Fisiología de la sangre

y la hemostasia

Jorge Sanhueza S., PhD

 Lectura recomendada

1. Hematopoyesis.

2. Breve historia de la hematología I: las anemias.

3. Anemia: consideraciones generales y clasi cación.

4. Interpretación clínica de la biometría hemática.

fi

Sangre Total

Volumen sanguíneo total 5-7% del peso

corporal total (volemia)

Funciones generales:

• Transporte de oxigeno y nutrientes.

• Transporte de hormonas, fármacos, etc.
• Respuesta inmune.
• Termoregulación.
nar y renal se tratan en los capítulos 34 y 37. Por otra parte, la
función de la sangre como portadora de muchas células efectoras
inmunitarias no se describe aquí, sino en el capítulo 3.
Células
sanguíneas “Hematopoyesis”

100
Celularidad (%)

Vértebras

50 Esternón
Costilla
Tibia Fémur
0
10 30 50 70
Años

FIGURA 312 Cambios en la celularidad de la médula ósea en

varios huesos con la edad. El 100% corresponde al grado de
celularidad al nacer. (Con autorización de Whitby LEH, Britton CJC: Disorders of the
Blood. 10th ed. Churchill Livingstone, 1969.)
 Célula madre hematopoyética

• Osteoblastos.
• Macrógafos tisulares.
• Células dendríticas.

IL-1 GM-CSF
IL-6 G-CSF
IL-3 SCF
Precursor
linfocítico en
médula ósea
Células madre dirigidas
(célula progenitora)

GM-CSF GM-CSF GM-CSF GM-CSF IL-4 Equivalente

Timo
eritro trombo IL-5 IL-3 a la bolsa

Megacariocito

M-CSF G-CSF
Diferenciación
Normoblasto tardío
Juvenil

Monocito

Reticulocito
Segmentado

Monocito

Eritrocito Plaquetas Neutrófilo Eosinófilo Basófilo B T

Macrófago Células Linfocitos

hístico polimorfonucleares
Eritrocitos
• Células transportadoras de oxigeno.
• Hemoglobina.
• Biconcavo, membrana exible.
• VM: 120 dias.
• Destrucción intravascular 10%
fl
Parámetros sanguíneos
HEMATOCRITO NORMAL (HCT) (%)

Hombres 39-47

Mujeres 36-45

Niños 33-40

Embarazadas 33-42
Parámetros físicos sanguíneos

Circulación sistémica Circulación pulmonar

Arterias 550 ml 400 ml

Capilares 300 ml 60 ml

Venas 2150 ml 840 ml

Total 3000 ml 1300 ml

 materna a la feta
cuando aumentan
nes jóvenes, hay, a
CUADRO 312 Características de los eritrocitos humanosa Gower 1 (ζ2ε2) y G
globina a otra dur
Varón Mujer
por la disponibilid
Hematócrito (Hct) (%) 47 42 ducción de hemog
Eritrocitos (RBC) (106/μl) 5.4 4.8 del gen para globi
ción de eritropoye
Hemoglobina (Hb) 16 14
(g/100ml)

Volumen corpuscular Hct × 10

= ___________
87 87 SÍNTESIS D
medio (MCV) (fl) RBC (106/μl)
El contenido sang
Hemoglobina 29 29
Hb × 10 g/100 ml en varon
corpuscular media = ___________
RBC (106/μl) eritrocitos. En el c
(MCH) (pg)
hemoglobina; cad
Concentración 34 34
corpuscular media de
truyen 0.3 g (fig. 3
Hb × 100
= ________
hemoglobina (MCHC) Hct bina se sintetiza
(g/100 ml) (Recuadro clínico
Diámetro celular medio = diámetro 7.5 7.5
(MCD) (μm) promedio de
500 células en CATABOLIS
frotis
DE LA HEM
a Las células con volumen corpuscular medio >95 fl se denominan macrocitos;

aquéllas con dicho volumen <80 fl se llaman microcitos; las células con
Cuando se destru
hemoglobina corpuscular media <25 g/100 ml se consideran hipocrómicas. cos, la porción glo
fl, fentolitros. hem se convierte e

https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0370-41062001000500012
VALORES NORMALES DE SERIE ROJA EN EDAD PEDIÁTRICA
 HemoglobinFrom
research and the origins
www.bloodjournal.org of molecular
by guest medicine
on August 15, 2017. For personal use only.

Alan N. Schechter1
3928 SCHECHTER BLOOD, 15 NOVEMBER 2008 ! VOLUME 112, NUMBER 10
1Molecular Medicine Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD

Figure 1. The X-ray determined structure of the

Much of our understanding of human rounding DNA. In the last few decades, droxyurea tohemoglobin elevate fetal hemoglobin
molecule and ainrepresentation of its
physiology, and of many aspects of pa- research has opened up new paradigms sickle cell disease. very high concentration
It is in the erythrocyte. (A) The
likely that current
thology, has its antecedents in laboratory for hemoglobin related to processes such research willarrangement of the "-helices
also have significant (shown as tubes) in each
clinical
and clinical studies of hemoglobin. Over as its role in the transport of nitric oxide implications,"! asunit—one on the left
well as lessons forand one, 180° rotated, on the
other
right—is shown, as are the 4 heme groups with their
the last century, knowledge of the genet- and the complex developmental control aspects of molecular medicine, the origin
iron atoms where gas molecules bind. The site of the
ics, functions, and diseases of the hemo- of the !-like and "-like globin gene clus- of which can be largely traced to this
sickle mutations on mutant !-chains as well as the !93
globin proteins has been refined to the ters. It is noteworthy that this recent work research tradition. conserved (Blood. 2008;112:
cysteine residues is also shown. Hemoglo-
molecular level by analyses of their crys- has had implications for understanding 3927-3938) bin molecules in the red blood cell, shown in an inset on
tallographic structures and by cloning and treating the prevalent diseases of the right, are very tightly packed (at a concentration of
and sequencing of their genes and sur- hemoglobin, especially the use of hy- approximately 34 g/dL) and have little access to sol-
vent; this allows efficient oxygen transport by each cell
Introduction but also affects the chemical behavior of the molecules,
such as promoting sickle cell hemoglobin polymeriza-
During the past 60 years, the study of human hemoglobin, probably of the globin proteins, including 7 stretches
tion uponof the deoxygenation.
slight peptide !-helix(B) A representation of
more than any other molecule, has allowed the birth and maturation in the !-chains and 8 in the "-chains the Hemoglobina
(Figure •
1).1,2 These
quaternary A:
helices
structural arecadenas
changes α y cadenas β.
in the hemoglobin
of molecular medicine. Laboratory research, using physical, chemi- in turn folded into a compact globuletetramer,
that heterodimerizes
in a top-down and view,then
in the transition from the
cal, physiological, and genetic methods, has greatly contributed to, forms the tetramer structure.3 These 4oxy Hemoglobina
conformation
polypeptides
The iron atoms
• of(left)
the to A2:
the deoxy
hemoglo- 2.5% α2δ2(right).
conformation
but also built upon, clinical research devoted to studying patients bin tetramer each have a large central space intoshift
which relative
a hemeto the planes of the heme
with a large variety of hemoglobin disorders. During this period, prosthetic group, an iron-protoporphyrin groups and a central cavity between the !-chains
IX molecule, is bound by
HbA
the pioneering work of Linus Pauling, Max Perutz, Vernon Ingram, noncovalent forces, and thus the iron atom isfacilitating
opens, •
1c: tiene unabinding.
2,3 BPG
protected from access
molécula de glucosa unida
These diagrams
are based on drawings of Irving M. Geis. Illustration by
Karl Singer, Herman Lehmann, William Castle, Ruth and Reinhold of the surrounding aqueous solution. a The
Alice Y.
laChen.
valina
iron atoms terminal
in this en cada cadena β.
Benesch, Titus Huisman, Ernst Jaffé, Ernest Beutler, and many environment are primarily in the physiologic ferrous (FeII) chemi-
others still active has been instrumental in these studies. Our •
Metahemoglobina
cal valence state, coordinated to 4 pyrrole nitrogen atoms in one , el sistema de
understanding of the molecular basis of hemoglobin developmental plane, to an imidazole nitrogen atomdinucleótido
of the invariant de dihidronicotinamida adenina
histidine
and genetic control, structure-function relations, and its diseases amino acid at position 8 of the “F”-helix, and to a gas atom on the
and their treatment is probably unparalleled in medicine. Indeed, (NADH) metahemoglobina reductasa,
side opposite (with respect to the porphyrin plane) the histidine
this field, especially during the first 25 years of the existence of the residue. The reversible binding of gasesconvierte
to these 4la metahemoglobina
ferrous iron de nuevo en
American Society of Hematology, provided the model for develop- hemoglobina.
atoms in the tetramer of globin polypeptides allows hemoglobin to
ments in many other areas of research in hematology and other transport O2, CO, and NO.4 CO2 is transported in the blood in
subspecialities. This review attempts to highlight some recent
developments in hemoglobin research most relevant to the hema-
•
Hemoglobina
solution and by interactions with the amino-terminal F?of
residues .
hemoglobin as a weak carbamino complex and not by binding to
tologist in the context of the current understanding of the functions
the iron atoms.
of these proteins and their genes. I am occasionally asked, “What’s
In recent years, knowledge of the properties of the character-
new in hemoglobin?” I believe that this review will show that we
istic folds of each of the globin polypeptides and their ability to
are still learning much that is very relevant to our understanding of
bind heme prosthetic groups has led to the development of a
human physiology and disease.
detailed evolutionary tree to describe the ontogeny of this
 roposed evolutionary
globin proteins as in-
ses. NGB, neuroglobin;
globin. Reprinted from
;3:1146-1151) with per-
Chen.
 ASH 50th anniversary review

