Professional Documents
Culture Documents
Vascular disorders
agulable state.
thrombocytosis, including
each
examples
of
disorders
within
Apply the laboratory data to the stated case studies and discuss the
or plasma proteins
purpura,
mucous
by
which
a
is
variety of
following:
supporti
for
heparin
the
with hep
practice
platelet
counts in
normal cell
lines
of
the
bone
marrow and
result from
acquired
damage to
hematopoietic
cells
lupus
clinical
bleeding.
If
platelets
are
disorders
syndrome,
venous thrombosis,
associated
May-Hegglin
with
itwhich
anomaly,
and
syndrome).
Formation of
PF4Cheparin complexes
IgG antibody
Heparin-like
molecules
vessel wall
Formation of
immune complexes
(PF4CheparinCIgG)
PF4 release
Disorders of Destruction or Utilization
Increased destruction or utilization of platelets may result
from a number of mechanisms.
Destruction Caused by Immune Mechanisms, Antigens,
activation
Antibodies, or Complement
Drugs or foreign substances can produce platelet destruction.
FC receptor
include
These
drugs
include
quinidine,
sulfonamide
derivatives,
presence
destruction
of
platelet
circulating
platelets
to
form
PF4-heparin
because of the attachment of platelets to bacterial antigenC
Certain microbial
antigens
platelet
activation
(3)
releases
PF4
thrombocytopenia
is
autoimmune
reserved.)
thrombocytopenia. This condition occurs in infants born
PART 5
rare
the
platelet
occurs in
most
patients
after
is
ing hepa
caused by
a
combination
of
d
before the platelet count declines.
and
increase
platelet
activation
of
approxi-
and
hemodilution
clearance.
decrease
antibodies
against
antibody
then
binds
to
complexes
tal
of
charged
the
heparin-PF4
complex,
molecules
are
which
of
fundamen
endogenous
proteins,
b2
glycoprotein
consumption
of
platelets
is
most
important
and
another cause
thrombocytopenic
In
ion
ITP,
the
acute
is
mechanism
of
platelet
destruct
GPs
(e.g., GPIIb/IIIa,
GPIb/IX,
GPIa/IIa,
thrombocytopenia
is
the
essential
Diagnosis requires exclusion of other causes of thrombocytopenia. Antibodies to speci? c platelet-membrane GPs can
be detected in most patients, but neither these assays nor
disorder characterized by isolated thrombocytopenia (
count < 100 10 /L) and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia. ITP
occurs in children and adults and is characterized by a low
platelet count, normal bone marrow, and the absence of
measurements of platelet IgG, which are often erroneously
referred to as antiplatelet-antibody tests, are important for
the diagnosis or management.
The American Society of Hematology has established the
following guidelines for the diagnosis of ITP:
other causes of thrombocytopenia. Various characteristics
Presence of thrombocytopenia, lack of anemia
exist in ITP (Table 24.1).
loss has occurred, and lack of white
abnormalities
Absence of other causes of thrombocytopenias (e.g.,
Epidemiology
vascular diseases or lymphoproliferative disorders)
ITP is a fairly rare, generally benign illness in the pediatric
3. Absence of infections, particularly human immunode? population. About two thirds of children recover spontaneciency virus (HIV)
ously. In adults, the incidence is approximately equal for both
abnormal
transfusions
are
seldom indicated.
Survival
severe hemorrhage.
The
ef?
Intravenous
immune globulin
is
an
are
unusual.
adults, ITP is most common in young women (approxiimportant agent in managing acute bleeding and in preparmately 70% of patients are 10 to 40 years old). Chronic ITP
ing for procedures, such as delivery. Treatment of pregnant
is a destructive thrombocytopenia caused by an autoantiwomen with ITP is a complex problem.
body. Approximately 80% of patients experience remisSplenectomy was a well-recognized treatment for ITP for
sions after either corticosteroid therapy or splenectomy.
more than 30 years before glucocorticoids were introduced in
Some patients respond to other therapy; in a substantial
1950, and its success in achieving complete responses in two
group of patients, the disease is refractory to therapy.
thirds of patients has been remarkably consistent for more
Clinical Signs and Symptoms
than 60 years. A response to splenectomy typically occurs
within several days; responses
after 10
days
Onset is
gingival
often
insidious.
Purpura,
epistaxis,
and
and
symptoms,
it
must
be
with
examples of disorders
mediate impaired platelet production by damaging megaconsumption of platelets. In
karyocytes and/or blocking their ability to release proplatethe case of bacterial sepsis, thrombin-induced platelet aggrelets. T cellCmediated effects are believed to play a role
gation in vivo contributes to the thrombocytopenia.
