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Disorders of Hemostasisand Thrombosis

Vascular disorders

Describe the physiology of the destruction and consumption of

De? ne the term purpura and describe various vascular conditions

coagulation factors, including the role of factor VIII, protein C, and


that can produce this condition.
thrombin in the process of ? brinolysis.
Abnormal platelet morphology

Compare the laboratory test results in conditions of disseminated


intravascular coagulation (DIC) and ? brinolysis.

Name and compare four types of disorders in which abnormal

Name and describe the factors that contribute to the pathological

platelet morphology can be observed.


inhibition of coagulation.
Quantitative platelet disorders
The hypercoagulable state

Cite at least two symptoms of thrombocytopenia.

Explain the role of vascular damage and blood ? ow in the hyperco-

List the three major mechanisms that produce thrombocytopenias.

agulable state.

Summarize the major characteristics of each of the three thrombo-

Detail how platelets contribute to hypercoagulation.

cytopenic categories, including examples of disorders within each

Describe the activity of blood coagulation factors in increasing the

of the categories or subcategories.


tendency toward thrombosis.

List and summarize the characteristics of the two categories of

Describe the relationship between impaired ?

thrombocytosis, including
each

examples

C, antithrombin III, and plasminogen.

of

disorders

within

Describe the laboratory assessments that illustrate the condition of

Qualitative characteristics of platelets:


hypercoagulation.
thrombocytopathy
Case studies

Compare the four categories of platelet dysfunctions, including

Apply the laboratory data to the stated case studies and discuss the

examples of disorders within each category.


implications of these cases to the study of hematology.
Bleeding disorders related to blood clotting factors

Give examples and describe conditions that contribute to the defec-

tive production of blood coagulation factors.


VASCULAR DISORDERS
Bacterial toxins produce de-endothelialization induced by
Disorders of the microcirculation, platelets,
may cause abnormal bleeding. Abnormal
the loss of red blood cells from the
itself as
the
condition
of
by
hemorrhages
into
the
skin,
internal organs.
Purpura
may
be
produced
vascular
abnormalities. These abnormalities include the

or plasma proteins
purpura,
mucous
by

which
a

is

variety of

following:

an endotoxin. Antibody vascular injury, vasculitis, may be


induced by drug reactions, insect bites, or the activation of
complement.
2. Purpura associated with an inherited disease of the connective
tissue. Alterations
of
the
vascular
ve
framework can occur in disorders such as diabetes.
3.
Purpura associated with decreased mechanical strength of
the microcirculation. Decreased strength can be seen in
conditions such as scurvy and amyloidosis.
1. Purpura associated with direct endothelial cell damage.
4. Purpura associated with mechanical disruption of small
The overall action of endothelins, a family of peptides, is
venules. The principal cause of this type of purpura is
to increase blood pressure and vascular tone. Endothelial

supporti

increased intraluminal pressure. This condition can be


damage may result from physical or chemical injury to
observed around the ankles with prolonged standing and
the tissue caused by microbial agents such as in rickettmay be caused by the presence of abnormal proteins in
sial disease or immunological antibody-mediated injury.
macroglobulinemias or hyperviscosity disorders.
PART 5

Principles and Disorders of Hemostasis and Thrombosis

5. Purpura associated with microthrombi (small clots). This


lation (DIC),
type of disorder is associated with abnormal intravascular
myocardial infarction, and ischemic injury to the legs or
coagulation conditions.
armscan produce severe morbidity and mortality. Serum
6.

Purpura associated with vascular malignancy. Purpura of this

from patients with HIT contains immunoglobulin G (IgG)


origin is observed in Kaposi sarcoma and vascular
that, in the presence of small amounts of heparin, activates
normal platelets and causes them to aggregate and release
the contents of their granules, including serotonin. PlateABNORMAL PLATELET MORPHOLOGY
let-activating antibodies
are
speci? c
not
but
for complexes formed between heparin and platelet factor

for

heparin

the

with hep

When examining a peripheral blood smear for platelets, the


morphology of the platelets should be observed. Abnormal
variations in size should be noted. Disorders of platelet size
include the following:
4, a heparin-binding protein normally found in the alphagranules of platelets. IgG and IgM also react with endothelial
cells coated with platelet factor 4 (Fig. 24.1). This suggests a
mechanism of antibody-mediated vascular injury that could
predispose a patient to thrombosis or DIC when challenged
1. Wiskott-Aldrich
syndrome,
which demonstrates
arin. To prevent these complications, it has become

smallest platelets seen


medical

practice

platelet

counts in

2. May-Hegglin anomaly, which is characterized by the


in for any extended period.

patients receiving hepar

presence of large platelets and the presence of D?hle-like


Most thrombocytopenic conditions can be classi?
bodies (see Chapter 15) in the granulocytic leukocytes
major categories. These categories are
3. Alport syndrome, a disorder that exhibits giant platelets
and thrombocytopenia
4. Bernard-Soulier syndrome, which demonstrates the largest platelets seen and is also referred to as giant platelet
syndrome. In this disorder, it has been demonstrated
that the giant platelets are probably an artifact of the slide
1. Disorders of production
destruction,
including
decreased
megakaryocytopoiesis and ineffective platelet production, and
disorders of utilization
3. Disorders of platelet distribution and dilution
preparation. Actual measurement of the platelets reveals
that their mean platelet volume (MPV) is normal
Disorders of Production
Decreased production of platelets may be caused by hypoproliferation of the megakaryocytic cell line or ineffective
thrombopoiesis caused by acquired conditions or herediQUANTITATIVE PLATELET DISORDERS
frequently
affects other

normal cell

lines

of

the

bone

marrow and

The normal range of circulating platelets is 150 10 /L to


hypoproliferation
450 10 /L. When the quantity of platelets decreases to
can

result from

acquired

damage to

hematopoietic

levels below this range, a condition of thrombocytopenia


of the bone marrow caused by factors such as irradiation,
exists. If the quantity of platelets increases, thrombocytosis

cells

drugs (e.g., chloramphenicol and chemotherapeutic agents),


is the result. Disorders of platelets can be classi?
chemicals (e.g., insecticides), and alcohol. In?
tative (thrombocytopenia or thrombocytosis) or qualitative
bone marrow by malignant cells in the conditions of meta(thrombocytopathy).
static cancer, leukemia, and Hodgkin disease can produce
a hypoproliferative state. Hypoproliferation may also result
Thrombocytopenia
from
nonmalignant
conditions,
such
as
infections,
erythematosus, granulomatous disease such as sarcoidosis,

lupus

A correlation exists between severe thrombocytopenia and


and idiopathic causes.
spontaneous
absent or

clinical

bleeding.

If

platelets

are

Ineffective thrombopoiesis may result in decreased platelet


severely decreased below 100 10 /L, clinical symptoms usuproduction. Thrombocytopenias of this type may be the manially include the presence of petechiae or purpura. Petechiae
festation of a nutritional disorder, such as a de?
appear as small, purplish hemorrhagic spots on the skin or
or folic acid. In these megaloblastic anemias caused by
mucous membranes; purpura is characterized by extensive
or folic acid, the defect in thymidine
areas of red or dark-purple discoloration.
Thrombocytopenia
can
result from
a
wide
variety of
or ineffective thrombopoiesis. Another disorder related to inefconditions, such as after the use of extracorporeal circulafective thrombopoiesis is iron de?
tion in cardiac bypass surgery or in alcoholic liver disease.
decrease in megakaryocyte

and the suppresHeparin-induced thrombocytopenia (HIT) and associated


endoproliferation and size. Hereditary
thrombotic events, relatively common side effects of hepathrombocytopenias include Fanconi syndrome, constitutional
rin therapy, can cause substantial morbidity and mortality.
aplastic anemia and its variants, ameiosis thrombocytopenia
Thrombocytopenia in itself rarely poses a threat to affected
(TAR syndrome), X-linked amegakaryocytic thrombocytopepatients,
but
nia, Wiskott-Aldrich
deep

disorders
syndrome,

venous thrombosis,

associated
May-Hegglin

with
itwhich
anomaly,
and

disseminated intravascular coagu-

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,

venom. Sulfonamide derivative


reactions involve the interaction of platelet antigens with
FIGURE 24.1. Proposed
explanation
for
the
of
both
thrombocytopenia and thrombosis in heparin-sensitive patients

presence

drug antibodies. Morphine reactions involve the activation


of complement.
who are treated with heparin. Researchers believe that injected
heparin reacts with platelet factor 4 (PF4) that is normally
Bacterial Sepsis
Bacterial
sepsis causes increased
s
ties
from
complexes

destruction

of

platelet

circulating
platelets
to
form
PF4-heparin
because of the attachment of platelets to bacterial antigenC

Speci? c IgG antibodies react with these conjugates to form


immune complexes.

