Clinical Chemistry 46: 1260-1269, 2000;
(Clinical Chemistry. 2000;46:1260-1269.)
© 2000 American Association for Clinical Chemistry, Inc.
Coagulation and Bleeding Disorders: Review and Update
Douglas A. Triplett1
1
Indiana University School of Medicine and Midwest Hemostasis and Thrombosis Laboratories, Ball Memorial Hospital, Muncie, IN 47303.
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Abstract
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Hemostasis is initiated by injury to the vascular wall, leading to the
deposition of platelets adhering to components of the subendothelium.
Platelet adhesion requires the presence of von Willebrand factor and
platelet receptors (IIb/IIIa and Ib/IX). Additional platelets are
recruited to the site of injury by release of platelet granular
contents, including ADP. The "platelet plug" is stabilized
by interaction with fibrinogen. In this review, I consider laboratory
tests used to evaluate coagulation, including prothrombin time,
activated partial thromboplastin time, thrombin time, and
platelet count. I discuss hereditary disorders of platelets and/or
coagulation proteins that lead to clinical bleeding as well as acquired
disorders, including disseminated intravascular coagulation and
acquired circulating anticoagulants.
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Primary Hemostasis
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Platelets are anuclear cellular fragments derived from bone marrow
megakaryocytes. They have a complex internal structure, which reflects
their hemostatic functions (1)(2). Two major
intracellular granules are present, the 
granules and dense bodies
(Fig. 1
) The granules contain platelet thrombospondin, fibrinogen,
fibronectin, platelet factor 4, von Willebrand factor
(VWF),1
platelet-derived growth factor,
ß-thromboglobulin, and coagulation factors V and VIII. The
dense granules contain ADP, ATP, and serotonin
(5-hydroxytryptamine). When platelets are stimulated, both the
granules and dense bodies are released through the open canalicular
system.
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Figure 1. Schematic of electron micrograph of equatorial section of
platelet.
SCCS, open canalicular system; M,
mitochondria; DTS, dense tubular system;
Gly, glycogen. Reprinted with permission from
White JG, Gerrard JM. Ultrastructural features of abnormal platelets. A
review. Am J Pathol 1976;83:589–632.
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Platelets and endothelial cells have biochemical pathways involving the
metabolism of arachidonic acid (AA; Fig. 2
) (3)(4)(5). AA is released from membrane phospholipids by
phospholipase A2. Subsequently, cyclooxygenase
converts AA to cyclic endoperoxides (6). The endoperoxides
are then converted by thromboxane synthetase to thromboxane
A2. Thromboxane A2 is a
potent agonist that induces platelet aggregation (7).
Endothelial cells also contain an AA pathway. However, endothelial
cells preferentially convert cyclic endoperoxides to
prostacyclin (8), which is a potent inhibitor of
platelet aggregation.
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Figure 2. AA pathway.
Platelets and endothelial cells contain pathways for metabolism of AA.
When platelets or endothelial cells are activated, an enzyme,
phospholipase A2, is activated, liberating AA. AA is then
converted to thromboxane A2 by cyclooxygenase and
thromboxane synthetase. Thromboxane A2 is a potent
activator of platelets, leading to platelet aggregation (Plt
Aggreg). In the endothelial cells, prostacyclin synthetase
converts cyclic endoperoxides to prostacyclin
(PGI2). Prostacyclin inhibits platelet
aggregation. Aspirin (ASA) inhibits cyclooxygenase. Modified
from Pallister C. Blood, physiology and pathophysiology.
Butterworth-Heinemann Ltd., 1994:452.
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Primary hemostasis is a process whereby platelets interact with
elements of the damaged vessel wall, leading to the initial formation
of a "platelet plug". The platelet/injured vessel wall interaction
involves a series of events that includes platelet adhesion to
components of the subendothelium, activation and shape change, release
of platelet granular contents (dense bodies and granules) with
subsequent formation of fibrin-stabilized platelet aggregates, and clot
retraction (8). In this process, the activation of platelets
with exposure of negatively charged phospholipids (e.g.,
phosphatidylserine and phosphatidic acid) facilitates the
assembly of coagulation factors on the activated platelet membrane,
leading to generation of thrombin and subsequent fibrin deposition. The
platelet plug and fibrin are analogous to the cork in a bottle of
champagne that is stabilized by a wire mesh.