Hemoglobin
From www.bloodjournal.org by guest on research and
August 15, the For
2017. origins of molecular
personal use only. medicine
Alan N. Schechter1

, 15 NOVEMBER 2008 ! VOLUME 112, NUMBERMolecular Medicine Branch, National Institute ofHEMOGLOBIN
Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 3931
1
10 GENETICS, FUNCTIONS, AND DISEASES

Much of our understanding of human rounding DNA. In the last few decades, droxyurea to elevate fetal hemoglobin in
. The genomic structure of the clusters of physiology, and of many aspects of pa- research has opened up new paradigms sickle cell disease. It is likely that current
nd "-like globin genes, on chromosomes 16 thology, has its antecedents in laboratory for hemoglobin related to processes such research will also have significant clinical
n human beings. The functional !-like genes and clinical studies of hemoglobin. Over as its role in the transport of nitric oxide implications, as well as lessons for other
wn in dark blue and the pseudogenes are in the last century, knowledge of the genet- and the complex developmental control aspects of molecular medicine, the origin
; 2 of these (# and $-1) code for small amounts ics, functions, and diseases of the hemo- of the !-like and "-like globin gene clus- of which can be largely traced to this
The functional "-like genes are shown in light globin proteins has been refined to the ters. It is noteworthy that this recent work research tradition. (Blood. 2008;112:
he important control elements, HS-40 and the molecular level by analyses of their crys- has had implications for understanding 3927-3938)
scussed in the text, are also shown at their tallographic structures and by cloning and treating the prevalent diseases of
and sequencing of their genes and sur- hemoglobin, especially the use of hy-
mate locations. The !-gene cluster is approxi-
wo thirds of the length of the "-gene cluster; it is Introduction
ed from telomere toward centromere, the oppo-
During the past 60 years, the study of human hemoglobin, probably of the globin proteins, including 7 stretches of the peptide !-helix
e " cluster. The various hemoglobin species
more than any other molecule, has allowed the birth and maturation in the !-chains and 8 in the "-chains (Figure 1).1,2 These helices are
formed from these genes, with their prime
of molecular medicine. Laboratory research, using physical, chemi- in turn folded into a compact globule that heterodimerizes and then
mental stages, are shown in the lower part of
e. Illustration by Alice Y. Chen. cal, physiological, and genetic methods, has greatly contributed to, forms the tetramer structure.3 These 4 polypeptides of the hemoglo-
but also built upon, clinical research devoted to studying patients bin tetramer each have a large central space into which a heme
with a large variety of hemoglobin disorders. During this period, prosthetic group, an iron-protoporphyrin IX molecule, is bound by
the pioneering work of Linus Pauling, Max Perutz, Vernon Ingram, noncovalent forces, and thus the iron atom is protected from access
Karl Singer, Herman Lehmann, William Castle, Ruth and Reinhold of the surrounding aqueous solution. The iron atoms in this
Benesch, Titus Huisman, Ernst Jaffé, Ernest Beutler, and many environment are primarily in the physiologic ferrous (FeII) chemi-
others still active has been instrumental in these studies. Our cal valence state, coordinated to 4 pyrrole nitrogen atoms in one
understanding of the molecular basis of hemoglobin developmental plane, to an imidazole nitrogen atom of the invariant histidine
and genetic control, structure-function relations, and its diseases amino acid at position 8 of the “F”-helix, and to a gas atom on the
and their treatment is probably unparalleled in medicine. Indeed, side opposite (with respect to the porphyrin plane) the histidine
this field, especially during the first 25 years of the existence of the residue. The reversible binding of gases to these 4 ferrous iron
American Society of Hematology, provided the model for develop- atoms in the tetramer of globin polypeptides allows hemoglobin to
ments in many other areas of research in hematology and other transport O , CO, and NO.4 CO is transported in the blood in
2 2
subspecialities. This review attempts to highlight some recent solution and by interactions with the amino-terminal residues of
developments in hemoglobin research most relevant to the hema- hemoglobin as a weak carbamino complex and not by binding to
tologist in the context of the current understanding of the functions
the iron atoms.
of these proteins and their genes. I am occasionally asked, “What’s
use of familial methemoglobinemia maynew
beinconsidered
hemoglobin?” theI believehemoglobin virtually
that this review will show thatcreated
we
Inthe field
recent years,of molecular
knowledge medicine
of the properties of the character-
32 istic folds of each of the globin polypeptides and their ability to
escription of an enzyme defect in a hereditary disorder.
are still learning andrelevant
much that is very moved research
to our hematology
understanding of to its forefront. It is sometimes
 ASH 50th anniversary review
The discovery by Linus Pauling and his associates in that 1949 35 especially in anima
Hemoglobin research and the origins of molecular medicine
the molecular basis of sickle cell anemia is due to an abnormal human pathophysiol
Alan N. Schechter1
1Molecular Medicine Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD

Much of our understanding of human rounding DNA. In the last few decades, droxyurea to elevate fetal hemoglobin in
physiology, and of many aspects of pa- research has opened up new paradigms sickle cell disease. It is likely that current
thology, has its antecedents in laboratory for hemoglobin related to processes such research will also have significant clinical
and clinical studies of hemoglobin. Over as its role in the transport of nitric oxide implications, as well as lessons for other
the last century, knowledge of the genet- and the complex developmental control aspects of molecular medicine, the origin
ics, functions, and diseases of the hemo- of the !-like and "-like globin gene clus- of which can be largely traced to this
globin proteins has been refined to the ters. It is noteworthy that this recent work research tradition. (Blood. 2008;112:
molecular level by analyses of their crys- has had implications for understanding 3927-3938)
tallographic structures and by cloning and treating the prevalent diseases of
and sequencing of their genes and sur- hemoglobin, especially the use of hy-

