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The Role of Enzymes in Disseminated Intravascular Coagulation: An Overview
Principles and practice The Role of Enzymes in Disseminated Intravascular Coagulation: An Overview H . M . HASSON, MD, FACOG The enzymatic mechanisms of blood coagulation and fibrinolysis d a y an important role in the crisis of disseminated intravascular coagulatron. They tend to protect the organism against death from extensive intravascular thrombosis, but in the process they produce a serious hemorrhagic state that could lead to exsanguination. Heparin inhibits clotting and minimizes fibrinolysis, thereby allowing the gradual natural restoration of decreased blood coagulation factors and subsequent hemostasis. The survival of the patient, in the meantime, will depend on the ruccesEfur treatment of the hypovolemic shock Resent and on preventing further passage into the circulation of thromboplastic material which triggers intravascular clotting.
Enzymes are proteins which function as organic catalysts. A catalyst alters the velocity of a chemical reaction without being consumed by the reaction or entering into its end products. Enzymes function as catalysts by offering certain sites of highly specialized shape and arrangement, within their macromolecular structure, to a specific chemical reINTRINSIC SYSTEM XI
+
action so that the reaction may proceed much more efficiently. One fascinating example of how enzymes affect the body’s response to crisis is observed in hemorrhage from blood coagulation defects in obstetrics. Most hemorrhagic complications of pregnancy are not associated with coagulation disturbances but result from purely mechanical causes such as in-
EXTRINSIC SYSTEM Tissue thromboplasti n
X I 1 + a c t i v e surface
complete detachment of the placenta and intrapartal genital lacerations, which require simple mechanical treatment. The small but significant number of cases of obstetric hemorrhage due to a coagulation dysfunction are often associated with profound disease processes such as abruptio placentae and septic shock. The coagulation defect in these patiems is essentially disseminated intravascular coagulation (DIC) (also known as consumption coagulopathy ) .
Two Coagulation Systems
active I X + V I I I + I11
+
IV
a c t i v a t o r complex + X
/ a c t i v e X + I V + 111 + V a c t i v a t o r complex + I1 Thrombin
Thrombin + Fibrinogen F i b r i n monomers o f peptides + XI11 + I V S t a b l e f i b r i n polymers @
May/June 1974 J O G N Nursing
Figure 1. Simplified Scheme of the Coagulation Mechanism
Blood coagulation mechanisms are considered as two major systems: clotting and fibrinolytic. In the clotting system, the enzyme thrombin, formed from prothrombin, transforms fibrinogen into fibrin. In the fibrinolytic system, the enzyme fibrinolysin, formed from profibrinolysin, lyses fibrin, and to a lesser extent fibrinogen, into various split products which can no longer form a fibrin net.l The main reactions in the fibrinolytic system are illustrated in Figure 2, modified from Stormorken and Owren.2 The nomenclature of blood clotting factors has been standardizedS (see Table 1). Recently, Factor XIII, or fibrin stabilizing factor (FSF), was added to the list.* The blood co27
Table 1. Blood Coagulation Factors Factor I Factor II Factor Ill ,Factor IV Factor. V
Factor VII
Factor Vlll
Factor IX Factor
X
Factor XI Factor XI1 Factor XIII*
Fibrinogen Prothrombin Thrombogen Th romboplastin Thrombokinase Platelet factor 3 Calcium Proaccelerin Prothrombin accelerator Labile factor of Quick Plasma Ac globulin Serum prothrombin conversion accelerator (SPCA) Proconvertin Serum accelerator Stable factor of Owen Antihemophilic globulin (AG) Antihemophilic factor (AF) Plasma thromboplastin component (PTC) Christmas factor Stuart factor Prower factor Plasma thromboplastin antecedent (PTA) Hageman factor Glass factor Fibrinase Fibrin stabilizing factor (FSF)
* Factor Xlll was not included in the cited reference. agulation mechanisms are diagramed in Figure 1, based on recent studies2 The coagulation and fibrinolytic systems are counter-balanced by welldeveloped inhibitors which shield them from significant spontaneous and simultaneous activation. However, the inhibitors can be overwhelmed by large amounts of tissue extracts or
other thromboplastic material. If the thromboplastic material enters the blood stream, both systems explode into activity.1 The blood is hypercoagulable in late pregnancy; levels of fibrinogen, Factors VII, VIII, and IX are elevated; fibrinolytic activity decreases5 These alterations are designed to compensate for blood loss and to effect rapid hemostasis during parturition, but they also leave the patient vulnerable to intravascular clotting and thromboembolic complications.
