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| Hemostasis
for the surgeon, An Overview
Jerrold
H Levy, MD |
|
| Introduction |
|
| 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. |
|
| Simplified
coagulation cascade approach |
|
|
Coagulation is initiated by the following mechanisms: 1.
Blood is exposed to tissue factor released from cell membranes following
injury. 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. |
|
| More
involved approach |
|
| 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. | |
| Inhibiting
Coagulation: Endogenous Pathways |
|
| 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. | |
| Inhibiting
Coagulation: Coagulopathy |
|
| 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. | |
| Hemophilia |
|
| 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. | |
| Hemostasis
and Coagulation in liver disease |
|
| 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). | |
| SELECTED REFERENCES | |
|
1.
|
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|
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|
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|
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|
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. |
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5.
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Coukell AJ, Markham A. Clopidogrel. Drugs. 1997;54:745-50. |
|
6.
|
Dahlback B. Blood coagulation. Lancet. 355(9215):1627-32, 2000 |
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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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