19–5 White Blood Cells
Unlike
red blood cells, white blood cells have nuclei and other organelles, but they
lack hemoglobin. White blood cells (WBCs), or
leukocytes, help defend the body against invasion by pathogens, and they remove
toxins, wastes, and abnormal or damaged cells.
Traditionally, WBCs
have been divided into two groups on the basis of their appearance after such
staining: (1) granular leukocytes , or granulocytes
(with abundant stained granules)–the neutrophils
, eosinophils
, and basophils
; and (2) agranular
leukocytes , or agranulocytes
(with few, if any, stained granules)–the monocytes
and lymphocytes .
A typical microliter
of blood contains 6000 to 9000 WBCs, compared with
4.2 to 6.3 million RBCs. Most of the WBCs in the body at any moment
are in connective tissues proper or in organs of the lymphatic system.
Circulating WBCs thus represent only a small fraction
of the total WBC population
WBC Circulation and Movement
Unlike
RBCs, WBCs circulate for
only a short portion of their life span. White blood cells migrate through the
loose and dense connective tissues of the body, using the bloodstream primarily
to travel from one organ to another and for rapid transportation to areas of
invasion or injury. As they travel along the miles of capillaries, WBCs can detect the chemical signs of damage to surrounding
tissues. When problems are detected, these cells leave the bloodstream and
enter the damaged area.
Circulating WBCs have
four characteristics:
They Are Capable of Amoeboid
Movement. Amoeboid movement is
a gliding motion accomplished by the flow of cytoplasm into a slender cellular
process extended in front of the cell. This mobility allows WBCs
to move along the walls of blood vessels and, when outside the bloodstream,
through surrounding tissues.
They Can Migrate Out of the
Bloodstream. When white blood cells in the bloodstream become
activated, they contact and adhere to the vessel walls in a process called margination .
After further interaction with the endothelial cells, the activated WBCs squeeze between adjacent endothelial cells and enter
the surrounding tissue. This process is called emigration
, or diapedesis
.
They Are Attracted to Specific
Chemical Stimuli. This characteristic, called positive
chemotaxis, guides WBCs to invading pathogens, damaged tissues, and other
active WBCs.
Neutrophils, Eosinophils,
and Monocytes Are Capable of Phagocytosis.
These
cells may engulf pathogens, cell debris, or other materials.
Neutrophils
and eosinophils are sometimes called microphages ,
to distinguish them from the larger macrophages in connective tissues.
Macrophages are monocytes that have moved out of the
bloodstream and have become actively phagocytic.
Types of WBCs
Neutrophils,
eosinophils, basophils, and
monocytes contribute to the body's nonspecific defenses . Such immune
defenses are activated by a variety of stimuli, but they do not discriminate
between one type of threat and another.
Lymphocytes, in contrast, are responsible for specific defenses:
the mounting of a counterattack against
particular invading pathogens or foreign proteins on an individual basis. .
Neutrophils
Fifty
to seventy percent of the circulating WBCs are neutrophils. This name reflects the fact that the
granules of these WBCs are chemically neutral and
thus are difficult to stain with either acidic or basic dyes. A mature neutrophil has a very dense, segmented nucleus that forms
two to five lobes resembling beads on a string.
Their cytoplasm is packed with pale granules
containing lysosomal enzymes and bactericidal
(bacteria–killing) compounds.
Neutrophils
are highly mobile, and consequently are generally the first of the WBCs to arrive at the site of an injury. They are very
active cells that specialize in attacking and digesting bacteria that have been
"marked" with antibodies or with complement
proteins –plasma proteins involved in tissue defenses.
Upon encountering a bacterium, the neutrophil quickly engulfs it, and
the metabolic rate of the neutrophil increases
dramatically. This respiratory burst accompanies
the production of highly reactive, destructive chemical agents, including hydrogen
peroxide and superoxide
anions which can kill bacteria.
Meanwhile, the vesicle containing the engulfed
pathogen fuses with lysosomes that contain digestive
enzymes and small peptides called defensins .
This process, which reduces the number of granules in the cytoplasm, is called degranulation .
