This document provides a basic overview of hemostasis and thrombosis with particular focus on the role of the clinical laboratory. Hemostasis can be defined as the physiological process that keeps blood flowing while allowing solid clot formation, or thrombosis, to prevent blood loss from sites of vascular damage.1,2 This requires a delicate balance between a potent coagulation mechanism that rapidly forms a stable clot and a regulatory system that limits clot formation to the site of injury. As the site of damage is repaired, fibrinolysis degrades the clot and restores unrestricted blood flow.
In general, there are four clinical situations that call for the use of coagulation tests in the assessment of patients. These are:
Primary Hemostasis. This term refers to the response to vascular injury that produces a platelet clot at the site of damage.1,3 Primary hemostasis serves to immediately limit bleeding through the formation of a loose platelet plug. Platelets play a key role in the rapid response to blood vessel injury by:
Defects in primary hemostasis are generally associated with mucocutaneous bleeding, characterized by epistaxis, ecchymosis, genitourinary bleeding, or gingival bleeding. A typical patient with defective primary hemostasis might experience profuse bleeding from small cuts and require the application of pressure for a prolonged period to stop the bleeding.2,4 This type of bleeding pattern is different from that typically seen in patients with defects in secondary hemostasis, where deep tissue bleeding and hemarthroses are more the norm.3
Platelet counts and platelet function tests are a useful aid in the assessment of primary hemostasis. von Willebrand factor (vWF) serves to attach platelets to the blood vessel walls and to each other during primary hemostasis. Defects in vWF concentration or activity are very common, affecting approximately 1% of the population.1 The role of the clinical laboratory in the assessment of vWF function is described in detail under the test descriptions below.
Secondary Hemostasis. Secondary hemostasis refers to the cascade of enzymatic reactions that ultimately results in the conversion of fibrinogen to fibrin monomers. Fibrin monomers are then cross-linked into insoluble strands that serve to stabilize the loose platelet clot formed in primary hemostasis. Secondary hemostasis is triggered by the release of tissue factor from epithelial cells that are exposed to the circulation at the site of vascular injury. Defects in secondary hemostasis decrease fibrin production and reduce the stability of the formed clot.1,2,3,5 In these conditions, bleeding is generally delayed compared to that observed in defective primary hemostasis. The loose platelet plug is not stabilized by fibrin strands and starts to leak. Typical symptoms of patients with defective secondary hemostasis include soft-tissue bleeding, hematomas, retroperitoneal bleeding, or hemarthrosis. The hemophilias are examples of defects in secondary hemostasis.2
Two simple screening tests are most often used in the initial assessment of secondary hemostasis. Both the prothrombin time (PT) and partial thromboplastin time (PTT) are performed on plasma separated from whole blood collected with sodium citrate anticoagulant. Citrate binds calcium in the blood and inhibits clot formation. Like all other clot-based coagulation tests, both the PT and PTT assays are initiated by adding excess calcium to the testing tube to overcome the effect of the citrate. The testing sequence for PT and PTT are explained below.
In normal hemostasis, tissue factor that is released into the circulation as the
result of vascular damage unleashes a coagulation cascade that ultimately
results in the production of fibrin.1,2,6 Phospholipid
membranes play an integral role in providing a surface for catalytic enzyme
complex formation for these reactions. Platelets that form the primary
hemostatic plug provide the phospholipid required to promote fibrin generation.3
The PT test brings these components (tissue factor and phospholipid)
together in the test tube. Since tissue factor is essentially absent in the
normal plasma and must be supplied from an external source, the cascade of
enzymatic reactions triggered in the PT test is referred to as the “extrinsic
pathway.”
The term “partial thromboplastin” is derived
from the fact that this assay differs from the PT (which uses “complete
thromboplastin”) in that no tissue factor is used to initiate clotting.1,2,5
Instead, the reagent for the PTT simply includes a source of phospholipid. The
clinical chemists who developed the PTT gave the name “intrinsic pathway”
to the cascade of reactions triggered in the PTT test based on the mistaken
perception that coagulation that occurs in the PTT test is initiated without the
addition of any external factors. It is now understood that an external factor
is, in fact, involved in the initiation of the PTT clotting cascade.7
The intrinsic pathway is actually activated by plasma contact with the
negatively charged glass surface of the test tube. This “contact
activation” can be enhanced by adding particulate matter like silica,
kaolin, or ellagic acid into the test mixture in what we now refer to as an
“activated” partial thromboplastin time, or aPTT.