2. Ten to twenty percent of cases are not antibody mediated
platelets because of
PART 5
Severe thrombocytopenia
Microangiopathic hemolytic anemia
Fever
Neurologic symptoms, for example, headache, stroke
Thrombocytosis
Renal disease
hematological
findings
of
thrombocytopenia
and
2. Secondary
JAK2[V617F], MPL, and additional currently unknown
3. Inherited (Upshaw-Shulman)
Idiopathic
has
been
TTP
has
an
unknown
etiology
but
ThromboSpondin-type
bocytosis. React
motifs), responsible for the breakdown of large von Willea variety of disorders and conditions, including chronic
brand
factor (vWF)
multimers.
HighCmolecular-weight
blood loss, chronic inflammatory diseases, chronic infecvWF in the plasma of patients with TTP promotes the
tions, drugs, asplenic states and splenectomy, malignanaggregation of platelets in vivo, which produces most of
cies,
rebound
thrombocytosis following
treatment
of
thrombocytopenic
purpura,
pernicious
accounts
for
5%
to
10%
to normal.
of cases. It is the result of inheritance of a deficiency of
Because of a poorly understood mechanism of stimulaADAMTS13. This milder form of TTP is manifested in
tion associated with the hemolytic process, thrombocytosis
childhood
when
there
is
increased
vWF,
for
example,
of
Association
with
Escherichia
coli
O
157:H7 in
individual and family medical history, laboratory tests are
platelet
dysfunctional
diagnosis.
80%
clot
ness,
retraction,
platelet
aggregation,
platelet
adhesive
Myeloproliferative Syndromes
Acquired
in
the
platelet
dysfunction
is
commonly
seen
are often not characteristic and could represent any combination of platelet aggregation defects.
Uremia is commonly accompanied by bleeding caused by
platelet dysfunction. It is proposed that circulating guanidinosuccinic acid or hydroxy phenolic acid interferes with
platelet function. Dialysis often corrects or improves platelet
function. Other mechanisms of altered platelet function in
uremia, including altered prostaglandin metabolism, have
been proposed.
Paraprotein Disorders
Paraprotein disorders including malignant or benign
such as multiple myeloma, Waldenstr?m
other monoclonal gammopathies,
Types of Platelet Dysfunctions
Dysfunction results from the paraprotein coating the platelet
membranes but does not depend on the type of paraprotein
Three separate categories of platelet dysfunctions can be idened based on etiology (Table 24.2). These include the more
common acquired causes and the less frequent hereditary
present. Almost all patients with malignant paraprotein disorders will demonstrate clinically signi?
mal platelet function by aggregation.
causes. Disorders within these categories can be identi?
using speci?
lets associated with hypercoagulability and thrombosis make
up an additional category of abnormal platelet function.
Cardiopulmonary Bypass and Platelet Function
These conditions demonstrate severe platelet function de?
cit that assumes major importance in surgical bleeding after
Acquired
Acquired platelet function defects can be caused by a blood
plasma inhibitory substance. Examples of disorders or diseases that
may
exhibit
this
dysfunction
include
infused
dextran, uremia, liver disease, and pernicious anemia. Laboratory testing reveals the presence of ? brinolytic degradation
or split products (discussed later in this chapter).
The most common acquired platelet defects are summarized in Table 24.4. Many patients with these platelet function disorders, who are candidates for surgery, may bleed
profusely as a result of surgery or from trauma.
by
aspirin,
cyclosporine
(Sandimmune,
ibuprofen,
Neural,
hydrocortisone,
NOVARTIS,
Basel,
Switzerland).
The arachidonic acid platelet aggregation assay is the only
practical way to monitor the effects of aspirin therapy, now
widely used to prevent stroke and heart attacks.
Hereditary
Hereditary platelet dysfunctions are caused by an inherited platelet defect that is either structural or biochemical (Table 24.5). Examples of adhesion disorders include
Bernard-Soulier syndrome,
collagen
receptor
Glanzmann thrombasthenia, and storage granule abnormalities. Secondary aggregation disorders include hereditary
storage pool
defect and
hereditary
aspirin-like
defect,
Bernard-Soulier Syndrome
Bernard-Soulier syndrome,
an
autosomal
hereditary
Clinical
features
aggregation
ristocetin. Clinical features include easy bruising, epistaxis,
mucocutaneous hemorrhages and hematuria,
hypermenorrhagia, and petechiae (Table 24.6).
