Chapter 18 - BLOOD Flashcards
Total blood volume in adult WOMAN
70 mL/kg
Total blood volume in adult MAN
80 mL/kg
________ is a suspension of cellular elements in plasma.
Whole blood
If you spin down a sample of blood containing an anticoagulant for __________, the bottom fraction contains FORMED ELEMENTS (RBCs, WBCs and platelets).
5 minutes at 10,000 g
The top fraction is ____________.
Blood plasma
The _____ having the highest density are at the bottom of the tube.
RBCs
WBCs and platelets form a WHITISH GRAY layer - the ________ - between the RBCs and plasma.
Buffy coat
The __________ is the fraction of the total column occupied by RBCs.
Hematocrit
The normal hematocrit for ADULT WOMEN.
40%
The normal hematocrit for ADULT MEN.
45%
The hematocrit in the NEWBORN is ____ and falls to ____ at 2 months of age, from which time it rises during development to reach adult values at puberty.
55%
35%
The __________ is a measure of concentration of RBCs, not of total body red cell mass
Hematocrit
Total RBC volume is ______ body weight in the ADULT WOMAN
28 mL/kg
Total RBC volume is ______ body weight in the ADULT MAN.
36 mL/kg
______ is a pale-white watery solution of electrolytes, plasma proteins, carbohydrates and lipids.
Plasma
Pink-colored plasma suggests the presence of hemoglobin caused by _______ and release of hemoglobin into the plasma.
Hemolysis (lysis of RBCs)
A brown-green color may reflect elevated ________ levels.
Bilirubin
Plasma can also be cloudy in __________.
Cryoglobulinemias
Plasma proteins at a normal concentration of 7.0 g/dL account for a colloid osmotic pressure or oncotic pressure of _________.
25 mmHg
Principal plasma proteins are:
Fibrinogen
Albumin
Globulins
Other coagulation factors
The molecular weights of plasma proteins range up to _______ kDa.
970 kDa
The plasma concentration of albumin ranges from _____________.
3.5 to 5.5 g/dL
Total plasma albumin pool of the body.
135 g
Albumin is synthesized by the liver at a rate of ________ body weight per day and due to CATABOLISM, has a half-life in the circulation of _________.
120 mg/kg
20 days
Urinary losses of albumin are normally negligible - __________.
<20 mg/day
Hepatic synthesis of albumin is strongly enhanced by a ____ plasma colloid osmotic pressure.
Low
The _______ molecule is a dimer of identical heterotrimers, each composed of Aa-, Bb and y chains.
Fibrinogen
Fibrinogen is synthesized only by the liver and circulates in plasma at concentrations of ___________.
150 to 300 mg/dL
The _________ greatly enhances fibrinogen synthesis.
Acute-phase response
Subsequent interaction of myosin and actin in the platelets of clot allows the clot to shrink to a plug that expels a slightly yellow-tinged fluid.
Serum
Absence of fibrinogen and other coagulation factor
Serum
True or False: Plasma can also form a clot.
True
Note: A plasma clot does not retract because it lacks platelets.
Subtraction of the albumin and fibrinogen moeity from total protein concentration yields the concentration of all the proteins grouped as __________.
Globulins
___________ can be used to fractionate plasma proteins.
Electrophoresis
The electrophoretic mobility of a protein depends on its ___________ as well as its __________.
molecular weight (size and shape) electrical charge
Almost any acute stress to the body (trauma, infection, disease) induces a reaction called the _________________.
Acute-phase response
Causes the RBCs to cluster and increases their effective density.
Fibrinogen
When anticoagulated blood from a patient with ____________ is placed in a glass tube, the RBCs fall more quickly under the influence of gravity that when the blood is from a healthy subject.
Hyperfibrinogenemia
________ thick for NORMAL BLOOD.
<15 mm
________ thick in certain inflammatory disorders.
> 40 mm
It is still widely used by clinicians to assess the presence and severity of inflammation.
ESR
Note: It is the rate of fall.
An _______ ESR would suggest that these complains are due to the reactivation of the disease and not just to a poor night’s sleep or depression.
Elevated
Plasma proteins comprise the following in decreasing order of electrophoretic mobility:
- Albumin
- a1 - globulins
- a2 - globulins
- b - globulins
- fibrinogen
- y - globulins
The three most abundant peaks:
Albumin, fibrinogen and y - globulins
Immunoglobulins are synthesized by ________ and _______.
B lymphocytes and plasma cells
True or False: Clinical laboratories most often perform electrophoresis of blood proteins on serum instead of plasma.
True
Proteins present in plasma at LOW CONCENTRATIONS are identified by immunological techniques such as __________ or _______________.
Radioimmunoassay
ELISA
The ________ synthesizes most of the globulins and coagualation factors.