The enzymatic reactions of the extrinsic and intrinsic
pathways of coagulation are depicted in Figure 1. For many years clinical
scientists felt that these two pathways, corresponding to the PT and aPTT
laboratory tests respectively, represented unique physiologic mechanisms for the
initiation of normal coagulation.1,2,5 It turns out,
however, that while several steps of the intrinsic pathway are critical to
normal hemostasis, contact activation is not a physiologically relevant
mechanism for the initiation of normal coagulation. This became evident when it
was discovered that even severe deficiencies of the intrinsic pathway factors
(HMWK, prekallikrein, or factor XII) that will produce a markedly extended aPTT
in vitro will not cause bleeding
in vivo. It is now clear that extrinsic
activation by tissue factor is the primary initiator of normal coagulation.
Tissue factor forms a complex with activated VIIa that initiates the extrinsic
pathway. This leads to the formation of thrombin, which in turn activates factor
VIII. The tissue factor/factor VIIa complex also directly activates factor IX to
IXa. Together, activated factors VIIIa and IXa form the potent “tenase”
complex, effectively bypassing the contact activation pathway. Contact
activation is just a handy trick that allows the clinical chemist to assess the
functionality of several important intrinsic pathway factors in a test tube.
Contact activation can occur in vivo when
negatively charged surfaces, such as heart valve prostheses or vascular stents,
are installed in the blood stream.7
Gamma-carboxyl glutamate (gla) residues on factors II, VII,
IX, and X play a critical role in effective secondary hemostasis.1,4
These gla residues are formed by vitamin K-dependent enzymes and facilitate
calcium-dependent complex-binding to phospholipid membranes. This serves to
concentrate the catalytic activity at the point of injury and to prevent
thrombosis from spreading throughout the vasculature. These complexes consist of
a proteolytic enzyme associated with a catalytic cofactor that is anchored to a
negatively charged phospholipid surface by gla residues. Vitamin K deficiency or
inhibition of vitamin K-dependent enzymes by oral anticoagulants serves to block
the formation of gla residues and disrupt hemostasis. Since factor VII, an
extrinsic pathway factor, has the shortest half-life of the vitamin K-dependent
cofactors, the PT test is more sensitive to oral anticoagulant therapy or
vitamin K deficiency than the aPTT.5
It can be helpful to consider secondary hemostasis as a
process that occurs in two distinct phases.6 The
initiation phase, triggered by the release of tissue factor into the
bloodstream, results in the production of a relatively small amount of thrombin
through the extrinsic pathway. Once this first thrombin is produced, the
propagation phase of coagulation begins. Thrombin drives the conversion of
factors V and VIII to their activated forms. Activated factor VIII combines with
activated factor IX to produce the very powerful tenase complex. This complex
drives the accelerated production of thrombin in a cycle that feeds on itself in
an explosive manner. The second phase of coagulation rapidly becomes the
predominant mechanism of fibrin generation. In many ways, the two-phase process of coagulation can be
compared to the ignition and subsequent explosion of a stick of dynamite. The
first phase can be thought of as the slow-burning fuse that ignites the
explosion of the second phase. This mental construct can help one to understand
a fundamental limitation of one of the most common tests of coagulation: the
prothrombin time (PT). The minimal amount of thrombin generated through tissue
factor activation of the extrinsic pathway is adequate to produce quickly a
detectable clot in the PT assay. The amplified thrombin generation associated
with the second phase of coagulation is not required to produce a normal PT.
This explains the fact that deficiencies of intrinsic pathway factors VIII, IX,
and XI that produce the severe bleeding of hemophilia A, B, and C, respectively,
do not typically produce an extended PT. Effective physiologic coagulation
requires the second (explosive) phase of thrombin generation, but clot formation
in PT does not. PT is only sensitive to variations of components of the
extrinsic pathway: factors VII, X, V, II, and fibrinogen. A more complete review of the clinical relevance and
analytic testing for individual coagulation pathway factors can be found under
their individual test descriptions.