Defensins kill a variety of pathogens, including
bacteria, fungi, and some viruses, by combining to form large channels in their
cell membranes. The digestive enzymes then break down the bacterial remains. While actively engaged in attacking bacteria, a neutrophil
releases prostaglandins and leukotrienes. The
prostaglandins increase capillary permeability in the affected region, thereby
contributing to local inflammation and restricting the spread of injury and
infection. Leukotrienes are hormones of the immune
system that attract other phagocytes and help coordinate the immune response.
Most neutrophils have
a short life span, surviving in the bloodstream for only about 10 hours. When
actively engulfing debris or pathogens, they may last 30 minutes or less. A neutrophil dies after engulfing one to two dozen bacteria,
but its breakdown releases additional chemicals that attract other neutrophils to the site. A mixture of dead neutrophils, cellular debris, and other waste products form
the pus associated with
infected wounds.
Eosinophils
were so named because their granules stain darkly with eosin ,
a red dye. The granules also stain with other acid dyes, so the name acidophils
applies as well. Eosinophils, which generally
represent 2–4 percent of the circulating WBCs, are
similar in size to neutrophils.
Eosinophils
attack objects that are coated with antibodies. They are phagocytic
cells and will engulf antibody–marked bacteria, protozoa, or cellular debris.
However, their primary mode of attack is the exocytosis
of toxic compounds, including nitric oxide and cytotoxic
enzymes, onto the surface of their targets. Eosinophils
defend against large multicellular parasites, such as
flukes or parasitic worms; these WBCs increase in
number dramatically during a parasitic infection.
Because
they are sensitive to circulating allergens (materials
that trigger allergies), eosinophils increase in
number during allergic reactions as well. Eosinophils
are also attracted to sites of injury, where they release enzymes that reduce
the degree of inflammation produced by mast cells and neutrophils,
thus controlling the spread of inflammation to adjacent tissues.
Basophils have numerous granules that stain darkly
with basic dyes (high pH). In a standard blood smear, the inclusions are deep
purple or blue. Measuring in diameter, basophils are
smaller than neutrophils or eosinophils.
They are also relatively rare, accounting for less than 1 percent of the
circulating WBC population.
Basophils
migrate to injury sites and cross the capillary endothelium to accumulate in
the damaged tissues, where they discharge their granules into the interstitial
fluids. The granules contain histamine
, which dilates
blood vessels, and heparin , a compound
that prevents blood from clotting. Stimulated basophils
release these chemicals into the interstitial fluids, and their arrival
enhances the local inflammation initiated by mast cells. Although the same
compounds are released by mast cells in damaged connective tissues, mast cells
and basophils are distinct populations with separate
origins. Other chemicals released by stimulated basophils
attract eosinophils and other basophils
to the area.
Monocytes
in blood are spherical cells that may exceed 15 um in diameter, nearly twice
the diameter of a typical red blood cell.
The nucleus is large and tends to be oval or
kidney bean–shaped rather than lobed. Monocytes
normally account for 2–8 percent of the circulating WBCs.
An
individual monocyte uses the bloodstream as a
highway, remaining in circulation for only about 24 hours before entering
peripheral tissues to become a tissue macrophage. Macrophages are
aggressive phagocytes, often attempting to engulf items as large as or larger
than themselves. While phagocytically active, they
release chemicals that attract and stimulate neutrophils,
monocytes, and other phagocytic
cells. Active macrophages also secrete substances that lure fibroblasts into
the region. The fibroblasts then begin producing scar tissue, which will wall
off the injured area.
Lymphocytes
Typical
lymphocytes
are slightly larger than RBCs and lack abundant,
deeply stained granules. In fact, when you see a lymphocyte in a blood smear,
you generally see just a thin halo of cytoplasm around a relatively large,
round nucleus.
Lymphocytes
account for 20–30 percent of the WBC population of blood. Lymphocytes
continuously migrate from the bloodstream, through peripheral tissues, and back
to the bloodstream. Circulating lymphocytes represent only a minute fraction of
all lymphocytes, for at any moment most of your body's lymphocytes are in other
connective tissues and in organs of the lymphatic system.
