years

Production of cells in lymphocytic lineage, including T lymphocytes, B lymphocytes or NK cells

B lymphocytes and NK cells develop entirely in the bone marrow and are release into the peripheral blood

mature in the bone marrow until prothymocytes are released into peripheral blood to migrate to the thymus

Once in thymus, termed thymocytes

thymocytes matue/differentiate into T lymphocyte subsets

most thymocytes die in the thymus

once T lymphocytes leave the thymus, most populate lymphatic organs

production of platelets (thrombocytes)

role in hemostasis - limit bleeding, repair endothelium

stimulated by thrombopoietin

Long cytoplasmic extensions which constrict at various points and divide into fragments

each one = 100 - 1000 platelets

2-4 micrometers in size and anuclear

lifespan - 9 days

death - phagocytized in liver or spleen

emergency reserve in the spleen

lose nuclei before entering circulation

mRNA disappears 1-2 days after release

No protein synthesis - can't replace damaged molecules

old, ineslastic RBCs are trapped in the spleen and phagocytosed by macrophages (bilirubin produced)

RBCs lose flexibility and are destroyed in the spleen

Release of bilirubin from RBCs

Splenomegaly

possible jaundice

RBCs are damaged while circulating through the body

RBC components in the blood (Hb)

Hemoglobinuria

Keeping iron rdueced (Fe2+)

Maintaining K+/Ca2+ gradients

Keeping protein SH-groups reduced

Maintaining cell shape

Cells fill with calcium

cells release K+

Lose biconcave shape

Problems with the RBC cytoskeleton

extravascular hemolysis

metabolic, not cytoskeletal problems

both intra and extravascular hemolysis

Production is decreased at low pH

Decreases the affinity of Hb for oxygen

Not responsive to insulin

Very sensitive to pH - inhibited by acidic pH (less lactate)

Provides reduction equivalents in the form of NADH

Low NADPH concentration activates glucose-6-phosphate dehydrogenase

Pentose products are re-indtroduced into glycolysis

Protects RBCs from reactive oxygen species

Hemolytic anemia fom lack of NADPH

Most common RBC enzymatic defect (X-linked)

Lifespan of RBC is shortened because oxidative damage leads to loss of metabolic activity

Prevelant in African/Mediterrenean populations

Hemolytic crisis triggered by: infections, H2O2 producing drugs, fava beans

Splenomegaly, jaundice

Hemolytic anemia from lack of NADH/ATP

nonspherocytic hemolytic anemia without reactive oxygen induced crises

RBCs run out of ATP and degenerate prematurely

Splenomagaly, Jaundice

present as hereditary spherocytosis

Autosomal dominant

Most common: ankrin mutation

Less common: Band 3, spectrin, Protein 4.2 mutation

Form of intravascular hemolytic anemia

mutation in the PIGA gene

an example of somatic mosaicism

Function form of folate found in the body

formed from folate by dihydrofolate reductase

Inhibitor of dihydrofolate reductase

prevents generation of THF

antiproliferative effects

Most reduced form of THF

Form that most of the folate circulating in the blood is in

catalyzes the rxn providing the majority of the carbon for the one carbon pool

Serine  +  THF  -->  Glycine  +  N5, N10-methylene-THF + H2O

Receptor mediated endocytosis

Receptors have high affinity for folate monogluamases (particularly N5-methyl THF monoglutamate which is the most abundant form in the circulation)

Inracellular folate is rapidly metabolized by the addition of polygluatame (mechanism of folate retention)

Converts dUMP to dTMP

essential step in the synthesis of DNA

Most important rxn clinically

only synthesized by certain bacteria

best dietary sources are liver, kidney, meats, dairy and shellfish

Produced by the parietal cells of the stomach but is only active in the small intestine

Complexes with B12 so it can be taken up in the ileum

Lack of ability to absorb B12 from the ileum

autoimmune disease

No production of intrinsic factor

Complexes with B12 in the portal blood

synthesized by the cells of the ileal mucosa

Required for B12 uptake from the blood

Binds most of the B12 in circulation

complexes with B12 and is taken up by the liver

forms a circulating store of B12

Required for the metabolism of propionyl-CoA

Requireds adenosylcobalamin

Deficiency of B12 causes an accumulation of L-methylmonyl-CoA and hydrolysis of methylmalonic acid leading to organic acidemia

Methionine synthase

converts homocysteine to methionine

has an absolute requirement for methylcobalamin

Lack of B12 in the diet will cause a functional folate deficiency as the body's folate pool becomes trapped in the N5-methyl THF form

only the methionine synthase rxn can convert N5-methyl THF back to THF

Results in demylenation

likely caused by faulure of the methionine synthase rxn

B12 deficiency

accumulation of N5-methyl THF

Thymidine synthesis is blocked and DNA synthesis is prevented

Dietary insufficiency (not taking in enough folic acid)

Thymidine synthesis is blocked and DNA synthesis is prevented

Occurs in folate and B12 deficiency

block on DNA synthesis in the absence of other checks on growth will lead to an increase in cell size

