Coagulopathies and surgeons

JOTJRNAL

OF SURGICAL

16, 429-439

RESEARCH

(1974)

Coagulopathies

and Surgeons

DONALD

SILVER,

most often depends upon for hemostasis. The first stage of coagulation requires several minutes-usually 3 to 5-to complete, while the second stage requires only 10 to 15 set, and the third stage is usually completed in a few seconds. Theoretically the coagulation process with its autoactivation capability can progress to massive intravascular thrombosis. However, several inhibitory mechanisms usually prevent this from happening. Natural inhibitors, antithrombins, of blood coagulation appear after prothrombin activation. The first stage of coagulation proceeds relatively slowly and the activated components may be “washed away” in the circulation and inhibited or diluted. Also, factor 5 is consumed during the first stage and may become a limiting factor in additional coagulation. The split products of fibrin act as anticoagulants. Finally, fibrin deposition activates the fibrinolytic system which lyses fibrin (and other coagulation proteins).

THE SURGEON MUST COMPLEMENT his ability to obtain mechanical hemostasis with a firm understanding of the principles of the coagulation and fibrinolytic mechanisms, and be prepared to prevent or treat the various bleeding or clotting disorders, Coagulopathies i.e., the coagulopathies. may result: from derangements of the clotting and fibrinolytic mechanisms; from too few or too many platelets, or from platelets with abnormal function; and, finally, from an excess of natural or administered anticoagulants. The purpose of this report is not to make surgeons competent coagulationists, but to present current concepts of those bleeding and clotting disorders that are likely to be of concern to surgeons. COAGULATION The coagulation mechanism responds rapidly and efficiently to inhibit blood loss and has the capability to autoactivate itself (the “waterfall mechanism” of Macfarlane) [33] as needed to maintain hemostasis. Whether coagulation occurs within blood vessels via the intrinsic coagulation systern, or in tissue spaces via the extrinsic coagulation system, the final stage of coagulation-the conversion of fibrinogen to fibrin by thrombin and the polymerization to fibrin by factor 13 is the same for the two systems. The intrinsic coagulation system which utilizes all the coagulation factors, except 7, is the one the surgeon From the Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710. Supported by U.S. Public Health Service Grant HL-08929. Submitted for publication January 19, 1973.

Deficiencies

@ 1974 by Academic of reproduction in any

Press, form

Inc.

reserved.

of Coagulation

Factors

Although congenital deficiencies have been reported for each of the coagulation factors other than factors 3 and 4, only patients with factor 5 or 8 deficiencies are likely to have significant operative bleeding, because factors 5 and 8 are labile factors and are not present in adequate amounts in bank blood. Factor 8 is best replaced with fresh blood, fresh blood plasma, or various concentrated precipitates. Factor 5 remains at relatively normal concentrations in bank blood until the 4th day of storage, after which it progressively falls

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Table 1. Etiology

OF

SURGICAL

of Disseminated Coagulation

RESEARCH,

Intravascular

Increased coagulation (thromboplastic) Abruptio Incompatible placentae blood Cardiopulmonary Amniotic fluid embolism bypass Retained dead Malaria fetus Fat embolism Bacteria

activity Burns Transplant rejection Cancers Viruses

Decreased flow Shock Giant hemangioma Pulmonary embolism Cyanotic congenital heart disease

Endothelial damage Aneurysm Shock Heat stroke Viruses Rickettsiae

to 40% of its original concentration by the 14th day of storage (32). Thus, factor 5 deficiencies can be treated with blood that is up to lo-14 days old. Fortunately, most hemophiliacs are recognized before surgery and tolerate surgery quite well if adequate factor 8 levels are maintained during the operation and throughout the recovery phase. If a surgeon should encounter excessive bleeding while operating upon a patient with a deficiency of one of the other factors, the deficiency will probably be adequately corrected with the bank blood administered as blood replacement. Disseminated

Intravascular

Coagulation

The surgeon is much more likely to encounter acquired causes of bleeding than bleeding from congenital deficiencies. A common cause of bleeding which has received increasing attention in the past few years is the disseminated intravascular COAccelerated