Certain microbial

antigens

(2) that bond to Fc receptors on circulating


attach initially to platelets followed by
antibodFc-mediated
from

platelet

activation

(3)

releases

ies to the microorganism. This mechanism has been reported


alpha- granules in platelets (4). Newly released PF4 binds to addiimmune complexes,
establishing a cycle of platelet activation. PF4 released in excess of
the amount that can be neutralized by available heparin binds to
heparin-like molecules (glycosaminoglycans) on the surface of endothelial cells (ECs) to provide targets for antibody binding. This
to cause the thrombocytopenia that frequently complicates
the Plasmodium falciparum type of malaria. Thrombocytopenia occurs within 1 to 3 weeks following viral infections
(e.g., rubella, mumps, or chickenpox), parasitic or bacterial
infections, or hepatitis vaccination.
process leads to immune-mediated EC injury (5) and heightens
the risk of thrombosis and disseminated intravascular coagulation. (Adapted with permission from Aster RH. Heparin-induced
Immune thrombocytopenia
Antibodies of either autoimmune or isoimmune origin may
thrombocytopenia and thrombosis, N Engl J Med, 332(20):1375,

PF4

produce increased destruction of platelets. An example of an


1995. Copyright 1995 Massachusetts Medical Society. All rights
autoimmune

thrombocytopenia

is

autoimmune
reserved.)
thrombocytopenia. This condition occurs in infants born
PART 5

Principles and Disorders of Hemostasis and Thrombosis

to mothers with chronic immune thrombocytopenia following


least 30% of thrombocytopenic patients develop venous
transplacental passage of maternal IgG platelet
and/or arterial thrombosis.
Examples of thrombocytopenias of isoimmune origin
The lowest platelet counts range between 20 and 150
include posttransfusion purpura and isoimmune neonaabout 5
tal
thrombocytopenia.
Posttransfusion purpura is
the onset of the declining platelet count. The platelet count

rare

the

platelet

form of isoimmune thrombocytopenia. Isoimmune neodays after heparin therapy


natal thrombocytopenia results from the immunization of
normal within 4
a pregnant female by a fetal platelet antigen. The antigen
cases, it can take
is inherited by the fetus from the father and is absent on
disappears within
maternal platelets.
2 to 3 months after discontinuing heparin administration.
Thrombocytopenia in pregnancy
Thrombosis

occurs in

most

patients

count diminishes by 30% to 50% of the normal level. The

after

Pregnant women generally have lower platelet counts than


risk of thrombosis persists for up to 30 days after discontinunonpregnant
women. Gestational
thrombocytopenia
rin. Rare cases of thrombosis have been reported

is

ing hepa

caused by
a
combination
of
d
before the platelet count declines.

and

increase

platelet
activation
of
approxi-

and

hemodilution

clearance.

decrease

A rare manifestation of delayed-onset HIT has been observed.


mately 10% in the platelet count is typical toward the end of
In these cases, thrombocytopenia began at least 5 days after disthe third trimester of pregnancy.
Bleeding is uncommon.
Heparin-Induced Thrombocytopenia
Pathophysiology
HIT is the most common drug-induced thrombocytopeImmune HIT is caused by an antibody that recognizes heparin
nia. HIT and antiphospholipid syndrome (APS) are two
bound to platelet factor 4 (PF4) on the platelet
which

antibodies

against

antibody
then

binds

to

complexes
tal

of

charged

the

heparin-PF4

complex,

molecules

are

which
of

fundamen

allows the antibody to bind the Fc receptor on the platelet.


importance. In the case of APS, the antibodies are autoantiInteraction with the Fc receptor activates the platelet that
bodies compared to the drug-induced antibodies of HIT. In
results in the loss of platelets, thrombocytopenia, and platelet
both syndromes, IgG antibodies directed against positively
aggregation (thrombosis). A small number of cases of HIT
charged
(GP
I)

endogenous

proteins,

b2

glycoprotein

may involve an antigen other than the PF4 complex.


in APS and platelet factor 4 (PF4) in HIT, are of major
importance.
Laboratory Data
HIT is a serious complication of heparin therapy. This
In addition to the platelet count, three speci? c laboratory
condition is also called white clot syndrome because it
assays can be used in patients with HIT:
poses a high risk of potentially catastrophic venous or arterial
thrombosis. The mortality rate of patients with thrombosis
is approximately 25%.
Thrombocytopenia and thrombosis are the predominant
1. Enzyme-linked immunosorbent assay (ELISA)
2. Platelet aggregation
3. Serotonin release
clinical symptoms of HIT.
The ELISA assay and serotonin release assay have sensitivities
Two types of HIT exist
of more than 90%, with very high speci? city for HIT anti1. Nonimmune HIT: Type I
2. Immune HIT: Type II
body. Platelet aggregation is between 50% and 80% and is
very speci? c.
Increased Utilization of Platelets
Nonimmune Heparin-Induced Thrombocytopenia
Accelerated

consumption

of

platelets

is

Nonimmune HIT is a benign disorder affecting up to 10%


the

most

important

and

frequently encountered forms of increased consumption


mechanism of action is direct interaction between heparin
of platelets is
immune (idiopathic) thrombocytopenic purpura
and platelets.
This antibody-related response, which

another cause

Typically, the platelet count is greater than 100.00 10


infection, is believed
devastating effect
Although a rapid decline is observed within the ?
on platelet survival. ITP may complicate other antibodyheparin administration, the platelet count returns to normal
associated disorders such as systemic lupus erythematosus
levels within 5 days despite continued heparin use or within
immunological

thrombocytopenic

2 days if heparin therapy is discontinued.


petechiae, bruising,
Immune Heparin-Induced Thrombocytopenia
rhagia, and bleeding after minor trauma.
Approximately 8% of patients who receive heparin therapy
Immune Thrombocytopenia
develop HIT antibody but do not experience thrombocytopeimmune thrombonia. Another 1% to 5% of patients receiving heparin therapy
cytopenia (ITP), to
the term, idiopathic thrombodo develop HIT antibody and manifest
cytopenic purpura.
an acquired immune-mediated
CHAPTER 24

Disorders of Hemostasis and Thrombosis

In
ion

ITP,

the

acute
is

mechanism

of

platelet

suggested to be either by absorption of viral antigen onto


the platelet surface followed by antibody binding or by formation of an immune complex on the surface of platelets
via the platelet Fc (immunoglobulin) receptors. In chronic

destruct

ITP, the target for the autoantiplatelet antibodies is platelet


membrane
and

GPs

(e.g., GPIIb/IIIa,

GPIb/IX,

GPIa/IIa,

GPIV). The majority of platelet autoantigens are present on


either GPIIb/IIIa or GPIb/IX complex. The mechanism of
autoantibody formation is unknown.
Laboratory Data
Isolated
ity.

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

genders except in the mid-adult years (30 to 60 years), when


Treatment
the disorder is more prevalent in women. ITP is classi?
Platelet
time

transfusions

are

seldom indicated.

Survival

duration into newly diagnosed, persistent (3 to 12 months


of transfused platelets is short, but they are important for
controlling

severe hemorrhage.

The

ef?

Typically, adult ITP is a chronic disease. ITP in children


may improve immediately after an infusion of intravenous
is a clinically distinct disorder and is usually acute. Among
immune globulin.

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

When treatment is considered for patients with more severe


bleeding are common. Hematuria and gastrointestinal bleedthrombocytopenia
the

and

symptoms,

it

must

be

with

ing are less common, and intracerebral hemorrhage is rare.


understanding that complete and permanent correction of
Serious bleeding does not occur in most patients.
thrombocytopenia is infrequent with any therapy.
Pathophysiology
The old concept was that thrombocytopenia resulted from
antibody-mediated platelet destruction. There are two new
concepts:
Thrombocytopenia
Intravascular coagulation, vascular injury or occlusion, andtissue injury can al
l contribute to the increased utilization of
platelets. DIC rapidly consumes platelets. Trauma, obstetrical
1.

The same antibodies that mediate platelet destruction also

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

Principles and Disorders of Hemostasis and Thrombosis

the direct consumption of platelets at the sites of endothelial


Disorders of Platelet Distribution
loss without appreciable depletion of clotting factors such as
brinogen.
A platelet distribution disorder can result from a pooling
of platelets in the spleen, which is frequent if splenomegaly
Thrombotic Thrombocytopenic Purpura

is present. This type of thrombocytopenia develops when


more than a double or triple increase in platelet producThrombotic thrombocytopenic purpura (TTP) is a clinical
tion is required to maintain the normal quantity of circusyndrome with a high mortality rate that is characterized by
lating platelets. Disorders that may produce splenomegaly
formation of microthrombi in the microvasculature.
with resultant splenic pooling or delayed intrasplenic transit
Clinical signs and symptoms include
include alcoholic or posthepatic cirrhosis with portal hyper

Severe thrombocytopenia
Microangiopathic hemolytic anemia

tension, lymphomas and leukemias, and lipid disorders such


as Gaucher disease.