Liver
_____________ is the source of most blood cells.
Bone marrow
The process of generation of all the cell types present in blood.
Hematopoiesis
Serves multiple roles ranging from the carriage of gases to immune responses and hemostasis.
Hematopoiesis
Pluripotent ___________ constitute a population of ADULT STEM CELLS found in bone marrow that are MULTIPOTENT and able to SELF-RENEW.
Long-term hematopoietic stem cells (LT-HSCs)
The __________ give rise to COMMITTED STEM CELLS or progenitors which after proliferation are able to differentiate into lineages that in turn give rise to ______________, each of which ultimately will produce one or a limited number of mature cell types.
Short-term hematopoietic stem cells (ST-HSCs)
Burst - forming units (BFUs) or colony - forming units (CFUs)
A gylcoprotein that stimulates proliferation of a common myeloid progenitor and promotes the production of neutrophils, eosinophils and monocytes-macrophages.
GM-CSF
is used clinically after bone marrow transplantation and in certain acute leukemias.
Recombinant GM-CSF (sargramostim [Leukine])
Are glycoproteins that guide the ultimate development of granulocytes and monocytes-macrophages/dendiritic cells
G-CSF
Are glycoproteins that guide the ultimate development of monocytes-macrophages/dendiritic cells
M-CSF
Is used therapeutically in neutropenia (e.g., after chemotherapy).
Recombinant G - CSF
Is also required for osteoclast development.
M - CSF
Has a broad effect on multiple lineages.
IL-3 (also known as MULTI-CSF)
Constitutively produce the IL-3
Liver and kidney
A homodimeric glycoprotein, sustains the terminal differentiation of eosinophilic precursors.
IL-5 (Colony-stimulating factor, eosinophil)
TPO binds to a TPO receptor called ________, which is the cellular homolog of the viral oncogene v-mpl (murine myeloproliferative leukemia virus).
c - Mpl
On stimulation by TPO, the __________ induces an increase in the number and size of megakaryocytes - the cells that produce platelets which thereby greatly augments the number of circulating platelets.
Mpl receptor
________ which is homologous to TPO, is produced by the KIDNEY and to a lesser extent by the liver.
EPO
This cytokine supports ERYTHROPOIESIS or red cell development.
EPO
HYPOXIA increases the abundance of the ______________, which enhances production of EPO messenger RNA.
a subunit of hypoxia-inducible factor 1 (HIF-1a)
Is not absolutely required for early commitment of progenitor cells to the erythroid lineage, it is essential for the differentiation of burst-forming unit-erythroid cells (BFU-Es) to colony-forming unit-erythroid cells (CFU-Es) or ___________ which still lack hemoglobin.
EPO
Proerythroblasts (also known as PRONORMOBLASTS)
The further maturation of cells downstream of proerythroblasts does not require _______.
EPO
Has proved effective in the treatment of anemia.
Recombinant EPO
Hemoglobin FIRST APPEARS at the stage of _________ and is CLEARLY EVIDENT in __________.
Polychromatic erythroblasts
Orthochromatic erythroblasts
The subsequent exocytosis of the nucleus produces __________, whereas the loss of ribosomes and mitochondria yields _________ which enter the circulation.
Reticuloyctes
Erythrocytes
_____________ may also appear in the ciirculation when erythropoiesis is HEAVILY ACTIVATED.
Immature reticulocytes
RBC are mainly composed of:
Hemoglobin
RBCs are non nucleated biconcave cells with a diameter of ________ and a volume of 90 fL.
7.5 um
Maintaining the shape pf the RBC is a CYTOSKELETON that is anchored to the plasma membrane by _____________ and the ______________.
Glycophorin
Band 3 Cl-HCO3 exchanger
The distinctive shape of the RBC provides a much larger ________________ than that of a spherical cell, thereby maximizing diffusion area and minimizing intracellular diffusion distances for gas exchange.
surface-to-volume ratio
The RBC performs three major tasks:
- carrying of O2 from the lungs to the systemic tissues
- carrying of CO2 from tissues to the lungs
- assisting in the buffering of acids and bases.
The most important constituent of the RBC is ______________.
hemoglobin
Globin synthesis begins in the ______________.
proerythroblast
By the end of the ______________ stage, the cell has synthesized all the hemoglobin it will carry.
orthochromatic-erythroblast
Normal blood hemoglobin content is _______ in the adult woman and ________ in the adult man.
- 0 g/dL
15. 5 g/dL
The hemoglobin concentration in red cell cytosol is extremely high, ________.
5.5 mM
The mean cell hemoglobin concentration is __________, or about five times the concentration of proteins in plasma.