Introduction
During the past 60 years, the study of human hemoglobin, probably of the globin proteins, including 7 stretches of the peptide !-helix
more than any other molecule, has allowed the birth and maturation in the !-chains and 8 in the "-chains (Figure 1).1,2 These helices are
of molecular medicine. Laboratory research, using physical, chemi- in turn folded into a compact globule that heterodimerizes and then
cal, physiological, and genetic methods, has greatly contributed to, forms the tetramer structure.3 These 4 polypeptides of the hemoglo-
but also built upon, clinical research devoted to studying patients bin tetramer each have a large central space into which a heme
with a large variety of hemoglobin disorders. During this period, prosthetic group, an iron-protoporphyrin IX molecule, is bound by
the pioneering work of Linus Pauling, Max Perutz, Vernon Ingram, noncovalent forces, and thus the iron atom is protected from access
Karl Singer, Herman Lehmann, William Castle, Ruth and Reinhold of the surrounding aqueous solution. The iron atoms in this
Benesch, Titus Huisman, Ernst Jaffé, Ernest Beutler, and many environment are primarily in the physiologic ferrous (FeII) chemi-
others still active has been instrumental in these studies. Our cal valence state, coordinated to 4 pyrrole nitrogen atoms in one Figure 6. The
understanding of the molecular basis of hemoglobin developmental plane, to an imidazole nitrogen atom of the invariant histidine
and genetic control, structure-function relations, and its diseases amino acid at position 8 of the “F”-helix, and to a gas atom on the from early sta
and their treatment is probably unparalleled in medicine. Indeed,
this field, especially during the first 25 years of the existence of the
side opposite (with respect to the porphyrin plane) the histidine
residue. The reversible binding of gases to these 4 ferrous iron
birth and in
American Society of Hematology, provided the model for develop-
ments in many other areas of research in hematology and other
atoms in the tetramer of globin polypeptides allows hemoglobin to erythropoiesis
transport O2, CO, and NO.4 CO2 is transported in the blood in
subspecialities. This review attempts to highlight some recent solution and by interactions with the amino-terminal residues of periods. Thes
developments in hemoglobin research most relevant to the hema- hemoglobin as a weak carbamino complex and not by binding to
tologist in the context of the current understanding of the functions
the iron atoms. samples made
of these proteins and their genes. I am occasionally asked, “What’s
new in hemoglobin?” I believe that this review will show that we
In recent years, knowledge of the properties of the character- Wood (Br Med
istic folds of each of the globin polypeptides and their ability to
are still learning much that is very relevant to our understanding of
human physiology and disease.
bind heme prosthetic groups has led to the development of a Chen.
Transporte de O2
HbA1c
Neutró los

“Fagocitos profesionales”

Responden a mediadores solubles migrando al sitio de

daño, ingiriendo y destruyendo patógeno invasor.

Gránulos primarios y secundarios conteniendo

mediadores in amatorios.
fl
fi
Migración de neutró los

fi
Gránulos inespecí cos:

– Mieloperoxidasas.
– Hidrolasas ácidas.
– Glucoronidasas.

Gránulos especí cos:

– Fosfatasas alcalinas.
– Colagenasas.
– Lisozima.
– Lactoferrina.
– Fagocitina.

Gránulos terciarios:

– Gelatinasas.
– Catepsinas.
– Glucoproteinas.
fi
fi
CPA?
 Monocitos-Macrógagos

• Macrófagos activados fagocitan y liberan proteínas antibacterianas y mediadores proinflamatorios.

• Complementan función de neutrófilos en la fase aguda.

• Cumplen papel central durante la inflamación crónica.

• Macrofagos CPA clásicas.

EOSINÓFILOS

• Participan en respuesta frente a alergenos respiratorios,

gastrointestinales y dermatológicos y frente a parásitos
helmínticos (respuesta alérgica).

• Malos fagocitos, liberan contenido de sus gránulos al medio

extracelular.

• Gránulos: proteína básica mayor, proteína catiónica

eosinofílica, neurotoxina derivada de eosinófilos y fosfatasa
ácida.
BASÓFILOS

• Población menos abundante.

• Participan de procesos alérgicos e inflamación.

• Poseen receptores de IgE.

• Gránulos: histamina, heparina, factor quimiotáctico de

eosinófilos, factor quimiotáctico de neutrófilos.
Plaquetas
Linfocitos
Componentes Orgánicos
% Concentración

PROTEINAS TOT. 100 7g/dL

Albúmina 59,2 3,4-4,8 g/dL

Globulina-α1 3,9 0,3-0,7 “

Globulina-α2 7,5 0,4-0,9 “

Globulina-β 12,1 0,4-0,8 “

Globulina-γ 17,3 0,6-1,2 “

Fibrinógeno 0,15-0,3 “
CUADRO 316 Algunas de las proteínas sintetizadas por el hígado: actividades fisiológicas y propiedades
Concentración
Nombre Función principal Características de fijación en suero o plasma

Albúmina Proteína transportadora; regulador Hormonas, aminoácidos, 4 500-5 000 mg/100 ml

osmótico esteroides, vitaminas, ácidos grasos

Orosomucoide Incierta, tal vez participe en la Trazas, aumenta en inflamación

inflamación

Antiproteasa α1 Inhibidora de tripsina y en general de Proteasas en suero y secreciones 1.3-1.4 mg/100 ml

proteasa hísticas

Fetoproteína α Regulación osmótica, proteína fijadora y Hormonas, aminoácidos Componente normal de sangre
transportadoraa fetal

Macroglobulina α2 Inhibidora de endoproteasas séricas Proteasas 150-420 mg/100 ml

Antitrombina III Inhibidora de proteasa del sistema Unión 1:1 con proteasas 17-30 mg/100 ml
intrínseco de coagulación

Ceruloplasmina Transporte de cobre Seis átomos de cobre/mol 15-60 mg/100 ml

Proteína C reactiva Incierta, participa en la inflamación Complemento C1q <1 mg/100 ml; se eleva en
hística inflamación

Fibrinógeno Precursor de fibrina en la hemostasia 200-450 mg/100 ml

Haptoglobina Fijadora, transporte de hemoglobina Unión 1:1 con hemoglobina 40-180 mg/100 ml
libre

Hemopexina Se une con porfirinas, sobre todo con 1:1 con hem 50-100 mg/100 ml
hem para su reciclado

Transferrina Transporte de hierro Dos átomos de hierro/mol 3.0-6.5 mg/100 ml

Apolipoproteína B Ensamblado de partículas de Portadora de lípidos

lipoproteína

Angiotensinógeno Precursor del péptido presor

angiotensina II

Proteínas, factores de Coagulación sanguínea 20 mg/100 ml

coagulación II, VII, IX, X

Antitrombina C, proteína C Inhibición de coagulación sanguínea

Factor de crecimiento similar Mediador de efectos anabólicos de la Receptor IGF-I

a la insulina tipo I hormona del crecimiento

Globulina transportadora de Proteína transportadora de esteroides Hormonas esteroides 3.3 mg/100 ml

hormonas esteroides en sangre

Globulina transportadora de Proteína transportadora de hormona Hormonas tiroideas 1.5 mg/100 ml

tiroxina tiroidea en sangre

Transtiretina (prealbúmina Proteína transportadora de hormona Hormonas tiroideas 25 mg/100 ml

de unión tiroidea) tiroidea en sangre

a La función de la fetoproteína α es incierta, pero por su homología estructural con la albúmina, a menudo se le asignan estas funciones.
 Albúmina

Funciones:

• Proteína de transporte por excelencia (iones, bilirrubina,

hormonas esteroídeas, fármacos, etc.).
Especi cidad
Saturación

• Reserva energética.

• Amortiguación (pH).
fi
γ-GLOBULINAS
Inmunidad humoral:

Las producen los linfocitos, neutralizan a los agentes externos

 α y β -GLOBULINAS
• Enzimas.

• Inhibidores enzimáticos.

• Proteínas transportadoras:
• Trasferrina
• Ceruloplasmina
• Haptoglobina
• Hemopexina

• Hormonas peptídicas, factores de crecimiento, citoquinas.

• Factores de coagulación y complemento.

• Marcadores tumorales.

• Proteínas de fase aguda.

Presión oncótica
Lípidos: Clasificación

Principales lípidos del organismo:

1. Triglicéridos.
2. Colesterol libre.
3. Colesterol esterificado.
4. Fosfolípidos.
Lipoproteínas

Núcleo central
Cubierta externa
 Clasificación de las Lipoproteínas

método de inmunoseparación. Aunque requiere de mayor evaluación, parece ser

promisorio especialmente para los casos con las limitaciones en el Col-LDL calcu-
lado.

3.3. Interpretación de los resultados

Los valores de referencia considerados en este documento son aquellos del NCEP
de los Estados Unidos. Son aplicables para población adulta, de bajo riesgo
cardiovascular (menos de 2 factores de riesgo), sin evidencia clínica de enferme-
dad coronaria ni diabetes, Tabla 6.