The
circulating blood contains three functional classes of lymphocytes, which
cannot be distinguished with a light microscope:
T Cells. T cells are
responsible for cell–mediated immunity ,
a defense mechanism against invading foreign cells and tissues,
and for the coordination of the immune response. T cells either enter
peripheral tissues and attack foreign cells directly or control the activities
of other lymphocytes.
B Cells. B cells are
responsible for humoral
immunity ,
a defense mechanism that involves the production and distribution of
antibodies, which in turn attack foreign antigens throughout the body.
Activated B cells differentiate into plasma
cells ,
which are specialized to synthesize and secrete antibodies. Whereas the T cells
responsible for cellular immunity must migrate to their targets, the antibodies
produced by plasma cells in one location can destroy antigens almost
anywhere in the body.
NK Cells. Natural killer
(NK) cells are responsible for immune
surveillance –the detection and subsequent destruction
of abnormal tissue cells. These cells, sometimes known as large
granular lymphocytes ,
are important in preventing cancer.
The Differential Count and Changes in WBC
Profiles
A
variety of disorders, including pathogenic infection, inflammation, and
allergic reactions, cause characteristic changes in circulating populations of WBCs. By examining a stained blood smear, we can obtain a differential count of the WBC
population. The values reported indicate the number of each type of cell in a
sample of 100 WBCs.
The term leukopenia indicates
inadequate numbers of WBCs. Leukocytosis
refers to excessive numbers of WBCs. A modest leukocytosis is normal during an infection. Extreme leukocytosis ( or more) generally
indicates the presence of some form of leukemia.
There are many types of leukemias. Treatment helps in
some cases; unless treated, all are fatal.
WBC Production
Stem
cells responsible for the production of WBCs
originate in the bone marrow, with the divisions of hemocytoblasts.
As we noted earlier, hemocytoblast divisions produce
myeloid stem cells and lymphoid stem cells. Myeloid stem cell division creates progenitor cells , which give
rise to all the formed elements except lymphocytes. One type of progenitor cell
produces daughter cells that mature into RBCs; a
second type produces cells that manufacture platelets. Neutrophils,
eosinophils, basophils, and
monocytes develop from daughter cells produced by a
third type of progenitor cell.
All
WBCs except monocytes
complete their development in the bone marrow. Monocytes
begin their differentiation in the bone marrow, enter the bloodstream, and
complete development when they become free macrophages in peripheral tissues.
Each of the other types of cell goes through a characteristic series of
maturational stages, proceeding from blast cells to
myelocytes
to band cells before
becoming mature WBCs. For example, a cell
differentiating into a neutrophil goes from a myeloblast to a neutrophilic
myelocyte and then
becomes a neutrophilic
band cell .
Some band cells enter the bloodstream before completing their maturation;
normally, 3–5 percent of all circulating WBCs are
band cells.
Mast cells are a different type of connective
tissue cells that release histamine, serotonin, and heparin- they initiate
inflammation.
Figure 19-12
The
Origins and Differentiation of Formed Elements.
Hemocytoblast
divisions give rise to myeloid stem cells or lymphoid stem cells. Lymphoid stem
cells produce the various lymphocytes. Myeloid stem cells produce progenitor
cells that divide to produce the other classes of formed elements. The targets
of EPO and the four colony–stimulating factors (CSFs)
are indicated.
Many of the lymphoid stem cells responsible for
the production of lymphocytes migrate from the bone marrow to peripheral lymphoid tissues , including the thymus,
spleen, and lymph nodes. As a result, lymphocytes are produced in these
organs as well as in the bone marrow. The process of lymphocyte production is
called lymphopoiesis .
19–6 Platelets are flattened
discs, round when viewed from above and spindle shaped when seen in section or
in a blood smear. Platelets in nonmammalian
vertebrates are nucleated cells called thrombocytes.
Because in humans they are cell fragments rather
than individual cells, the term platelet is
preferred when referring to our blood. Platelets are a major participant in a
vascular clotting system that
also includes plasma proteins and the cells and tissues of the blood vessels.