Platelet adhesion is accentuated by increased shear rate. For platelets
to adhere to a damaged vascular surface, both fibrinogen and VWF are
necessary (8). The platelet glycoprotein (GP) receptor
(Ib/IX and V) is the principal receptor for VWF (9).
VWF also binds to GP IIb-IIIa, which is expressed when platelets are
activated. Both fibrinogen and VWF interact with GP IIb-IIIa. In
addition to VWF, other proteins (laminin, thrombospondin, and
vitronectin) may be involved in platelet adhesion.
Platelet activation results from exposure of the platelet to damaged
endothelium or underlying components of the vessel wall
(8)(9). Other biological agonists are involved
in platelet activation, including thrombin, epinephrine, ADP, and
thromboxane A2. With activation, platelets
transform from a disk to a "spiny sphere" with long pseudopodia.
The initial generation of trace amounts of thrombin leads to
amplification of the coagulation response. Thrombin activates factor XI
in the contact system and coagulation cofactors V and VIII
(10). The initial formation of fibrin at the site of
vascular injury is unstable. Factor XIII (fibrin-stabilizing factor) is
activated by thrombin, causing cross-linking of fibrin strands and
stabilization of the fibrin/platelet plug.
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Hereditary and Acquired Disorders of Platelet Function
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Abnormalities of platelet function are characterized by clinical
bleeding of varying severity. In most cases, patients present with
mucocutaneous bleeding or excessive hemorrhage following surgery or
trauma. A platelet count and careful examination of the peripheral
smear is essential in the initial evaluation of patients with
mucocutaneous bleeding. When examining the peripheral smear, it is
important to evaluate the relative size of platelets. Large platelets
may be seen as a result of accelerated marrow production of platelets
attributable to a hemorrhagic event or recovery from bone marrow
suppression as a result of infections or drugs. Large platelets are
also encountered in the setting of patients with accelerated platelet
turnover (idiopathic thrombocytopenic purpura) (11).
The bleeding time (BT) test has also been widely utilized as a means of
accessing primary hemostatic response (platelet-injured vessel wall
interaction) (12). Unfortunately, the BT is relatively
insensitive and, in many cases, nonspecific with respect to identifying
abnormalities of primary hemostasis (13). The major
variables are the inherent differences between individuals performing
the BT and the various BT devices. The introduction of BT devices
designed to decrease the variability of the depth of the induced wound
was a major advance over the traditional Ivy BT test
(12)(13). Despite the introduction of the newer
devices, there remains substantial variability between individuals
performing BTs as well as the possible complication of scar formation
at the test site (typically, the anterior-lateral aspect of the arm).
There are several variables in the BT in addition to the technical
aspects of performing the test. BTs tend to be longer in females and
decrease with aging. One cosmetic complication frequently seen in
elderly patients who have experienced extensive sun exposure is the
formation of a somewhat symmetrical subepidermal hemorrhage, which is
attributable to blood dissecting into the subepidermis as opposed to
exiting onto the surface of the skin at the site of the BT incision.
The BT is also affected by the hematocrit and platelet mass. Patients
with chronic renal disease and decreased hematocrit often have a
prolonged BT (14)(15). Increasing the hematocrit
to >30% often will correct a prolonged BT in a patient with chronic
renal disease (16). Abnormalities of connective tissue
(e.g., Ehlers-Danlos syndrome) may produce abnormal BTs
(17).
The BT together with the Rumpel-Leede test were the first attempts to
evaluate platelet/vascular response to injury (18). The
Rumpel-Leede test involved inflating a blood pressure cuff midway
between systolic and diastolic pressure and leaving the cuff on for a
period of time, which was variable depending on the patient’s
tolerance for the procedure. The arm distal to the blood pressure cuff
was evaluated for the presence of petechiae.
Platelet aggregation is an important component of laboratory testing in
a patient with clinical findings suggestive of a primary hemostatic
abnormality (19)(20). The addition of an agonist
(e.g., ADP, epinephrine, or collagen) to normal platelet-rich plasma
produces an aggregation pattern characterized by a biphasic response
when epinephrine is used as the agonist. The primary wave results from
the addition of exogenous epinephrine, and the secondary wave reflects
the "release reaction" of the dense bodies. With release, granular
components are excreted through the open canalicular system.