Petechiae are
Glanzmann Thrombasthenia and Essential Athrombia
less common than in other qualitative platelet disorders.
Hereditary aspirin-like defects are a rarer form of secondGlanzmann thrombasthenia and essential athrombia are similar,
ary aggregation defect. Clinical features are similar to other
bleed-
hematomas,
and
petechiae.
Intra-articular
syndrome,
storage
pool
defect is
secondary
hereditary
storage pool
disorder.
Overall,
disorder
related to a coagulation factor. Disorders of the blood coagulaare more common than primary aggregation disorders of
tion factors (Table 24.7) can be grouped into three
PART 5
production
destruction
Hemophilia
Etiology
Hemophilia has been used as a paradigm for understanding
Defective Production
the molecular pathological processes that underlie hereditary disease. The cloning of factor VIII facilitated the identiVitamin K De?
A condition of defective production may be related to a
de? ciency of vitamin K. The synthesis of vitamin K and
dependent factors can be disrupted because of disease or
drug
therapy
(e.g., cephalosporin antibiotics). Vitamin
de? ciencies are also encountered in neonates, malabsorption syndrome, biliary obstruction, and patients taking oral
anticoagulants. Vitamin K depletion develops within 2 weeks
if both intake and endogenous production are eliminated.
Factors II, VII, IX, and X are vitamin K dependent. Factor
VII has the shortest half-life and usually declines in the early
stages of vitamin K depletion. A mild de?
cation of mutations that lead to hemophilia A, an inherited
ciency of factor VIII coagulant activity that causes severe
hemorrhage. Two types of mutations dominate the defects
identi? ed so far: gene deletions and point mutations. Gene
deletions are associated with severe hemophilia A in which
no factor VIII circulates in the blood. To date, approximately
50 deletion mutations in the gene for factor VIII have been
characterized at the molecular level, and 34 independent
deletion mutations in the factor IX gene have been found
to be the cause of hemophilia B. Point mutations, in which
a single base in DNA is mutated to another base, represent a
second type of mutation that causes hemophilia.
may present as an asymptomatic prolongation of a patients
Epidemiology
PT assay.
Individuals with hereditary clotting defects may be either
Severe Liver Disease
genetically homozygous or heterozygous carriers of the trait.
(hemophilia
A)
and
von
Willebrand
of
procoagulant
the
activity
disease was
and
be
an
acquired
or
broad
types
of
primary
lymphoproliferative and autoimmune disorders, and prosynthesis and release of plasma vWF; the other type of cell
degradation
of
synthesizes vWF is
Approximately
vWF
complicates
myeloprolifera-
recog-
inherite
Pathophysiology
and protects it from rapid removal from the circulation. The
vWF portion represents more than 95% of the mass of the
von Willebrand disease is characterized by abnormal platecontrols the molecular stereochemislet function, expressed as a prolonged bleeding time. This is
The vWF consists of repeating multimers, with the smalla consistent ? nding and may be accompanied by decreased
dimer or tetramer.
factor VIII procoagulant activity.
Circulating
vWF
undergoes
proteolytic
cleavage
under
vessel
a
bridge. Patients
with
decreased
levels
Willebrand disease and its subtypes. The genetic transmis-
adhesion
ingly low
(the
assay
and
are
levels of
responsible
ristocetin
for
the
cofactor
of
severity
of
symptoms
among
patients
with
von
Willebrand disease varies greatly. Severe cases are not easily
distinguishable clinically from severe hemophilia A, in which
bleeding occurs into the joints and fascial planes. Characteristically, in patients with von Willebrand disease, the bleeding is mucosal in origin, with epistaxis, menorrhagia, and
gastrointestinal bleeding being the most common. Bleeding associated with surgical procedures and oral surgery is
a particular problem. Homozygous patients may experience
severe bleeding, including hemarthrosis, or potentially lethal
gastrointestinal tract or central nervous system hemorrhage.
cation of von Willebrand Disease
Type
nd
is
the
most
common variant of
von
Willebra
uses
electrophoresis and
radiolabeled
antibody
to vWF may be implicated in some cases. Another mechathe different molecular weight multimers.
nism responsible for decreased amounts of vWF in acquired
states is the absorption of the coagulation component onto
Other Hereditary De?
abnormal cell surfaces. Hemorrhagic complications are genas hemophilia B or Christerally more severe in patients with acquired von Willebrand
This
form
nonCsex
disease. Bleeding from mucous membranes is more common
and occurs at a
of 1/50,000 in the general population,
and re? ects the much lower levels of vWF activity in these
molecule being the usual cause. It
individuals. vWF activity is typically 20% or less of normal.