Platelets are continuously replaced. Each
platelet circulates for 9–12 days before being removed by phagocytes, mainly in
the spleen. Each microliter of circulating blood
contains 150,000–500,000 platelets; is the average concentration. Roughly
one–third of the platelets in the body at any moment are held in the spleen and
other vascular organs, rather than in the bloodstream. These reserves are
mobilized during a circulatory crisis, such as severe bleeding.
An abnormally low platelet count ( or less) is known as thrombocytopenia.
Thrombocytopenia generally indicates excessive platelet destruction or
inadequate platelet production. Symptoms include bleeding along the digestive
tract, within the skin, and occasionally inside the CNS.
In thrombocytosis, platelet
counts can exceed Thrombocytosis generally results
from accelerated platelet formation in response to infection, inflammation, or
cancer
Platelet Functions
The
functions of platelets include:
The Transport
of Chemicals Important to the Clotting Process. By releasing
enzymes and other factors at the appropriate times, platelets help initiate and
control the clotting process.
The Formation
of a Temporary Patch in the Walls of Damaged Blood Vessels. Platelets clump
together at an injury site, forming a platelet
plug ,
which can slow the rate of blood loss while clotting occurs.
Active Contraction After Clot
Formation Has Occurred. Platelets contain filaments of actin and myosin. After a blood clot has formed, the
contraction of platelet filaments shrinks the clot and reduces the size of the
break in the vessel wall.
Platelet Production
Platelet
production, or thrombocytopoiesis , occurs in the
bone marrow. Normal bone marrow contains a number of megakaryocytes ,
enormous cells (up to 160 um in diameter) with large nuclei. During their
development and growth, megakaryocytes manufacture
structural proteins, enzymes, and membranes. They then begin shedding cytoplasm
in small membrane–enclosed packets. These packets are the platelets that enter
the bloodstream. A mature megakaryocyte gradually
loses all of its cytoplasm, producing about 4000 platelets before the nucleus
is engulfed by phagocytes and broken down for recycling.
The
rate of megakaryocyte activity and platelet formation
is stimulated by (1) thrombopoietin
(TPO), or thrombocyte–stimulating
factor , a peptide hormone produced in the kidneys and
perhaps other sites as well, which accelerates platelet formation and
stimulates the production of megakaryocytes; (2) interleukin–6
(IL–6), a hormone of the immune system, which
stimulates platelet formation; and (3) multi CSF, which stimulates platelet
production by promoting the formation and growth of megakaryocytes.
19–7 Hemostasis
The process of hemostasis, the cessation
of bleeding, prevents the loss of blood through the walls of damaged vessels.
At the same time, it establishes a framework for tissue repairs. Hemostasis consists of three phases: (1) the vascular
phase ,
(2) the platelet phase ,
and (3) the coagulation phase .
In reality, however, the entire process is more like a chain reaction than
separate, identifiable phases.
The Vascular Phase
Cutting
the wall of a blood vessel triggers a contraction in the smooth muscle fibers
of the vessel wall ( Figure 19–13 ). The Vascular and
Platelet Phases of Hemostasis This
local contraction of the vessel is a vascular
spasm ,
which decreases the diameter of the vessel at the site of injury. The vascular
spasm lasts about 30 minutes, a period called the vascular phase of hemostasis.
During
the vascular phase, changes occur in the endothelium of the vessel at the
injury site:
The Endothelial Cells Contract
and Expose the Underlying Basal Lamina to the Bloodstream.
The Endothelial
Cells Begin Releasing Chemical Factors and Local Hormones.
Endothelial cells also release endothelins ,
peptide hormones that (1) stimulate smooth muscle contraction and promote
vascular spasms and (2) stimulate the division of endothelial cells, smooth
muscle cells, and fibroblasts to accelerate the repair process.