Pregnancy-Induced Disturbances The pathogenesis of DIC is relatively simple. Thromboplastic-like substances enter the maternal circulation and trigger diffuse intravascular clotting and deposition of fibrin thrombi. The fibrinolytic system is stimulated as a result of the intravascular clotting. This system breaks down the deposited fibrin and, to a lesser extent, fibrinogen. Products of the degradation, such as fibrin split products and fraction D, inhibit blood coagulation and platelet function and greatly aggravate the hemorrhagic diathe+. The two major enzymes of the blood coagulation and fibrinolytic systems, thrombin and fibrinolysin, play a central role in the development of DIC. Thrombin is the autocatalytic enzyme of the coagulation mechanism; it also inactivates key
Plasminogen (Profibrinolysin1
Plasmin (Fibrinolysin
FibrinogedFibrin
I
Inactive peptides Fraction D Fraction E 28
Figure 2. The Fibrinolytic System, Simplified
-
Fibrin split products, FSP
clotting Factors V and VIII.' Fibrinolysin degrades fibrin and fibrinogen into powerful anticoagulant fragments.E Thus, the natural inhibitors are overwhelmed by large amounts of thromboplastic material entering the circulation and triggering explosive intravascular clotting, while the body's natural enzymatic response tends to prevent the accelerated clotting from progressing to fatal disseminated thrombosis. But at the same time it exposes the patient to the threat of death from exsanguination. Thromboplastic-like substances may be infused into the maternal circulation from the placenta and/or the serum expressed from the retroplacental clot, as in abruptio p1acentae;S from amniotic fluid contaminated with catabolic products of fetal autolysis, as in missed abortion and the dead fetus syndrome;8 and from amniotic A uid and particulate amniotic debris, as in amniotic fluid embolism.8 In septic shock, the continuous release of endotoxin into the blood stream stimulates intravascular coagulation.10Jl DIC may also occur through the action of locally enhanced fibrinolysin at the site of fibrin deposition in a retroplacental
Management Principles Management of DIC is based on the following principles: 1. Treatment of hypovolemic shock by fluids and whole fresh blood replacement. 2 . Use of the anticoagulant heparin, which has unique and paradoxic therapeutic role. Heparin is the most potent antithrombin known. It completely inhibits intravascular clotting and it thus prevents further depletion of fibrinogen and Factors V and VIII, and minimizes fibrinolysis.' Through this action, affected clotting factors are gradually restored t o more normal levels. 3. Removal of the source of the triggering mechanism. 4. Constant careful monitoring of circulatory and renal functions and of blood coagulation.
It should be noted that the treatMay/June 1974 JOGN Nursing
orrhage.’’ Clin Obstet Gynecol 7:286,
ment modalities fibrinogen and/or antifibrinolysins, notably epsilon aminocaproic acid, are least helpful in DIC. Fibrinogen may activate further fibrinolysis and €-aminocaproic acid may trigger harmful thrombosis.8
1964
7. Quick, A. J.: Bleeding Problems in Clinical Medicine. Philadelphia, W. B. Saunders Company, 1970, pp 124-174 8. Hodgkinson, C. P., R. J. Thompson, and A. A. Hodari: “Dead Fetus Syndrome.’’ Clin Obstet Gynecol 7: 349, 1964 9. Albrechtsen, 0. K.: “Hemorrhagic Disorders Following Amniotic Fluid
References 1. Mammen, E. F.:
“Physiology of Blood Coagulation in Pregnancy.” Clin Obstet Gynecol 7:271, 1964 2. Stormorken, H., and P. A. Owren: “Physiopathology of Hemostasis.” Semin Hematol 8:3, 1971 3. International Committee for the Nomenclature of Blood Clotting Factors: “Communication on the Nomenclature of Blood Clotting Factors.” J A M A 180:733, 1962. 4. Messer, R. H.: “Coagulation Problems in Obstetrics.” Med Clin North
Am 53:1085, 1969 5. Sutton, D. M. C., R. Hauser, P. Kulapongs, and F. Bachman: “Intravascular Coagulation in Abruptio Placenta.” Am J Obstet Gynecol 109:604, 1971 6. Bang, N. U., P. C. Harpel, and F.
Streuli: “Hypofibrinogenemic Hem-
Embolism.” Clin Obstet Gynecol
7:361, 1964 10. Simone, J. V.: “Disseminated Intra-
vascular Coagulation.” A d v lntern Med 15:339, 1969 11. Kitzmiller, J. L.: “Septic Shock: An Eclectic View!’ Obstet Gynecol Surv 26:105, 1971
Address reprint requests to H. M. Hasson, MD, FACOG, 2424 North Clark Street, Chicago, IL 60614.