cally indistinguishable from hemophilia A and must be difPseudoCvon Willebrand Disease
ferentiated by laboratory testing. A de? ciency of factor XI
is referred to as hemophilia C. This genetic defect is an autoThis is a rare disorder in which patients resemble those with
trait that occurs almost exclusively in people
von Willebrand disease because of low levels or absence of
mild disorder characterized
large multimeric forms of vWF in the plasma. Patients with
epistaxis, and hemorrhage in conjunction
pseudoCvon Willebrand disease have a platelet abnormality
with trauma. The laboratory
results in this defect, as well
in which spontaneous platelet aggregation occurs. Low levthose of other hemophilias and von
els of larger multimers result from increased consumption
presented in Table 24.13.
during platelet aggregation.
absent or
Increased Levels of vWF
decreased
levels of
? brinogenemia, respectively.
? brinogen, a? brinogenemia,
or
Production
of
dysfunctional
hypo-
degradation
or
by
pathological
activation
associated
with
this
consumption
of
coagulation
factors
activation
of
the
? brinolytic
mechanism
with
detect-
important in treatment.
Pathophysiology
The overall DIC process involves coagulation factors, platelets,
vascular endothelial cells, ?
This major breakdown of the hemostatic mechanism occurs
when the procoagulant factors outweigh the anticoagulant
mechanisms.
Initiation of DIC can be caused by a number of factors. If
vascular endothelial damage results in the exposure of collagen and basement membrane, collagen can activate factor
XII. Factor XII has multiple roles in the direct or indirect
activation of coagulation including
Disseminated Intravascular Coagulation
Initiation of the intrinsic clotting cascade resulting in
Etiology
thrombin formation
DIC is actually a complication or intermediary phase ofmany diseases and does no
t constitute a disorder in itself.
cofactor for the conversion of prekallikrein to kallikrein
It is also known as consumptive coagulopathy or de?
3. Initiation of ?
nation syndrome. Triggering events that may predispose
patients
to
DIC
include alterations
in
the
ium,
direct activation of ? brinogen, release of thromboplastinlike
substances,
and
erythrocyte
or
platelet
ion.
Extravascular trauma, abruptio placentae, advanced malignancy, leukemia, and retained fetal syndrome are examples
of clinical situations in which tissue thromboplastin can
activate coagulation.
Infections, most commonly Gram-negative microorganisms, can trigger DIC by producing endotoxins that expose
Regardless of the initiating event, DIC is characterized by
excess thrombin
formation,
conversion
of
brin, and platelet consumption and deposition. Secondary
? brinolysis occurs as a result of ? brin deposition and can
decrease plasma coagulation factors, leading to a
diathesis.
Thrombin is central to the mechanism of consumptive
coagulopathy. The action of thrombin on the coagulation
systems includes
collagen. Stasis, shock, or tissue necrosis can have the same
Proteolytic cleavage of
brinogen to
endothel
destruct
brin monomer,
effect. Snakebites may introduce substances that initiate coagreleasing
(? brin monomer may
ulation by direct activation of ?
form soluble complexes with ?
blood cell or platelet injury may contribute to the consumpthrombi that entrap platelets during thrombus
tive coagulopathy by releasing phospholipids that accelerate
2. Activation of factor XIII, which stabilizes ?
coagulation. Red cell injury may be a result of intravascular hemolysis caused by malaria, incompatible transfusion
3. Stimulation of platelets, resulting in decreased circulating
products, and other clinical states. Platelet destruction also
platelets. These stimulated platelets undergo shape change,
releases coagulation factors V, VIII, XII, and XIII.
adhesion, aggregation, and secretion. The contents of the
CHAPTER 24
Coagulation
factors
than
they
system cannot
4. Activation of factors V and VIII; however, thrombin actithe activated coagulation proteins.
vation results in unstable end products that have decreased
factor V and VIII activity
Alternate Forms of DIC
5.