Tabla 6
Niveles de referencia para lípidos sanguíneos en sujetos de bajo
riesgo cardiovascular

Deseable Límite alto Elevado

MINSAL 2010
Col-total < 200 mg/dL 200 – 239 mg/dL ≥240 mg/dL
Col-LDL <130 mg/dL 130 – 159 mg/dL ≥160 mg/dL
Col-HDL > 35 mg/dL
Triglicéridos <200 mg/dL 200 – 399 mg/dL ≥400 mg/dL
Lipoproteínas
Velocidad de Sedimentación Globular
(VSG)
20 mg/dl, tienen infección bacteriana19. go (>3 mg/L)5, 20. En un estudio prospectivo reali-
zado en una cohorte multiétnica de pacientes con

Proteína C
Los métodos usuales para la determinación de
las concentraciones de PCR son menos precisos LES, altos niveles de PCR ultrasensible (>16.5 mg/
cuando éstas son menores de 1 mg/dl, así que el L) se asociaron significativamente con la ocurren-
uso de métodos de alta sensibilidad, PCR cia de eventos vasculares21.

Reactiva (PCR)
ultrasensible, son de gran utilidad para distinguir En varias enfermedades reumáticas hay una
los niveles basales de PCR de niveles mayores buena correlación entre la actividad clínica y la
que se presentan durante la inflamación aguda, elevación de la PCR (Tabla 4). También, hay un

Tabla 3. Entidades asociadas con elevación de la proteína C reactiva 18.

Normal o ligeramente Elevación moderada Elevación marcada

elevada (<1 mg/dl) (1-10 mg/dl) (>10 mg/dl)

Ejercicio fuerte Infarto de miocardio Infección bacteriana aguda

(80-85%)
Embarazo Neoplasias Trauma mayor
Gingivitis Pancreatitis Vasculitis sistémicas
Resfriado común Infección de mucosas
(bronquitis, cistitis)
Convulsiones La mayoría de enfermedades
del tejido conectivo
Depresión Artritis reumatoide
Resistencia a la insulina y diabetes
Obesidad
Polimorfismos genéticos

Tabla 4. Enfermedades reumáticas y PCR elevada.

Artritis reumatoide Lupus eritematoso sistémico (Infección, serositis, sinovitis)

Artritis reumatoide juvenil Polimialgia reumática
Espondilitis anquilosante Arteritis de células gigantes
lores normales no descartan el diagnóstico de AR, policitemia vera . En la tabla 5 se resumen los
LES, vasculitis u otra enfermedad reumática. Tam- diversos factores que pueden modificar la VSG38.

Tabla 5. Factores que modifican la VSG38.

Aumentan Disminuyen La alteran sin significado

clínico o con efecto dudoso

Edad avanzada Leucocitosis marcada Obesidad

Sexo femenino Policitemia Alimentación reciente

Embarazo Anormalidades de las proteínas: Temperatura corporal

Anemia · Hipofibrinogenemia, Aspirina

Anormalidades de · Hipogamaglobulinemia, Antiinflamatorios no esteroideos

los eritrocitos: · Disproteinemia con estados de hiperviscocidad
· Macrocitosis

Factores técnicos: Factores técnicos:

· Problemas
de dilución · Problemas de dilución
· Temperatura
elevada de la
muestra · Mezcla inadecuada de la muestra
· Inclinación del tubo · Formación de coágulos
· Vibración durante la ejecución de la prueba
· Inclinación del tubo

Niveles elevados Anormalidades de los

de fibrinógenos: eritrocitos:
· Infección · Esferocitosis
· Inflamación · Acantosis
· Malignidad · Microcitosis

41
 ALGORITMO 1. Diagnóstico de diabetes, glicemia en ayunas alterada (GAA) e
intolerancia a la glucosa oral (IGO)

Glicemia
Sin síntomas clásicos Síntomas clásicos de diabetes
En individuos ≥ 45 años sin otros factores de (polidipsia, poliuria y baja de peso)
riesgo, solicitar glicemia en ayunas c/3 años.
Realizar examen a edades más tempranas o más
frecuentemente en personas con factores de Glicemia a cualquier hora del día
riesgo.

Glicemia en ayunas ≥ 200 mg/dl

< 100 mg/dl 100-125 mg/dl ≥ 126 mg/dl

en al menos dos
exámenes

PTGO:
glicemia en ayunas y 2 horas post-carga glucosa (75 g)

Clasificación del paciente según glicemia:

ayunas 2h post-carga

Normal <100 y < 140

GAA 100-125 y <140
IGO <126 y 140-199
GAA y IGO 100-125 y 140-199
Diabetes * ≥ 126 o ≥ 200

Pre-diabetes:
Normal sólo GAA o sólo IGO o Diabetes *
GAA + IGO

Realizar nuevo tamizaje Estrategias para prevenir la diabetes y modificar Iniciar tratamiento
con la periodicidad que factores de riesgo CV.
corresponda al nivel de Realizar nuevo tamizaje con la periodicidad que
riesgo. corresponda al nivel de riesgo.

* Realizar un examen de laboratorio confirmatorio en un día distinto en todos aquellos casos en que no
hay síntomas clásicos de diabetes o una descompensación metabólica inequívoca.
Productos catabólicos
Urea 8-20 mg/dL

Creatinina 0,4-1,4 mg/dL

Acido úrico 2,3-7,3 mg/dL

Bilirrubina total 0,25-1,5 mg/dL

Bilirrubina
 Cell Stem Cell

Review

Hematopoiesis: A Human Perspective

Sergei Doulatov,1,2 Faiyaz Notta,1,2 Elisa Laurenti,1,2 and John E. Dick1,2,*
1Division
of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto,
ON M5G 1L7, Canada
2Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada

*Correspondence: [email protected]
DOI 10.1016/j.stem.2012.01.006

Despite its complexity, blood is probably the best understood developmental system, largely due to seminal
experimentation in the mouse. Clinically, hematopoietic stem cell (HSC) transplantation represents the most
widely deployed regenerative therapy, but human HSCs have only been characterized relatively recently. The
discovery that immune-deficient mice could be engrafted with human cells provided a powerful approach for
studying HSCs. We highlight 2 decades of studies focusing on isolation and molecular regulation of human
HSCs, therapeutic applications, and early lineage commitment steps, and compare mouse and humanized
models to identify both conserved and species-specific mechanisms that will aid future preclinical research.