Fever
Neurologic symptoms, for example, headache, stroke

Thrombocytosis

Renal disease

Thrombocytosis is generally de? ned as a substantial increase


The

hematological

findings

of

thrombocytopenia

in circulating platelets over the normal upper limit of 450


red blood cell schistocytes are diagnostic of the disease.
10 /L. Thrombocytosis can be classi?
Coagulation testing will demonstrate normal prothrombin and activated partial thromboplastin time (aPTT) but
elevated D-dimer and fibrinogen levels. TTP is in contrast
to DIC that demonstrates abnormal prothrombin time
(PT) and aPTT.
Three types of TTP have been identi? ed
1.
Hereditary or familial thrombocytosis associated with germline mutations of the thrombopoietin (THPO) gene in
the THPO receptor (MPL) gene
2. Thrombocytosis
associated
with
myeloproliferative
neoplasms
and/or myelodysplastic disorders
(clonal
1. Idiopathic
thrombocytosis associated with somatic mutations of

and

2. Secondary
JAK2[V617F], MPL, and additional currently unknown
3. Inherited (Upshaw-Shulman)
Idiopathic
has
been

TTP

has

an

unknown

etiology

but

3. Reactive (secondary thrombocytosis)


linked to an enzyme, ADAMTS13 (A Disintegrin-like And
Many patients with thrombocytosis have reactive thromMetalloprotease
domain with
ive thrombocytosis may be observed in

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

the clinical symptoms.


immunological

thrombocytopenic

purpura,

pernicious

Secondary TTP is diagnosed in patients with a history of


anemia, discontinuance of myelosuppressive drugs, acute
medications, for example, quinine, immunosuppressants, or
blood loss, exercise, and myelodysplastic and hemolytic
some cytotoxins used in cancer therapy. This form of TTP
anemias. After splenectomy, increases are noted because
has been seen in some conditions, for example, HIV, autoimof the loss of the spleen. As the bone marrow adjusts to
mune disorders, and allogeneic bone marrow transplants.
new requirements, platelet numbers progressively return
Upshaw-Shulman syndrome

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,

may also be seen in autoimmune hemolytic anemia.


inflammation.
Another disorder, hemolytic uremic syndrome (HUS)
is a clinical syndrome with presentation and manifestations similar to TTP. Unlike TTP, which has a peak age
incidence in the third decade, HUS has a peak incidence
QUALITATIVE CHARACTERISTICS OF PLATELETS:THROMBOCYTOPATHY
between 6 months and 4 years of age. Unlike TTP, HUS is
characterized by
If platelets are normal in number but fail to perform effectively, a platelet dysfunction exists. In addition to both an

of

Association
with
Escherichia
coli
O
157:H7 in
individual and family medical history, laboratory tests are

platelet

dysfunctional

diagnosis.

80%

Renal failure and limited to the kidneys

tests of platelet function include bleeding time,

Small vWF multimers predominate

clot
ness,

retraction,

Normal level of ADAMTS13 activity

platelet

aggregation,

platelet

adhesive

and antiplatelet antibody


CHAPTER 24

Disorders of Hemostasis and Thrombosis

Myeloproliferative Syndromes
Acquired
in
the

platelet

dysfunction

is

commonly

myeloproliferative syndromes. Platelet aggregation patterns

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.

Miscellaneous Disorders Associated With Platelet


Dysfunction
Acquired defects are seen in autoimmune disorders, such
as SLE, rheumatoid arthritis (RA), ITP, and scleroderma.
Fibrinogen degradation products or ? brinogen split products (FDPs or FSPs) including the later degradation products,
fragments D and E, have a high af?
brane and produce a severe platelet function defect. Patients
with severe iron, folate, or cobalamin de? ciency may also
have platelet function defects.
Acquired Platelet Function Defects
penicillin, and alcohol. In addition, prostaglandin pathways
inhibited
and

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

Also included among hereditary disorders are defects of


connective tissue, such as collagen, and failure of platelets
to adhere to the subendothelium because of a decrease or
defect in plasma coagulation factors. An example of a defect
of platelet plug formation owing to decreased platelet adhesion to the subendothelium is von Willebrand disease (see
discussion later in this chapter).

defect,

Bernard-Soulier Syndrome
Bernard-Soulier syndrome,

an

autosomal

hereditary

ing disorder, is a platelet adhesion disorder in which platelet


membrane GPs Ib, V, and IX are missing. Heterozygotes are
often asymptomatic. The condition is characterized by the
presence of giant platelets. In this syndrome, there is mild
thrombocytopenia, but the predominant abnormality is of the
CHAPTER 24

Disorders of Hemostasis and Thrombosis

membrane GP Ib. This abnormal platelet membrane lacks the


platelet function defects. In
instances,
receptor site for vWF, which is necessary for platelets to adhere
storage pool defects are
to vascular subendothelium. A blood ?
syndrome,
Bernard-Soulier syndrome may resemble that from a patient
syndrome,
Chdiak-Higashi
with ITP. Platelet aggregation is normal with all agents except
syndrome.

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-

rare, primary aggregation disorders. Glanzmann thrombasplatelet function defects.


thenia is an autosomal recessive disorder. Clinical features
Storage granule abnormalities, primarily an absence of the
involve platelet dysfunction, easy and spontaneous bruising,
dense granules, exist in conjunction with other clinical dissubcutaneous

hematomas,

and

petechiae.

Intra-articular

orders, such as Chdiak-Higashi syndrome, Wiskott- Aldrich


bleeding with hemarthrosis may occur in some patients but
and
Hermansky-Pudlak
syndrome.
In
these

syndrome,

tends to diminish with age.


disorders, platelet aggregation with weaker agents, such as
This disorder involves an abnormality of the surface memADP and epinephrine, is diminished.
brane GP complex IIb/IIIa. On a peripheral blood ? lm, platelets from patients with this disorder remain isolated and do not
exhibit the clumping that is normally seen. Epinephrine, collagen, and thrombin fail to induce aggregation. This results in
a prolonged bleeding time in the presence of a normal platelet
BLEEDING DISORDERS RELATED TO BLOODCLOTTING
count, decreased platelet retention in glass bead columns, and
an absence of a primary wave of aggregation in response to adenosine diphosphate (ADP). Clot retraction is also decreased.
Vascular response and platelet plug formation are responsible for the initial phases of hemostasis. Subsequent to these
activities, the clotting factors are initiated to form the ?
Hereditary Storage Pool Defect
clot. Fibrin formation can occur if the activity of various
factors is at least 30% to 40% of normal.
Hereditary
aggrega-

storage

pool

defect is

secondary

hereditary

storage pool

Bleeding and defective


frequently
tion
s

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

Principles and Disorders of Hemostasis and Thrombosis


Defective
Excessive
inhibition

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.

The level of factor activity ranges from 0% to 25% in persons


Because the liver is the primary site of synthesis of coagulation
homozygous for the trait and from 15% to 100% in persons
factor, severe liver disease can cause defective production of
heterozygous for the trait. Defects of this origin may result
coagulation factors. Severe liver disease may produce decreased
from the decreased production of a clotting factor, factor
plasma levels of ? brinogen, although low levels of ? brinogen
VIII, or the production of functionally inactive molecules of
rarely produce hemorrhage. In patients with liver disease, the
the clotting factor. Hemophilia A, a sex-linked homozygous
PT is noticeably prolonged, whereas the aPTTs are variable.
disorder expressed in males, occurs in 1 in 10,000 males.
Hereditary Clotting Defects
Pathophysiology
Classic hemophilia

(hemophilia

A)

and

von

Willebrand

Classic hemophiliacs have an intact highCmolecular-weight


disease are examples of hereditary disorders that represent
moiety and a de? cient lowCmolecular-weight procoagulant
functionally inactive factor VIII.
portion. This disorder of procoagulant synthesis expresses
CHAPTER 24

Disorders of Hemostasis and Thrombosis

Von Willebrand Disease


In 1926, Erik von Willebrand ? rst described a hemorrhagic
disorder characterized by a prolonged bleeding time and an
autosomal inheritance pattern that distinguished the
from classic hemophilias. In the early 1950s, an additional
component
VIII

of

procoagulant

the
activity

disease was

identi? ed: a de? ciency of

(Table 24.8). These

other observations distinguish von Willebrand disease from

and

classic factor VIII:C de? ciency (hemophilia A). In addition,


evaluation of the multimeric structures of vWF has aided
in the classi? cation of the variant forms of von Willebrand
disease. Three major types of von Willebrand disease have
been identi? ed.
Etiology
von Willebrand disease may
d

be

an

acquired

or

The congenital disorder is autosomally dominant


in most cases. Inherited abnormalities in von Willebrand
disease are associated with a defect of the vWF gene on
chromosome 12, but in some patients, the coexistence of an
impaired response of plasminogen activator and telangiectasia suggests the presence of a regular defect or more extensive endothelial abnormalities. In several families, a large
vWF gene deletion has been identi? ed as the basis for von
More than 20 distinct clinical and laboratory subtypes
of von Willebrand disease have been described (Table 24.9).
Three

broad

types

of

von Willebrand disease are

nized. In addition, a platelet-type von Willebrand disease


(pseudoCvon Willebrand disease) is caused by an abnormal platelet receptor for vWF. In addition, acquired von
cation of von Willebrand Disease (continued )
Willebrand disease may complicate other diseases such as
the