Most apparent in rapidly-diving cells

pregnancy

lactation

growth

chronic hemolytic anemia

Pregnancy

periods of growth

very useful for binding oxygen and transferring electrons

must be in the bound form at all times - no free form

no regulated loss through urine

Blood loss - intravascular hemolysis, menstruation

Sloughing off of iron-containing cells in the intestines and kidney

80% in active forms - Hg, myoglobin, cytochromes, bound to transferrin

20% in inactive forms - dynamic storage in ferritin, degenerated long term storage in hemosiderin

shuts down Ferroportin and is the master regulator of iron in the body – it is released from the liver in stress conditions – by temorarilly restricting the availablity of iron it inhibits the growth of microbial organisms that need the iron to grow

Also regulates the release of iron from macrophages

Mutation of HFE causes low expression

5' UTR contains a sequence that fuctions as an IRE

IRP binds to the IRE and blocks translation

If there is free iron in the cytoplasm, it binds to IRP and displaces displaces it from the mRNA (turning off the inhibition)

Translation begins quickly

Test to diagnose iron poisoning or overload

limited diagnostic value since it provides no info about body iron stores

Measures unoccupied transferrin

The higher the value the lower the iron stores

Chronic blood loss

Chronic disease (hepcidin production)

poor dieatary intake

intestinal parasites (compete for iron)

malabsorptive disease (Celiacs)

Iron depletion - serum ferritin falls

deficient erythropoiesis - Hb still normal but protoporphyrin levels up, transferrin saturation falls

iron deficiency anemia - hypochromic (low Hb), microcytosis

Blood transfussions for treatment of hemolytic disease (iron accumulates in macrophages)

Slow erythropoiesis (renal failure)

Hereditary hemochromatosis type 1 (HFE mutations)

Look for: high transferrin saturation and hemosiderin deposits (show up first in WBCs)

Common hereditary iron uptake disorder

caused by a mutation in the HFE gene leading to a repression of hepcidin expression

causes an increase of iron release from enterocytes

Hb has 4 subunits, each with a heme prosthetic group

These heme groups do not bind O2 with equal affinity

Hb does not bind O2 effectively at low O2 concentrations

As O2 levels increase, Hb becomes more efficient at binding O2 - Sigmoid shape of the Hb binding curve

Binds O2 with high affinity at low O2 concentrations

exibits a hyperbolic O2 binding curve

Hb Gower 1, Hb Gower 2, HB Portland

Replaced by Hb F (major form of fetal Hb)

Major form of fetal Hb

as development progresses, switch from gamma chain synthesis to beta chain synthesis occurs

Very high O2 affinity

Histidine residue in the beta chain required for 2-3 BPG bidning is replaced with a serine in the gamma chain

mutations that produce unstable Hb that have a tendency to form insoluble complexes

often form hemichrome and precipitate as Heinz bodies

form methemoglobin (Fe3+) more easily

Beta-subunit mutation (Lys to Met) at 2,3 BPG bidning site

increased O2 affinity

Beta-subunit mutation (Asn to Thr) at alpha1beta2 contact site

decreased O2 affinity

alpha-subunit mutation

readily forms methemoglobin

Beta-subunit mutation

Readily forms methemoglobin

Found in sickle cell disease

glutamate replaced with a valine at position 6 of the beta-globin chain

Polymers distort shape of red cell - misshapen cells block microcirculation

chronic hemolytic anemia

treatment of choice for sick cell disease in adults

increases expression of Hb F

promotes Hb solubility

Reduces sickling, painful crisis, hospitalizations

Glutamate relplaced with a lysine at position 6 of the beta-globin chain

less soluble than Hb A so it precipitates - does not sickle

hemolytic anemia

Glutamate at position 26 of the beta-globin chain is replaced by a lysine

mutant beta-globin chain is not synthesized effictively

imbalanced globin chain synthesis leads to symptoms of a mild thalassemia

Heterozygotes are asymptomatic

homozygotes experience microcytosis, hypochromia

Two genes for alpha-globin on chromosome 16

manifest during development and adult life

Most often arise by deletion

gamma4 Hb tetramer

1 functional alpha-globin gene and 3 defective

poor oxygen carrier

beta4 Hb tetramer

1 functional alpha-globin gene and 3 defective

poor oxygen carrier

precipitates, shortening RBC lifespan

4 defective alpha-globin genes

only embryonic Hb's can be produced (Hb Gower 1 and Hb Portland)

Incompatible with life

T is replaced by C - stop codon converted to codon for glu

alpha-globin chain length increased from 141 to 172 aa

mRNA is unstable

behaves like a alpha-thalassemia

Only one gene for beta-globin on chromosome 11

can lead to hereditary persistence of fetal Hb

recombination events delete part of both beta and delta-globin genes

generates a poorly functioning globin chain

Typically used in neonatal sceening for hemoglobinopathies

Insensitve and cannot resolve all abberant Hb

control point of heme synthesis

amount of enzyme can be controlled by presence of iron

ALA synthase synthesizes ALA from succinyl-CoA and glycine

2 molecules of ALA are joined to form PBG

4 molecules of PBG are joined to form uroporphyriogen

modifications of the side-chains generates coporphyrinogen and protoporphyrinogen