T h e author is on the staffs of Grant, Cook County, and S t . Joseph hospitals in Chicago and is an Associate in the OB-GYN Department of Northwestern. University Medical School. His previous articles have been published in the American Journal of Obstetrics and Gynecology and in Obstetrics and Gynecology. Doctor Hasson took his M D degree at Ein Shams University, Cairo, Egypt, and served his residency in pathology at St. Jolm’s Episcopal Hospital, Brooklyn, N e w York, m d in OB-GYN at Presbyterian St. Luke’s Hospital, Chicago, and West Suburban Hospital, Oak Park, Illinois. In 1964 and 1965 k served with the Kuwait Ministry of Health, Kuwait. H e is a Fellow of ACOG and an active member of the Chicago Medical Society, the AFS, and the Pan American Medical Association.
DIC in the Pregnant Patient MARY M. CONKLIN, RPJ, BSN, MS Disseminated intravascular coagulopathy is relatively unconzmvn though it may develop in various states during pregnancy. Once DIC becomes apparent, the patient demands expert medical m a g e m e n t and skilled nursing care. Attention is given to changes in blood coagulation which occur, to the etiology, to alternative approaches to medical management, and to nursing care.
Disseminated intravascular coagulopathy (DTC) is a condition in which the blood clotting and the fibrinolytic (fibrin breakdown) systems are simultaneously active. The results are hypocoagulability of the blood and diminution of blood clotting factors. While DIC is a potential sequela of many conditions, the focus here will be on the pregnant patient. The life-threatening potential of the disorder warrants an in-depth look at the pathology, treatment, and implications for nursing care.
Incidence Although
relatively
uncommon,
May/June 1974 JOGN Nursing
DIC may appear in patients with fetal death in utero, saline infusion, amniotic fluid embolus, abruptio placentae, and sepsis. The incidence will depend somewhat on the number of patients with Rh negative sensitization, hypertension, and toxemia, for these are the patients in whom some of the above-mentioned conditions occur.* The number of abortions by saline infusion will also influence the incidence.
Mechanism of Blood Coagulation A stable clot may be formed via two pathways: the intrinsic or the extrinsic. The extrinsic system acti-
vates when tissue damage results in the release of thromboplastin, a tissue extract, into the tissue fluids. Blood Factors X, VII, and V, along with calcium, are involved in the formation of the extrinsic prothrombin activator. The intrinsic system may activate when blood vessel damage occurs. When Factors XI and XI1 come into contact with the roughened blood vessel wall, the contact activation product is formed and activates the intrinsic system? Factors X, IX, VIII, and V, as well as platelet factor three, are involved in the formation of the intrinsic prothrombin activator. Prothrombin, formed by the liver, 29
Enzymes are proteins which function as organic catalysts. A catalyst alters the velocity of a chemical reaction without being consumed by the reaction or entering into its end products. Enzymes function as catalysts by offering certain sites of highly specialized shape and arrangement, within their macromolecular structure, to a specific chemical reINTRINSIC SYSTEM XI
+
action so that the reaction may proceed much more efficiently. One fascinating example of how enzymes affect the body’s response to crisis is observed in hemorrhage from blood coagulation defects in obstetrics. Most hemorrhagic complications of pregnancy are not associated with coagulation disturbances but result from purely mechanical causes such as in-
EXTRINSIC SYSTEM Tissue thromboplasti n
X I 1 + a c t i v e surface
complete detachment of the placenta and intrapartal genital lacerations, which require simple mechanical treatment. The small but significant number of cases of obstetric hemorrhage due to a coagulation dysfunction are often associated with profound disease processes such as abruptio placentae and septic shock. The coagulation defect in these patiems is essentially disseminated intravascular coagulation (DIC) (also known as consumption coagulopathy ) .