The Endothelial Cell Membranes
Become "Sticky." In small capillaries, endothelial cells
on opposite sides of the vessel may stick together and close off the passageway
The Platelet Phase
Platelets
now begin to attach to sticky endothelial surfaces, to the basal lamina, and to
exposed collagen fibers. This attachment marks the start of the platelet phase of hemostasis. The attachment of platelets to exposed surfaces
is called platelet adhesion
. As more and
more platelets arrive, they begin sticking to one another as well. This
process, called platelet aggregation
, forms a platelet plug that may close
the break in the vessel wall if the damage is not severe or the vessel is
relatively small. Platelet aggregation begins within 15 seconds after an injury
occurs.
As they arrive at the injury site, platelets
become activated. The first sign of activation is that they change shape,
becoming more spherical and developing cytoplasmic
processes that extend toward adjacent platelets. At this time, the platelets
begin releasing a wide variety of compounds, including (1) adenosine
diphosphate ( ADP
), which stimulates platelet aggregation and
secretion; (2) thromboxane
and serotonin ,
which stimulate vascular spasms; (3) clotting
factors , proteins that play a role in blood clotting;
(4) platelet–derived growth factor (
PDGF ), a peptide
that promotes vessel repair; and (5) calcium ions, which are required for
platelet aggregation and by several steps in the clotting process.
Several key factors limit the growth of the
platelet plug: (1) prostacyclin , a prostaglandin that inhibits platelet
aggregation and is released by endothelial cells; (2) inhibitory compounds
released by white blood cells entering the area; (3) circulating plasma enzymes
that break down ADP near the plug; (4) compounds that, when abundant, inhibit plug
formation (for example, serotonin at high concentrations will block the action
of ADP); and (5) the development of a blood clot, which reinforces the platelet
plug, but separates it from the general circulation
The Coagulation Phase
The
vascular and platelet phases begin within a few seconds after the injury. The coagulation phase
does not start until 30 seconds or more after
the vessel has been damaged. Coagulation ,
or blood clotting , involves a
complex sequence of steps leading to the conversion of circulating fibrinogen
into the insoluble protein fibrin. As the fibrin network grows, it covers the
surface of the platelet plug. Passing blood cells and additional platelets are
trapped in the fibrous tangle, forming a blood
clot ,
which effectively seals off the damaged portion of the vessel.
Figure 19-14a The Coagulation Phase
of Hemostasis.
(a) Events
of the coagulation phase. (b) The
network of fibrin that forms the framework of a clot. Red blood cells trapped
in the fibers add to the mass of the blood clot and give it a red color.
Clotting Factors
Many are identified by Roman numerals; for
example, is also known as clotting Factor IV. All but three of the clotting
factors (Factors III, IV, and VIII) are synthesized and released by the liver,
and all but two (Factors III and VIII) are always present in the bloodstream.
Activated platelets release five clotting factors (Factors III, IV, V, VIII,
and XIII) during the platelet phase. During the coagulation phase, enzymes and proenzymes interact. The activation of one proenzyme commonly creates an enzyme that activates a
second proenzyme, and so on in a chain reaction, or cascade .
Figure
19–14a surveys the cascades involved in the extrinsic
, intrinsic
, and common pathways
. The extrinsic pathway begins outside the
bloodstream, in the vessel wall; the intrinsic pathway begins inside the
bloodstream, with the activation of a circulating proenzyme.
These two pathways converge at the common pathway.
The
Extrinsic Pathway
The
extrinsic pathway begins
with the release of Factor III , also known as tissue factor ( TF ), by damaged endothelial cells or
peripheral tissues. The greater the damage, the more tissue factor is released
and the faster clotting occurs. Tissue factor then combines with and another
clotting factor (Factor VII) to form an enzyme complex capable of activating
Factor X, the first step in the common pathway.
The
Intrinsic Pathway
The
intrinsic pathway begins
with the activation of proenzymes (usually Factor
XII) exposed to collagen fibers at the injury site (or a glass surface on a
slide or collection tube). This pathway proceeds with the assistance of PF–3 ,
a platelet factor released by aggregating platelets. Platelets also release a
variety of other factors that accelerate the reactions of the intrinsic pathway.
After a series of linked reactions, activated Factors VIII and IX combine to
form an enzyme complex capable of activating Factor X.