35 g/dL
Enclosure of hemoglobin in red cells has the advantage of minimizing the loss of hemoglobin from the plasma through _________ across the blood capillary walls.
filtration
Because the mature RBCs contain no nucleus or other organelles, they can neither synthesize proteins nor engage in ______________.
oxidative metabolism
The RBC can engage in two metabolic pathways: ___________, which consumes 90% of glucose uptake and the ______________ which consumes the remaining 10% of glucose.
Glycolysis
Pentose shunt
The cell generates its ______ exclusively by glycolysis.
ATP
An important constituent of the RBC is _____________.
2,3-diphosphoglycerate (2,3-DPG)
RBCs use __________ to convert 1,3-diphosphoglycerate (1,3-DPG), part of the normal glycolytic pathway into 2,3-DPG.
DPG mutase
In RBCs, the cytosolic concentration of 2,3-DPG is normally _________, about the same as the concentration of hemoglobin.
4 to 5 mM
_________ acts on hemoglobin by reducing the O2 affinity of hemoglobin
2,3-DPG
Erythrocytes contain __________ at ∼2 mM, more than any other cell of the body outside the hepatocyte.
glutathione
*A high ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) protects the RBC against oxidant damage.
_____________ regenerates GSH from GSSG in a reaction that consumes NADPH.
Glutathione reductase
The RBC generates all its ________ from the glycolytic intermediate glucose 6-phosphate through the pentose phosphate pathway.
NADPH
RBCs carry two cytoplasmic isoforms of carbonic anhydrase, _______ and _______.
CA I and CA II
*These enzymes which rapidly interconvert CO2 and HCO3−, play a critical role in carrying metabolically produced CO2 from the systemic tissues to the pulmonary capillaries for elimination in the exhaled air.
______ has one of the fastest known enzymatic turnover rates.
CA II
CO2 carriage also depends critically on the _______________ in the RBC membrane.
Cl-HCO3 exchanger AE1
The transporter was originally known as ____________ because of its position on an SDS-polyacrylamide gel of RBC membrane proteins.
band 3 protein
_______ is the most abundant membrane protein in RBCs, with ∼1 million copies per cell.
AE1
One ______ molecule can transport as many as 50,000 ions per second—one of the fastest known transporters.
AE1
AE1 and most other members of the SLC4 family of HCO3− transporters are blocked by a disulfonic stilbene known as ______.
DIDS
The water channel _______ is the second most abundant membrane protein in RBCs, with 200,000 copies per cell.
AQP1
_______ appears to contribute more than half of the CO2 permeability of the RBC membrane.
AQP1
The name _______________ applies to all three types of granulocytes but often is used to refer specifically to neutrophils.
polymorphonuclear leukocytes
The average diameter of a neutrophil is _____, smaller than that of a monocyte (_____) or eosinophil (_____), somewhat larger than that of a basophil and much larger than that of a lymphocyte (______).
12 um
14 to 20 um
13 um
6 to 10 um
Granulocytes have a brief life span in the blood (_______) but on activation can migrate into the tissues.
<12 hours
The most abundant leukocytes, neutrophils are identified on the basis of the shape of the nucleus as ____________ (56% of leukocytes) and __________ (3% of leukocytes).
Mature segmented neutrophils
Immature band neutrophils
___________ have at least two lobes separated by a thin filament whereas ___________ have a nucleus of more uniform thickness.
Segmented neutrophils
Band neutrophils
Neutrophils have two types of granules (________ and _______) that contain lysosomal enzymes, peroxidase, collagenase, and other enzymes capable of digesting foreign material.
specific and azurophilic
In the presence of a ___________, neutrophils approach foreign substances such as bacteria to phagocytose them within a phagocytic vacuole.
chemotactic attractant
Bacteria are destroyed within the vacuole by the action of ___________ and ___________.
hydrogen peroxide (H2O2) and superoxide anion radical (O2−)
The granules of eosinophils contain ______________, which is toxic to parasites, as well as other enzymes. These cells are important in the response to parasites and viruses. Eosinophils also play a role in allergic reactions.
major basic protein (MBP)
Basophils, the least common granulocytes are a major source of the _________ which in turn stimulates B lymphocytes to produce IgE antibodies.
cytokine IL-4
The granules of basophils which nearly obscure the nucleus—contain __________, __________ and _________. Like eosinophils, basophils also play a role in allergic reactions.
histamine, heparin, and peroxidase
The lymphocyte precursors originate in the __________, where lineage commitment occurs.
bone marrow
T lymphocytes or T cells which represent _______ of peripheral lymphocytes in blood undergo maturation primarily in the thymus.
70% to 80%
T lymphocytes are responsible for ___________.
cell-mediated immunity
B lymphocytes or B cells which represent _________ of peripheral lymphocytes in blood undergo maturation in bone marrow and peripheral lymphoid tissue.