Ferrochelatase inserts an Fe2+ into the molecule to yield heme

low heme concentraions activate ALA synthase

Liver - excess heme converted to hemin causing a downregulation of ALA synthase transcription

Bone marrow - ALA synthase transcription is controlled by EPO and availability of intracellular iron

inhibits the formation of PBG and ferrochelatase

leads to the accumulation of ALA and other heme precursors in heme producing tissues

causes production of zinc-protoporphyrin

causes symptoms similar to porphyrias

degree based on amount of ALA in urine

deficiency is HMBS (aka PBG deaminase)

Autosomal dominant

ALA and PBG accumulate in the urine (dark red color)

can be life threatening - causes periods of confusion and sharp abdominal pain

Porphyria Cutanea Tarda (PCT)

Most common of the porphyrias

Deficiency of UROD

Buildup of porphyrins which can be detected in the urine - (fluorescent urine)

photosensitivity of the skin laeding to blistering of exposed areas

Late age of onset (40s or 50s)

Autosomal dominant

Defect in UROS

Red, fluorescent teeth

Hairy skin

extremely photosensitive

Symptoms may be relieved by drinking blood

Autosomal recessive

Elevated destruction of RBCs can lead to serum bilirubin levels that exceed the liver's capacity for glucuronation and excretion

unconjugated bilirubin in blood

no bilirubin in urine

Blood analysis shows hemolysis (reticulocyte count is up)

Hb is low

Liver disease impairs the liver's function to glucuronate bilirubin leading to a rise in indirect bilirubin in the plasma and tissues

bilirubin in urine

Pale feces and urine

markers for liver disease may be present (ALT and AST)

Gallstones or neoplasias can obstruct the biliary duct, impairing the liver's ability to excrete unconjugated bilirubin into the feces

pale feces but intense urine

conjugated bilirubin in blood and urine

markers of cholestasis (alkaline phosphatase)

deficiency in bilirubin glucuronyl transferase

genetic prehapatic jaundice

Damage to vessel wall exposes collagen and tissue factor to flowing blood

causes downregulation of anti-coagulationg substances

collagen - activates intrinsic pathway and activates platelets

tissue factor - activates extrinsic pathway

coagulation pathways result int he activation of thrombin

anucleated cells produced from megakaryotes in response to the hormone thromboprotein

life span of 9-10 days

normal levels are 200,00-400,000 per microliter of blood

have surface receptors that bind to collagen

Required for adhesion of the platelet to the matrix (plug)

Binds to factor VIII

mild/moderate quantitative deficiency of vWF and factor VIII

Autosomal Dominant

qualitative abnormalities of vWF

Autosomal Dominant

Very low or undetectable levels of vWF (very rare)

Autosomal recessive

Bleeding time is prolonged (in some cases longer than 20 minutes)

Platelets are large

No platelet aggregation in response to vWF

Caused by a defect in the GPIb complex

initiated by the partial activation of XII by interaction with collagen or other negatively charged surface

Leads to activation of factor X

activated by tissue factor

Tissue factor binding to factor VII brings about activation

VIIa/TF/Ca2+ complex activates factor X

Xa complexed with its cofactor Va and calcium ion activates prothrombin to thrombin

Thrombin cleaves fibrinogen to form a soft fibrin clot

Fibrin cross-linking forms a hard clot

Factor IIa

Coagulation inhibitor - binds to thrombomodulin

Activates protein C, which together with its cofactor Protein S inactivates factors VIIIa and Va

Also can activate factors XI, V and VIII, convert fibrinogen to fibrin and activate platelets to promote coagulation

necessary for the formation of II, VII, IX, X, protein S and protein C

deficiency can result in acquired bleeding disorders

Archidonic acid - PGI2

Nitric oxide - L-arginine

Endothelial ectoadenosine disphosphate

inhibits platelet function by elevating cAMP level in cells

also acts as a vasodilator

anticoagulation

diffuses into platelets and stimulates production of cGMP

cGMP supresses conformational change in glycoprotein IIb/IIIa - which is required to bind fibrinogen

anticoagulation

rapid lysis of fibrin clots

cleaves plasminogen into plasmin

caused by a R506Q mutation in the factor V gene

prevents cleavage by protein C and leads to prolonged activity causing hypercoagulability and increases risk of venous thrombosis

Left supraclavicular node

common site of lymphatic metastasis for many malignancies

Hypersplenism

Chemotherapy

Post infection

Immune mediated disorders

Allergic rxn to drugs

Allergies

Helminthic infections

Maligninacies

Collagen vascular disease

subtle physical sign in a neutropenic patient