DIC
presents
forms
in
in
brinogen
is a proteolytic enzyme that destroys ? brin, ? brinogen, and
most instances, the simultaneous generation of
clotting factors V and VIII. Circulating plasmin may lead to
plasmin will dissolve
brin. Both the clotting and ?
brinolysis, causing increased hemorrhagic events.
performing at abnormally high
In
the
microcirculation,
plasmins
action is
lysis does not occur, a different form of DIC exists. In this
directed against ? brin. In the circulation, the breakdown of
case, the prognosis is very
type is represented
? brin results in FSPs, labeled X, Y, D, and E, which inhibit
brinolythrombin and normal platelet function.
brinogenolysis. Coagulation
brinogen is degraded by plasmin, FSPs form. Degrathe excess plasmin being generated.
dation occurs whether the plasmin comes from DIC or pribrinogen
The Role of Factor VIII
molecules for thrombin molecules. This competitive binding
close relationship exists between factor VIII:C (procomakes the thrombin unavailable for the conversion of ?
(procoagulant antigen). In DIC,
brin. In this situation, patients with high FDP/FSP
lesser extent
levels have a circulating anticoagulant behaving like heparin.
than VIII:C by enzymes released during the process. It is known
If the FSP level is high, the thrombin clotting time is sig-
primarily
is destroyed by
amounts of
brinogen quantitation is low. The
thrombin, plasmin, and activated protein C (aPC).
second effect is on platelets. These split products coat the
inactivation of
platelet surface, blocking the receptor site needed for further
the degree of severity
platelet activation.
DIC. Furthermore, low values of factors VIII:C and VIIIR:Ag
When pathological ? brinolysis occurs, not only are facpatients with
tors destroyed, but, through the destruction of ? brinogen,
irreversible shock indicate
clinical outcome. Discrepa profound anticlotting effect inhibits secondary hemostasis
exist between VIII:C and VIIIR:Ag
and platelets.
ratios are
brinolytic system is activated, it will contribute to
of DIC. Current
the consumption of many coagulation factors. Plasmin, the
thinking indicates that data on the factor VIII complex show
primary proteolytic enzyme of ? brinolysis, directly attacks
characteristic decrease of the factor VIII
and destroys them. This becomes another form of consumpin DIC formulated in the past is
tive
t
coagulopathy
originating
generally valid.
from
an
activation
entirely
differen
begins, the
body
diseases, for example, sepsis or asthma. When in? ammamechanisms, the coagulation process
tion occurs, coagulation is also set in motion and actively
can return to normal. This negative feedback mechanism has
participates in enhancing in?
slow the formation of excess thrombin and
PC is a vitamin KCdependent serine protease that is
to stop DIC.
synthesized, predominantly in the liver, as a single polypeptide chain of 461 amino acids and is a natural antiClinical Signs and Symptoms
coagulant protein. The conversion of PC to activated PC
The DIC phenomenon has varied clinical and laboratory
(aPC) is enhanced by interaction of PC with endothelial
physiologiPC receptor (EPCR) on the cell surface. Activation can cal abnormalities associ
ated with the syndrome. DIC may
also be triggered by thrombin alone at a less ef? cient rate
(chronic). Chronic DIC is more
and is probably not relevant in the circulation. The funcDIC but is often more
cult to diagnose.
tion of aPC as an anticoagulant is manifested by its ability
being
manifested
in
the
same
patient.
thrombin and suppress the activation of thrombin actimay predominate in chronic or low-grade DIC. Thrombotic
vatable ? brinolytic inhibitor, which indirectly promotes
complications can include deep venous thrombosis.
? brinolysis. Fibrinolysis is also stimulated because of the
Acute DIC is severe and often life threatening. Its onset
ability of aPC to inhibit plasminogen activator inhibitor-1
is rapid, and both ?
(PAI-1).
Patients with chronic DIC may have mild manifestations
The induction of ?
of the disorder or be recognizable only by laboratory data.
tem may facilitate the clearance of excess thrombi and genHemorrhagic complications are also seen but are generally
eration of FSPs. If aPC is being consumed too rapidly, the
milder than in acute DIC.
regulatory ability of the protein C system is sharply reduced,
Clinical manifestations of DIC include petechiae, purpura,
which results in uncontrollable thrombosis.
Thrombos
hemorrhagic
bullae,
surgical
wound
bleeding,
bleeding,
venipuncture
site
bleeding,
arterial
Fatal
neonatal
purpura develops
in
individu
cavernous
hemangiomas,
and
Rocky
Mountain
involved
in
DIC
result in
the
generati
addition
its
to
cleaving
? brinogen
and
performi
Laboratory Findings
AT-III have also been suggested to be of prognostic value. The
Although
the
quantitative
measurement
of
FSPs
distinguish
between primary and
secondary
? brinolysis,
such measurement plays the major role in diagnosing and
monitoring these conditions. Laboratory diagnosis of DIC
requires the availability of tests that are rapid and simple to
perform. There is no single test that con?