In many cases, a clinician must deal with an extended PT or
aPTT in a patient who is not receiving anticoagulant therapy. Often, the key to
identifying the cause of this laboratory finding is knowledge of the patient's
clinical history. These tests are commonly ordered as part of the diagnostic
work-up of a patient with a history of bleeding. This clinical situation is
significantly different from the patient with no history of bleeding who is
tested prior to surgery to rule out possible coagulation defects. The aPTT, or
the more sensitive aPTT-LA, can be ordered as part of an antiphospholipid
syndrome work-up of a patient with a history of thrombosis or recurrent
miscarriage. Three distinct test algorithms should be employed for these three
very different clinical situations.
In order to choose an optimal diagnostic algorithm, one
should understand the many potential causes of an abnormal screening test. In
the absence of prescribed anticoagulant therapy, prolongation of these tests
generally can be attributed to five common causes: (1) specimen collection and
transport issues, (2) medication, (3) pathologic conditions, (4) factor
inhibitors, and (5) mixing studies: distinguishing factor deficiency from
inhibitors.
A mixing study is used to study the cause of a prolonged
screening test. This study can determine if the cause is a deficiency of one or
more factors or an inhibitor.4 In a mixing study,
platelet-free, normal plasma that is replete with all coagulation factors (near
100% activity for each) is mixed with the patient's sample. For example, in a
1:1 mix, one part patient sample is mixed with one part normal plasma, and the
mixture is tested. In this case, the lowest possible concentration for any
individual factor in the mixture would be approximately 50% (in the case of a
patient with a factor concentration of zero and the normal pool has an activity
of 100%). The mixture is tested using the same test system that produced the
extended screening result. Some inhibitors are time- and/or
temperature-dependent. In these cases, the sample that is tested immediately
after mixing will correct, while results after the sample has been incubated for
1 hour at 37° will not correct. All plasma samples that correct upon
immediate mix are retested after an incubated mix to rule out time- and/or
temperature-dependent inhibitors.
Three different types of results can be observed in mixing
studies:
Venous thromboembolism (VTE) is responsible for more than
300,000 hospital admissions per year, and resultant pulmonary embolism is a
contributing factor in approximately 12% of deaths among hospitalized patients.13
Pulmonary embolus is the most common cause of death associated with childbirth
and is, overall, the third most common cause of death in the United States.14
The coagulation laboratory plays a central roll in determining the cause of VTE
and the risk of recurrence after an initial thrombotic event.
The risk factors associated with venous thromboembolism are
different from those associated with arterial thrombosis that cause heart
attack, stroke, and peripheral artery diseases.15 Venous
and arterial thromboses are distinct clinical entities that differ in the
microenvironment of clot formation and the structure of the clots formed.13
Because of their very distinct physiology, the tests used in the assessment of
these two conditions are different.13
Arterial Thrombosis
Venous Thrombosis
It is generally thought that most cases of venous
thrombosis result from the convergence of an acquired “precipitating”
condition (ie, a cause of blood stasis or vessel injury) with an underlying
genetic predisposition for hypercoagulability.15 For more
than a century clinicians have understood that the risk of venous thrombosis is
increased in individuals with any of three predisposing conditions –
referred to as Virchow's triad:16
Specific genetic defects should be suspected when a
thrombotic event has any of the following characteristics14,16,17:
Three general categories of test methodology are useful in
the assessment of congenital thrombotic conditions:
Genetic conditions associated with thrombophilia are listed
below in order of their relative frequency of occurrence.14,16,18
Table 1. Genetic Conditions Associated With Thrombosis
Genetic testing is useful for the diagnosis or confirmation
of MTHFR, factor V Leiden, and the prothrombin 20210 mutations. Regardless of
clinical status, genetic testing can be definitive because the patient's DNA
remains constant. Antigen and activity levels must be measured to diagnose the
other congenital thrombotic conditions. It is important to understand, however,
that the results of activity and antigen level tests can be affected by the
clinical state of the patient. In many clinical circumstances, such as those
listed below, tests for activity or antigen levels may produce misleading
results.16,18
Table 2. Clinical Conditions That Affect Tests for Congenital Thrombotic Risk
The incidence of venous thrombosis increases dramatically
with age. The rate of occurrences changes from approximately one per 100,000
individuals younger than 40 years of age to one per 1000 individuals older than
75.14 A number of acquired conditions that are associated
with an increased risk of thrombosis have been identified. They are listed in
Table 3.17
Antiphospholipid (APL) antibodies can be detected in as
many as 2% of unselected individuals,11 and they justify
special consideration. These antibodies are the most common acquired cause of
increased thrombotic risk.4,10,12,13,19,20,21 The term
“antiphospholipid antibody syndrome” (APS) refers to a spectrum of
clinical conditions that is associated with the presence of antiphospholipid
antibodies. Both clinical and laboratory features must be present for the
diagnosis of APS to be made.20,21,22 Any one or more of
the conditions discussed below can occur in patients with the antiphospholipid
antibody syndrome.