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

tive disorders. Variant forms of von Willebrand disease can


produced in the megakaryocyte.
identi? ed by their patterns of genetic transmission and
vWF circulates in platelets, being stored primarily in the alpha
the vWF abnormalities in the plasma and the cellular comgranules, in association with factor VIII procoagulant protein
partment. Distinguishing between various subtypes of von
released from the alpha granules
important in determining appropriate
the GP IIb/
therapy (Table 24.10).
IIIa complex. The site synthesis of VIII:Ag remains unknown,
Epidemiology
although the liver is thought to play an important role.
vWF is a large, adhesive, multimeric GP present in plasma,
von Willebrand disease is recognized as one of the most platelets, and subendoth
elium. It is synthesized as a large
common hereditary bleeding disorders in humans. The exact
precursor that consists of a signal peptide, a propeptide (von
cult to determine because milder forms are
has the two
often not clinically recognized, but it has been estimated to
(VIII:C) and
have a prevalence as high as 1% in the general population.
subendothelial cell
No racial or ethnic predisposition has been determined.
circulating blood, vWF is
Both genders are affected, but there is a higher frequency of
with the factor VIII
clinical manifestation in women.
stabilizes

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

vWF circulates in the blood in two distinct compartments,


can be distinguished from
with two types of cells being responsible for vWF producplatelet vWF,
is not proteolyzed. The pathogenesis of
CHAPTER 24

Disorders of Hemostasis and Thrombosis

von Willebrand disease is based on quantitative or qualitahomozygous type I


(or compound heterozygous)
tive abnormalities, or both, of vWF. When an abnormality
and type III disease
is present, the decreased factor VIII procoagulant activity is
is unclear but is characterized
decreased circulating levattributable to the reduced concentration of vWF.
decreased proportionally with
vWF is essential in providing the basis for formation of a
respect to vWF.
c sites on the

under

Most patients with von Willebrand disease (50% or more)


platelet, namely GP Ib and GP IIb/IIIa, while concurrently
abnormalities and no evidence
binding
to
the
subendothelium of
damaged
walls, tional abnormality of vWF, which corresponds to type I von
forming
of
vWF,

vessel

a
bridge. Patients
with
decreased
levels
Willebrand disease and its subtypes. The genetic transmis-

especially the larger multimeric forms, will lack adequate


sion of the disease is dominant, except possibly for subtype
bridging
action that
produces
prolonged
bleeding
times. I-3. Most patients have low plasma levels of vWF antigen
Qualitative or quantitative abnormalities of vWF result in
(usually between 5% and 30% of normal) and corresponddecreased
bleeding
activity

adhesion
ingly low
(the
assay

and
are
levels of

responsible
ristocetin

for
the
cofactor

associated with von Willebrand disease.


of vWF to
GP Ib and mediate
The
signi? cance
of
vWF
in
the
regulation
VIII:C platelet agglutination). The factor VIII procoagulant protein

of

remains unclear. The increase in VIII:C following infusion of


the decrease in vWF.
ed vWF suggests a possible role of vWF in the syntheinsuf? cient levels
sis, release, or stabilization of VIII:Ag. Therefore, decreased
circulating vWF and factor VIII. Bleeding manifestations are
levels of vWF may prolong the rate of blood clotting.
in patients who have
normal concentration of
Clinical Signs and Symptoms
platelet vWF than in others (Table 24.11).
The

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

disease and appears to be based on a quantitative de? ciency


of vWF. It is expressed as an autosomal dominant trait and
is presumed to be caused by an inheritance of one normal
cient allele. Patients with severe type III disease
PART 5

Principles and Disorders of Hemostasis and Thrombosis

In all patients whose vWF shows low ristocetin cofactor


phenomena. vWF may be an indicator of vascular
activity, except for those designated as having type B disease,
status. Drugs such as 1-deamino-8-D-arginine vasopressin
the vWF has an abnormal multimeric structure and there is
(DDAVP), steroids, and hormones may also result in elevated
a decrease in or absence of the large multimers.
levels of vWF.
Type II is characterized by structurally abnormal vWF.
The circulating levels of vWF may be decreased or normal,
Laboratory Findings
and VIII:C may be affected similarly. Type IIA and type IIB

Willebra

The following laboratory results are typical of von


are autosomally dominant, whereas type IIC is recessive.
Patients with type III, the most severe form of von Willebrand disease, are likely to have a major episode of bleeding early in life because signi? cantly decreased amounts of
vWF and VIII:C are produced. Genetically, they are thought
to be homozygous or double heterozygous. These patients
probably comprise a separate group because of the typically

Bleeding time: mildly to moderately prolonged


Platelet retention: typically decreased
Platelet agglutination: ristocetinabnormal
Platelet aggregation: normal with all but ristocetin
vWF function (ristocetin cofactor activity)

recessive modality of genetic transmission (Table 24.12).


Quantitation of vWF antigen (vWF:Ag) can be determined by
Acquired von Willebrand Disease
immunoelectrophoresis. These assays measure total amounts
of vWF protein, independent of its ability to function. Finally,
von Willebrand disease is occasionally seen as an acquired
vWF multimeric analysis is useful in distinguishing between
condition. Associations have been made with lupus erythesubtypes and in determining therapeutic management. vWF
matosus and other autoimmune disorders as well as myeloanalysis

uses

sodium dodecyl sulphate

proliferative disorders. The presence of a circulating antibody


agarose gel

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

Increased levels of vWF have been associated with stress,


molecules produces dys? brinogenemia. A? brinogenemia is

hypo-

in? ammation, postsurgical states, pregnancy, renal disease,


associated with a severe bleeding tendency but is less common
diabetes, rheumatoid disorders, scleroderma, and Raynaud
than hypo?
CHAPTER 24

Disorders of Hemostasis and Thrombosis

are usually asymptomatic except in situations of surgery or


apparent, and factor XIII de? ciency,
associated
brinogenemia may be asymptomwith spontaneous abortion and poor wound healing.
atic or experience a mild bleeding tendency if heterozygous
bleeding tendency if
Disorders of Destruction and Consumption
homozygous for the defect.
ciencies of the other coagulation factors are
brin deposits can result in thrombosis and damrelatively rare (Box 24.2). Examples of rare defects include
ow and ischemia. The
factor XII de? ciency, in which no clinical bleeding tendencies
? brinolytic system serves as a protective mechanism against
brin deposits by lysing both ?
Blood coagulation factors can be destroyed in vivo by
enzymatic
of

degradation

or

by

pathological

coagulation with excessive utilization of the clotting factors.


Enzymatic destruction can result from bites by certain species
of snakes whose venom contains an enzyme that degrades
brin monomer. In vivo activation
of coagulation by tissue thromboplastinClike materials can
produce excessive utilization of clotting factors. Conditions

activation

associated

with

this

consumption

of

coagulation

factors

include obstetrical complications, trauma, burns, prostatic


and pelvic surgery, shock, advanced malignancy, septicemia,
and intravascular hemolysis.
General Features of Fibrinolysis
Primary and secondary ?brinolysis are recognized as extreme
complications of a variety of intravascular and extravascular disorders and may have life-threatening consequences.
PART 5

Principles and Disorders of Hemostasis and Thrombosis


? brinolysis is associated with conditions in which

Other causes can include liver disease, lymphoproliferagross


sub-

activation

of

the

? brinolytic

mechanism

with

tive disorders, and renal disease. In addition, DIC can also


sequent

be triggered by trauma including shock, hypothermia, and


occurs. The important characteristic of primary ? brinolyextensive tissue damage, such as in myocardial infarction
sis is that no evidence of ? brin deposition occurs. Primary
and eclampsia. It has been associated with multiple surgical,
brinolysis occurs when large amounts of plasminogen actiobstetrical, and medical disorders. Coma and convulsions
vator enter the circulatory system as a result of trauma, surcan result.
gery, or malignancies.
Although the same clinical conditions may also induce
secondary ? brinolysis or DIC, the distinction between the
two is essentially in the demonstration of ? brin formation.
In secondary ? brinolysis, excessive clotting and ? brinolytic
activity occur. Increased amounts of ? brin split (degradation) products
(FSPs) and
? brin monomers
are
able because of the action of thrombin on the ? brinogen
molecule. This ?
clotting; therefore, it is a secondary condition. Distinguishing
between primary and secondary ?

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

Disorders of Hemostasis and Thrombosis

dense alpha-granules are released, leading to an acquired


mechanisms are
ciency. If, during perhaps a 3-hour span,
process.

Coagulation

factors

brinogen levels decrease signi? cantly


rapidly

than

they

in a critically ill patient, DIC should be the prime suspect


be replaced,
antithrombin III (AT-III) levels
depleted,
as the cause of this change

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.

Activation of protein C, which degrades factors V and VIII

DIC

presents

forms

in

in

brinolytic system is suddenly actibrin thrombi in the vasculature, primarily


In essence, it is a systemic pathobrinolysis. This secondary
logical process. Because two
involved,
brinolysis is responsible for the hemorrhagic complication
brinolytic system, several types of
ed clinically:
When the ? brinolytic system is activated, plasminogen is
brinolytic
1.

DIC: Clotting and lysis strongly activated (most common

inhibitor uniquely designed to cope with plasmin. The more


plasmin generated, the more alpha-2 antiplasmin the patient
consumes. This produces a vicious cycle in which increased activation leads to decreased inhibitors; this, in turn, allows more
increased activation to continue. This is known as a positive
2. DIC: Clotting predominates with little or no lysis (poor
prognosis)
3. Primary ? brinogenolysis: Only lysis activated, but many
coagulation factors consumed
feedback loop and leads to a situation incompatible with life.
clotting system and
Damaged tissue, especially renal cells, releases plasminosystemigen activators that convert plasminogen to plasmin. Plasmin

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.

source with the same end result.