Introduction tified and measured with functional repopulation assays, raising

Blood is one of the most highly regenerative tissues, with an obvious barrier to studying human HSCs. However, with the
approximately one trillion (1012) cells arising daily in adult human advent of xenotransplantation, robust in vitro clonal assays,
bone marrow (BM). Early anatomists examining the BM noted and refined sorting strategies, significant progress toward
a wide variety of cellular morphologies corresponding to cells defining the human blood hierarchy has been made. We will
of various blood lineages and stages of differentiation. To explain divide this review into three parts, the first describing the
this diversity, Russian biologist A. Maximow astutely postulated advances in purification of human HSCs, the second focusing
that hematopoiesis is organized as a cellular hierarchy derived on the molecular regulation of human HSCs and how it can be
from a common precursor, a hematopoietic stem cell (HSC) harnessed for therapy, and the third on how human lineage
(Maximow, 1909). The best evidence for the existence of HSCs commitment occurs.
came during the atomic era. The lethal consequence of radiation
was found to be due to BM failure, but exposed recipients could Purification and Clonal Analysis of Human HSCs
be rescued following injection of spleen or marrow cells from The Importance of Combined Mouse and Human Studies
unirradiated donors (Lorenz et al., 1951). Although these studies Since the seminal experiments demonstrating that blood line-
firmly established the existence of blood-forming cells and the ages are derived from multipotent cells that form macroscopic
benefits of regenerating the blood system upon HSC transplan- colonies in the spleen (CFU-S) following transplantation (Till
tation (HSCT), they could not resolve whether there were multiple and McCulloch, 1961), the mouse has become an indispensable
stem cells restricted to each blood lineage, or whether a single model system for studying normal and malignant hematopoiesis.
multipotential HSC existed. Genetic approaches that direct loss or gain of gene function to
The study of hematopoiesis moved from observational to precisely defined cellular compartments have identified the
functional when Till and McCulloch showed that the regenerative basic developmental principles that control the emergence of
potential of HSCs could be assayed with clonal in vivo repopula- hemogenic tissues during ontogeny and maintain lifelong hema-
tion assays, thus establishing the existence of multipotential topoiesis in the adult. The molecular regulation of HSCs eluci-
HSCs (Becker et al., 1963; Till and McCulloch, 1961). This finding dated from studies in the mouse is documented in a number of
stimulated others to develop clonal in vitro assays that, reviews (Orkin and Zon, 2008). Despite these advances, the
combined with the advent of a wide array of cell surface anti- need to complement mouse studies with those in primary human
bodies and flow sorting, have culminated in today’s finely cells has been driven by the growing appreciation for species-
detailed view of the blood system as a developmental hierarchy specific differences in basic biology and hematology, and their
with multipotent HSCs at the apex and terminally differentiated more direct relevance in developing therapeutics. Mouse strains
cells on the bottom. HSCs are critical for lifelong blood produc- used in research are inbred, and it is often difficult to predict how
tion and are uniquely defined by their capacity to durably self- the choice of a specific genetic background can influence the
renew, or generate daughter stem cells, while still contributing observed phenotype. By contrast, human populations are genet-
to the pool of differentiating cells. As they differentiate, HSCs ically diverse, and this variation becomes an intrinsic parameter
give rise to a series of progenitor cell intermediates that undergo in human studies that experimental models must take into
a gradual fate restriction to assume the identity of a mature blood account. Mice and humans differ in size, ecology, lifespan, and
cell. Lineage relationships between stem cells, progenitors, and age to reproductive maturity, imposing different selective trade-
mature cells form a complex ‘‘roadmap’’ that can guide investi- offs in dealing with tumorigenesis, genotoxic stress, telomerase
gations of the molecular basis for these developmental transi- function, and other factors. Larger body size increases the prolif-
Figure
tions. Much 2. understanding
of our Current Models of Lineage
of hematopoiesis comes Determination in thestem
erative demand on human Adult Mouse cells,
and progenitor and altering
Human Hematopoietic Hierarchies
from the mouse because, operationally, HSCs can only be iden- the balance between self-renewal and differentiation, as well
The major classes of stem and progenitor cells described in the text are defined by cell surface phenotypes, which are listed next to each population and in the
Figure 2. Current Models gray
120 Cell
ofCellLineage
Stembars below
10, each
February
Determination
schematic.
3, 2012 Terminally
ª2012 Elsevier Inc.
in the
differentiated cellsAdult
are shownMouse
on the right, and Human
and inferred Hematopoietic
lineage relationships are depicted withHierarchies
arrows. In mice (A),
The major classes of stem and
HSCsprogenitor
can be separatedcells described
into long-term in the text(IT),are
(LT), intermediate-term and defined byclasses
short-term (ST) cell based
surfaceon thephenotypes, which
duration of repopulation. are (B),
In humans listed
HSCs next
are to each population and in the
defined by the expression of CD49f and other markers, but their heterogeneity has not been investigated. In mice, differentiation of HSCs gives rise to transiently
gray bars below each schematic.
engraftingTerminally differentiated
multipotent progenitors cellsof immature
(MPPs), and a series are shown on theprogenitors
lymphoid-biased right, and
(such inferred lineage
as LMPPs) that relationships
undergo gradual are depicted with arrows. In mice (A),
lymphoid specification.
HSCs can be separated intoIn humans, MPPs can
long-term be identified
(LT), by the loss of CD49f expression;
intermediate-term (IT), and however, only one population
short-term (ST) of immaturebased
classes lymphoid progenitors
on the (MLPs) has been
duration of
Both mice and humans have well-defined populations of myelo-erythroid progenitors: CMPs, GMPs, and MEPs. Lin: cocktail containing cell surface markers for
described.
repopulation. In humans (B), HSCs are
defined by the expression ofallCD49f
terminally and otherpopulations
differentiated markers, but
(B cell; their
T cell; NK; heterogeneity has
dendritic cell, monocyte, not been
granulocyte, investigated.
megakaryocyte, In mice, differentiation of HSCs gives rise to transiently
and erythrocyte).
engrafting multipotent progenitors (MPPs), and a series of immature lymphoid-biased progenitors (such as LMPPs) that undergo gradual lymphoid specification.
Factores de crecimiento
hematopoyéticos
 Eritropoyesis
Primeras semanas:

Saco vitelino

Segundo trimestre de gestación:

Hígado – bazo- ganglios linfáticos

Ultimo mes de gestación y tras nacimiento:

Medula ósea.

“Sobre los 20 años la mayoría se produce en la medula de los huesos membranosos como los de las costillas, vértebras, esternon y coxales”
 Factores reguladores de la eritropoyesis
• El principal factor regulador es la oxigenación tisular.

• La eritropoyetina, se forma como respuesta a la hipoxia:

• Forma proeritroblastos a partir de las células madres hematopoyéticas.
• 90% se produce en el riñón.
• Sensor extrarrenal.
• Noradrenalina, adrenalina y prostaglandinas.
• Insu ciencia renal
fi
 Factores reguladores de la eritropoyesis

Células madres hematopoyéticas

Eritropoyetina

Proeritroblasto

Eritrocitos
Oxigenación tisular

Oxigenación tisular
-
 Koury and Haase Pag

Author Manuscript

Figure 5.
Cellular basis of erythropoietin deficiency in renal failure. In the normal kidney, EPCs are
Author Ma

recruited from peritubular interstitial fibroblast-like cells and pericytes. Tubular epithelial
cellsharnessing
Koury, M. J. & Haase, V. H. (2015) Anaemia in kidney disease: do not produce EPO. Under
hypoxia responses conditions of injury, EPCs or interstitial cells with EPC
for therapy
Nat. Rev. Nephrol. DOI: 10.1038/nrneph.2015.82
potential transdifferentiate into myofibroblasts, which synthesize collagen and lose their
Maduración de los eritrocitos
Vitamina B12 y acido fólico.

• Trifosfato de timidina (ADN).

• Carencias generan malformaciones del citoesqueleto y membrana plasmática.
• Macrocitos.
• Grandes reservas y bajos requerimientos.

Otros factores:
• IL-3, GM-CSF
• Steel factor
• ILGF-1
• Activina y factores de crecimiento del
hepatocito.
• Linfocitos T e IL2
Hierro (Fe)
 HIF/EPO
REVIEWS

Bone
Gut marrow
HIF-2 EPO

Kidney
and liver GDF15
Erythroferrone
1-2 mg/dia Inflammation Fe3+
Hepcidin
TF
Fe3+ Enterocyte FPN Liver
Spleen
HIF-2 DCYTB HIF-2
Nucleus

Fe2+ DMT1 Fe2+ FPN Hepcidin FPN

Reticulo-
endothelial
system
HIF-2 Fe3+ Fe3+
HIF TF

Figure 3 | HIF coordinates erythropoietin production with iron metabolism. HIF-2 stimulates renalNatureand hepatic
Reviewserythropoietin
| Nephrology
synthesis, which raises serum erythropoietin levels, stimulating erythropoiesis in the bone marrow. In the duodenum, DCYTB
reduces Fe3+ to Fe2+, which then enters enterocytes via DMT1. DCYTB and DMT1 are both regulated by HIF-2. Iron is then
released into the circulation via FPN, which is also HIF-2-inducible. In the circulation iron is transported in a complex with TF
to the liver, bone marrow and other organs; cells of the reticuloendothelial system acquire iron through the phagocytosis of
senescent red cells. TF is HIF-regulated, and hypoxia and/or pharmacologic PHD inhibition raises TF serum levels. Increased
erythropoietic activity in the bone marrow produces GDF15 Reciclaje de eritrocitos
and erythroferrone, 20 mg/dia
which suppress hepcidin in hepatocytes.
Hepcidin suppression increases FPN expression on enterocytes, hepatocytes and macrophages, resulting in increased iron
Hierro (Fe)
 Hierro (Fe)
75-175 µg/dL

• Se requiere para la formacion de hemoglobina, mioglobina, peroxidasas, citocromo oxidasas, etc.