Antiphospholipid antibodies can be subclassified into
several clinical categories:
Note: Because it is not
possible to distinguish infection-induced antiphospholipid antibodies from
clinically significant antiphospholipid antibodies, all patients that test
positive for antiphospholipid antibodies should be retested after 6-8 weeks to
rule out transient antibodies.19
Antiphospholipid antibodies can be detected indirectly with
tests that are based on their effect on clot-based, in
vitro coagulation assays (ie, lupus anticoagulants) or directly by
solid-phase immunoassay.24 Due to the heterogeneity of
antibodies associated with APS, both clotting and solid-phase immunoassay
testing is recommend when APS is suspected.10,21
Lupus anticoagulants (LA) are antiphospholipid antibodies
that prolong phospholipid-dependent coagulation assays.4,10,19
Lupus anticoagulants derive their name from the fact that they were first
observed in patients with systemic lupus erythematosus (SLE); however, the vast
majority of individuals with lupus anticoagulants do not have SLE. These
antibodies were referred to as anticoagulants because they delay clotting in
in vitro clotting assays. It has
subsequently been shown that lupus anticoagulants are actually associated with
an increased clinical tendency toward thrombosis, not anticoagulation.4
While lupus anticoagulants are occasionally found in patients with arterial
thrombosis, they are much more frequently observed in patients with venous
thrombosis and/or resultant pulmonary embolism.12
In clot-based assays, lupus anticoagulants neutralize
anionic phospholipids that are involved in the coagulation cascade. Coagulation
screening assays such as the activated partial thromboplastin time (aPTT),
Russell viper venom time (RVVT), and prothrombin time (PT) can be affected by
lupus anticoagulants. The extent of clotting time prolongation is highly
dependent on the sensitivity of the reagent employed. Reagents with reduced
amounts of phospholipid, such as the aPTT-LA and dilute Russell viper venom time
(dRVVT), have enhanced sensitivity for lupus anticoagulants.10
The standard prothrombin time (PT) is rarely affected by lupus anticoagulants
because of the high concentration of phospholipid in the reagent thromboplastin.19
However, a dilute prothrombin time test can be used to detect some lupus
anticoagulants.25 Many lupus anticoagulants are discovered
as the result of routine screening with the standard aPTT test – despite
the fact that this reagent is not as sensitive for lupus anticoagulants as the
aPTT-LA reagent.4,13
Due to the heterogeneity of lupus anticoagulant antibodies,
no single assay identifies all cases.10 The International
Society on Thrombosis and Haemostasis (ISTH) has established criteria for the
diagnosis of lupus anticoagulants (see Figure 4).
The ISTH has defined the minimum diagnostic criteria for lupus anticoagulants to
include:10,19,20
Often the evaluation for lupus anticoagulants is confounded
by the acute phase response or anticoagulant therapy. This is particularly the
case when a patient is hospitalized and started on anticoagulant therapy before
samples for coagulation testing can be drawn. If the patient has a deep vein
thrombosis, many acute phase proteins such as fibrinogen, factor VIII, and
C4B-binding protein will be elevated and can affect coagulation assays.
The serendipitous detection of an extended aPTT during a
preoperative screen should trigger a thorough review of the patient's history.
Testing for antiphospholipid antibodies may not be indicated if the patient's
clinical history is not suggestive of APS.4,13,19
Alternatively, an extended aPTT may be detected in an individual who presents
with the clinical features consistent with APS. In this case solid-phase ELISA
tests for antiphospholipid antibodies should also be performed in order to
establish or exclude the diagnosis. If the lupus anticoagulants or
antiphospholipid antibody testing is positive, the testing should be repeated in
6-8 weeks to confirm the persistence of the antibody.