Two Coagulation Systems
active I X + V I I I + I11
+
IV
a c t i v a t o r complex + X
/ a c t i v e X + I V + 111 + V a c t i v a t o r complex + I1 Thrombin
Thrombin + Fibrinogen F i b r i n monomers o f peptides + XI11 + I V S t a b l e f i b r i n polymers @
May/June 1974 J O G N Nursing
Figure 1. Simplified Scheme of the Coagulation Mechanism
Blood coagulation mechanisms are considered as two major systems: clotting and fibrinolytic. In the clotting system, the enzyme thrombin, formed from prothrombin, transforms fibrinogen into fibrin. In the fibrinolytic system, the enzyme fibrinolysin, formed from profibrinolysin, lyses fibrin, and to a lesser extent fibrinogen, into various split products which can no longer form a fibrin net.l The main reactions in the fibrinolytic system are illustrated in Figure 2, modified from Stormorken and Owren.2 The nomenclature of blood clotting factors has been standardizedS (see Table 1). Recently, Factor XIII, or fibrin stabilizing factor (FSF), was added to the list.* The blood co27
Table 1. Blood Coagulation Factors Factor I Factor II Factor Ill ,Factor IV Factor. V
Factor VII
Factor Vlll
Factor IX Factor
X
Factor XI Factor XI1 Factor XIII*
Fibrinogen Prothrombin Thrombogen Th romboplastin Thrombokinase Platelet factor 3 Calcium Proaccelerin Prothrombin accelerator Labile factor of Quick Plasma Ac globulin Serum prothrombin conversion accelerator (SPCA) Proconvertin Serum accelerator Stable factor of Owen Antihemophilic globulin (AG) Antihemophilic factor (AF) Plasma thromboplastin component (PTC) Christmas factor Stuart factor Prower factor Plasma thromboplastin antecedent (PTA) Hageman factor Glass factor Fibrinase Fibrin stabilizing factor (FSF)
* Factor Xlll was not included in the cited reference. agulation mechanisms are diagramed in Figure 1, based on recent studies2 The coagulation and fibrinolytic systems are counter-balanced by welldeveloped inhibitors which shield them from significant spontaneous and simultaneous activation. However, the inhibitors can be overwhelmed by large amounts of tissue extracts or
other thromboplastic material. If the thromboplastic material enters the blood stream, both systems explode into activity.1 The blood is hypercoagulable in late pregnancy; levels of fibrinogen, Factors VII, VIII, and IX are elevated; fibrinolytic activity decreases5 These alterations are designed to compensate for blood loss and to effect rapid hemostasis during parturition, but they also leave the patient vulnerable to intravascular clotting and thromboembolic complications.
Pregnancy-Induced Disturbances The pathogenesis of DIC is relatively simple. Thromboplastic-like substances enter the maternal circulation and trigger diffuse intravascular clotting and deposition of fibrin thrombi. The fibrinolytic system is stimulated as a result of the intravascular clotting. This system breaks down the deposited fibrin and, to a lesser extent, fibrinogen. Products of the degradation, such as fibrin split products and fraction D, inhibit blood coagulation and platelet function and greatly aggravate the hemorrhagic diathe+. The two major enzymes of the blood coagulation and fibrinolytic systems, thrombin and fibrinolysin, play a central role in the development of DIC. Thrombin is the autocatalytic enzyme of the coagulation mechanism; it also inactivates key
Plasminogen (Profibrinolysin1
Plasmin (Fibrinolysin
FibrinogedFibrin
I
Inactive peptides Fraction D Fraction E 28
Figure 2. The Fibrinolytic System, Simplified
-
Fibrin split products, FSP
clotting Factors V and VIII.' Fibrinolysin degrades fibrin and fibrinogen into powerful anticoagulant fragments.E Thus, the natural inhibitors are overwhelmed by large amounts of thromboplastic material entering the circulation and triggering explosive intravascular clotting, while the body's natural enzymatic response tends to prevent the accelerated clotting from progressing to fatal disseminated thrombosis. But at the same time it exposes the patient to the threat of death from exsanguination. Thromboplastic-like substances may be infused into the maternal circulation from the placenta and/or the serum expressed from the retroplacental clot, as in abruptio p1acentae;S from amniotic fluid contaminated with catabolic products of fetal autolysis, as in missed abortion and the dead fetus syndrome;8 and from amniotic A uid and particulate amniotic debris, as in amniotic fluid embolism.8 In septic shock, the continuous release of endotoxin into the blood stream stimulates intravascular coagulation.10Jl DIC may also occur through the action of locally enhanced fibrinolysin at the site of fibrin deposition in a retroplacental
Management Principles Management of DIC is based on the following principles: 1. Treatment of hypovolemic shock by fluids and whole fresh blood replacement. 2 . Use of the anticoagulant heparin, which has unique and paradoxic therapeutic role. Heparin is the most potent antithrombin known. It completely inhibits intravascular clotting and it thus prevents further depletion of fibrinogen and Factors V and VIII, and minimizes fibrinolysis.' Through this action, affected clotting factors are gradually restored t o more normal levels. 3. Removal of the source of the triggering mechanism. 4. Constant careful monitoring of circulatory and renal functions and of blood coagulation.