Abnormalities of the release reaction may be seen in patients with
storage pool disease (characterized by loss of platelet nucleotides and
serotonin from the dense granules; Table 1
) (21). Dense body storage pool abnormalities have been
described in Hermansky-Pudlak, Chédiak-Higashi, and
Wiskott-Aldrich syndromes and thrombocytopenia with absent
radii (22)(23)(24)(25)(26). Patients with afibrinogenemia or
Glanzmann thrombasthenia (abnormalities of the GP IIb-IIIa
receptor) lack both primary and secondary responses to various platelet
agonists (27). Glanzmann thrombasthenia is an autosomal
recessive defect that frequently is encountered in patient populations
in which there is a high incidence of consanguinity.
There are numerous reports of patients with selectively impaired
aggregation response to various platelet agonists (28). Lack
of response to epinephrine has been reported in patients with decreased
2 adrenergic receptors (29).
Isolated collagen receptor defects have been reported (decreased
platelet GP Ia) (30). It is important to appreciate the
variability one may see in platelet aggregation studies. Often a lack
of a secondary response is attributable to drugs (classically aspirin)
that inhibit cyclooxygenase. The pharmaceutical industry is intensively
developing various inhibitors of ADP receptors (ticlopidine and
clopidogrel) and IIb-IIIa receptors (Table 2
and Fig. 3
) (31).
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Figure 3. Targets for platelet inhibitors.
The activation of platelets occurs when platelets adhere to
subendothelial components of the vessel wall. After adhesion, release
of platelet granular contents leads to platelet aggregation. Various
drugs have been used to inhibit platelet activation. Ticlopidine and
clopidogrel inhibit the ADP-induced activation pathway. Aspirin
irreversibly blocks cyclooxygenase enzyme (Cox-1). This
prevents the generation thromboxane A2
(TXA2), which is a potent activator of platelets.
Various inhibitors of GP IIb/IIIa complex prevent platelet aggregation.
Among the inhibitory drugs that have been developed recently are
Abciximab (c7E3 Fab fragments), Eptifibatide (a cyclic peptide), and
two peptidomimetics (lamifiban and tirofiban). Oral inhibitors include
xemilofiban, DMP 802, and SR 121787. These three drugs are oral
inhibitors of platelet function. Reprinted with permission
from Nurden AJ, Poujol C, Darrieu-Jacs C, Nurden P. Platelet
glycoprotein IIb/IIIa inhibitors. Basic and clinical aspects.
Arterioscler Thromb Vasc Biol 1999;19:2835–40.
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Other tests that have been used in evaluating platelet function include
the prothrombin consumption test (a test to evaluate the platelet
contribution of activated phospholipids), flow cytometry to quantify
surface GPs, receptor occupancy, and electron microscopy for evaluating
ultrastructural anatomy (32)(33)(34)(35).
Several recently developed instruments have been designed to assess the
global platelet response. Examples include
Xylum®, PFA-100®
(Dade-Behring), and test systems marketed by Array and Medtronics
(36)(37)(38)(39). The Xylum and PFA-100 represent
instruments that attempt to simulate the in vivo response of platelets
to vascular injury (40). In the case of the PFA-100, two
collagen-impregnated membranes, one with ADP and the other with
epinephrine, are used to evaluate the platelet response
(40). The patient’s citrated blood sample is aspirated
under high shear rates (5000–6000 dyn/cm2) through
a 150-µm diameter aperture in the center of a collagen-impregnated
membrane. The endpoint is obtained when the flow of blood ceases. This
test system is extremely sensitive to the presence of aspirin
(epinephrine abnormal/ADP normal). The PFA-100 may be used to monitor
antiplatelet drug therapy. Other new instruments under development
offer promise in the monitoring of patients who are increasingly
exposed to a greater variety of platelet antagonists (41).
The PFA-100 has been used to screen patients for von Willebrand disease
(VWD) and has been very effective in identifying these patients
(42).
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Therapeutic Options in Management of Platelet Disorders
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Increasingly, desmopressin (DDAVP) is being used to manage
patients with abnormalities of primary hemostasis, e.g., VWD, patients
exposed to aspirin, and cirrhotic patients with bleeding complications
(43). DDAVP triggers the release of VWF from Weibel-Palade
bodies of vascular endothelium. DDAVP has also been used in the
management of patients with mild to moderate hemophilia A (deficiencies
of factor VIII) (44).