When
systemic
clotting

from

an

activation

entirely

differen

begins, the

body

The Role of Protein C


stop it. The two major inhibitor systems
mechanism of hemoof coagulation are antithrombin and the protein C and S
stasis. In addition, PC is now recognized as playing a
systems. These inhibitors are consumed in the DIC process.
and chronic in? ammatory
PART 5

Principles and Disorders of Hemostasis and Thrombosis

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

to acute consumption if the


to inactivate two important cofactors of the coagulation
of procoagulant-anticoagulant is lost.
cascade: factor V/Va and factor VIII/VIIIa. These eventsare enhanced by the pres
ence of Ca
, phospholipids, and
cofactor protein S.
initially be seen with varying degrees
of thrombosis and hemorrhage, but bleeding is usually the
major symptom, particularly in acute cases. Both hemorOther functions of aPC in hemostasis are in maintaining
rhagic and thrombotic complications may accompany DIC,
uid state of blood. aPC has the ability to downregulate
often
is

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,

Thromboembolic complications occur in patients with


wound
line

bleeding,

venipuncture

site

bleeding,

arterial

hereditary de? ciencies of protein C (levels 60% or less of


oozing, and subcutaneous hematomas.
normal).
als

Fatal

neonatal

purpura develops

in

individu

TTP is a condition that is similar to DIC (Tables 24.16


born with a homozygous protein C de? ciency. The stimuli
and 24.17). In addition, pediatric respiratory distress synthat can induce DIC may ultimately result in abnormal levdrome (PRDS), adult respiratory distress syndrome (ARDS),
els of protein C. Both normal and abnormal levels of protein
HUS, preeclampsia or frank eclampsia, circulating immune
C antigen can be found, depending on the sample time relacomplex,

cavernous

hemangiomas,

and

Rocky

Mountain

tive to the onset of DIC. Plasma levels of protein C antigen


spotted fever can resemble DIC.
and activity have been found to be decreased in patients
with DIC. Whereas three fourths of DIC patients have a
decrease in protein C antigen, almost all DIC patients have
a decreased level of protein C activity. Monitoring patients
reveals that protein C antigen and activity decrease progressively during the initial stages of DIC and remain at a low
level for 24 to 48 hours before gradually returning toward
normal in nonfatal cases.
The Role of Thrombin
Mechanisms
on
of

involved

in

DIC

result in

thrombin in the circulating blood. Among its many feedback

the

generati

reactions, thrombin participates indirectly in the activation


of the ? brinolytic system secondary to DIC and activates
protein C. The latter reaction is accelerated by the presence
of the endothelial cell cofactor, protein S.
In
ng

addition
its

to

cleaving

? brinogen

and

performi

other procoagulant functions, some of the excess thrombin


binds to protein S on the endothelial cell surface. This event
leads to increased levels of APC in the plasma. Once the generation of excess thrombin is decreased by the action of APC
CHAPTER 24

Disorders of Hemostasis and Thrombosis

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

extremely variable, diagnosis depends on laboratory testing.


The normal level of serum FSPs is less than 10 mg/mL. Serum
Coagulation assays such as the platelet count, ?
values can vary owing to exercise or stress. Elevated urinary
els, FSP test, factor V assay, ethanol gelation test, and thromlevels are always indicative of a disease state. High levels of
bin timeCreptilase test can all be useful. Prekallikrein and
FSPs indicate renal dysfunction. Normal urinary FSP values
PART 5

Principles and Disorders of Hemostasis and Thrombosis

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.

mediated by in? ammatory cytokines, including IL-1, IL-6


and tumor necrosis factor (TNF).
The processes of coagulation, thrombosis, and in? ammaSecondary States of Hypercoagulability
tion do not occur in isolation. There is interaction between
Secondary hypercoagulation states may be seen in a numthese
as

systems.

Thrombosis

and

coagulation

can

ber of heterogeneous disorders. In many of these conditions,

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

the hypercoagulable state.


in? ammation due primarily to an increase in procoagulant
Thrombosis is promoted by vascular damage, by retarded
functions, an inhibition of ? brinolysis, and a downregulaow, and by alterations in the blood that increase the
tion of the three major physiologic anticoagulant systems of
likelihood of clotting. A variety of high- and low-incidence
protein C, AT-III, and tissue factor inhibitor.

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

tors VII, VIII, and X and von Willebrand factor. In addition,


acquired
increased

clinical

disorders

characterized

by

an

a signi? cant change in ? brinogen is noted. Free protein S,


risk for thromboembolism. Primary hypercoagulable states
the active, unbound form, is decreased during pregnancy.
(Table 24.18) include
ns

relatively

rare

inherited

Plasminogen
are

inhibitor

type

activator

conditio

(PAI-1) levels

that lead to disordered endothelial cell thromboregulation.


vefold. PAI-2 produced by the placenta increases
These

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

Disorders of Hemostasis and Thrombosis

against the bleeding challenges of childbirth or miscarriage.


ow at critical sites with the accumulation of
Pregnant women are at a four- to ? vefold increased risk of
activated clotting factors.
thromboembolism during pregnancy and the postpartum
period compared to nonpregnant women. Eighty percent of
Platelets
the thromboembolic events in pregnancy are venous with an
Stasis makes
easier for

platelets

detached

from

to

incidence of 0.49 to 1.72 per 1,000 pregnancies.


circulating
Risk factors for developing hypercoagulability include
platelets may
tendency toward thrombosis. Platelets

History of thrombosis

Inherited and acquired thrombophilia

Maternal age less than 35 years of age

Certain medical conditions and/or complications of pregnancy and childbirth


accumulate at the site of vascular damage, where they can
phospholipid for the intrinsic pathway and also promote thrombin formation by adsorbing activated factor X
from plasma to their surfaces. High platelet counts additionally foster thrombosis.
Another possibility is that a thrombotic tendency may be
caused by qualitative alterations in platelets. These alteraGeneral Features
tions may be caused by intrinsic platelet defects or by changes

in the surrounding plasma. Qualitative abnormalities may


Vascular Damage and Blood Flow
result in spontaneous aggregation, enhanced sensitivity to
Vascular endothelial damage exposes circulating blood to
aggregating agents, or increased adhesiveness.
subendothelial structures that initiate thrombosis. Constriction of blood vessels additionally creates stasis. Thrombosis
ow or in situations in which
the viscosity of blood is increased. In patients with a high risk
of thrombosis, the concentration of ? brinogen is often elebrinogen may induce aggregation of circulating erythrocytes, which produces increased
blood viscosity. This may encourage thrombosis by decreasBlood Clotting Factors
Congenital and acquired hypercoagulable states arise when
there is an imbalance between the anticoagulant and prothrombotic activities of plasma in which the prothrombotic
activities predominate.
A tendency toward thrombophilia (abnormal thrombosis) may be caused by qualitative alterations in blood
PART 5

Principles and Disorders of Hemostasis and Thrombosis

factors or an increased titer of activated clotting factors that


limitations
the

inherent

aPTT-based

can create a tendency toward thrombosis. These factors can


method, which
requires a
and may
contribute
to
thrombosis
in
that
activated
might be affected by high concentrations of factor VIII, LA, and
reach critical levels in the circulating blood.
anticoagulant therapy.
The DRWT also eliminates the techFactor V (Leiden)
nical requirement of prediluted patient samples with factor
cient plasma.
The factor V gene is an autosomal, codominantly inherited
gene. Factor V R506Q (Leiden) mutation is the most com-

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

-Gly substitution in the proestimated


per

1,000

base

tein. This mutation renders factor V resistant to the activity


pairs. APC-resistant patients may be con? rmed for factor V
of APC and induces a defect in the natural anticoagulation
cation of a segment
system. The overall effect of this mutation is an alteration in
of the potentially affected gene. General population screenthe anticoagulant properties of factor V.
ing is not recommended. At this point, the recommendations
Factor V,

like

thrombin,

possesses

both

anticoagulant

for testing focus primarily on individuals younger than age


and procoagulant properties. The APC-mediated cleavages,
50 who have already had an idiopathic thrombotic event.
if performed on factor V, transform it into an APC cofacThe three most common assays ordered to investigate a
tor (FVac). FVac acts in unison with APC and protein S to
genetic predisposition to thrombosis are
increase the rate of inactivation of factor VIII.
In
contrast
to
other coagulopathies, factor V
poses a lifelong risk of deep venous thrombosis with a greater
frequency of occurrence of thrombi in the lower limbs than
1. Factor V (Leiden)
mutation

(Leiden)

3. Methylenetetrahydrofolate reductase enzyme (MTHFR)


in the chest. Fortunately, everyone who has the mutation
an increased risk
will not suffer a thrombotic event. Heterozygotes have a low
vascular thrombosis. MTHFR de? ciency leads
(approximately 10%)
lifetime
to
hyperhomocysteinemia
that

risk,
may

but
homozygotes
can
injure the
vascular

experience a 50- to 100-fold increase in risk.


endothelium. It
role in venous thromboemboLaboratory Assessment
lism. These three assays can be performed simultaneously by
analyzing genomic DNA in peripheral blood mononuclear
A panel of assays is required to assess hypercoagulability.
cells using polymerase chain reaction (PCR).
Functional screening tests include the following:
Circulating Anticoagulants