The
Common Pathway
The
common pathway begins
when enzymes from either the extrinsic or intrinsic pathway activate Factor X,
forming the enzyme prothrombinase . Prothrombinase converts the proenzyme
prothrombin into the enzyme thrombin. Thrombin then completes the clotting
process by converting fibrinogen, a plasma protein, to insoluble strands of
fibrin.
Interactions
among the Pathways
When
a blood vessel is damaged, both the extrinsic and the intrinsic pathways
respond. The extrinsic pathway is shorter and faster than the intrinsic
pathway, and it is usually the first to initiate clotting. In essence, the
extrinsic pathway produces a small amount of thrombin very quickly. This quick
patch is reinforced by the intrinsic pathway, which produces more thrombin, but
somewhat later.
The
time required to complete clot formation varies with the site and the nature of
the injury. In tests of the clotting system, blood held in fine glass tubes
normally clots in 8–18 minutes (the coagulation time ),
and a small puncture wound typically stops bleeding in 1–4 minutes (the bleeding
time ).
Feedback
Control of Blood Clotting
Thrombin
generated in the common pathway stimulates blood clotting by (1) stimulating
the formation of tissue factor and (2) stimulating the release of PF–3 by
platelets. Thus, the activity of the common pathway stimulates both the
intrinsic and extrinsic pathways. This positive feedback loop accelerates the
clotting process, and speed can be very important in reducing blood loss after
a severe injury.
Blood
clotting is restricted by factors that either deactivate or remove clotting
factors and other stimulatory agents from the blood. Examples include the
following:
Normal
plasma contains several anticoagulants
–enzymes that inhibit clotting. One, antithrombin–III ,
inhibits several clotting factors, including thrombin.
Heparin ,
a compound released by basophils and mast cells, is a
cofactor that accelerates the activation of antithrombin–III.
Heparin is used clinically to impede or prevent clotting.
Thrombomodulin is released by endothelial cells. This
protein binds to thrombin and converts it to an enzyme that activates protein
C. Protein C is
a plasma protein that inactivates several clotting factors and stimulates the
formation of plasmin ,
an enzyme that gradually breaks down fibrin strands.
Prostacyclin
released during the platelet phase inhibits platelet aggregation and opposes
the stimulatory action of thrombin, ADP, and other factors.
Abnormal Hemostasis
Excessive or Abnormal
Blood Clotting
If the clotting response is inadequately controlled, blood clots will begin to
form in the bloodstream rather than at the site of an injury. These blood clots
do not stick to the wall of the vessel, but continue to drift around until
either plasmin digests them or they become stuck in a
small blood vessel. A drifting blood clot is a type of embolus,
an abnormal mass within the bloodstream. An embolus that becomes stuck in a
blood vessel blocks circulation to the area downstream, killing the affected
tissues. The blockage is called an embolism ,
and the tissue damage caused by the circulatory interruption is an infarct
. Infarcts at the brain are known as strokes
; infarcts at the heart are called
myocardial infractions , or heart
attacks .
An
embolus in the arterial system can get stuck in capillaries in the brain,
causing a stroke. An embolus in the venous system will probably become lodged
in one of the capillaries of the lungs, causing a pulmonary
embolism .
A thrombus,
or blood clot attached to a vessel wall, begins to form when platelets stick to
the wall of an intact blood vessel. Often, the platelets are attracted to areas
called plaques , where endothelial and smooth
muscle cells contain large quantities of lipids. The thrombus gradually
enlarges, projecting into the lumen of the vessel and reducing its diameter.
Eventually, the vessel may be completely blocked, or a large chunk of the clot
may break off, creating an equally dangerous embolus.
To treat
these circulatory blockages, clinicians may attempt surgery to remove the
obstruction or may use enzymes to attack blood clots and prevent further clot
formation. Important anticoagulant drugs include:
Heparin, which activates antithrombin–III.
Coumadin, or warfarin,
and dicumarol,
which depress the synthesis of several clotting factors by blocking the action
of vitamin K.
Recombinant DNA–synthesized tissue plasminogen activator (t–PA),
which stimulates plasmin formation.