Recombinant human erythropoietin has been used to manage bleeding in
uremic patients (45). In cases of severe thrombocytopenia or
iatrogenic inhibition of platelet function, the use of platelet
concentrates is indicated.
In renal failure patients with hemorrhagic complications, correction of
the hematocrit to >30% often will alleviate bleeding problems
(45)(46). The red cell mass is instrumental in
"marginating" platelets to the endothelial-blood interface. The
proximity of platelets to endothelium facilitates the primary
hemostatic response after vascular injury.
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Coagulation Factors: Formation of Fibrin Clot
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Fibrin is critical in stabilizing the initial platelet
plug. The formation of fibrin involves several enzymatic steps
culminating in the generation of thrombin, which converts fibrinogen to
fibrin. Fig. 4
represents a simplified coagulation cascade incorporating the intrinsic
and extrinsic pathways (47). The coagulation proteins may be
classified into three groups: fibrinogen family, vitamin K-dependent
proteins, and the contact family (Table 3
). The fibrinogen family of proteins includes fibrinogen, factor V,
factor VIII, and factor XIII. This family of proteins has relatively
large molecular weights, and its members are substrates for thrombin.
The formation of a stable fibrin clot is dependent on the ability of
thrombin to convert fibrinogen to fibrin and simultaneously activate
factor XIII to XIIIa, which stabilizes
the fibrin clot. The initiation of coagulation begins with exposure of
tissue factor (TF) to the circulating blood (48). TF binds
factor VII, producing a TF-VIIa complex. The
TF-VIIa complex triggers the final common pathway
by converting factor X to factor Xa in the
presence of factor VIII. In addition, TF-VIIa
activates factor IX to IXa. This dual activation
mediated by TF-VIIa explains the initiation of
coagulation following tissue damage. Once trace amounts of thrombin are
generated, there is marked amplification through thrombin feedback to
activate factors V, VIII, and XI.
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Figure 4. Simplified coagulation cascade.
HMWK, high molecular weight kininogen;
Kal, kallikrein; PL, phospholipid;
Ca++, ionic calcium; subscript
a denotes the activated form of the coagulation factors (e.g.,
factor XIIa, factor VIIa). The initiation of
coagulation involves two separate pathways: intrinsic and extrinsic.
Physiologically, the extrinsic pathway, which is initiated by tissue
damage and exposure of tissue factor, is the most important pathway to
initiate the hemostatic response. Tissue factor forms a complex with
factor VIIa, leading to activation of the final common
pathway at factor X. The extrinsic pathway is evaluated in vitro by PT.
The intrinsic pathway involves exposure of factor XII to activated
cellular surfaces or subendothelium. Activation of factor XII (Hageman
factor) initiates the intrinsic pathway.
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The enzymatic reactions involved in the generation of thrombin
occur on the surface of damaged cells (e.g., endothelial cells,
monocytes, platelets, and tumor cells) (49). With
activation of platelets, phosphatidylserine is mobilized from the inner
leaflet of the platelet membrane and exposed on the external surface
(50). Table 4
summarizes the key procoagulant complexes necessary for normal
coagulation. A cofactor for the activation of factor IX by factor
XIa has not been identified. The
TF-VIIa complex is capable of activating both
factors IX and X.
There are physiologic inhibitors in plasma that serve to localize
procoagulant activity to the site of injury and maintain hemostatic
balance (Table 5
). Antithrombin (known as antithrombin III in old terminology) is the
principle inhibitor of thrombin, factor Xa, and
the other serine proteases (Table 6
) (51). Antithrombin serves as a "pseudosubstrate" for
thrombin and "traps" thrombin in an antithrombin-thrombin complex,
which is cleared from the circulation (52). In the presence
of heparin, there is marked acceleration of the antithrombin-thrombin
interaction, leading to anticoagulation of the patient. Heparin
cofactor II is also an inhibitor of thrombin. Heparin cofactor
II inhibition is accentuated by dermatan sulfate
(53)(54). Other members of the serpin (serine
protease inhibitors) family inhibit thrombin but to a substantially
lesser degree than antithrombin.