It should be noted that the treatMay/June 1974 JOGN Nursing
orrhage.’’ Clin Obstet Gynecol 7:286,
ment modalities fibrinogen and/or antifibrinolysins, notably epsilon aminocaproic acid, are least helpful in DIC. Fibrinogen may activate further fibrinolysis and €-aminocaproic acid may trigger harmful thrombosis.8
1964
7. Quick, A. J.: Bleeding Problems in Clinical Medicine. Philadelphia, W. B. Saunders Company, 1970, pp 124-174 8. Hodgkinson, C. P., R. J. Thompson, and A. A. Hodari: “Dead Fetus Syndrome.’’ Clin Obstet Gynecol 7: 349, 1964 9. Albrechtsen, 0. K.: “Hemorrhagic Disorders Following Amniotic Fluid
References 1. Mammen, E. F.:
“Physiology of Blood Coagulation in Pregnancy.” Clin Obstet Gynecol 7:271, 1964 2. Stormorken, H., and P. A. Owren: “Physiopathology of Hemostasis.” Semin Hematol 8:3, 1971 3. International Committee for the Nomenclature of Blood Clotting Factors: “Communication on the Nomenclature of Blood Clotting Factors.” J A M A 180:733, 1962. 4. Messer, R. H.: “Coagulation Problems in Obstetrics.” Med Clin North
Am 53:1085, 1969 5. Sutton, D. M. C., R. Hauser, P. Kulapongs, and F. Bachman: “Intravascular Coagulation in Abruptio Placenta.” Am J Obstet Gynecol 109:604, 1971 6. Bang, N. U., P. C. Harpel, and F.
Streuli: “Hypofibrinogenemic Hem-
Embolism.” Clin Obstet Gynecol
7:361, 1964 10. Simone, J. V.: “Disseminated Intra-
vascular Coagulation.” A d v lntern Med 15:339, 1969 11. Kitzmiller, J. L.: “Septic Shock: An Eclectic View!’ Obstet Gynecol Surv 26:105, 1971
Address reprint requests to H. M. Hasson, MD, FACOG, 2424 North Clark Street, Chicago, IL 60614.
T h e author is on the staffs of Grant, Cook County, and S t . Joseph hospitals in Chicago and is an Associate in the OB-GYN Department of Northwestern. University Medical School. His previous articles have been published in the American Journal of Obstetrics and Gynecology and in Obstetrics and Gynecology. Doctor Hasson took his M D degree at Ein Shams University, Cairo, Egypt, and served his residency in pathology at St. Jolm’s Episcopal Hospital, Brooklyn, N e w York, m d in OB-GYN at Presbyterian St. Luke’s Hospital, Chicago, and West Suburban Hospital, Oak Park, Illinois. In 1964 and 1965 k served with the Kuwait Ministry of Health, Kuwait. H e is a Fellow of ACOG and an active member of the Chicago Medical Society, the AFS, and the Pan American Medical Association.
DIC in the Pregnant Patient MARY M. CONKLIN, RPJ, BSN, MS Disseminated intravascular coagulopathy is relatively unconzmvn though it may develop in various states during pregnancy. Once DIC becomes apparent, the patient demands expert medical m a g e m e n t and skilled nursing care. Attention is given to changes in blood coagulation which occur, to the etiology, to alternative approaches to medical management, and to nursing care.
Disseminated intravascular coagulopathy (DTC) is a condition in which the blood clotting and the fibrinolytic (fibrin breakdown) systems are simultaneously active. The results are hypocoagulability of the blood and diminution of blood clotting factors. While DIC is a potential sequela of many conditions, the focus here will be on the pregnant patient. The life-threatening potential of the disorder warrants an in-depth look at the pathology, treatment, and implications for nursing care.
Incidence Although
relatively
uncommon,
May/June 1974 JOGN Nursing
DIC may appear in patients with fetal death in utero, saline infusion, amniotic fluid embolus, abruptio placentae, and sepsis. The incidence will depend somewhat on the number of patients with Rh negative sensitization, hypertension, and toxemia, for these are the patients in whom some of the above-mentioned conditions occur.* The number of abortions by saline infusion will also influence the incidence.
Mechanism of Blood Coagulation A stable clot may be formed via two pathways: the intrinsic or the extrinsic. The extrinsic system acti-
vates when tissue damage results in the release of thromboplastin, a tissue extract, into the tissue fluids. Blood Factors X, VII, and V, along with calcium, are involved in the formation of the extrinsic prothrombin activator. The intrinsic system may activate when blood vessel damage occurs. When Factors XI and XI1 come into contact with the roughened blood vessel wall, the contact activation product is formed and activates the intrinsic system? Factors X, IX, VIII, and V, as well as platelet factor three, are involved in the formation of the intrinsic prothrombin activator. Prothrombin, formed by the liver, 29