10% to 15%
When B cells interact with antigen in the presence of T cells and macrophages, B cells can transform into _________, which abundantly make and secrete antibodies that are directed against specific antigens
plasma cells
B cells are responsible for ___________.
humoral immunity
Because they migrate from the bone marrow to peripheral tissues, __________ are not abundant in blood.
monocytes
The macrophage (from the Greek macros [large] + phagein [eat]) serves two functions:
- the phagocytosis of pathogens or cellular debris
2. the presentation of antigens to lymphocytes.
Platelets form in the bone marrow by budding off from large cells called __________, the maturation of which depends on TPO and IL-3.
megakaryocytes
Normal blood contains ____________ platelets per microliter.
150,000 to 450,000
Thus, a hypoplastic marrow generating few megakaryocytes leads to ______________ (platelet shortage) and thereby little removal of TPO, which in turn stimulates megakaryocyte production and corrects the lack of platelets.
thrombocytopenia
Conversely, a hyperplastic marrow creating many megakaryocytes leads to _____________ and thereby greater TPO removal, which ultimately turns off megakaryocyte production.
thrombocytosis (platelet excess)
The life span of platelets is about _______.
10 days
*In their unactivated state, these nucleus-free fragments are disk shaped and 2 to 3 μm in diameter.
The external coat is rich in platelet receptors, which are ___________.
glycoproteins
A circumferential band of microtubules composed of ________ provides an inner skeleton.
tubulin
_________ and _______ contractile filaments are present in the platelet interior.
Actin and myosin
The ________ store von Willebrand factor, platelet fi brinogen and clotting factor V.
Alpha granules
The _________ inside the platelets actually originates in the liver which secretes it into the blood plasma, where megakaryocytes and platelets then endocytose the fibrinogen.
fibrinogen
The ____________ store ATP, ADP, serotonin, and Ca2+.
dense-core granules
_________ has an anomalous viscosity.
Whole blood
Water and saline solutions are homogeneous or newtonian liquids. For these, the relationship between _________ (force needed to move one lamina faster than its neighbor) and _________ (velocity gradient between laminae) is linear and passes through the origin.
Shear stress
Shear rate
The shear stress to shear rate relationship for a non-newtonian fluid, such as latex house paint is _________.
nonlinear
True or False:
Blood plasma and serum are nearly newtonian.
True
Normal whole blood is __________; it has a nonlinear shear stress to shear rate relationship that intersects the y-axis above the origin.
non-newtonian
*In other words, one has to apply some threshold force (i.e., the yield shear stress) before the fluid will move at all.
At lower forces, the fluid is ________.
immobile
Blood viscosity _________ with the hematocrit and the fibrinogen plasma concentration.
increases
The effective viscosity of whole blood depends on several physiological factors:
- fibrinogen concentration
- hematocrit
- vessel radius
- linear velocity
- temperature
The viscosity of whole blood in the linear (or newtonian) region is __________ assuming a typical fibrinogen concentration of 260 mg/dL, a hematocrit of 40%, and a temperature of 37°C.
3.2 cP
__________ a major protein component of human plasma, is a key element in the coagulation cascade.
Fibrinogen
The main reason for the non-newtonian behavior of blood is the interaction of this _________ with RBCs.
fibrinogen
________ (which contains fibrinogen but not RBCs) is newtonian, as is a suspension of washed RBCs in saline (without fibrinogen).
Plasma
At normal hematocrits, fibrinogen and perhaps low-density lipoproteins, electrophoretically seen as β-lipoproteins, are the only plasma proteins capable of creating a yield __________.
shear stress
At normal hematocrits, the absence of fibrinogen (in _____________) eliminates the yield shear stress altogether.
congenital afibrinogenemia
____________ elevates yield shear stress and in the extreme, leads to a clustering of RBCs that increases their effective density.
Hyperfibrinogemia
__________ levels tend to increase with age and with smoking.
Fibrinogen
__________ in hematocrit elevate blood viscosity by two mechanisms: one prevails at physiological hematocrits, the other at higher hematocrits.
Increases
Starting from values of ______, raising of the hematocrit increases the interactions among RBCs—both directly and by proteins such as fibrinogen—and thereby INCREASES VISCOSITY.
30%
At hematocrits above ______, the cells are so tightly packed that further increases lead to cell-cell interactions that increasingly deform the RBCs, thereby increasing viscosity.
60%
In patients with _____________, not only is viscosity high but the yield stress can be more than 4-fold higher than normal.
Polycythemia
*Obviously, the combination of a high hematocrit and a high fibrinogen level can be expected to lead to extremely high viscosities.
In reasonably large vessels (radius > ∼1 mm), blood viscosity is __________ of vessel radius.
independent
The viscosity decreases steeply at lower radii.