but rather a combination of tests. Because DIC is a dynamic
process, values from tests performed a single time, whether
normal or abnormal, cannot be used as diagnostic indicators. Sequential testing is necessary to provide an accurate
diagnosis and effectively manage therapy. The most important consideration in the treatment of DIC is the resolution
key feature is an elevation of
Typical results in DIC include
thrombin time and an increased
levels and
the
total
circulating ? brinogen-FSPs.
prolonged aPTT, PT, and
level of D-dimers.
platelet
count may
vary,
decrease
in
? brinogen
are
common. The platelet count decreases earlier than ?
endotoxin-induced DIC. The reverse is true when tissue factor release is responsible, such as in obstetrical accidents or
trauma. Excessive ? brinolysis with the release of FSPs occurs
secondary
to
intravascular ? brin formation. Although
presence of FSPs is characteristic, the ?
DIC and cannot be used as the sole criterion for diagnosis.
of the underlying disease or triggering event.
Tests for Fibrinolysis and DIC
Disorders Related to Elevated Fibrin SplitProducts
Because the
manifestations of
cannot
although
the
are generally less than 0.25 mg/mL but may rise to as high as
50 mg/mL in certain kidney disorders.
Elevated levels of FSPs can be found in diseases of the
neonate, in sepsis, or in the DIC that these conditions may
generate. In cases of pulmonary embolism, levels can exceed
100 mg/mL; however, in rare cases, values can reach more
than 400 mg/mL. These excessively high levels return to near
normal within 24 hours after the cessation of the disorder
(e.g., sepsis). FSP levels are elevated, frequently as high as 80
mg/mL, in cases of mild chronic intravascular coagulation,
which occurs when the placenta slowly releases thromboplastic substances into the circulation. The FSP test can help
distinguish between eclampsia and hypertension and edema
associated with pregnancy.
THE HYPERCOAGULABLE STATE
Systemic in? ammation has long been recognized as being
associated with hypercoagulability. It commonly occurs in
patients with DIC in severe sepsis. Recently, the molecular
ammation has been recognized.
Most
of
the
hypercoagulable effects of
in? ammation are
sis or occlusion in an unusual location such as a mesenteric,
brachial, or cerebral vessel.
systems.
Thrombosis
and
coagulation
can
act
ammation, and severe or systemic in?ammaendothelial activation by cytokines leads to the loss of normal
tory responses can trigger coagulation. A laboratory assay,
vessel-wall anticoagulant surface functions, with conversion
high-sensitivity C-reactive protein (hsCRP), may herald an
to a proin? ammatory thrombogenic phenotype. Important
impending acute thrombotic event.
clinical syndromes associated with substantial thromboemThrombi may form because coagulation is enhanced or
bolic events include the APS, heparin-induced thrombopabecause protective devices such as ? brinolysis are impaired.
thy, myeloproliferative syndromes, and cancer.
An increase in the likelihood of blood to clot is referred to as
Hypercoagulability
can
be
associated
with
systemic
disorders are associated with thrombosis (Box 24.3). A number of factors may contribute to hypercoagulation.
Pregnancy-Associated Thrombosis
Primary States of Hypercoagulability
Normal pregnancy beginning at the time of conception is
associated with increased concentrations of coagulation facHypercoagulable states include
various
inherited
and
clinical
disorders
characterized
by
an
relatively
rare
inherited
Plasminogen
are
inhibitor
type
activator
conditio
(PAI-1) levels
conditions
include
decreased
thrombomodulin-
signi? cantly during the third trimester. Thrombin generadependent activation of APC, impaired heparin binding of
tion markers, for example, prothrombin F1+2, and thromAT-III, or downregulation of membrane-associated plasmin
bin-antithrombin (TAT) complexes are also increased. It may
generation.
take up to 8 weeks after delivery (postpartum) for the levels
The major inherited inhibitor disease states include ATof the cited constituents to return to the reference range.
ciency, and protein S de?
Pregnant women have an increased risk of thromboemboThese
conditions
should be
considered
in
patients
who
lism due to hypercoagulability. The condition of hypercoaguhave recurrent, familial, or juvenile deep venous thrombolability in pregnancy is most likely evolved to protect women
CHAPTER 24
platelets
detached
from
to
History of thrombosis
inherent
aPTT-based
factors
Genetic Testing
mon underlying genetic cause of thrombophilia (e.g., venous
Single-nucleotide polymorphisms (SNPs) are major contribthrombosis).
utors to genetic variation, comprising approximately 80%
Factor V
G-A
point
(Leiden)
mutation
results
from
a
of all known polymorphisms. Their density in the human
1,000
base
like
thrombin,
possesses
both
anticoagulant
(Leiden)
risk,
may
but
homozygotes
can
injure the
vascular
APC assay
arise
in
following
transfusion
of
blood
products
but
certain
populations
have
higher incidence
inhibitor
CHAPTER 24
exhibits
an
anticoagulant
effect, it
24.4)
Anticardiolipin antibodies
Anti-b2-glycoprotien-1 antibodies.