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agulation syndrome [19, 481. This syndrome is characterized by intravascular accelerated utilization of clotting factors and platelets and secondary activation of fibrinolysis. The accelerated coagulation may be acute or chronic and generalized or localized [47]. The microcirculation may become obstructed by thrombi, and cellular and organ death may occur. If the procoagulant stimulus is removed, the syndrome becomes self-limiting. The intravenous coagulation may be activated by conditions which cause the release of thromboplastin, which cause vessel damage, or which produce stasis (Table 1). Conditions which activate the coagulation system primarily through the release of red cell thromboplastin include incompatible blood transfusions, cardiopulmonary bypass, and malaria. Tissue thromboplastin may be released during abruptio placenta, amniotic fluid embolism, burns, cancer, etc. Changes in vessel walls from endothelial damage and exposure of the procoagulant collagen may occur in aneurysms, after shock and heat stroke, or secondary to virus or Rickettsial infections. The stasis and resultant acidosis of shock are potent initiators of coagulation. The “stasis coagulation” which occurs in giant hemangiomas was first described by Kasabach and Merritt in 1940 [28]. Cyanotic heart disease with its high hematocrit and poor perfusion may also result in “stasis coagulation” changes. Besides accelerating coagulation, many of the conditions that are associated with disseminated intravascular coagulation also cause alterations in hepatic function so that

Intravascular

Coagulation

FE!lIl.%.*~:F:~* 4 Vasoactive

Rg.

c Bleeding

1. Pathophysiology

1 Bleeding

of disseminated

Bleeding

intravascular

coagulation.

DONALD

SILVER:

COAGULOPATHIES

activated clotting factors are not removed and the consumed clotting factors are not replaced rapidly. There is also a reduction of the activity of the reticuloendothelial mechanism for clearing macromolecular and particulate substances such as fibrindegradation products, activated clotting factors, etc. [35]. Although a variety of events may initiate the accelerated intravascular coagulation, the chain reaction which follows is fairly uniform, albeit of varying intensity (Fig. 1). The intravascular coagulation may lead to depletion of fibrinogen, prothrombin, and factors 5, 8, 9, 10, 12, and 13. The platelet count is depressed from aggregation of platelets on exposed collagen or in microthrombi. The factors released from platelets tend to accelerate the coagulation process. Bleeding may occur if the coagulation factors become sufficiently depressed. In addition to the hemorrhagic diathesis, fibrin deposition may cause microvascular obstruction with subsequent cell and organ dysfunction. If necrosis occurs, bleeding may result and additional thromboplastic materials will be released and will be an additional stimulus to the coagulation process. Fibrin deposition also causes red cell damage. The resultant hemolysis can be another stimulus to the intravascular coagulation. A secondary fibrinolysis is caused by the fibrin-stimulated release of fibrinolytic activators from the vessels of the microcirculation. The fibrinolysis may cause clot lysis and bleeding. The breakdown products of fibrin and fibrinogen enhance the hemorrhagic tendency by interfering with the proteolytic action of thrombin, by interfering with the polymerization of fibrin monomer, and by interfering with the action of platelet factor 3 [62]. The vasoactive action of the fibrin-degradation products contributes to the hypotension frequently seen in these patients. Most often the intravascular coagulation is unrecognized. The coagulation process may not consume all the coagulation fac-

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tors so that enough remain for hemostasis and the fibrinolytic process maintains patency of the microcirculation; or rapid resynthesis of the clotting factors occurs and thrombocytopenia and fibrin-degradation products may be the only demonstrable abnormalities. The diagnosis is usually suspected only when major or minor bleeding and/or single or multiple organ failure occurs. A peripheral blood smear will demonstrate distorted and fragmented red cells-a microangiopathic hemolytic anemia. The cells apparently are damaged by passage through fibrin strands in the microcirculation [ 121. The platelet count usually is decreased, unless there is a preexisting thrombocytosis, to 20,00040,000 platelets per cubic millimeter, and almost always will be less than 100,000 per cubic millimeter. The thrombin time, partial thromboplastin time, and prothrombin time will be prolonged while specific testing usually reveals marked reductions of coagulation factors. High titers of fibrin split products can usually be detected while fibrin monomers can be recognized by the protamine paracoagulation [18] and the ethanol gelation [lo] tests. Finally, secondary hyperfibrinolysis can be demonstrated by the whole blood lysis time, euglobulin lysis time, and other appropriate tests. At autopsy, one may assume that intravascular coagulation has occurred if fibrin can be demonstrated in the microvasculature by immunofluorescent staining with antifibrin antiserum or by the finding of fibrin in the capillaries, especially of the kidneys or lung. Treatment of disseminated intravascular coagulation should be first directed toward eliminating the underlying cause of the COagulation. Draining the abscess and stopping the gram-negative septicemia, removing the retained dead fetus or the rejected transplant organ, eliminating the hypotension, etc., will usually stop the process. Occasionally the underlying cause cannot be eliminated, the intravascular coagulation persists after the cause is eliminated, or the bleeding must be controlled