Activate and partial thromboplastin time (aPTT)

Lupus anticoagulant (LA) screening


brinogen (factor I) assays

APC assay

Protein C and protein S assays

D-dimer screening test


Acquired inhibitors of clotting proteins, also known as circulating anticoagulants, inactivate or inhibit the usual procoagulant activity of coagulation factors. Inhibitors are frequently
c, those directed against a coagulation
factor, or nonspeci? c, those directed against a complex of
factors, such as the LA.
The majority of these inhibitors exhibit biochemical propIn addition, acute-phase reactants (e.g., C-reactive protein
erties, suggesting that they are immunoglobulins. Inhibitors
[CRP]) may be assayed.
may
or

arise
in

following

transfusion

of

blood

Traditionally, the APC resistance assay identi? es patient


patients with no previous hemostatic disorders. Acquired

products

insensitivity to APC. The assay is based on the aPTT assay


cant cause of hemorrhage.
with and without reagent APC. The aPTT in the presence of
Speci? c inhibitors against factors II, V, VII, VIII, IX, XII,
XIII, and vWF have been detected in patients with individto yield a unitless ratio. A ratio of greater than 2 (a longer
ual factor de? ciencies. However, some inhibitors of factors
clotting time) generally indicates an unaffected condition.
II, V, VII, IX, XII, and vWF have been observed in patients
A ratio of less than 2 (a shorter clotting time) indicates a
having no de? ciencies of coagulation factors. Patients with
potential factor V (Leiden) mutation and resistance to APC.
acquired speci? c inhibitors may exhibit hemorrhagic epiFactor VCde? cient plasma may be added to the test system
c inhibitors are not generally associencies. The APC resisciated with bleeding tendencies.
tance assay may be affected by other conditions (e.g., LA,
brinogen levels, oral contraceptive
Etiology
use, or pregnancy).
The incidence of circulating anticoagulants has been benchAnother method of testing for the mutation is by a dilute
marked
population,

but

certain

Russells viper venom time (DRVVT) based test. The DRWT


patient

populations

have

higher incidence
inhibitor
CHAPTER 24

Disorders of Hemostasis and Thrombosis

development. Inhibitors, found in both serum and plasma,


platelet poor and free of
are not inactivated by heating at 56C for 30 minutes and
remain stable when stored at C20C. Inhibitors are more
comparison, anticardiolipin antibodies (ACAs), IgM,
stable than clotting factors and more tolerant of changes in
the phospholipids
pH and temperature. Inhibitors may remain in the circulaof beta 2-GP 1-cardiolipin comtion for months and in some instances have been found in
may be detected in healthy patients and in those with
patients years after development.
of conditions (e.g., SLE).
c Inhibitors
LA and ACA are risk factors for thrombosis but the mechanism of action is unclear.
Antiphospholipid Antibodies (Lupus Anticoagulant and
Anticardiolipin Antibodies)
Antiphospholipid Syndrome
The lupus anticoagulant (LA) occurs in approximately 30% to40% of patients with
SLE. LA is the most common coagulaThe APS is de? ned by the persistent presence of antiphospholipid antibodies. APS is a prothrombotic disorder with
tion inhibitor found in SLE patients, although these patients
various manifestations in patients with a history of recurmay have other acquired inhibitors as well. LA occurs in the
rent venous or arterial thromboembolism or a history of
presence of disease states other than SLE, such as acquired
miscarriages. APS is an important cause of acquired thromimmunode? ciency syndrome (AIDS) and malignancy, and
bophilia. APS can occur alone or in association with other
in procainamide, hydralazine, or chlorpromazine therapy.

autoimmune conditions, particularly SLE. The core clinical


Although
LA
is
rarely

exhibits

an

anticoagulant

effect, it

manifestation is thrombosis. In women, it can be associated


associated with bleeding.
with recurrent fetal loss. Fetal morbidity and mortality may
LA, an IgM, IgG, or IgA immunoglobulin, interferes with
be due to factors such as placental thrombosis and placental
phospholipid-dependent coagulation reactions in laboratory
ammation due to complement activation.
assays but does not inhibit the activity of any speci? c coaguAntiphospholipid antibodies include
lation factor. LA is an inhibitor that prolongs phospholipiddependent clotting tests in vitro. LA is the most common
cause of prolonged aPTT.
In
1995, the
Subcommittee
on
Lupus Anticoagulant
Standardization Committee
published
criteria
(Box
for the diagnosis of LA. This guideline recommends at least
two screening tests based on different assay principles. In
addition, a mixing study for the veri? cation of the presence of a coagulation inhibitor and a con? rmation test for
documentation of
phospholipids dependency
should
also be performed. All assays should be performed on citrate

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

the majority occur in patients with severe hemophilia (those


having less than 1% factor VIII activity). Inhibitors have
developed in patients exposed to factor VIII after as few as
10-exposure

days

but

may

develop after

several hundred

days. Approximately 65% of patients with hemophilia who


develop inhibitors do so before the age of 20. Nonhemophiliac
women have been reported to develop factor VIII inhibitors
during the
the

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

Principles and Disorders of Hemostasis and Thrombosis

Inhibitors

against vWF

Nonhemophiliac patients
inhibitors

occur

in

patients

with

of

Willebrand disease, underlying diseases such


as malignancy
major bleeding requiring transfusion.
or SLE, and in previously healthy persons. A familial tendency
Patients with inhibitors to
factor XI, and factor XII
for the development of vWF inhibitors has been noted.
However,
Factor IX Inhibitor
therapy for these patients can be complicated by the

with

von

of the inhibitor. Patients with acquired factor IX inhibitors


Inhibitors are found in approximately 2% to 3% of factor
patients with
IXCde? cient (hemophilia B) patients, but the incidence of
inhibitors. Factor V inhibitors may cause clinical bleeding,
inhibitors in severe hemophilia B may be as high as 12%.
although

the

degree of

hemorrhage

Although
of

these

inhibitors

are

varies considerably.

predominantly

result

Inhibitors of factors XIII, II, VII, IX, and X; ?


transfusion of blood products, spontaneous inhibitor forgen can result in serious hemorrhagic events.
mation has been reported.
Laboratory Findings
Factor V Inhibitor
Prolonged
findings.

PT

or

aPTT

are

classic

laboratory

Factor V inhibitors are rare and are not generally associated


plasma with

normal plasma at

with hereditary factor V de? ciency. Some patients have had


37C

(mixing study) and

determination

of

aPTT

and

exposure to streptomycin but no causal relationship has been


PT may detect the presence of an inhibitor. The mixing
established.
study will be prolonged in the presence of an inhibitor.
Fibrinogen, Fibrin, and Factor XIII Inhibitors
Inhibitors
are
more
time
and
temperature
their specific clotting factors. To quantitate the levels of

stable than

Inhibitors of ? brinogen, ? brin, and factor XIII have been


inhibitors,
used

the

Bethesda

assay

is

most

reported. These inhibitors have occurred following plasma

commonly

in the United States. One Bethesda unit is defined as the


transfusions or appeared spontaneously. Some patients have
amount of antibody that will neutralize 50% of the inhiba common denominator of taking isoniazid, an antitubercuitor activity in a mixture of equal parts of normal plasma
losis drug.
and antibody containing plasma that has been incubated
Factor II, VII, IX, and X Inhibitors
for 2 hours at 37C.
Detection of antiphospholipid antibody is based on proFactor II, VII, IX, and X inhibitors are rare. The causes for
longation

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

cholesterolemia demonstrate impairment of ?


abnormalities, the LA is rarely associated with bleeding tenhigh incidence of recurrent thrombosis has been noted in
dencies, even with surgical procedures. Bleeding episodes
patients with hereditary de? ciencies of protein C or AT-III.
in these patients are usually the result of thrombocytopenia
Protein S de? ciency also joins the group of other plasma
or another anomaly. Paradoxically, patients with LA are at
protein de?
increased risk for arterial and venous thromboembolism.
(Table 24.19). De?
Venous thrombosis

involving

the

leg

veins, with

associ-

have also been correlated with recurrent thrombosis.


ated pulmonary emboli, is the most frequent complication.
Spontaneous
abortion
and
intrauterine
deaths are
Protein C De?
increased in patients with LA.
Protein C activity has been demonstrated to be related to the
The presence of a speci? c factor inhibitor can be suscommonly occurring thrombotic episodes in patients with
pected in patients with no history of bleeding episodes who
and protein S.
experience hemorrhage from various sites or in hemophiliac
in patients with proteinuria
patients not responsive to their usual dosage of blood proddecreased levels of protein C. Elevated prouct infusion. Bleeding episodes in hemophiliac patients with
mechanism to
inhibitors do not appear to be any more frequent or severe
because

also

than in patients without inhibitors. When hemorrhagic events


the anticoagulant activities of AT-III and protein C are probdo occur, treatment of a patient with inhibitor is dif? cult.
ably complementary.
CHAPTER 24