Fahraeus-Lindqvist phenomenon
Poiseuille observed not only that RBCs move faster in the center of an arteriole or venule than at the periphery but also that the ____________ of RBCs is greater at the center.
concentration
One consequence of ____________ is that local viscosity is LOWEST in the cell-poor region near the vessel wall and GREATEST in the cell-enriched core.
axial accumulation
The net effect in smaller vessels is that the overall viscosity of the blood is _________ because the cell-poor plasma (low intrinsic viscosity) moves to the periphery where the shearing forces are the greatest whereas the cell-enriched blood (high intrinsic viscosity) is left along the central axis where the shearing forces are least.
decreased
A second consequence of axial acummulation is that branch vessels preferentially _____________ from the main stream of the parent vessel, leading to a lower hematocrit in branch vessels.
skim the plasma (plasma skimming)
However, some anatomical sites prevent skimming by means of an ________.
arterial cushion
If we were to re-derive a Poiseuille-like equation to model a small vessel, it would predict a viscosity that is ________ than that predicted by Poiseuille’s equation for a large vessel.
lower
Instead, in small capillaries the membrane of the RBC rolls around the cytoplasm in a movement called _________, similar to that of the track of a bulldozer
tank treading
As two treading erythrocytes shoot down a capillary, they spin the bolus of plasma trapped between them (________).
bolus flow
As for an ideal fluid, the dependence of flow on pressure is _______ for blood plasma
linear
However for __________, the pressure flow relationship deviates slightly from linearity at velocities close to zero and the situation is even worse for polycythemia.
whole blood
Cooling normal whole blood from 37°C to 0°C _________ its viscosity 2.5-fold.
increases
The presence of ____________ in the blood can cause an abnormal rise in viscosity even with less intense cooling of limbs.
cryoglobulins
______________ are immunoglobulins that precipitate at a temperature that is less than 37°C but can partially resolubilize on warming.
Cryoglobulins
Different cryoglobulins are associated with infections, particularly ___________ as well as with several autoimmune and lymphoproliferative disorders.
hepatitis C
High blood viscosity from the precipitated _________ can lead to vessel obstruction and local thrombosis.
cryoglobulins
Blood is normally in a liquid state inside blood vessels because it does not come into contact with NEGATIVELY charged surfaces (e.g., the collagen beneath endothelial cells) that activate an _________ coagulation pathway nor does it contact tissue factors (e.g., released from damaged tissue) that activate an ______ pathway.
Intrinsic
Extrinsic
Furthermore, _________ keep the coagulation pathways in check.
thrombolytic pathways
Indeed, plasma contains proteins that can be converted to _______ that digest fibrin and thereby lyse blood clots.
proteases
Hemostasis (from the Greek hemos [blood] + stasis [standing]), or the prevention of hemorrhage can be achieved by four methods:
1) vasoconstriction
2) increased tissue pressure
3) formation of a platelet plug in the case of capillary bleeding
4) coagulation or clot formation.
_____________ contributes to hemostasis because it raises the critical closing pressure and thus collapses vessels that have an intravascular pressure below the critical closing pressure.
Vasoconstriction
___________ is also promoted by chemical byproducts of platelet plug formation and of coagulation.
Vessel constriction
For example, activated platelets release the vasoconstrictors thromboxane A2 and serotonin.
THROMBIN, a major product of the clotting machinery triggers the endothelium to generate ____________ the most powerful physiological vasoconstrictor.
endothelin 1
______________ contributes to hemostasis because it decreases TRANSMURAL PRESSURE which is the difference between intravascular pressure and tissue pressure.
Increased tissue pressure
____________ is the main determinant of blood vessel radius.
Transmural pressure
Given the _____________ between flow and blood vessel radius, an increase in tissue pressure that causes radius to decrease by a factor of 2 would diminish flow by a factor of 16.
fourth-power relationship
A __________ increases extravascular pressure and can thus halt an arterial hemorrhage in a limb. Finally, surgeons routinely make use of this principle when applying hemostatic clamps to close off “bleeders.”
tourniquet
In a highly controlled fashion, PLATELTS plug small breaches in the vascular endothelium. ____________ is a process that includes adhesion, activation and aggregation.
Plug formation
_________ normally do not adhere to themselves, to other blood cells or to endothelial membranes.
Platelets
*One preventive factor may be the negative surface charge on both platelets and endothelial cells.
In the case of endothelial cells, the negative surface charge reflects the presence of proteoglycans, mainly ____________.
heparan sulfate
______________ occurs in response to an increase in the shearing force at the surface of platelets or endothelial cells and in response to vessel injury or humoral signals.
Platelet adhesion
Platelet adhesion, the binding of platelets to themselves or to other components is mediated by ____________, which are glycoproteins in the platelet membrane.
platelet receptors
These platelet receptors are integral membrane proteins belonging to a class of matrix receptors known as __________. They are usually heterodimers linked by DISULFIDE BONDS.
integrins
One ligand naturally present in the blood plasma is ________________, a glycoprotein made by endothelial cells and megakaryocytes.
von Willebrand factor (vWF)
*High shear, certain cytokines and hypoxia all trigger the release of vWF from endothelial cells.
vWF is found in _____________ of the endothelial cells and in α granules of platelets.