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before treating the underlying cause. Heparin appears to be the agent of choice in these settings because it stops coagulation and permits reaccumulation of the coagulation factors. The thrombin time, activated partial thromboplastin time, and clotting time may be prolonged by the consumption of the coagulation products and the anticoagulating effects of the fibrin split products and, therefore, cannot be utilized to monitor the heparin administration. We usually give 500-1000 units per hour (to adults) and carefully follow the platelet count, and thrombin fibrinogen concentration, time. It usually takes 4-12 hr, occasionally longer, for the coagulation defects to begin to correct and the bleeding to decrease and stop. If the patient requires blood transfusions, it is better to give them after the heparin therapy has begun because the blood components will contribute to the coagulation process. Most often the secondary hyperfibrinolysis resolves when the intravascular coagulation stops. If hyperfibrinolysis persists, it should be treated cautiously with epsilon aminocaproic acid while the patient is maintained on heparin. Of course, during and after the treatment program, the various organ systems, i.e., heart, lung, kidney, etc., should have appropriate support. FIBRINOLYSIS Although incoagulable blood has been noted since the time of John Hunter [24], most of the meaningful observations on the fibrinolytic system have occurred in the last 40 yr. Recent investigators have attempted to gain information about the roles of spontaneous fibrinolysis, induced fibrinolysis, and hypofibrinolysis in clotting and bleeding disorders. A variety of enzymes called “activators,” act upon an inactive proenzyme, plasminogen, and convert it to the active proteolytic enzyme, plasmin. Plasmin preferentially digests fibrin but also attacks fibrinogen, prothrombin, antihemophiliac factor,

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and other plasma proteins. Plasminogen is closely bound to fibrinogen. Consequently, when thromboses form, plasminogen is incorporated into the thrombus and, thus, each thrombus has a potential self-destruct mechanism. Because there are sufficient quantities of circulating antiplasmins, activation of circulating plasminogen, provided it is not unduly rapid, produces no effect. However, when plasminogen in a thrombus is activated to plasmin, lysis is likely to occur because the plasmin in the thrombus is somewhat protected from the circulating antiplasmins. A variety of substances activate plasminogen. Trace amounts of activator are present in normal plasma and are responsible for the physiological plasma fibrinolytic activity. The plasma fibrinolytic activity is increased after trauma, shock, strenuous exercise, surgical operation, electric shock, etc. [7]. The plasma activator most likely is circulating tissue activator. Most tissues contain plasminogen-activator activity, and most of the tissue activator is found in blood vessel walls, especially the walls of veins, venules, vasa vasorum, and capillaries, and of the pulmonary artery [61]. Most of the fibrinolytic activity of arteries resides in the adventitia. All ducts and body cavities contain fibrinolytic activator activity which helps maintain their patency. The intravascular fibrinolytic activator appears to be primarily responsible for maintaining vessel patency. Most vascular trauma will reduce the vascular fibrinolytic potential [56]. We have demonstrated that the intravascular fibrinolytic activity may be reduced 40-100% by trauma in more than 70% of the vessels studied [a]. Vascular activity is released by trauma from the vessel wall into the blood where it activates plasminogen. The resultant plasmin is carried away by the circulation and inactivated by the circulating antiplasmins. The end result is a section of the damaged vessel which, in addition to having an increased propensity to clot, has a reduced propensity

DONALD

SILVER:

toward lysis, so that any thrombus forms is less likely to be lysed. Fibrinolytic

COAGULOPATHIES

which

Agents

Urokinase and streptokinase are being evaluated as agents for inducing thrombolysis. Urokinase probably activates plasminogen by splitting lysine and/or arginine bonds. Although it is still not entirely settled whether urokinase is produced in the urinary tract or whether it is excreted plasma (vascular) activator, recent evidence strongly suggests that urokinase is different from the vascular activator [3, 291. Bernik and Kwaan have demonstrated that renal cells in tissue culture can produce an activator identical to urokinase [6]. The commercial preparation of urokinase by extracting it from human urine has been a costly, time-consuming procedure. Currently attempts are underway to extract urokinase from tissue cultures of renal epithelial cells. Urokinase has been utilized successfully in patients with arterial and venous thromboses and pulmonary embolism [52, 57, 591. The incidence of bleeding is twice that which occurs with heparin [59] and bleeding is the only undesirable side effect. Streptokinase is again being evaluated as a thrombolytic agent. It was utilized in the late fifties and early sixties and partially discarded because of the high incidence of febrile and sensitivity reactions. Current infusions of streptokinase are associated with approximately a 50% incidence of febrile reactions and a 10-250/O incidence of other (bleeding, sensitivity, etc.) reactions [27, 411. Although streptokinase is a potent activator of plasminogen, the problems of antigenicity, febrile and sensitivity reactions, and the difficulty in monitoring its action suggest that if urokinase becomes readily available there will be little, if any, indication for streptokinase therapy. Brinolase, the fibrinolytic enzyme from Aspergillus oryxae [40, 491, anabolic steroids, the biguanides [23], and numerous other agents are undergoing evaluation as

