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| Hemostasis
for the surgeon, An Overview
Jerrold
H Levy, MD
Emory University School of Medicine and Emory Healthcare
Atlanta, Georgia
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Introduction
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Hemostasis is
a complex physiologic mechanism that maintains blood in a fluid
state within the circulation, yet provides important defense mechanisms
against bleeding when injury occurs to a blood vessel. The intraluminal
(insides) lining of the blood vessels, also called the vascular
endothelium, provides an anticoagulant surface to prevent clot from
occurring. However, the coagulation system is initiated in response
to injury or rupture of endothelium or injury to the blood vessel,
which allows exposure of blood to the extravascular tissue. The
responses of the coagulation system are coordinated with the formation
of the hemostatic plug that occludes the bleeding vessel. This includes
platelets, but also fibrin, fibrinogen, and other inflammatory cells
including white cells (neutrophils). The textbook teaching of hemostasis
often involves separating coagulation cascades into extrinsic and
intrinsic systems, but this is more important in understanding laboratory
testing rather than how clots actually forms in patients.
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Simplified
coagulation cascade approach
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Coagulation is initiated by the following mechanisms:
1.
Blood is exposed to tissue factor released from cell membranes following
injury.
2. Tissue factor interacts with factor VIIa.
3. This complex with additional activated factors convert
factor X to factor Xa
4. Factor Xa generates factor IIa (thrombin) from factor
II (prothrombin).
5. Once factor IIa (thrombin) is generated, it cleaves
plasma fibrinogen to generate fibrin.
Each of these reactions takes place on an activated cell surface. Thrombin that
forms is also a potent activator of platelets. Platelets can also
can bind to damaged blood vessels, activate, and bind fibrin to
create clot as well. This is how platelet inhibitors produce bleeding.
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More
involved approach
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Because hemostasis
and clot formation is important as part of host defense mechanisms,
multiple pathways can initiate clot formation to prevent bleeding
following injury. The coagulation of blood is mediated by both cellular
components (platelets, but also other inflammatory cells) and soluble
plasma proteins (coagulation factors). In response to vascular injury,
circulating platelets adhere, aggregate, and provide cell-surface
materials (phospholipid) for the assembly of blood clotting enzyme
complexes. The extrinsic pathway of blood coagulation is initiated
when blood is exposed to non-vascular-cell-bound tissue factor in
the subendothelial space. Tissue factor binds to activated factor
VII (factor VIIa), and the resulting enzyme complex activates subsequent
factors in a cascade: factors IX and X, respectively. Factor IX
activated by the tissue factor-VIIa pathway in turn activates additional
factor X, in a reaction that is greatly accelerated by a cofactor,
factor VIII. Once activated, factor X converts prothrombin to thrombin
(factor IIa) in a reaction that is accelerated by factor V. In the
final step of the coagulation pathway, thrombin cleaves fibrinogen
to generate fibrin monomers, which then polymerize and link to one
another to form a chemically stable clot. Thrombin also is a potent
activator of platelets, thereby amplifying the coagulation mechanism. |
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Inhibiting
Coagulation: Endogenous Pathways
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To prevent widespread
clotting following injury, hemostatic inactivation of coagulation
occurs whenever clotting is initiated. The potentially explosive
nature of the coagulation cascade is offset by natural anticoagulant
mechanisms. The maintenance of adequate blood flow and the regulation
of cell-surface activity limit the local accumulation of activated
blood-clotting enzymes and complexes. Thrombin, when formed, binds
to thrombomodulin that activates protein C and protein S pathways
that inactivates factors Va and VIIIa. Antithrombin III, a circulating
protein, inactivates factors Xa, and IIa (prothrombin) in a reaction
that is accelerated by the presence of heparin. Endothelium, when
activated, release tissue-type plasminogen activator (t-PA) and
other activators that convert plasminogen to plasmin, a serine protease
that acts on fibrin to dissolve preformed clots. |
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Inhibiting
Coagulation: Coagulopathy
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Clinically acquired
conditions that produce bleeding problems, or conditions of coagulopathy,
are unfortunately too common in patients. Common problems include
hemophilia where there are extremely low levels of factors VIII
or IX. There are other inherited bleeding disorders produced by
platelet disorders including the lack of glycoprotein 1b receptors
(Bernard Soulier's disease) or Glanzmann's thrombasthenia where
there is a lack of IIa/IIIb receptors on platelets. More commonly
acquired platelet disorders occur following the use of potent antiplatelet
agents for coronary disease and coronary percutaneous interventions
including Plavix (clopidogrel), ReoPro (abciximab), Aggrastat (tirofiban),
and Integrelin (eptifibatide). Of particular interest, is the coagulopathy
that occurs in patients with liver disease. This is especially of
major concern because the key role the liver plays in producing
the vitamin K dependent factor II, VII, IX and X, and in also clearing
breakdown products of fibrin (d-dimers). The coagulopathy of liver
disease is quite complex and often very difficult to treat in clinical
medicine. Further, hemorrhagic disseminated intravascular coagulation
(DIC) is responsible for bleeding problems associated with surgical
procedures acquired hemostatic inhibitors and sepsis and other things
that may activate blood vessels and produce complex bleeding disorders.
And finally, anticoagulation treatment with warfarin derivatives
(coumadin and coumarin) produces a marked inhibition of II, VII,
IX and X disorders. This also can be a major cause of bleeding problems
especially in patients receiving warfarin therapy. |
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Hemophilia
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Hemophilia is
an inherited disorder in which patients lack the necessary factor
proteins for hemostasis to occur. They are therefore, at increased
risk of bleeding, especially after trauma and surgical procedures.