Very rarely, individuals with lupus anticoagulants will
present with an extended prothrombin time and significant clinical bleeding due
to a decreased concentration of prothrombin.4,10,13,19 It
is thought that the lupus anticoagulants in these individuals bind to
prothrombin and cause it to be removed from the circulation. In these cases,
lupus anticoagulants are not acting as inhibitors of prothrombin but are rather
“non-neutralizing” antibodies. This can cause confusion in the
assessment of lupus anticoagulants since mixing study results are consistent
with a factor deficiency and can be corrected with the addition of normal
plasma.4 Unlike most patients with lupus anticoagulants,
these patients will have an extended protime due to the prothrombin deficiency.
When the protime is extended in a patient with evidence of lupus anticoagulants,
antibodies to prothrombin should be considered in the differential diagnosis.
The first anticardiolipin antibody (ACA) tests were
developed in the early 1900s as a screening test for syphilis.20
The Venereal Disease Research Laboratory (VDRL) test is a manual agglutination
assay that detects antibodies to cardiolipin extracted from bovine heart tissue.
Mass screening studies with the VDRL revealed that this test was not specific
for syphilis. False-positive VDRL screening results were found to be
significantly associated with lupus anticoagulants and risk of thrombosis. The
first solid-phase immunoassays for antibodies to cardiolipin were developed in
the early 1980s. These assays, designed to detect anticardiolipin IgA, IgG, and
IgM isotypes, are approximately 100-fold more sensitive than the classical VDRL
assay.20 The presence of anticardiolipin antibodies
(especially those of moderate to high titer for IgG) is strongly associated with
both arterial and venous thrombosis and recurrent pregnancy loss.12,21,26
The IgM and IgA isotypes of anticardiolipin antibody have also been shown to be
associated with venous thrombosis.12,19,21 The
distribution of isotypes of anticardiolipin antibody-positive patients with
thrombosis has been found to be as follows:12
In general, anticardiolipin antibodies are considered to be
more sensitive than lupus anticoagulants for APS and are implicated in
approximately five times more cases.12,21
Lupus anticoagulants are more specific for APS than
anticardiolipin antibodies.12,23
While there is frequent concordance between lupus
anticoagulant and anticardiolipin antibody results, clinical situations occur in
which one is present in the absence of the other.20,23
Recently, an international consensus group of experts in
the diagnosis and management of antiphospholipid syndrome (APS) concluded that
β2 glycoprotein 1 (β2 GP-1) IgG and IgM antibodies should be included
as diagnostic criteria for APS.22 This group determined
that the presence of one or both of these antibodies is an independent risk
factor for thrombosis and pregnancy complications.22
The term “antiphospholipid” does not fully
describe the target of anticardiolipin antibody assays. A common aspect to all
assays for anticardiolipin antibodies is the requirement that the assay system
include a source of plasma proteins.21 In many cases,
antiphospholipid antibodies require the presence of specific proteins to
facilitate phospholipid binding.4,13,20 It has been
determined that, in many patients, the required plasma factor is β
Two Phases of Coagulation
086231 Factor II Activity
086249 Factor V Activity
800599 Factor VII Activity
086264 Factor VIII Activity
086298 Factor IX Activity
086306 Factor X Activity -
Clot Based
086314 Factor XI Activity
086322 Factor XII Activity
001610 Fibrinogen Activity
500436 Contact Factor
Evaluation Profile
500041 Extrinsic Pathway
Coagulation Factor Profile
500460 High Molecular Weight
Kininogen (HMWK)
500033 Intrinsic Pathway
Coagulation Factor Profile
500194 Prekallikrein (Fletcher
Factor) Assay
Causes of Abnormal Screening Results
Specimen Collection and Transport Issues
Medication
Pathologic Conditions
Factor Deficiencies
Factor Deficiency
Cases per Million Individuals1
Screening Tests
Specific Factor Level Test
Comments vWF
>100
von Willebrand Profile
084715
aPTT can sometimes be extended XII
aPTT
086322
It should be noted that factor XII deficiency is quite common but is not
associated with bleeding VIII