Disorders of Hemostasis and Thrombosis

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

prevalent in patients with venous thrombosis. This defect


liver disease, vitamin K de? ciency, and oral anticoagulation
appears to be at least 10 times more common in such patients
therapy. Congenital de? ciencies are transmitted in an autothan any of the other known inherited de? ciencies of antisomal dominant fashion. Thrombotic complications usually
coagulant proteins. The anticoagulant cofactor that corrects
involve the venous system, although more recently protein S
inherited APC resistance is identical to unactivated factor
has been associated with arterial thrombosis as well.
V. APC-resistant
Several types

plasma contains
of

protein

normal levels of
C

defects have

procoagulant, which suggests that APC resistance may be

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

ciency of an anticoagulant factor


that functions as a cofactor to APC. APC resistance appears
to be inherited as an autosomal dominant trait, suggesting
C4b-binding protein
that a single gene is involved. It is possible that patients with
severe APC resistance are homozygous for the genetic defect,
whereas an APC response closer to the normal range indicates heterozygosity. The genetically determined defect in
Thrombin
FIGURE 24.2. The protein C anticoagulant pathway. Thrombin
converts factor VIII and factor V to their activated forms, factor

VIIIa and factor Va. A complex of thrombin with the endothelial


cell receptor thrombomodulin activates protein C. APC inactivates
factor VIIIa and factor Va on the platelet surface, and this reaction
is accelerated by APC cofactor and free protein S. (Adapted with
permission from Bauer KA. HypercoagulabilityA new cofactor
in the protein C anticoagulant pathway, N Engl J Med, 330(8):566,
1994. Copyright 1994 Massachusetts Medical Society. All rights
reserved.)
PART 5

Principles and Disorders of Hemostasis and Thrombosis

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

AT-III de? cien

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

genic protein S along with a normal


decrease in free/functional protein S caused by increased
synthesis of C4b-BP can occur transiently during acutephase reactions.
A protein S functional assay should be used to screen for
Decreased AT-III Levels: Acquired
Acquired AT-III de? ciency can be caused by decreased synthesis, increased consumption, or other disorders; it can also
be drug induced. The associated disorders are
all types of protein S de? ciencies. Antigenic levels of both
free and total forms of protein, as well as C4b-BP, will then
be determined to differentiate types I, II, and III.
Decreased synthesis: arteriosclerosis, cardiovascular disease, chronic hepatitis, cirrhosis, type II diabetes mellitus
Increased
consumption:
DIC,
homocystinuria, nephsyndrome,

postoperative, postpartum,

protein-losing

Antithrombin III De?


enteropathy, pulmonary embolism, stroke, thrombophlebitis
Drug induced: ? brinolysin, heparin, L-asparaginase, oral
Hereditary
defects of AT-III
may
tive or qualitative defects. Quantitative de?

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

lems usually begin to be manifested in late adolescence or


recurrent

thrombotic

complications

early adulthood. Manifestations of AT-III de?

have

been

associ-

common,

ated with a deficiency of heparin cofactor II. The latter


CHAPTER 24

Disorders of Hemostasis and Thrombosis

defect is
manner.

inherited

in

an

autosomal

dominant

Patients with venous thromboembolism can be divided


Sympathetic heterozygous patients exhibit about half the
groups. The ?
normal plasma levels of heparin cofactor II activity. This
as cancer,
as recent
deficiency results from defective protein synthesis rather
or an acquired abnormality
as the LA that is
than from a qualitative abnormality. Heparin cofactor II
known to increase the risk of thrombosis. The pathophysioldeficiency can also be demonstrated in patients with DIC.
is poorly understood (Table 24.22).
In these situations, both AT-III and heparin cofactor II
consists of patients without the usual
levels are diminished in parallel.
risk factors that predispose people to venous thrombosis. In
some of these patients, it is possible to identify a de? ciency
Clinical Signs and Symptoms
of AT-III, protein C, or protein S, and family studies show
Clinical presentations of patients with de? ciencies of naturally occurring
anticoagulants are
similar.
De?
50% of normal for protein C, protein S, and AT-III may lead
to serious thrombotic events. Frequent presenting conditions include
thrombophlebitis,
deep
venous thrombosis,
pulmonary emboli. The frequency of protein de? cienhereditary defects. APC resistance occurs in about one third
of
patients.
Precipitating factors for
thrombosis,
as
pregnancy and the use of oral contraceptives, are identi? ed

such

in 60% of these patients. APC resistance appears to be 5 to 10


times more common than a de? ciency of AT-III, protein C,
or protein S in patients with venous thrombosis.
cies correlated with recurrent thromboembolic disease is as
Protein S: 5% to 10%
Protein C: 7%
Laboratory Assessment of HypercoagulableStates
AT-III: 2% to 4%
Four major areas of clinical testing are available to evaluate a
patient for hypercoagulability. These categories are
Venous Thromboembolism
1. Natural anticoagulantsprotein C de? ciency, protein S
Venous thromboembolism has

an

incidence

of

300,000

de? ciency, factor V (Leiden), antithrombin de? ciency,


episodes per year in the United States, and the complication
and heparin cofactor II de?
of pulmonary embolism causes 5% to 10% of all deaths in
Fibrinolysisplasminogen
ciency, poor tissue plasmithe hospital. Venous thrombosis can result from hereditary
nogen activator release, excessive plasminogen activator
or acquired factors or both.
inhibitor, and dys?
PART 5

Principles and Disorders of Hemostasis and Thrombosis

3. Antiphospholipid antibodiesACAs, LA
Another disorder related to ineffective thrombopoiesis is
4.

Hyperhomocysteinemia

ciency anemia, which usually results in a decrease in


megakaryocyte size and the suppression of megakaryocyte
endoproliferation and size. Hereditary thrombocytopenias
CHAPTER HIGHLIGHTS

include Fanconi syndrome, constitutional aplastic anemia


and its variants, amegakaryocytic thrombocytopenia (TAR
Vascular Disorders
thrombocytopenia,
Wiskott-Aldrich syndrome,

May-Hegglin

anomaly,

Abnormal bleeding involving the loss of red blood cells from


and

hereditary

macrothrombocytopenia

(e.g., Alport

the microcirculation expresses itself as purpura, which is


characterized by hemorrhages into the skin, mucous membranes, and internal organs.
Purpura may be associated with a variety of vascular abnormalities including direct endothelial cell damage, an inherited
disease of the connective tissue, decreased mechanical strength
of
the
microcirculation,
mechanical
disruption
small
venules, microthrombi (small clots), and vascular malignancy.

of

Increased destruction or utilization of platelets may result


from a number of mechanisms. It can be caused by antigens,
antibodies,
drugs, or
foreign
substances.
Bacterial
sepsis
causes increased destruction of platelets owing to the attachment
of
platelets
to
bacterial
antigen-antibody
immune
complexes. Antibodies of either autoimmune or isoimmune
origin may produce increased destruction of platelets.
Accelerated
consumption
of
platelets
is
another cause
Abnormal Platelet Morphology
of thrombocytopenia. One of the most important and frequently
encountered
forms of
increased
of
When examining a peripheral blood smear for platelets, the
morphology of the platelets should be observed. Abnormal
variations in size should be noted. Disorders of platelet size
include Wiskott-Aldrich syndrome, May-Hegglin anomaly,
Alport syndrome, and Bernard-Soulier syndrome.
platelets is ITP. This antibody-related response, which may
be preceded by infection, is believed to have a devastating
effect on platelet survival. ITP may complicate other antibody-associated disorders such as SLE. Patients with ITP
usually demonstrate petechiae, bruising, menorrhagia, and
bleeding after minor trauma.
Quantitative Platelet Disorders
Disorders of Platelet Distribution
The normal range of circulating platelets is 150 10 /L to
A platelet distribution disorder can result from a pooling

consumption

450 10 /L. When the quantity of platelets decreases to levels


of platelets in the spleen, which is frequent if splenomegaly
below this range, a condition of thrombocytopenia exists. If the
is present. This type of thrombocytopenia develops when
quantity of platelets increases, thrombocytosis is the result.
more than a double or triple increase in platelet production
Thrombocytopenia

can

result from

wide

variety of

is required to maintain the normal quantity of circulating


conditions,
poreal

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

in circulating platelets over the normal upper limit of 450


common side effects of heparin therapy, can cause substan10 /L. Thrombocytosis is usually grouped according to cause:
tial morbidity and mortality. Most thrombocytopenic condireactive or benign etiologies versus platelet elevations linked
ed into the major categories of disorders
c hematological disorder.
of production, disorders of destruction, and disorders of
platelet distribution and dilution.
Decreased production of platelets may be caused by hypoQualitative Platelet Disorders
proliferation of the megakaryocytic cell line or ineffective
If
platelets
function

are

normal in

number but

fail

thrombopoiesis caused by acquired conditions or hereditary


properly, one of four separate categories of platelet dysfunction

can

exist. These

include the

more

common

to

Thrombocytopenia

caused by

hypoproliferation

can

acquired and less frequent hereditary causes. Hyperactive


result from acquired damage to hematopoietic cells of the
platelets associated with hypercoagulability and thrombobone marrow caused by factors such as irradiation, drugs
sis make up an additional category of abnormal platelet
and cancer chemotherapeutic agents, chemicals, and alcohol.
function.
Hypoproliferation may also result from nonmalignant conAcquired platelet function defects can be caused by a
ditions,

such

as

infections,

lupus

erythematosus, granu-

blood plasma inhibitory substance. In addition, acquired


lomatous disease such as sarcoidosis, and idiopathic causes.
platelet dysfunction is commonly seen in the myeloproIneffective thrombopoiesis may result in decreased platelet
liferative

syndromes

and

production.
the

Thrombocytopenias

uremia. Miscellaneous

disor-

of

may

this

type

be

ders can be associated with platelet dysfunction. Many


manifestation of a nutritional disorder, such as a de?
drugs can induce platelet function defects, resulting in
of vitamin B

or folic acid.