• Cantidad total de hierro 4-5 grs. (2.5 grs en la Hb) 25-30 mg reciclados del metabolismo de los
eritrocitos, perdidas < 1mg (renales, digestivas o sudor).

• Capacidad absortiva intestinal 1-2 mg/dia (3-4 mg día en de cit).

• De cits: microciticos-hipocrómicos
fi
fi
Grupos sanguíneos
Las células sanguíneas poseen alrededor de 30 anticuerpos
diferentes y antígenos raros que producen respuesta antígeno-
anticuerpo sin mayor importancia.

Los más importantes son los sistemas de antígenos ABO y Rh.

Importancia biol gica de los
ant genos de los grupos sangu neos
Las siguientes funciones se han atribuido a los ant genos de los grupos sangu neos:

• Transportadores de mol culas biol gicamente importantes a trav s de la membrana del eritrocito

• Receptores de est mulos externos y c lulas de adhesi n

• Reguladores del complemento para prevenir la destrucci n de los eritrocitos

• Enzimas

• Anclaje de la membrana del eritrocito al citoesqueleto

• Proveedor de matriz extracelular de carbohidratos para proteger a la c lula de da os mec - nicos y ataques por agentes infecciosos.
í
í
é
ó
é
ó
ó
ó
é
é
í
ñ
á
í
í
Sistema ABO
Grupo sanguíneo/
Antígeno Anticuerpo Gen Genotipo
Fenotipo

A A antiB IA IA IA e IA i

B B antiA IB IB IB e IB i

AB A+B ninguno IA e IB IAIB

0 ninguno antiA + antiB i ii

o en mujeres multíparas. Una vez que el correspondiente antígeno es identificado,
La mayoría de las el patrón de
técnicas empleadas en banco de sangre para detectar las reacciones entre
antígenos y anticuerpos se basan en la aglutinación y en ocasiones, en la lisis de los glóbulos rojos
(hemólisis).

Sitio de unión Aglutinación

para el antígeno

La aglutinación resulta de la fi-

Valor relativo
jación de los anticuerpos a los antí-
genos que están en la membrana de
Cadena
Cadena los eritrocitos, formando una red que IgG
liviana mantiene unidas las células. Este pro-
pesada
ceso se divide en dos etapas: IgM
0 3 6 9 12
„„Los anticuerpos se fijan a los an-
tígenos eritrocitarios en cuanto se Meses
Arbeláez-García CA.
IgG ponenIgMen contacto con ellos. Este
fenómeno no causa aglutinación, Figura 8. Respuesta inmune a antígenos extraños. La respuesta inicial se
directa
Figura 7. Representación de los glóbulos
esquemática rojos,
de las moléculas pero los anti-
de inmunoglobulinas y M. recubrimiento y sensibiliza- caracteriza por la generación de anticuerpos tipo IgM, los cuales desa-
Gsólo
+– –+ +– –+
+– + –parecen– gradualmente con el tiempo. Posteriormente aparecen los anti-
cuerpos IgG sólo los recubren y sensibilizan.ción de +los –
–+
+ – glóbulos– rojos.
+ +–
+
+ – cuerpos tipo– + IgG, que permanecen detectables de por vida.
+– –+ +– –+
Medicina & Laboratorio, Volumen 15, Números 1-2, 2009 +– –+ +– –+
La carga negativa de los eritrocitos deri- +– –+ +– –+
Medicina & Laboratorio: Programa de EducaciónMedicina
Médica&Contínua
+– Certificada
IgG15, 49
+– –+
va de los grupos de ácido neuramínico de la
Universidad de Antioquia, Edimeco
Laboratorio,
+–
+–
Volumen
–+
–+
Números
+–
+–
1-2, 2009
–+
–+
membrana. La fuerza que mantiene la sepa- + – – + +– –+
Medicina & Laboratorio: Programa de Educación Médica Contínua Certificada 53
ración entre las células se denomina poten- Universidad de Antioquia, Edimeco
cial zeta (ver figura 11). Con el fin de reducir
la fuerza iónica e incrementar la velocidad
de la reacción antígeno-anticuerpo, en los
bancos de sangre se utiliza solución salina de +– –+ +– –+
+– –+
baja fuerza iónica (LISS), la cual será revisa- +–
+– –+
+–
+– –+
+– –+ +– –+
da más adelante. +– –+ –+
+– IgM –+
+– –+
Temperatura +–
+–
+– –+
–+
–+
+–
+–
+– –+
–+
–+

Los anticuerpos de los grupos sanguíneos

difieren con respecto a su actividad térmica
óptima y son reactivos en un rango de tem- Figura 11. Potencial Z. Las cargas iónicas en la superficie de los
peratura restringido. Los anticuerpos fríos, ge-
Sistema ABO
Herencia de los grupos ABO
Alelo Grupo (fenotipo)
Alelo materno Genotipo hijo
paterno hijo

A A AA A

A B AB AB

A O AO A

B A AB AB

B B BB B

B O BO B

O O OO O
 Sistema Rhesus (Rh)
Haplotipo?

C, D, E, c, d, e

CDe (Rh+) y cde (Rh-)

Rh +: CCDEE, CCDEe, CCDee, CcDEE, CcDEe, CcDee,

ccDEE, ccDEe y ccDee.

Rh - : CCdEE, CCdEe, CCdee, CcdEE, CcdEe, Ccdee,

ccdEE, ccdEe y ccdee

Rh +, Rh -
 Hemostasia
“Mecanismo de defensa primario del organismo, que tiene como principal función
mantener la integridad vascular y al mismo tiempo evitar la pérdida de sangre al
exterior”

Cinco fases:

Fase celular o Hemostasia

1. Fase Vascular Primaria
2. Fase Plaquetaria

3. Fase plasmática (coagulación)

4. Fase fibrinolítica Fase plasmática o
5. Fase de control Hemostasia secundaria
 Hemostasia

Fase celular Fase plasmática

“rapida” “lenta”
Célula endotelial
Mecanismos para evitar la trombosis intravascular:

1. Síntesis de proteoglicanos: heparan, tissue factor pathway inhibitor (TFPI), endothelial protein
C receptor (EPCR), thrombomodulin (TM).
2. Síntesis antiagregantes plaquetarios: oxido nítrico (NO), PGI2 (prostaciclina) y CD39 (inhibidor
de ADP).
3. Producción de factores brinolíticos: tissue and urinary plasminogen activator (t-PA and u-PA,
respectively).
fi
Hemostasia
Fase vascular
Vasocontricción re eja: disminuye la perdida de sangre y la velocidad del ujo.

Además activa:
1. Fase plaquetaria: Al exponerse membrana subendotelial.
2. Coagulación: Vía intrínseca y extrínseca.
3. Fase brinolítica: activador titular del plaminógeno (t-PA).
fi
fl
fl
 Fase vascular