60-100
aPTT
086264
Affects males predominantly IX
10-20
aPTT
086298
Affects males predominantly XI
1
aPTT
086314
Fibrinogen
1
aPTT, PT
001610
II
<0.5
aPTT, PT
086231
V
<0.5
aPTT, PT
086249
VII
<0.5
PT
800599
X
<0.5
aPTT, PT
086306
XIII
<0.5
086330
Both PT and aPTT will be normal. Must test directly
1More
information about clinical aspects and testing for individual factor
deficiencies can be found under the individual test descriptions. Factor Inhibitors
117157 Factor VIII Inhibitor
Profile, Comprehensive
117892 Lupus Anticoagulant
With Reflex
117054 Lupus Anticoagulant
Comprehensive
Mixing Studies: Distinguishing Factor Deficiency From Inhibitors
Thrombophilia
Clinical Aspects of Pathologic Thrombosis
Genetic Causes of Venous Thrombosis
Genetic Condition
Testing Method
Test Number Methylenetetrahydrofolate
reductase (MTHFR) gene mutation
Screen: Homocysteine level
706994 Confirmation: MTHFR genetic testing
511238 Factor V Leiden mutation
Screen: Activated protein C resistance
117762 Confirmation: Genetic testing
511154 Prothrombin 20210
Genetic testing only
511162 Increased factor VIII1
Factor VIII activity
086264 Protein S deficiency
Protein S (activity, total/free antigen profile)
117754 Protein C deficiency
Protein C (activity and antigen profile)
080465 Antithrombin deficiency
Antithrombin (activity and antigen profile)
015594 Dysfibrinogenemia
Fibrinogen activity
001610 Fibrinogen antigen
117052 1While
factor VIII elevation is associated with a number of acquired conditions, some
individuals appear to have congenitally elevated factor VIII levels that are
associated with increased risk of thrombosis.14 Clinical Condition
Effect Heparin therapy or contamination
Decreases antithrombin Warfarin therapy/vitamin K deficiency
Decreases protein C and protein S Recent thrombosis or surgery
Decreases antithrombin, protein C, protein S DIC, liver disease, sepsis, L-asparaginase therapy
Decreases antithrombin, protein C, protein S Kidney disease/nephrotic syndrome
Decreases antithrombin and protein S Acute phase reaction, inflammation, infection
Decreases protein S Pregnancy or postpartum period
Decreases protein S and APCR Oral contraceptives or estrogen replacement
Decreases antithrombin and protein S Lupus anticoagulants (LA)
Decreases APCR, protein S, and factor VIII Vitamin B
Increases homocysteine Acquired Causes of Venous Thrombosis
Antiphospholipid antibodies (see below)
Malignancy Atrial fibrillation
Myeloproliferative disorders Congestive heart failure
Nephrotic syndrome Diabetes mellitus
Oral contraceptive therapy Estrogen therapy
Paroxysmal nocturnal hemoglobinuria Heparin-induced thrombocytopenia
Postoperative state Hypertension
Pregnancy Hyperviscosity
Thrombotic thrombocytopenic purpura Immobilization
Trauma Antiphospholipid Antibody Syndrome
Represent the majority of cases
Twice as common in women as men11,19
Occur in individuals who are otherwise healthy with no predisposing
conditions
Often characterized by antibodies to just one phospholipid or protein12
Associated with systemic lupus erythematosus (SLE), other autoimmune
disorders, malignancies
A variety of therapeutic drugs can induce the production of
antiphospholipid antibodies
calcium channel blockers
chlorpromazine
hydralazine
hydantoin
isoniazidmethyldopa
phenytoin
phenothiazine
procainamidequinine
quinidine
thorazine
various
antibiotics
Often observed during the
convalescent phase of acute bacterial and viral infections
Often observed in individuals with syphilis
Generally not associated with an increased risk of clinical
complications
Usually transient Lupus Anticoagulants
Anticardiolipin Antibodies
IgG
36% IgM
17% IgA
14% Multiple
33% β
Footnotes
1. Brandt JT, “Overview of Hemostasis,”
McClatchey KD, ed, Clinical Laboratory Medicine,
2nd ed, Baltimore, MD: Lippincott Williams and Wilkins, 2002, 987-1009.
2. Liu MC and Kessler CM, “A Systemic Approach
to the Bleeding Patient,” Kitchens CS, Alving BM, and Kessler CM, eds,
Consultative Hemostasis and Thrombosis,
Philadelphia, PA: WB Saunders, 2002, 181-96.
3. Kottke-Marchant K and Corcoran G, “The
Laboratory Diagnosis of Platelet Disorders,”
Arch Pathol Lab Med, 2002, 126(2):133-46.
4. Triplett DA, “Coagulation Abnormalities,”
McClatchey KD, ed, Clinical Laboratory Medicine,
2nd ed, Baltimore, MD: Lippincott Williams and Wilkins, 2002, 1033-49.