Weibel-Palade bodies
vWF binds to the platelet receptor known as ____________, which is a dimer of Gp Ib linked to Gp Ia.
glycoprotein Ib/Ia (Gp Ib/Ia)
A breach of the endothelium exposes platelet receptors to ligands that are components of the subendothelial matrix. These ligands include ________ which binds to Gp Ia/IIa and ___________ and ___________ both of which bind to Gp Ic/IIa.
Collagen
Fibronectin
Laminin
The binding of these ligands or of certain other agents (e.g., thrombin) triggers a conformational change in the platelet receptors that initiates an intracellular signaling cascade which leads to an exocytotic event known as the release reaction or ___________.
platelet activation
The signal transduction cascade involves the activation of ___________ and an influx of ______.
Phospholipase C
Ca2+
Activated platelets exocytose the contents of their dense storage granules which include ____________.
ATP
ADP
serotonin
Ca2+
Activated platelets also exocytose the contents of their alpha granules which contain several proteins including a host of growth factors and three hemostatic factors: ________ and two clotting factors, _________ and _________.
vWF
Factor V
Fibrinogen
Activated platelets also use ____________ to initiate the breakdown of arachidonic acid to thromboxane A2 which they release.
cyclooxygenase
______________ is also associated with marked cytoskeletal and morphological changes as the platelet extends first a broad lamellipodium and then many finger-like filopodia.
Platelet activation
ADP (which binds to P2Y12 receptors on platelets), serotonin, and thromboxane A2 all activate additional platelets and this recruitment promotes _____________.
platelet aggregation
_________, an inhibitor of cyclooxygenase inhibits clotting by reducing the release of thromboxane A2.
Aspirin
vWF released by activated platelets binds to the platelet receptor ___________, thereby activating even more platelets and forming molecular bridges between platelets.
Gp Ib/Ia
Platelet activation also induces a conformational change in _____________, another platelet receptor endowing it with the capacity to bind fi brinogen.
Gp IIb/IIIa
Thus, as a result of the conformational change in Gp IIb/IIIa, the ___________ that is always present in blood forms bridges between platelets and thus participates in the formation of a platelet plug.
fibrinogen
A ________ is a semisolid mass composed of both platelets and fibrin and entrapped in the mesh of fibrin—erythrocytes, leukocytes and serum.
blood clot
A ________ is also a blood clot, but the term is usually reserved for an intravascular clot.
thrombus
*Thus, the blood clot formed at the site of a skin wound would usually not be called a thrombus.
The relative composition of thrombi varies with the site of __________ (i.e., thrombus formation).
thrombosis
A higher proportion of ________ is present in clots of the ARTERIAL circulation whereas a higher proportion of _______ is present in clots of the VENOUS circulation.
Platelets
Fibrin
True or False:
Platelet plug formation and blood clotting are related but distinct events that may occur in parallel or in the absence of the other.
True
On the one hand, inadequate clotting would lead to the leakage of blood from the vascular system and ultimately, to ___________.
hypovolemia
On the other hand, overactive clotting would lead to thrombosis and ultimately to _________ of blood flow.
cessation
Promoting an ____________ is a normal layer of endothelial cells which line all luminal surfaces of the vascular system.
antithrombotic state
Promoting a ____________ are events associated with vascular damage:
1) the failure of endothelial cells to produce the proper antithrombotic factors
2) the physical removal or injury of endothelial cells which permits the blood to come into contact with thrombogenic factors that lie beneath the endothelium.
prothrombotic state
*Also promoting a prothrombotic state is the activation of platelets by any of the ligands that bind to platelet receptors.
For instance, as platelets flow past artificial mechanical heart valves, the __________ can activate the platelets.
shearing forces
It is the ___________ that becomes activated when blood comes into contact with a negatively charged surface—in the laboratory, we can mimic this process by putting blood into a glass test tube.
intrinsic pathway
The ____________ is activated when blood comes in contact with material from damaged cell membranes.
extrinsic pathway
Most of these “precursors” are __________ that give rise to “activated factors” that are __________.
Zymogens
Serine proteases
*Thus, CONTROLLED PROTEOLYSIS plays a central role in amplifying the clotting signals.
In the case of the intrinsic pathway, the chain reaction occurs mainly at the ____________ of activated platelets.
membrane
In the case of the extrinsic pathway, the reactions occur mainly at a “____________” that is membrane bound.
tissue factor
Both pathways converge on a common pathway that culminates in generation of thrombin and ultimately, ___________.