Endothelial cell functions that maintain hemostasis. Endothelial cells are primary anticoagulants that prevent platelet and immune cell adherence and restrict the activation of clotting cascades (Hoffman and Monroe, 2001;
Feletou, 2011). ECs display tissue plasminogen activator (t-PA) but constitutively secrete plasminogen activator inhibitor type I (PAI-I). ECs constitutively express tissue factor pathway inhibitor (TFPI) on their surfaces that
counteracts tissue factor activated coagulation. ECs regulate thrombin (Throm) activation by presenting anti-thrombin-III (AT-III) and thrombomodulin (TM) on their surfaces which respectively bind and inactivate thrombin
or direct thrombin activation of protein C (APC). ECs express eNOS which directs the production of nitric oxide and secrete prostaglandin I2 (PGI2, prostacyclin) that both inhibit platelet activation and aggregation and are
potent vasodilators that increase blood flow (Pober and Sessa, 2007). However, ECs also express von Willebrand factor within storage granules and secrete the platelet activating factor that activate platelets. ECs restrict
responses of immune cells by expressing the T-cell activation inhibitor PD-LI on their surfaces and secreting NO and by preventing the expression of immune recruiting receptors like intercellular cell adhesion molecule-1
(ICAM) or vascular cell adhesion molecule (VCAM). ECs constitutively express αvβ3 integrins on their surface that are required for EC migration and regulate vascular endothelial growth factor receptor 2 (VEGFR2)
responses to the VEGF, a potent edemagenic factor, first discovered as a permeability factor. Hypoxia, angiogenesis and extravasation of immune cells requires dissociation of adherens junctions in order to restore tissue
oxygenation and effect EC migration and vascular repair. These processes and responses to histamine, platelet activating factor VEGF, bradykinin along with shear stress and dilatory stretching of the endothelium can
increase vascular permeability and are regulated by circulating soluble receptors or degradative systems which normally limit VEGF and bradykinin effects in order to maintain hemostasis. Viral infection of the endothelium
has the potential to alter the delicate balance of these interrelated systems and signals to direct fibrinoloysis and disseminated intravascular coagulation, activate permeability pathways, alter platelet responses, and
control immune cell recognition of the endothelium. Each virus mentioned appears to perturb these functions in unique ways that are enhanced by prolonged infection of ECs, platelet dysfunction and failed immune
clearance. A more complete analysis of hemostatic control mediated by ECs and extensive figures on the subject are present in several excellent reviews (Luscher and Barton, 1997; Hoffman and Monroe, 2001; Aird, 2004,
2008; Pober and Sessa, 2007; Martina et al., 2009; Feletou, 2011).
• Sellan espacios en el
endotelio.

• Plaquetas:

• Valor normal entre 130.000 y

450.000/uL.

• Vida media 10-12 días.

 Super cie
de la
plaqueta
fi
Zona de organelos y gel-sol de
la plaqueta
Formación del tapón plaquetario
 Fase plaquetaria

Figure 1: ❶The endothelium continuously releases small amounts of von Willebrand Factor, which circulates in the blood. Endothelial cells also store von Willebrand Factor in
Weibel-Palade bodies for release when appropriately stimulated. ❷If collagen becomes exposed to blood (because the endothelium is damaged), von Willebrand Factor binds to it.
❸Platelets express receptors for both collagen and von Willebrand Factor (although von Willebrand Factor seems to be more important) and become activated when these proteins
bind to them. Activated platelets change shape and express functional brinogen receptors, which are required for aggregation.
fi
Fase plaquetaria

Figure 2: ❶ Once activated, platelets begin to aggregate by binding to brinogen, which links them together. At the same time, platelets release multiple pro-activation/aggregation
signalling molecules such as adenosine diphosphate (ADP) and thromboxane A2 (TXA2). The activation and aggregation of platelets is often termed primary haemostasis. ❷ Tissue
factor (TF), expressed by nearly all sub-endothelial cells activates the coagulation cascade to initiate a minor burst of haemostasis. Factor FVIIa binds to Tissue Factor, and goes on
to activate Factor IX, which activates thrombin from prothrombin ❸. Thrombin activates receptors on platelets as well as the endothelium, amplifying platelet aggregation and
initiating release of stored von Willebrand Factor from endothelial cells
fi
.

 Fase plaquetaria

Figure 3: Thrombin activates two cofactors, Factor VIIIa ❶ and Factor Va ❷ which subsequently form calcium ion-dependent complexes on the surface of platelets with Factor Xa
(AKA the prothrombinase complex) and Factor IXa (AKA the tenase complex). These complexes greatly accelerate production of Factor Xa and thrombin, respectively. This is the
ampli cation stage of the coagulation cascade. Although there is probably some brin formation during the initial activation of thrombin via the TF pathway, the greatly increased
production of thrombin via tenase and prothrombinase contributes considerably more to the process. Fibrin formation is often termed secondary homeostasis.
fi
fi
Fármacos y perspectivas
 om http://physrev.physiology.org/ by 10.220.33.3 on August 22, 2017
(Un)stable adhesion Aggregation Thrombin generation Contraction/clotting

Autacoids
Au
utaco
oids FIX,
F X, FII
FIX
Thrombin
Thro
h ombin
n
FV,
FV, FVIII,
V FVVIIII,
FIX,
FIX
X, F
X FXX
Fibrin

FXII,
XIII, FXI
FX
X FXI

Collagen
Subendothelium
Sube
Subend
bend
be d
dot
doot
oth
thelium
he um

VWF GpIb-V-IX
Gp
pIb-V-IX Integrins
Integrrins Fibrinogen
Fibrino
oge
enn GP
G
GPVI
PVI G
GPCR
PCR PS

Resting Shape Integrin

Inttegrin Secretion
S ti Procoagulant
Procoag activity
gu ant act
gula tivity
change activation
actiivation

FIGURE 4. Stages of platelet activation and thrombus formation. Platelets adhere to a von Willebrand factor
(VWF)/collagen matrix, get activated, secrete granular contents, aggregate via integrins, produce thrombin
after developing a procoagulant surface, and form a contracted thrombus with fibrin. Heat map with color
codes from green (low Ca2! signal) to red (high Ca2! signal). Interactions of platelets with coagulation factor
are indicated, as described. Note that procoagulant platelets provide a phosphatidylserine (PS)-exposing
surface for the tenase complex (activated FVIII and FIX) and the prothrombinase complex (activated FV and FX).
Formed thrombin provides positive-feedback reactions to activate platelets via GPCR, to activate coagulation
factors, and to convert fibrinogen into fibrin.
Fase plasmática

https://www.youtube.com/watch?v=9xdOqpWTITE
 Palta, et al.: Overview: Coagulation system

Table 3: Nomenclature of the coagulation proteins/clotting factors

Clotting Clotting factor name Function Plasma Plasma
factor number half-life (h) concentration (mg/L)
I Fibrinogen Clot formation 90 3000
II Prothrombin Activation of I, V, VII, VIII, XI, XIII, 65 100
protein C, platelets
III TF Co factor of VIIa - -
IV Calcium Facilitates coagulation factor binding to - -
phospholipids
V Proacclerin, labile factor Co-factor of X-prothrombinase complex 15 10
VI Unassigned
VII Stable factor, proconvertin Activates factors IX, X 5 0.5
VIII Antihaemophilic factor A Co-factor of IX-tenase complex 10 0.1
IX Antihaemophilic factor B or Activates X: Forms tenase complex with 25 5
Christmas factor factor VIII
X Stuart-Prower factor Prothrombinase complex with factor V: 40 10
Activates factor II
XI Plasma thromboplastin antecedent Activates factor IX 45 5
XII Hageman factor Activates factor XI, VII and prekallikrein -
XIII Fibrin-stabilising factor Crosslinks fibrin 200 30
XIV Prekallikerin (F Fletcher) Serine protease zymogen 35
XV HMWK- (F Fitzgerald) Co factor 150
XVI vWf Binds to VIII, mediates platelet adhesion 12 10 μg/mL
XVII Antithrombin III Inhibits IIa, Xa, and other proteases 72 0.15-0.2 mg/mL
XVIII Heparin cofactor II Inhibits IIa 60 -
XIX Protein C Inactivates Va and VIIIa 0.4 -
XX Protein S Cofactor for activated protein C -
HMWK – High molecular weight kininogen; vWf – Von Willebrand factor; TF – Tissue factor