hemorrhage.
CHAPTER 24

Disorders of Hemostasis and Thrombosis

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;

bia; and secondary aggregation disorders, such as hereditary


extreme

complications

intravascular

and

of

storage pool defect and hereditary aspirin-like defects.


extravascular

disorders

and

life-threatening
consequences.
brinolysis

is

associated

with

Bleeding Disorders Related to Blood Clotting


conditions
ytic
mechanism

in

which

gross

with

subsequent

activation

of

the

? brinogen

and

coagulation

Bleeding and defective ? brin clot formation are frequently


related to a coagulation factor. Disorders of the blood coagulation factors can be grouped into three categories: defective
production,
excessive
destruction,
and
inhibition.
A condition of defective production may be related to a
de? ciency of vitamin K. Severe liver disease may produce
brinogen, although low levels of
? brinogen rarely produce hemorrhage. Hereditary clotting
defects including classic hemophilia (hemophilia A) and von
Willebrand disease are examples of hereditary disorders that
represent functionally inactive factor VIII.
understanding
the molecular pathological processes that underlie hereditary
factor consumption occurs. The important characteristic of
primary ? brinolysis is that no evidence of ? brin deposition
occurs. Primary ? brinolysis occurs when large amounts of
plasminogen activator enter the circulatory system as a result
surgery, or malignancies.
Although the same clinical conditions may also induce secbrinolysis or DIC, the distinction between the two is
essentially in the demonstration of ? brin formation. In secbrinolysis, excessive clotting and ? brinolytic activity
monomers are
detectable because of the action of thrombin on the ? brinogen molecule. This ? brinolytic process is only caused by
excessive clotting; therefore, it is a secondary condition. This
distinguishes between primary and secondary ? brinolysis.
disease. The cloning of factor VIII facilitated the identi?
of mutations that lead to hemophilia A, an inherited de? ciency
The Hypercoagulable State
of factor VIII coagulant activity that causes severe hemorrhage. von Willebrand disease may be an acquired or inherited

? brinol

pathological

disorder. The congenital disorder is autosomally dominant in


most cases. Three broad types of von Willebrand disease are
recognized. In addition, a platelet-type von Willebrand disease
(pseudoCvon Willebrand disease) is caused by an abnormal
platelet receptor for vWF. Acquired von Willebrand disease
may complicate other diseases such as lymphoproliferative
and autoimmune disorders, and proteolytic degradation of
vWF complicates myeloproliferative disorders.
A de? ciency of factor IX is known as hemophilia B or
Christmas disease. A de? ciency of factor XI is referred to
as hemophilia C. Fibrinogen de? ciency as a genetic disorder may represent a defect of production or dysfunctional
molecules. Hereditary de? ciencies of the other coagulation
factors are relatively rare. Examples of rare defects include
ciency, in which no clinical bleeding tendencies are apparent, and factor XIII de? ciency, which is associated with spontaneous abortion and poor wound healing.
Thrombi may
form
because coagulation
is
enhanced
or
because protective devices such as ? brinolysis are impaired.
An increase in the likelihood of blood to clot is referred to as
the hypercoagulable state.
Hypercoagulable states include
various
inherited
and
acquired
clinical
disorders
characterized by
an
increased
risk for thromboembolism. Primary hypercoagulable states
include relatively rare inherited conditions that lead to disordered endothelial cell thromboregulation. These conditions
include decreased thrombomodulin-dependent activation of
APC, impaired heparin binding of AT-III, or downregulation
of membrane-associated plasmin generation.
The major inherited inhibitor disease states include ATciency, and protein S de?
Secondary hypercoagulation states may be seen in many heterogeneous disorders.
Acquired inhibitors of clotting proteins, also known as
circulating
anticoagulants,
inactivate
or
inhibit
the
usual
procoagulant activity of coagulation factors. Inhibitors are
frequently characterized as speci? c, those directed against
Disorders of Destruction and Consumption
a coagulation factor, or nonspeci? c, those directed against
a complex of factors, such as the LA. The majority of these
Blood
by

coagulation

factors can

be

destroyed

in

vivo

inhibitors exhibit biochemical properties, suggesting they are


enzymatic
of

degradation

or

by

pathological

immunoglobulins. Inhibitors may arise following transfusion


coagulation with excessive utilization of the clotting factors.
of blood products or in patients with no previous hemostatic

activation

Enzymatic destruction can result from bites by certain species


disorders. Acquired inhibitors can be a signi? cant cause of
of snakes whose venom contains an enzyme that degrades
hemorrhage.
brin monomer. In vivo activation
Speci? c
IX,

inhibitors

against factors II,

V,

VII,

VIII,

of coagulation by tissue thromboplastinClike materials can


XII, and XIII and vWF have been detected in patients with
Conditions
individual factor de? ciencies. However, some inhibitors of
that

can

cause

this

consumption

of

coagulation

VII, IX, and XII and vWF have been observed in


include obstetrical complications, trauma, burns, prostatic
ciencies of coagulation factors.
PART 5

Principles and Disorders of Hemostasis and Thrombosis

In this case, an increased aPTT with a


that the patient is de?
VIII, IX, XI, or XII.
Factor substitution testing might be valuable before a
factor assay is performed. This screening test is
useful in isolating either speci?
tors that are de?
factor de? ciency, a
formed. In this case, a
cient in factor VIII.
physician was concondition. He did not rememnormal, 10 to 15 seconds), and the aPTT was 55 seconds
(continued)

factors

CHAPTER 24

Disorders of Hemostasis and Thrombosis

prolonged aPTT. Either a


would be more common.
2.

Factor substitution studies would be valuable. If the sub-

stitution studies reveal an abnormality, a


assay should be conducted.
3.

In this case, factor VIII activity was found to be decreased

(patient, 30% activity;


and the lack of a
not have
Further testing was performed. The results were
lows:

bleeding

time

increased,

platelet

aggregation

decreased, factor VIII decreased, and factor VIII/vWF


decreased. Based on these ?
sic hemophilia was excluded. The laboratory
diagnosis of von Willebrand disease.
The laboratory ?
as follows:
(continued)
PART 5

Principles and Disorders of Hemostasis and Thrombosis

the outpatient laboratory for a


hematocrit, and coagulation pro?
Hemoglobin 10.0 g/L
Hematocrit 27%
coagulation pro?
Bleeding time 7 minutes (normal, 1 to 3 minutes)
PT 11 seconds (control, 12.2 seconds)
aPTT 29 seconds (control, 34 seconds)
Clot retraction decreased

1. What additional tests would be suggested based on the


initial laboratory results?
2. What would the Wright-stained blood ?
3. What is the most likely diagnosis and prognosis?
A platelet count and qualitative platelet studies would
be appropriate follow-up procedures in view of the prolonged bleeding time and poor clot retraction.
platelet disorder is suspected, the peripheral blood
be valuable. Obviously,
would support
in platelet size
distribution and morphology
3.

Further testing for platelet function revealed a de?

in both platelet aggregation and adhesion. The diagnosis


of Glanzmann thrombasthenia was made. This autosomal recessive disorder usually becomes less severe as
patient ages. In this womans case, severe bleeding or
future surgical interventions would need to be supported
by the use of platelet concentrates.
_____ Bernard-Soulier syndrome
secondary

fibrinolysis

is

Giant platelets
presence of
B.

Smallest platelets seen

brin split products


C.

Large platelets

brin degradation products


? brin monomers
Questions 5 through 7: Match the etiologies of these plate-

all of the above


let dysfunctions with the appropriate associated disorder
(use an answer only once).
_____ Acquired
_____ Drug induced
_____ Hereditary
DIC is characterized by
microvascular thrombosis
? brin deposition
brinolysis
all of the above
von Willebrand disease
Which of the following factors can contribute to hypercoagulation?
Which of the following parameters can be abnormal in
classic von Willebrand disease type I?
Bleeding time
Vascular endothelial damage
Increased blood ?
Decreased platelets
Decreased titers of clotting factors
Platelet count
Questions 15 through 19: Match the following.
All of the above
_____ Antithrombin III de?
The most common form of von Willebrand disease is
_____ Oral contraceptives
_____ Protein C de?
_____ Cancer
_____ Pregnancy
all have about the same incidence
Primary hypercoagulable state
Laboratory results in acute DIC re?
Secondary hypercoagulable state
in which of the following coagulation components?
Platelet function
Excessive clotting and ?
Accelerated thrombin formation
Fibrin formation
Primary ?

gross activation of the ?


consumption of ?
consumption of coagulation factors
all of the above
Questions 20 through 22: Match the following terms with
the appropriate description.
_____ Circulating anticoagulants
_____ LA
_____ Factor VIII inhibitor
factor inhibitor
Acquired inhibitors of clotting proteins
Also known as antiphospholipid or
anticardiolipin
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