Thrombin also binds to an endothelial receptor, thrombomodulin. As the
name implies, thrombomodulin binds thrombin with resulting loss of
thrombin’s procoagulant activities (ability to convert fibrinogen to
fibrin, activation of platelets, and factors V, VIII, XI, and XIII). As
a result of binding to thrombomodulin, the thrombin-thrombomodulin
complex activates protein C to activated protein C (APC)
(55). The protein C/protein S pathway is one of the most
important regulatory systems. Once protein C is converted to APC, it
becomes an inhibitor of coagulation (56). This inhibition is
mediated by the inactivation of activated factors VIII and V (Fig. 5
). Protein S, a vitamin K-dependent protein, is an important cofactor
for this reaction. The formation of anticoagulant complexes is
analogous to procoagulant complexes described above (Table 7
).
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Figure 5. Down-regulation of activated factors V and VIII by protein
C/protein S system.
Protein C (PC) and protein S (PS) are
vitamin K-dependent proteins that participate in the down-regulation of
hemostasis. When thrombin is generated in vivo, it converts fibrinogen
to fibrin. In addition, thrombin may also bind to an endothelial
receptor, thrombomodulin (TM). As the name implies, once
thrombin binds to thrombomodulin, it loses it procoagulant activity and
actively participates in the protein C/protein S anticoagulant pathway.
Thrombin-thrombomodulin converts protein C to APC. APC in the presence
of protein S (a cofactor) will inactivate the activated forms of
factors V and VIII, thus inhibiting the generation of thrombin.
Patients who have hereditary deficiencies of protein C and protein S
are predisposed to venous thromboembolic events.
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Laboratory Evaluation of Coagulation Pathways
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The laboratory tests for evaluation of platelet function have been
discussed above. Evaluation of the coagulation pathways relies on four
relative simple tests: the activated partial thromboplastin time
(APTT), prothrombin time (PT), thrombin time (TT), and fibrinogen
assays (57)(58)(59)(60)(61). In addition, the availability of a test to
monitor D-dimer is of considerable value. D-Dimer is increased in
fibrinolysis; in addition, it is used as a negative predictor to rule
out deep vein thrombosis (62). Laboratories must carefully
select the correct test (sensitivity) and apply this test in an
appropriate clinical situation.
The APTT is a test that evaluates the intrinsic pathway of coagulation.
The APTT reagents comprise an activator (e.g., ellagic acid, celite, or
kaolin) and phospholipids. The phospholipids may be either synthetic or
derived from animal tissue (e.g., rabbit brain). With the exception of
factors VII and XIII, the APTT evaluates all of the coagulation
factors. The most common cause of a prolonged APTT is incorrect
collection of the blood sample. Most frequently, this is attributable
to obtaining blood through an indwelling line that has been flushed
with heparin. In addition, a traumatic venipuncture may produce an
abnormal APTT. A polycythemic blood sample may yield an abnormal APTT
because of the excess amount of citrate available to chelate calcium in
a polycythemic blood sample. Other causes of a prolonged APTT include
factor deficiencies [VWD, hemophilia A (factor VIII deficiency), and
hemophilia B (factor IX deficiency)] and the presence of circulating
anticoagulants (also known as inhibitors). The most common circulating
anticoagulant is the lupus anticoagulant (LA)
(63)(64). Antibodies to factor VIII are also
encountered in both hemophilia A patients and adults who occasionally
have an acquired autoantibody against factor VIII
(65)(66). Hereditary and acquired factor
deficiencies often produce an abnormal APTT. Most reagent manufacturers
provide reagents that will yield an abnormal APTT when the
concentration of factor VIII is <30–35% (0.30–0.35
kilounits/L). However, there is substantial variability between
reagents. There may also be lot-to-lot variability of APTT reagents
from the same manufacturer. Therefore, it is imperative when any aspect
of the "system" (e.g., reagent-instrument combination or collection
tubes) is changed to recalculate the reference interval and the
relative sensitivity of the system to factor deficiencies and heparin.