Fibrinogen is an essential coagulation protein endothelium leading to recruitment of monocytes

produced by liver (MW340 kDa) and is the precursor containing TF, thus initiating coagulation.[22,23] With
of fibrin that ultimately defines the strength of the exposure of TF to factor VII/VIIIa in the blood, it
clot.[18,19] allows for the formation of TF-VIIIa complex and thus
nase complex which
mbin. This thrombin It inhibits Factor Xa in reaction requiring PZ and
Table 4: Classification of coagulation factors
inogen to insoluble
Fibrinogen family Vitamin K dependent Contact family calcium.[29]
I, which covalently
Fibrinogen Factor II Factor XI
orated in the platelet
ork which stabilises
Factor V Factor VII Factor[Downloaded
XII COAGULATION
free CASCADE on Sunday, August 20, 2017, IP: 190.163.214.248]
from http://www.ijaweb.org
Factor VIII Factor IX HMWK
condary haemostatic
Factor XIIII Factor X Prekallikerin It has been traditionally classified into intrinsic
HMWK – High molecular weight kininogen
Palta, et al.: Overview: Coagulation system
and extrinsic pathways, both of which converge on
ATION factor X activation. The classical theory of blood
inhibitors are heparin cofactor II, α2 macroglobulin Table 1: Thrombogenic and antithrombogenic Normally plate
Fgure 1: Earlier concept of coagulation coagulationcomponents
is particularly useful for understanding
understanding that and α1-antitrypsin. [24,25] in the body endothelium.
l pathway but indeed Site
the InThrombogenic
vitro coagulation tests, but fails to incorporate
Antithrombogenic platelets adhe
n primarily initiated Tissue factor plasminogen inhibitor Vessel the
wall central
Exposed role of cell-based
endothelium Heparinsurfaces in In vivo
wer model describes coagulation process. [4]
Interestingly contact activation subendothelial
It is a polypeptide produced by endothelial cells. It TF Thrombomodulin
critical for In vivo haemostasis Tissuedoes not get activator
support change by a
acts as a natural inhibitor of the extrinsic pathway by Collagen plasminogen
inhibiting TF-VIIa complex.[25,26] Protein S enhances from Platelets
Circulating following observations. Persons lacking FXII,
Antithrombin numerous pse
amaged vessel which the interaction of factor Xa in the presence of calcium prekallikrein,
elements or high-molecular-weight
Platelet activating factor Protein C and S kininogen do their surface ar
tor IX and factor X. and phospholipids.[27] not bleed abnormally.
Clotting factor Second, patients with only trace
Plasminogen involves a serie
F-VIIa complex serves Figure 2: Current concept of coagulation (initiation phase) quantities of FXI can withstand major trauma without
Prothrombin
xtrinsic and intrinsic Protein C pathway unusual bleeding, and those who completely lack
Fibrinogen Platelet adhesio
to factor II to form The propagation phase of the coagulation is inhibited factorvWF XI (haemophilia C) exhibit mild haemorrhagic After vascular
generation through by the Protein C pathway that primarily consist of four disorder.
vWF – Von Deficiencies
Willebrand of FVIII
factor; TF – Tissue factor and FIX (both intrinsic
d can be effectively endothelial co
key elements: pathway factors) lead to haemophilia A and B,
tor [Figure 2]. GpIb and prom
• Protein C is a serine protease with various abnormalities
respectively, of the
however same,
the which
classic may have
description an
of two
glycoprotein co
potent anticoagulant, profibrinolytic impact
and pathways of coagulation
in the perioperative leaveand
period it unclear
ICU.Theyas can
to why
be
eitherastype for vWF.
n generated is not anti-inflammatory properties. It is activated by classified thoseofthathaemophiliac cannot not
affect the primary simply clot
haemostasis,
sitive feedback loops thrombin to form activated protein C (APC) and blood via the unaffected pathway.
h platelets. Thrombin
the coagulation pathways and the fibrinolytic system. Platelet secretio
acts by inhibiting activated factors V and VIII
hase further activates
(with Protein S and phospholipids acting as To answer all this, the modern time-based structuring of After adhesion
erves as a cofactor in Figure 3: Current concepts of coagulation (propagation phase) PRIMARY HAEMOSTASIS granules takes p
cofactors) blood coagulation provides more authentic description
elerates the activation
F IXa, respectively. • Thrombomodulin
DISORDERS OF COAGULATION ‑ A transmembrane receptor of the coagulation process. It is now appreciated that Release of calc
Primary haemostasis results from complex interactions
Factores de coagulación-clasificación
FACTORES DE
GRUPOS LUGAR DE SÍNTESIS
COGULACIÓN

Hígado (hepatocito)
II Hígado (hepatocito. Hemostasia.
Factores vitamina K VII Coagulación sanguínea.
dependientes IX Trasfusiones)
X Hígado (hepatocito)
Hígado (hepatocito)

Hígado, plaqueta, células

V
Cofactores endoteliales
VIII: C
Células endoteliales

XI Hígado (?)
Activadores del sistema XII Hígado (?)
de contacto Prekalicreína Hígado (?)
Kininógeno Hígado (?)

Fibrinógeno Hígado (hepatocito)

Fibrino-formación
XIII Hígado, plaqueta(?)
 Hemostasia:
cascada de la
coagulación
Fase plasmática VERSTEEG ET AL.
Complejo protrombinasa:
Va, Xa, fosfolípidos y Ca+2.

Subendothelium

Platelets

Poly P Ca+2 Ca+2

Fase de contacto

moléculas cargadas
Xa IIa Xa
+ IXa Va Va IXa negativamente: vidrio, caolín,
VIIIa VIIIa
Precalicreina
XIIa dextrán, membrana basal,
y comigenoXIa fosfolípidos, collageno y
de alto peso endotoxinas.
molecular

Downloaded from http://physrev.physiology.org/ by

IIa brin
in
n
Fibrin

yP
Poly

Xa
X
VIIa
VIIa IXa
IX
Xa
IIa
Ca+2
TF
F Endothelium

Subendothelium

FIGURE 1. The coagulation cascade. Upon endothelial damage, tissue factor (TF) is exposed to the blood-
stream and binds factor VII, which is activated to factor VIIa. The TF:VIIa complex enables subsequent activation
 Fase plasmática y activación del
186
complemento
Review TRENDS in Immunology Vol.28 No.4

Figure 1. Complement–coagulation reciprocal interactions. Complement and coagulation cascades are composed of serine proteases that are activated through partial
cleavage by an upstream enzyme. Zymogens are marked in light green, and active components are shown in red. Complement is activated through the classical, lectin or
alternative pathways (i) that converge at the central molecule of the complement system, C3 (ii). The C3 convertases, generated through various pathways, cleave C3 to C3a
 Hemostasia: Fase
brinolítica
fi
 Hemostasia: Fase
brinolítica

(Alfa2-antiplasmina)
fi
 to be cleaved into APC and bind to its cofactor, protein S, anticoagulant activity but are important in inflammation, a

nloaded from http://physrev.physiology.org/ by 10.220.33.3 on August 22, 2017

also a vitamin K-dependent protein (635 amino acids). Pro- link that will not be discussed here.
tein C, aside from an NH2-terminal phospholipid-binding
Gla domain, contains a thrombin-sensitive region, four There is evidence that binding of thrombin to thrombo-

Hemostasia: sistemas de
EGF-like domains that are required for protein S interac-
tion, and two laminin G-type domains which synergistically
with FV target FVIIIa (see below) (61).
modulin is not strictly required for protein C activation,
although its cleavage is extremely slow in the absence of
thrombomodulin (86). Due to the large endothelial surface

regulación
area in capillary beds, activation of protein C in these small
As its concentrations gradually rise during coagulation, vessels is relatively efficient. In larger vessels, where the
thrombin binds to thrombomodulin, a 60-kDa trans- endothelial surface area-blood volume ratio is low, addi-

IXa VIIIa

AT
APC Prot S

Xa Va

AT

AT TM
Prot C
TFPI
T IIa
X
Xa
TFPIα EPCR
IIa

Endothelium
Xa Prot S

Subendothelium

FIGURE 3. Negative regulation of the coagulation cascade. TFPI binds to FXa or the TF-FVIIa-FXa complex to
restrict coagulation function. Protein S (prot S) may additionally bind to TFPIa to further inhibit FXa activity.
Generated thrombin at sufficient amounts binds to thrombomodulin and is presented to protein C in complex
with EPCR, after which protein C (prot C) is activated (APC). APC in complex with its cofactor protein S then
inactivates FVa and FVIIIa. Antithrombin (AT) forms another level of control as it inhibits function of thrombin,
FIXa, and FX.

334 Physiol Rev • VOL 93 • JANUARY 2013 • www.prv.org

Hemostasia: sistemas de
regulación
s componentes del plasma
s componentes del plasma
Fisiología de la sangre
y la hemostasia

Jorge Sanhueza S., PhD