In
the
laboratory,
elevated
levels of
antibody
are
required
to
establish
a
diagnosis. The predominant antigenic targets in APS are
b 2-GP I and prothrombin. Complement activation is suspected because increased complement activation products
have been found in APS patients who have suffered from
a cerebral ischemic event. Dysregulated platelet activation
may contribute to thrombotic manifestations. Elevated
levels of platelet-derived thromboxane metabolic breakdown products have been demonstrated in the urine of
APS patients.
Factor VIII Inhibitor
Factor VIII inhibitors are the most common speci? c factor
inhibitors. Inhibitors of factor VIII develop in 10% to 15%
of patients with factor VIII de? ciency (hemophilia A), and
days
but
may
develop after
several hundred
postpartum
period,
most
frequently
after
birth of their ? rst child. Patients with underlying immunological disorders such as RA, SLE, drug allergies, ulcerative
colitis, and bronchial asthma also have an increased tendency
to develop factor VIII inhibitors. Many patients have been
observed to develop factor VIII inhibitors with no underlying disease. The majority of these patients are middle aged or
older, and both genders are affected.
PART 5
Inhibitors
against vWF
Nonhemophiliac patients
inhibitors
occur
in
patients
with
of
with
von
the
degree of
hemorrhage
Although
of
these
inhibitors
are
varies considerably.
predominantly
result
PT
or
aPTT
are
classic
laboratory
normal plasma at
determination
of
aPTT
and
stable than
the
Bethesda
assay
is
most
commonly
of
phospholipid-dependent coagulation
assays.
factor inhibitor development are varied and include congenAntiphospholipid antibody is considered one of the most
ciencies, immune disorders, and amyloidosis.
common causes of a prolonged aPTT. Assays include the RusFactor XI and XII Inhibitors
sells viper venom time, kaolin clotting time, platelet neutralization procedure, and tissue thromboplastin inhibition test.
Inhibitors
of
factors XI
and
XII
have
been
reported
other
hemostat
infrequently in patients with SLE, Waldenstr?m macroglobulinemia, and other disorders, as well as with chlorpromazImpaired Fibrinolysis
ine administration.
Impaired ?
Clinical Presentation
genetic and acquired in their origin. Impairment of ? brinolysis may predispose an individual to thrombosis. Patients
The LA is the most commonly acquired and has an interwith type II hyperlipoproteinemia caused by
familial hyperesting presentation.
ic
In
the
absence
of
involving
the
leg
veins, with
associ-
also
De? cient
Patients With Recurrent
Protein
All Patients
Thrombosis
Protein C
12%C18%
Protein S
15%C18%
De? ciencies of protein C and protein S can be acquired
anticoagulation characterized by resistance to APC is highly
or
congenital. Acquired
de? ciencies
occur
in
DIC,
severe
plasma contains
of
protein
normal levels of
C
defects have
been
reported
ciency is characterized by
caused by a selective defect in an anticoagulant function of
low antigenic and functional levels of the protein. In those
factor V (Fig. 24.2).
ciency, the antigenic level of protein C is normal, but the function of the molecule is impaired. Two subtypes of the type II defect have been described: classic type IIa,
Thrombin
in which both chromogenic and clotting functional assays are
abnormal, and type IIb, in which only the clotting functional
method is abnormal. Protein C de? ciencies should, accordFactor VIII
ingly, be screened by using a protein C functional assay (clot
based or chromogenic), because this will detect both types I
and II. Once a low level of protein C activity is determined,
an immunological assay should be performed to distinguish
type I from type II protein C de? ciency.
Activated Protein C Resistance
APC resistance, a new discovery, has been added to the list
of
may
causes of
be
thrombotic
disease.
APC
resistance
Protein S De?
in infancy.
Familial studies indicate that patients with a de?
protein S have an increased incidence of thrombosis. Early
descriptions indicate that protein S de?
common than either protein C or AT-III de?