The PT is the most commonly performed test of hemostasis. The PT
evaluates the extrinsic pathway of coagulation (factors VII, X, V, II,
and fibrinogen). The PT is used to monitor patients on oral
anticoagulant therapy. With the recent introduction of sensitive PT
reagents, the use of the international normalized ratio has become the
standard reporting format for PT results (67). Patients
receiving oral anticoagulant therapy in most cases have a targeted
therapeutic range of an international normalized ratio of 2.0–3.0
(68). There are exceptions, including mechanical valves,
patients who re-thrombose when in the therapeutic range of 2.0–3.0,
and patients with anti-phospholipid antibody syndrome. The PT may be
prolonged in patients with disseminated intravascular
coagulation, liver disease, or vitamin K deficiency.
The TT is a simple test. Thrombin (bovine or human) is added to
citrated plasma. There are two variations of the TT: one uses calcium
and the other does not. In individuals with fibrinogens <1000
mg/L, the TT will be prolonged. Other causes of a prolonged TT
include the presence of heparin in a blood sample, dysfibrinogenemias,
antibodies to thrombin, and gammopathies (e.g., multiple myeloma and
Waldenström macroglobulinemia).
A functional assay for fibrinogen is part of the initial analysis of
patients with bleeding disorders. Often, the TT is not prolonged in
patients with hypofibrinogenemia until it is <1000 mg/L. A discrepancy
between the functional assay and antigenic assay is encountered in
patients with dysfibrinogenemia (69).
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Hereditary Disorders of Coagulation Proteins
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VWD is the most common inherited disorder of hemostasis
(70). The incidence of VWD in the population is ~1%. It
is found in all ethnic groups, and in many cases, patients remain
undiagnosed. VWD is an autosomal dominant disorder affecting both males
and females (71)(72). Before puberty, easy
bruising and epistaxis are the most frequently encountered clinical
presentations. At the time of puberty, the frequency of epistaxis tends
to decrease. In affected females, the chief complaint becomes one of
menorrhagia (73). It is estimated that ~10% of
hysterectomies performed in the United States are the result of
underlying occult VWD (71). With appropriate diagnosis and
patient management, many unnecessary surgeries could be eliminated.
The diagnosis of VWD requires a careful patient/family history. Many
patients with VWD are first diagnosed following an accident/trauma or
surgery. Prolonged bleeding following surgery is often encountered in
VWD patients (71)(72). However, the laboratory
diagnosis may be very difficult because of the "fluctuation" of VWF
in the patient’s plasma. VWF responds to stress similar to other acute
phase proteins, e.g., fibrinogen, fibronectin, and vitronectin
(72). Therefore, it is not appropriate to test the patient
for VWD in the setting of acute bleeding or stress.
VWF is synthesized in endothelial cells and megakaryocytes. In the
endothelial cells, it is stored in the Weibel-Palade bodies with a
range of molecular masses from 0.5 to >20 million Da
(72). VWF is also found in the granules of platelets.
VWF will bind to collagen, particularly in situations of high shear
stress. In addition, as discussed above, VWF will bind platelet
receptors GP IIb/IIIa and GP Ib/IX/V. Many variants of VWD have been
described. These include both qualitative and quantitative
abnormalities as well as combinations of both defects. Table 8
summarizes the current classification of VWD (72).
Laboratory testing includes a BT or other means of analyzing platelet
function. Recent reports utilizing the PFA-100 suggest that this system
or similar new platelet analyzers are preferable to the classical BT
(42). Not infrequently, one may encounter variability of the
APTT in patients with VWD.
Tests to classify VWD include quantification of VWF. Initially, this
was determined by Laurell rocket immunoelectrophoresis. More recently,
ELISA assays as well as flow cytometry have been used with a greater
degree of sensitivity. The ristocetin cofactor is a test to assess VWF
activity. Ristocetin-induced platelet agglutination is the most widely
used procedure (74)(75). However, there are
recent reports on the use of antibodies to the collagen binding site as
a means of testing for VWF function. This assay system uses an ELISA
format (76). A factor VIII:C (coagulant activity) assay is
also a part of the evaluation for VWD. Multimeric analysis of VWF by
agarose gel electrophoresis is very helpful in identifying variants of
VWD (74). In many cases, this assay is not readily
available. There are several reference centers nationwide that have
substantial expertise in multimeric analysis of VWF.