5. Van Cott EM and Laposata M,
“Coagulation,” Jacobs DS, Oxley DK, and DeMott WR, eds,
Laboratory Test Handbook, Hudson, OH:
Lexi-Comp, 2001, 327-58.
6. Mann KG, Brummel K, and Butenas S, “What Is
All That Thrombin For?” J Thromb Haemost,
2003, 1(7):1504-14.
7. Adcock DM, Jensen R, Johns CS, et al,
Coagulation Handbook, Austin, TX: Esoterix
Coagluation, 2002.
8. Adcock DM, Kressin DC, and Marlar RA,
“Effect of 3.2% vs 3.8% Sodium Citrate Concentration on Routine
Coagulation Testing,” Am J Clin Pathol,
1997, 107(1):105-10.
9. Reneke J, Etzell J, Leslie S, et al,
“Prolonged Prothrombin Time and Activated Partial Thromboplastin Time Due
to Underfilled Specimen Tubes With 109 mmol/L (3.2%) Citrate Anticoagulant,”
Am J Clin Pathol, 1998, 109(6):754-7.
10. Brandt JT, Triplett DA, Alving B, et al,
“Criteria for the Diagnosis of Lupus Anticoagulants: An Update. On Behalf
of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the
Scientific and Standardization Committee of the ISTH,”
Thromb Haemost, 1995, 74(4):1185-90.
11. Jenson R, “The Antiphospholipid Antibody
Syndrome,” Clin Hemost Rev, 2001,
15(11):1-4.
12. Bick RL, “Antiphospholipid Thrombosis
Syndromes,” Clin Appl Thromb Hemost,
2001, 7(4):241-58.
13. Hirsh J, Anand SS, Halperin JL, et al, “Guide
to Anticoagulant Therapy. Heparin: A Statement for Healthcare Professionals
From the American Heart Association,”
Circulation, 2001, 103(24):2994-3018.
14. Adcock DM, “Laboratory Evaluation of Venous
Thrombosis Risk,” Clin Hemost Rev,
2003, 17(12):1,2,5,6,8.
15. Schafer AI, Levine MN, Konkle BA, et al,
“Thrombotic Disorders: Diagnosis and Treatment,”
Hematology (Am Soc Hematol Educ Program),
2003:520-39.
16. Marques MB, “Testing for Genetic
Predisposition to Venous Thrombosis,”
MLO, 2002, 34(1):8-13.
17. Marlar RA and Adcock DM, “The Multifactorial
Threshold Model of Thrombotic Risk,”
Clin Hemost Rev, 2003, 17(6):1,2,4-6.
18. Triplett DA, “Thrombophilia,”
McClatchey KD, ed, Clinical Laboratory Medicine,
2nd ed, Baltimore, MD: Lippincott Williams and Wilkins, 2002, 1033-49.
19. Alving BM, “The Antiphospholipid Syndrome:
Clinical Presentation, Diagnosis, and Patient Management,” Kitchens CS,
Alving BM, and Kessler CM, eds, Consultative
Hemostasis and Thrombosis, Philadelphia, PA: WB Saunders, 2002,
181-96.
20. Levine JS, Branch DW, and Rauch J, “The
Antiphospholipid Syndrome,” N Engl J Med,
2002, 346(10):752-63.
21. Carreras LO, Forastiero RR, and Martinuzzo ME,
“Which Are the Best Biological Markers of the Antiphospholipid Syndrome?”
J Autoimmun, 2000, 15(2):163-72.
22. Miyakis S, Lockshin MD, Atsumi T, et al,
“International Consensus Statement on an Update of the Classification
Criteria for Definite Antiphospholipid Syndrome (APS),”
J Thromb Haemost, 2006, 4(2):295-306..
23. Harris EN, Pierangeli SS, and Gharavi AE,
“Diagnosis of the Antiphospholipid Syndrome: A Proposal for Use of
Laboratory Tests,” Lupus, 1998,
7(Suppl 2):S144-8.
24. Schjetlein R and Wisloff F, “An Evaluation of
Two Commercial Test Procedures for the Detection of Lupus Anticoagulant,”
Am J Clin Pathol, 1995, 103(1):108-11.
25. Liestol S, Jacobsen EM, and Wisloff F,
“Dilute Prothrombin TIme-Based Lupus Ratio Test. Integrated LA Testing
With Recombinant Tissue Thromboplastin,”
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