Streptokinase
and urokinase,
enzymes that convert plasminogen to plasmin.
Aspirin,
which inactivates platelet enzymes involved with the production of thromboxanes and prostaglandins and inhibits the production
of prostacyclin by endothelial cells. Daily ingestion
of small quantities of aspirin reduces the sensitivity of the clotting process.
This method has been proven to be effective in preventing heart attacks in
people with significant heart disease.
It is
sometimes necessary to control clotting within a blood sample to avoid changes
in plasma composition. Blood samples can be stabilized temporarily by the
addition of heparin or EDTA ( e
thylene d iamine t etroacetic a cid). EDTA removes from plasma,
effectively preventing clotting. In units of whole blood held for extended
periods in a blood bank, citratephosphate
dextrose (CPD)
is typically added. Like EDTA, CPD ties up plasma
Inadequate Blood Clotting
Hemophilia
is one of many inherited disorders characterized by the inadequate production
of clotting factors. The condition affects about 1 in 10,000 people, 80–90
percent of whom are males. In hemophilia, the production of a single clotting
factor (most commonly, Factor VIII) is inadequate; the severity of the
condition depends on the degree of underproduction. In severe cases, extensive
bleeding accompanies the slightest mechanical stress; hemorrhages occur
spontaneously at joints and around muscles.
In many
cases, transfusions of clotting factors can reduce or control the symptoms of
hemophilia, but plasma samples from many individuals must be pooled (combined)
to obtain adequate amounts of clotting factors. This procedure makes the
treatment very expensive and increases the risk of blood–borne infections such
as hepatitis or AIDS. Gene–splicing techniques have been used to manufacture
clotting Factor VIII, an essential component of the intrinsic clotting pathway.
As methods are developed to synthesize other clotting factors, treatment of the
various forms of hemophilia will become safer and cheaper.
The condition known as von
Willebrand disease is the most common
inherited coagulation disorder.
The symptoms and severity of the
bleeding vary widely. Many individuals with mild forms of von Willebrand disease remain unaware of any bleeding problems
until they have an accident or undergo surgery. Treatment consists of the
administration of pooled Factor VIII, rather than synthetic forms, because
pooled Factor VIII contains normal vWF. In some forms
of this disease in which normal vWF is produced, but
plasma levels are abnormally low, bleeding can be controlled by the use of
nasal sprays containing a synthetic form of antidiuretic
hormone (ADH). The absorbed ADH appears to stimulate the release of vWF from endothelial cells.
Calcium
Ions, Vitamin K, and Blood Clotting
Calcium
ions and vitamin K affect
almost every aspect of the clotting process. All three pathways (intrinsic,
extrinsic, and common) require Any disorder that
lowers plasma concentrations will impair blood clotting.
Adequate
amounts of vitamin K must be present for the liver to be able to synthesize
four of the clotting factors, including prothrombin.
A diet inadequate in fats or in vitamin K, or a disorder that affects fat digestion
and absorption (such as problems with bile production), will lead to a vitamin
K deficiency. This condition will cause the eventual breakdown of the common
pathway due to a lack of clotting factors and, ultimately, deactivation of the
entire clotting system.
Clot
Retraction
Once
the fibrin meshwork has appeared, platelets and red blood cells stick to the
fibrin strands. The platelets then contract, and the entire clot begins to
undergo clot retraction
, or syneresis
. Clot retraction, which occurs over a period of
30–60 minutes, (1) pulls the torn edges of the vessel closer together, reducing
residual bleeding and stabilizing the injury site, and (2) reduces the size of
the damaged area, making it easier for fibroblasts, smooth muscle cells, and endothelial
cells to complete repairs
Fibrinolysis
As
the repairs proceed, the clot gradually dissolves. This process, called fibrinolysis ,
begins with the activation of the proenzyme plasminogen by two enzymes: thrombin, produced by the
common pathway, and tissue plasminogen
activator (t–PA), released by damaged tissues at the site
of injury. The activation of plasminogen produces the
enzyme plasmin,
which begins digesting the fibrin strands and eroding the foundation of the
clot.