Management of clinical bleeding in patients with VWD in many cases is
relatively simple (70)(72). DDAVP is used to
manage epistaxis and provide prophylaxis for minor surgery. Blood
product replacement therapy in the past relied primarily on
cryoprecipitate. However, because of the risk of infection (e.g.,
hepatitis and HIV), the recommended replacement therapy of choice is
Humate-P® or other factor VIII concentrates with
significant amounts of VWF (74). There is a VWF concentrate
available in France. Other therapeutic modalities include
-aminocaproic acid (Amicar®) and tranexamic
acid in the management of mucous membrane bleeding. Estrogens are also
helpful in the management of VWD-related menorrhagia.
Acquired VWD may be seen in a variety of settings, including
immunologic disorders, hypothyroidism, cardiac defects, and uremia
(77).
hemophilia (factor viii, ix, xi deficiencies)
Hemophilia A is the oldest recognized hereditary bleeding disorder
(78). It is sex-linked in transmission. The gene for
hemophilia A is located on the long arm of the X chromosome. The gene
spans 186 kb of DNA, and many mutations have been described. The
inversion mutation accounts for 25% of mutations in hemophilia A
patients. Fifty percent of patients with severe hemophilia A (<1%
activity) carry the inversion mutation (79). There are
several different variants of this mutation: type I distal (a3), type
II proximal (a2), and type III. Hemophilia A is classified based on the
amount of factor VIII activity. Patients with severe hemophilia A
(<1% factor VIII activity) have joint bleeding with resulting
hemarthroses as well as deep intramuscular bleeding. One of the major
complications seen in the recent past was transmission of HIV in
replacement blood products (factor VIII concentrates and
cryoprecipitate). As a result, in the early 1980s, a large portion of
the hemophilic population developed HIV positivity and AIDS. The recent
introduction of recombinant factor VIII replacement therapy has
immensely improved the management of hemophilia patients
(80). One complication of replacement therapy, however,
continues to present a challenge: the development of factor VIII
inhibitors in a large percentage of severe hemophilia A patients. In
these patients, replacement therapy or management of an acute bleed
presents a challenge. Porcine factor VIII and activated factor VII are
new products for this type of patient, and prothrombin complex
concentrates (Autoplex® and Feiba) are used
(79).
Hereditary factor IX deficiency (hemophilia B) and hereditary factor XI
deficiency (hemophilia C) are relatively common hereditary hemostatic
disorders. Factor IX deficiency is very heterogeneous. Factor XI
deficiency is primarily encountered in the Jewish population.
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Circulating Anticoagulants (Inhibitors)
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The most common acquired inhibitor of coagulation is the LA
(81). LA is a member of the anti-phospholipid antibody (APA)
family. When evaluating patients for potential APAs, it is necessary to
do both coagulation testing to identify LA as well as ELISA assays to
identify "anti-cardiolipin antibodies" and antibodies to
ß2-glycoprotein I (82). APAs
may be seen in many patient populations, e.g., after infection and in
patients with autoimmune disease (63). Most APAs
seen in the setting of infections have no clinical complications.
However, a large percentage of APA patients with underlying autoimmune
disease present with thrombotic complications involving both the
arterial and venous circulation, as well as recurrent fetal
loss/spontaneous abortion in women. APA syndrome is diagnosed based on
the presence of clinical complications (e.g., thrombosis or recurrent
spontaneous abortion) and positive laboratory testing for LA and/or
anti-cardiolipin antibodies.
The laboratory diagnosis of LA requires a well-coordinated work-up
using three screening procedures as recommended by the Scientific
Subcommittee of the International Society of Thrombosis and Hemeostasis
(83). The three most commonly used tests are a LA-sensitive
APTT reagent, Staclot LA®, and a dilute Russell
viper venom time. More recently, the dilute PT has been used.
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Footnotes
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Address for correspondence: Ball Memorial Hospital, 2401 West
University Ave., Muncie, IN 47303. Fax 765-747-0137; e-mail
dtriplett{at}cami3.com
1 Nonstandard abbreviations: VWF, von Willebrand factor; AA, arachidonic acid; GP, glycoprotein; BT, bleeding time; VWD, von Willebrand disease; DDAVP, desmopressin (1-desamino-8-D-arginine vasopressin); TF, tissue factor; APC, activated protein C; APTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; LA, lupus anticoagulant; and APA, anti-phospholipid antibody. 
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Abstract
Primary Hemostasis
