Le anemie

Anemia

La anemia è definita da ridotta quantità di emoglobina nel sangue: <13 g/100 ml (uomo),

<12 g/100 ml (donna) (W.H.O.)

……. oppure del numero di globuli rossi

Anemia

La condizione in cui la massa degli eritrociti circolanti è insufficiente a soddisfare la richiesta di ossigeno dei tessuti.

Anemia is most often recognized by abnormal screening laboratory tests.

Eritropoiesi è un processo regolato dalla tensione di ossigeno nei tessuti

La fisiologia della produzione e del ricambio dei globuli rossi fornisce la chiave per la comprensione dei meccanismi che provocano la anemia

Impaired O2 delivery to the kidney can result from a decreased red cell mass (anemia), impaired O2 loading of the hemoglobin molecule or a high O2 affinity mutant hemoglobin (hypoxemia), or, rarely, impaired blood flow to the kidney (renal artery stenosis).

When the hemoglobin level falls to 120 g/L (12 g/dL), plasma EPO levels increase logarithmically.

In circulation, EPO has a half-clearance time of 6–9 h.

I livelli di EPO sono inferiori in presenza di chronic kidney disease or chronic inflammation.

I livelli di EPO diminuiscono con l'età: serve più EPO per sintesi normale.

Dietro stimolazione con EPO, i livelli di produzione dei globuli rossi aumenta fino a 4-5 volte in 1-2 settimane, but only in the presence of adequate nutrients, especially iron.

Il buon funzionamento dell' erythron richiede normale produzione di EPO, un midollo in buone condizioni e una sufficiente disponibilità di fattori necessari alla sintesi della emoglobina.

A defect in any of these key components can lead to anemia.

Anemia is recognized in the laboratory when a patient's hemoglobin level or hematocrit is reduced.

EPO e l'eritrone

Fattore chiave nella regolazione del gene EPO è rappresentato da hypoxia-inducible factor (HIF)-1.

In presenza di O2, HIF-1 viene idrossilato a livello di una prolina che da il via libera alla ubiquitinazione della molecola e la sua degradazione per mezzo del sistema proteasomico.

If O2 è limitato, la idrossilazione non avviene e HIF-1 si associa ad altre molecole partner per traslocare nel nucleo e stimolare la trascrizione del gene EPO.

Methemoglobin is normally reduced (regenerating normal hemoglobin) by protective enzyme systems, e.g., NADH methemoglobin reductase (cytochrome-b5 reductase) (major pathway), NADPH methemoglobin reductase (minor pathway) and to a lesser extent the ascorbic acid and glutathione enzyme systems. Disruptions with these enzyme systems lead to methemoglobinemia.

Methemoglobinemia can also arise in patients with pyruvate kinase deficiency due to impaired production of NADH – the essential cofactor for diaphorase I. Similarly, patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency may have impaired production of another co-factor NADPH

The Rapoport-Luebering The Rapoport-Luebering PathwayPathway

OverviewOverview In RBCs, glycolysis is modified by the Rapoport-

Luebering shunt.

It is a biochemical pathway in mature erythrocytes involving the formation of 2,3-bisphosphoglycerate and which regulates oxygen release from hemoglobin and delivery to tissues. Hence, the name “ 2,3- bisphosphglycerate (2,3-BPG) shunt.

The PathwayThe Pathway

There are 2 steps in this shunt:

1.Bisphosphoglycerate mutase converts 1,3-BPG in to 2,3-BPG.

2.2,3-BPG is hydrolysed to 3-phosphoglycerate by 2,3-bisphosphoglycerate phosphatase.ATP Yield:

Mature RBCs contain no mitochondria, thus they depend only upon glycolysis for energy production

2 ATP.

Role of 2,3-BPG in haemoglobin function

2,3 BPG acts as an allosteric regulator of hemoglobin that has the ability to decrease the

affinity of O2 to hemoglobin . ,

When a hemoglobin molecule is O2 deficient, 2,3 BPG inserts itself between the two beta chains, where it contains positively charged amino acids that form salt bridges with the negatively

charged phosphate groups of 2,3-BPG .The lower affinity for O2 means that the

hemoglobin’s delivery of O2 to the tissues is enhanced when needed .

Eliminazione del ferro

La mucosa intestinale funziona come un semaforo per l'ingresso del Fe nell' organismo

è incluso in derivati dei lisosomi chiamati siderosomi

TESTS OF IRON SUPPLY AND STORAGE

Serum iron (50–150 ug/dL)TIBC (300–360 ug/dL)% transferrin saturation 25-50% SI x100/TIBC

The serum ferritin is used to evaluate total body iron stores. Adult males have serum ferritin levels that average ~100 ug/L, corresponding to iron stores of ~1 g. Adult females have lower serum ferritin levels averaging 30 ug/L, reflecting lower iron stores (~300 mg).

A serum ferritin level of 10–15 ug/L represents depletion of body iron stores. Attenzione: ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise several-fold above baseline levels.

Ferro

TIBC(transferrina)

Ferritina

Diagnosis of anemia Lab investigation. A complete blood count, CBC, will

include: An RBC count:

At birth the normal range is 3.9-5.9 x 106/ul The normal range for males is 4.5-5.9 x 106/ul The normal range for females is 3.8-5.2 x 106/ul Note that the normal ranges may vary slightly depending

upon the patient population. Hematocrit (Hct) or packed cell volume in % or (L/L)

At birth the normal range is 42-60% (.42-.60) The normal range for males is 41-53% (.41-.53) The normal range for females is 38-46% (.38-.46) Note that the normal ranges may vary slightly depending

upon the patient population.

RBC

HCT

Diagnosis of anemia Hemoglobin concentration in grams/deciliter - the

RBCs are lysed and the hemoglobin is measured spectrophotometrically

At birth the normal range is 13.5-20 g/dl The normal range for males is 13.5-17.5 g/dl The normal range for females is 12-16 g/dl Note that the normal ranges may vary slightly

depending upon the patient population.

HGB

Diagnosis of anemia

RBC indices – these utilize results of the RBC count, hematocrit, and hemoglobin to calculate 4 parameters:

Mean corpuscular volume (MCV) – is the average volume/RBC in femtoliters (10-15 L)

Hct (in %)/RBC (ix 1012/L) x 10 At birth the normal range is 98-123 In adults the normal range is 80-100 The MCV is used to classify RBCs as: Normocytic (80-100) Microcytic (<80) Macrocytic (>100)

MCV

Diagnosis of anemia Mean corpuscular hemoglobin (MCH) – is the

average weight of hemoglobin/cell in picograms (pg= 10-12 g)

Hgb (in g/dl)/RBC(x 1012/L) x 10 At birth the normal range is 31-37 In adults the normal range is 26-34 This is not used much anymore because it does

not take into account the size of the cell.

MCH

Diagnosis of anemia

Mean corpuscular hemoglobin concentration (MCHC) – is the average concentration of hemoglobin in g/dl (g%)

Hgb (in g/dl)/Hct (in %)x 100 At birth the normal range is 30-36 In adults the normal range is 31-37 The MCHC is used to classify RBCs as: Normochromic (31-37) Hypochromic (<31) Some RBCs are called hyperchromic, but they

don’t really have a higher than normal hgb concentration.

MCHC

Diagnosis of anemia

Red cell distribution width (RDW) – is a measurement of the variation in RBC cell size

Standard deviation/mean MCV x 100 The range for normal values is 11.5-14.5% A value > 14.5 means that there is increased

variations in cell size above the normal amount (anisocytosis)

A value < 11.5 means that the RBC population is more uniform in size than normal.

RDW