“stable” fibrin
The ____________ domain is required for the translocation of the polypeptide into the endoplasmic reticulum where the signal peptide is cleaved.
signal peptide
The ___________ or γ-carboxyglutamic acid–rich domain (Gla domain) is rich in glutamic acid residues that undergo γ-carboxylation under the influence of the γ-carboxylase that is vitamin K dependent.
propeptide
*The presence of these γ-carboxyglutamic acid residues is required for Ca2+ binding.
The __________ domain may appear multiple times and play a role in forming protein complexes.
epidermal growth factor–like (EGF-like)
The ________ domain is a loop structure created by several disulfide bonds that also play a role in forming protein complexes and attaching the protease to its target.
kringle
The ________ domain confers the serine protease function to the coagulation proteins and is homologous to trypsin, chymotrypsin and other serine proteases.
catalytic
A cascade of protease reactions initiated by factors that are all present within blood.
Intrinsic pathway
Once a small amount of factor XIIa accumulates, this protease converts prekallikrein to kallikrein with ________ as an anchor.
HMWK
In turn, the newly produced _________ accelerates the conversion of factor XII to factor XIIa—an example of positive feedback.
kallikrein
An interaction between kallikreins and kininogens (e.g., HMWK) in which the proteolytic activity of kallikreins on kininogens leads to the release of small vasodilatory peptides called _______.
kinins
________ then converts factor X (Stuart factor) to factor Xa yet another protease.
Tenase
A cascade of protease reactions initiated by factors that are outside the vascular system.
Extrinsic pathway
Nonvascular cells constitutively express an integral membrane protein called __________ (tissue thromboplastin or factor III), which is a receptor for a plasma protein called factor VII.
tissue factor
An interesting feature is that when ________ binds to the trimolecular complex, factor VIIa undergoes a conformational change that prevents it from dissociating from tissue factor.
factor X
_________ is highly homologous to factor VIII and in both cases, the proteolytic activation clips a single protein into two peptides that remain attached to one another.
Factor V
Factors Xa and Va, together with Ca2+ and phospholipids, form yet another trimolecular complex called ____________.
prothrombinase
*Prothrombinase acts on a plasma protein called prothrombin to form thrombin.
Thrombin is the central protease of the coagulation cascade, responsible for three major kinds of actions:
- Activation of downstream components in the clotting cascade.
- Positive feedback at several upstream levels of the cascade.
- Paracrine actions that influence hemostasis.
The main action of _______ is to catalyze the proteolysis of fibrinogen by cleaving the Aα chain releasing fibrinopeptide A, and cleaving the Bβ chain releasing fibrinopeptide B.
thrombin
The release of the __________ results in the formation of fibrin monomers that are still soluble.
fibrinopeptide
FIBRIN MONOMERS now composed of α, β, and γ chains then spontaneously polymerize to form a gel of _________ that traps blood cells.
fibrin polymers
Thrombin also activates factor XIII to factor XIIIa which mediates the covalent cross-linking of the α and γ chains of fibrin polymers to form a mesh called _________ that is even less soluble than fibrin polymers.
stable fibrin
_________ can catalyze the formation of new thrombin from prothrombin and can also catalyze the formation of the cofactors Va and VIIIa.
Thrombin
First, _________ causes endothelial cells to release nitric oxide, PGI2, ADP, vWF, and tissue plasminogen activator.
thrombin
Second, thrombin can activate platelets through _______, a protease-activated receptor that belongs to the family of G protein–coupled receptors.
PAR-1
_________ is a key part of the molecular crosstalk introduced earlier between platelet activation and blood clotting, both of which are required for optimal clot formation.
Thrombin
_________ is a strong catalyst for platelet activation and on the other hand, activated platelets offer the optimal surface for the intrinsic pathway leading to additional thrombin generation.
thrombin
The intrinsic pathway and extrinsic pathway are strongly interconnected to form a _________.
network
Clinical evidence suggests that coagulation depends largely on the ____________.
extrinsic pathway
Although tissue factor is normally absent from intravascular cells, _________ can trigger peripheral blood monocytes and endothelial cells to express tissue factor increasing the risk of coagulation.
inflammation
Indeed, during sepsis, the _________ produced by circulating monocytes initiates intravascular thrombosis.
tissue factor
___________ are the main sources of the agents that help maintain normal blood fluidity. These agents are of two general types: paracrine factors and anticoagulant factors.
Endothelial cells
Endothelial cells generate prostacyclin (PGI2) which promotes __________ and thus blood flow and also inhibits platelet activation and thus clotting.
Vasodilation
Stimulated by thrombin, endothelial cells also produce nitric oxide. Through ______, NITRIC OXIDE inhibits platelet adhesion and aggregation.
cGMP
_______ is a plasma protein that binds to the trimolecular complex [tissue factor + factor VIIa + Ca2+] in the extrinsic pathway and blocks the protease activity of factor VIIa.