Recurrent spontaneous hemarthrosis may result in significant joint
damage and require surgical intervention. There are 2 forms of hemophilia;
hemophilia A in which Factor VIII is deficient, and hemophilia B
in which Factor IX is deficient. Further classification based on
the factor level has predictive clinical implications. Persons with
severe hemophilia have factor levels less than 1% and suffer from
spontaneous hemorrhage. Patients with factor levels greater than
5% are classified as having mild hemophilia and may require treatment
with factor concentrates only after trauma or during surgery. Patients
who receive factor concentrates may develop antibodies to factors
and prevent their effectiveness. Recombinant factor VIIa (rFVIIa,
NovoSeven®) is a potentially effective hemostatic drug. Its
beneficial effect was demonstrated in hemophilia patients with inhibitors
to factor VIII or IX , and it has been suggested in a growing variety
of hemostatic disorders such as thrombocytopenia, thrombocytopathia,
and disorders related to liver disease. |
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Hemostasis
and Coagulation in liver disease
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In patients
with liver disease all vitamin K dependent coagulation factors (II,
VII, IX and X) are low depending on the severity of the liver dysfunction.
Furthermore, the patients experience different degrees of thrombocytopenia.
Therefore, liver patients experience prolonged PT and increased
risk of bleeding after surgical procedures or spontaneously in connection
with variceal bleedings. NovoSeven® increases the TF occupancy
and directly enhances thrombin generation on activated platelets.
Recent studies have shown that NovoSeven® dose dependently normalizes
prolonged PT in patients with chronic liver disease, reviewed in
(6). |
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| SELECTED
REFERENCES |
|
1.
|
Antman EM. Handin
R. Low-molecular-weight heparins: an intriguing new twist with profound
implications Circulation. 1998;98:287-9 |
|
2.
|
Bernstein D.
Effectiveness of the recombinant Factor VIIa in Patients with Coagulopathy
of advanced Child's B and C Cirrhosis. Seminars in Thrombosis and
Hemostasis 26(4): 437-438, 2000. |
|
3.
|
Coller BS. GP
IIb/IIIa antagonists. Pathophysiologic and therapeutic insights
from studies of c7E3 Fab. Thromb Haemost. 1997;78:730-735. |
|
4.
|
Coller BS. Monitoring
of platelet GP IIb/IIIa antagonist therapy. Circulation. 1997;96:3828-3832. |
|
5.
|
Coukell AJ,
Markham A. Clopidogrel. Drugs. 1997;54:745-50. |
|
6.
|
Dahlback B.
Blood coagulation. Lancet. 355(9215):1627-32, 2000 |
|
7.
|
Davie EW, Fujikawa
K, Kisiel W. The coagulation cascade: initiation, maintenance, and
regulation. Biochemistry. 1991; 30:10363-10370. |
|
8.
|
Davie EW. Biochemical
and molecular aspects of the coagulation cascade. Thromb Haemost
1995; 74: 1-6. |
|
9.
|
Despotis GJ,
Filos K, Gravlee G, Levy JH: Anticoagulation monitoring during cardiac
surgery: a survey of current practice and review of current and
emerging techniques. Anesthesiology 1999; 91:1122-1151. |
|
10.
|
Furie B, Furie
BC. Molecular and cellular biology of blood coagulation. N Engl
J Med 1992; 326: 800-06. |
|
11.
|
Harker LA, Hanson
SR, Runge MS. Thrombin hypothesis of thrombus generation and vascular
lesion formation. Am J Cardiol. 1995; 75:12B. |
|
12.
|
Hoffman M. Monroe
DM 3rd. Roberts HR. Activated factor VII activates factors IX and
X on the surface of activated platelets: thoughts on the mechanism
of action of high-dose activated factor VII. Blood Coagulation &
Fibrinolysis. 9 Suppl 1:S61-5, 1998 |
|
13.
|
Allen GA. Monroe
DM 3rd. Roberts HR. Hoffman M. The effect of factor X level on thrombin
generation and the procoagulant effect of activated factor VII in
a cell-based model of coagulation. Blood Coagulation & Fibrinolysis.
11 Suppl 1:S3-7, 2000 |
|
14.
|
Levi M, Ten
Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999
19;341:586-92 |
|
15.
|
Levy JH, Morales
A, Lemmer JH: Pharmacologic approaches to prevent or decrease bleeding
in surgical patients. Chapter in Transfusion Medicine, Speiss B,
Counts R, Gould S (eds), Williams & Wilkins, 383-398, 1997 |
|
16.
|
Levy JH. Anaphylactic
Reactions in Anesthesia and Intensive Care. 2nd Edition. Butterworth-Heinemann,
1992. |
|
17.
|
Levy JH: Hemostatic
agents and their safety. J Cardiothorac Anesth 1999;13 (Suppl 1):
6-11. |
|
18.
|
Levy JH: Novel
intravenous antithrombins. Am Heart J (Suppl), Am Heart J 2001:141;1043-1047 |
|
19.
|
Rosenberg RD.
Aird WC. Vascular-bed--specific hemostasis and hypercoagulable states.
N Engl J Med. 340(20):1555-64, 1999 |
|
20.
|
Shattil SJ.
Function and regulation of the ß3 integrins in hemostasis
and vascular biology. Thromb Haemost. 1995;74:149-155. |
|
21.
|
Weitz JI. Low-molecular-weight
heparins. N Engl J Med. 1997;337:688-698 |
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