The congenital de? ciency of protein S is associated with
an increased risk of recurrent juvenile venous and arterial
thromboembolism. The association of a thrombotic diathesis with acquired protein S de?
incidence of thrombosis because pregnancy, delivery, and
oral contraceptives are causative factors.
Defects of a qualitative nature (type II de?
characterized by decreased heparin cofactor activity. This
functional manifestation of defective AT-III is not associated
with a reduction in molecular concentration. More than half
of patients with type II de? ciency develop
venous thrombosis.
Congenital Protein S De?
Decreased AT-III Levels: Congenital
Diagnosis of protein S de?ciency differs signi?
that of vitamin KCdependent plasma proteins owing to
protein S binding with C4b-BP and repartitioning between
free (functional) and bound (nonfunctional) forms. The
cation of congenital protein S is based on the comparison of functional and antigenic (free and total) as well
as C4b-BP levels (Table 24.21). Currently, three types of
congenital de? ciencies have been identi? ed: type I, low
functional and antigenic protein S levels; type II, low functional protein S levels with a normal antigenic repartition
(molecule
dysfunctional); and
type
III,
low
functional
protein S levels corresponding to a decrease in free antiThe
relative
incidence
of
congenital
cy
is
between 1:2,000 and 1:5,000. AT-III de? ciency is inherited
as an autosomal dominant disorder. Homozygotes have not
been reported in AT-III de? ciency. Patients manifest signs
and symptoms of between 10 and 30 years of age, their ? rst
thrombotic event. An initial event is spontaneous in approximately half of patients. Women frequently experience manifestations during pregnancy or because of oral contraceptive
use.
Decreased
levels of AT-III
usually correlate
the
severity of venous thrombosis. Arterial thrombosis is a less
common ?
with
postoperative, postpartum,
protein-losing
be
caused by
quantita
contraceptives
Other disorders: burns, malignancies
is transmitted as an autosomal dominant disorder. Type I
(quantitative) de? ciencies represent the majority of cases.
Heparin Cofactor De?
Familial studies reveal that severe thromboembolic probAlthough
deficiency
of
AT-III is
the
most
thrombotic
complications
have
been
associ-
common,
defect is
manner.
inherited
in
an
autosomal
dominant
such
an
incidence
of
300,000
3. Antiphospholipid antibodiesACAs, LA
Another disorder related to ineffective thrombopoiesis is
4.
Hyperhomocysteinemia
May-Hegglin
anomaly,
hereditary
macrothrombocytopenia
(e.g., Alport
of
consumption
can
result from
wide
variety of
such
as
following
the
use
of
extracor
platelets.
circulation in cardiac bypass surgery or in alcoholic liver
ned as a substantial increase
disease.
ly
HIT
and
associated
thrombotic
events, relative
are
normal in
number but
fail
can
exist. These
include the
more
common
to
Thrombocytopenia
caused by
hypoproliferation
can
such
as
infections,
lupus
erythematosus, granu-
syndromes
and
production.
the
Thrombocytopenias
uremia. Miscellaneous
disor-
of
may
this
type
be
or folic acid.
hemorrhage.
CHAPTER 24
Hereditary
disorders
include
adhesion
and pelvic surgery, shock, advanced malignancy, septicemia,
Bernard-Soulier syndrome; primary aggregation disorders,
and intravascular hemolysis.
such as Glanzmann thrombasthenia and essential athromand
secondary
recognized
disorder;
complications
intravascular
and
of
disorders
and
life-threatening
consequences.
brinolysis
is
associated
with
in
which
gross
with
subsequent
activation
of
the
? brinogen
and
coagulation
? brinol
pathological
coagulation
factors can
be
destroyed
in
vivo
degradation
or
by
pathological
activation
inhibitors
V,
VII,
VIII,
can
cause
this
consumption
of
coagulation
factors
CHAPTER 24
bleeding
time
increased,
platelet
aggregation
fibrinolysis
is
Giant platelets
presence of
B.
Large platelets
ME.
Immune thrombocytopenic
purpura-the
changing
Molecular
basis
of
thrombocytosis,
Haematol
Federici
AB.
VWD,
Blood,
VWF
propeptide:
useful marker in
GA.
Sci,
Managing
16(2):
the
bleeding
patient,
unravels
platelet
function,
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Provan D, et al. International consensus report on the investigation
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George JN,
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Chronic idiopathic
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WW,
Telatar M.
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Multiplex
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Factor V
LeidenAn
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Schneider M. Thrombotic microangiopathy (TTP and HUS): advance
Kakkar N, Gupta V. Spurious thrombocytopenia in a young male,
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