Tissue factor pathway inhibitor (TFPI)
______ is GPI linked to the endothelial cell membrane, where it maintains an antithrombotic surface.
TFPI
______ binds to and inhibits factor Xa and thrombin.
Antithrombin III (AT III)
The sulfated glycosaminoglycans _________ and __________ enhance the binding of AT III to factor Xa or to thrombin, thus inhibiting coagulation.
heparan sulfate and heparin
__________ is present on the external surface of most cells, including endothelial surfaces.
Heparan sulfate
*Mast cells and basophils release heparin.
A glycosaminoglycan product of endothelial cells, ___________ can form a complex with thrombin thereby removing thrombin from the circulation and inhibiting coagulation.
Thrombomodulin
*In addition, thrombomodulin also binds protein C.
After protein C binds to the thrombomodulin portion of the thrombin-thrombomodulin complex, the thrombin activates ________.
protein C
Activated protein C (Ca) is a PROTEASE. Together with its cofactor ________, Ca inactivates the cofactors Va and VIIIa, thus inhibiting coagulation.
protein S
This is the cofactor of protein C and is thus an anticoagulant.
Protein S
Finally, clearance of activated clotting factors by the _________ of the liver also keeps hemostasis under control.
Kuppfer cells
Through the interaction of actin and myosin in the platelets, the clot shrinks to a plug and thereby expels ______.
serum
After plug formation, ___________ —the breakdown of stable fibrin breaks up the clot in a more general process known as thrombolysis
fibrinolysis
The process of fibrinolysis begins with the conversion of plasminogen to plasmin catalyzed by one of two activators:
- tissue-type plasminogen activator
2. urokinase-type plasminogen activator.
The source of tissue plasminogen activator (t-PA), a serine protease is _________.
endothelial cells
_________ consists of a single peptide chain with two kringles at the N-terminal portion of the molecule and a protease motif in the C-terminal portion.
t-PA
_________ are loop structures created by THREE DISULFIDE BONDS and serve to anchor the molecule to its substrate.
Kringles
t-PA converts the plasma zymogen plasminogen to the active fibrinolytic protease ________.
plasmin
The presence of _______ greatly accelerates the conversion of plasminogen to plasmin.
fibrin
Besides t-PA, the other plasminogen activator, _____________ is present in plasma either as a single-chain protein or as the two-chain product of a proteolytic cleavage.
urokinase-type plasminogen activator (u-PA)
*Like t-PA, u-PA converts plasminogen to the active protease plasmin.
However, this proteolysis requires that u-PA attach to a receptor on the cell surface called ___________.
urokinase plasminogen activator receptor (u-PAR)
__________, mainly made by the LIVER is a large, singlechain glycoprotein that is composed of an N-terminal heavy chain (A chain) and a C-terminal light chain (B chain).
Plasminogen
*The N-terminal heavy chain contains five kringles and the Cterminal light chain contains the protease domain.
t-PA cleaves plasminogen at the junction between the heavy and light chains, yielding ________.
plasmin
The two chains in plasmin remain connected by ___________.
disulfide bonds
________ is a serine protease that can break down both fibrin and fibrinogen.
Plasmin
*The five kringles of the heavy chain of plasminogen are still present in plasmin.
________ can also cleave t-PA between the kringle and protease motifi s of t-PA.
Plasmin
*The C terminus of single-chain t-PA nonetheless retains its protease activity.
The cardiovascular system regulates ________ at several levels using both enhancing and inhibitory mechanisms.
fibrinolysis
________ and ________ increase the levels of circulating t-PA.
Catecholamines and bradykinin
Two serine protease inhibitors (serpins) reduce the activity of the plasminogen activators:
plasminogen activator inhibitor 1 (PAI-1)
plasminogen activator inhibitor 2 (PAI-2)
______ complexes with and inhibits both single-chain and two-chain t-PA as well as u-PA.
PAI-1
*Produced by ENDOTHELIAL CELLS
__________ is important only in pregnancy as it is produced by the placenta and may contribute to increased risk of thrombosis in pregnancy.
PAI-2
*PAI-2 mainly inhibits u-PA
It is of interest that ______________, which inhibits coagulation also inhibits PAI-1 and PAI-2, thereby facilitating fibrinolysis.
activated protein C
Only one serpin targets plasmin, __________ made by liver, kidney, and other tissues.
a2-antiplasmin (a2-AP)
When plasmin is not bound to fi brin (i.e., when the plasmin is in free solu-tion), _________ with and thereby readily inactivates plasmin.
α2-AP complexes
*However, when plasmin is attached to lysine residues on fi brin, the inhibition by α2-AP is greatly reduced.