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plasminogen activators [43], but at present none appears suitable for widespread clinical usage. Hyperfibrinolysis Although primary hyperfibrinolysis is frequently mentioned as a cause of bleeding, it occurs very infrequently. It occurred only once in the last 125 patients studied in our coagulation laboratory. Primary hyperfibrinolysis usually follows a stimulus that causes a massive release of the tissue intravascular fibrinolytic activator, i.e., profound shock, hypoxia, electric shock, or sudden death. Secondary hyperfibrinolysis coagulation, intravascular accompanies usually in direct proportion to the amount of fibrin produced. The differentiation between primary and the secondary hyperfibrinolysis which accompanies intravascular coagulation is frequently quite difficult. Although the platelet count is usually normal during primary hyperfibrinolysis, the coagulation factors may be normal or mildly depressed in either condition because of the proteolytic effect of plasmin or their consumption during the coagulation process. A marked depression of the coagulation factors occurs more often from intravascular coagulation than from fibrinolysis. The ethanol gelation test should be negative when intravascular coagulation is not occurring. The concentration of fibrin-degradation products depends on the relative amounts of fibrin and plasmin and should be higher during times of intravascular coagulation. Fibrinolytic

Inhibitors

acid epsilon-aminocaproic Although (EACA) is the most widely utilized fibrinolytic activator inhibitor, other synthetic fibrinolytic inhibitors are being evaluated. trans-Para-aminomethylcyclohexancarboxylic acid (AMCA), like EACA, is a competitive fibrinolytic inhibitor but is eight to ten times more potent than EACA [13 J. Para-aminomethylbenzoic acid (PAMBA) is less well defined but is comparable to

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Adenosine PGEl 1 Shy Adhesion C Ca++ ; Fib Ca+t ADP I A Primary Aggregation I Thrombln COllW@n Asprin-----Adrenalin Sulfinpyrazone t ,’

L- -Release

i

change

Dqxrsement

(ADP, ATP. if Secondary Aggregation L R.tra~n-+LT”

Ca*,

Fibrin

Release

Formation

Fig. 2. Platelet

Stimulus

P,a*llla

5 HT.

(Fib.,

PF4)

lysozymes)

function.

AMCA in activity [5]. The problem associated with these fibrinolytic inhibitors is that one must be quite certain they are needed, otherwise the protective fibrinolytic response might be inhibited and intravascular coagulation may proceed unchecked. EACA has been found to decrease the cerebrospinal fluid fibrinolytic activity that occurs after subarachnoid hemorrhage [30, 421 and currently is being evaluated as a means of preventing the high incidence of recurrence of subarachnoid hemorrhage from Berry aneurysms. Preliminary results from the Cooperative Study of Intracranial Aneurysms indicates that EACA has reduced the rebleed incidence from 25-30s to 12%. Relationships of Kallikrein-Kinin System and Complement System to the Coagulation-Pibrinolytic Systems. Recent evidence has demonstrated that factor 12 not only initiates coagulation but may also provide a link between coagulation and the kallikrein-kinin systems [38]. Activated factor 12, in addition to initiating the coagulation process, probably activates prekallikrein to kallikrein and the kallikrein splits kinins from the alpha-2 globulins. Fibrinopeptides A and B which have kinin-like actions, probably through their potentiation of the effect of bradykinin and other kinins, provide another link

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between the coagulation and kinin systems. Several investigators have demonstrated the ability of plasmin to release kinins from the prokinins [3.1, 441. The fibrin peptides released by plasmin also complement the activity of kinins. Zimmerman and associates [64] have recently suggested that complement activator substances may initiate blood coagulation. This process may be important in endotoxin-induced disseminated intravascular coagulation or in fibrin deposition associated with organ rejection. Plasmin digests several of the components of complement to active or inactive fragments. C, inactivator can block the action of plasma kallikrein [45], of activated factor 12 [15], and of plasmin [45]. Further studies of the interactions between components of the hemostatic process and the defenses against infection are being actively performed in several centers. PLATELETS Although platelets were first described in 1842 [SO], major investigations of platelets and plateIet function (Fig. 2) have occurred during the past l&15 yr. Platelets adhere to a variety of surfaces. Exposed collagen and basement membrane provide particularly strong stimuli for platelet adherence. Once adherence has occurred, primary aggregation follows. At this point all of the changes are reversible. However, in the presence of thrombin, collagen, and other inducers of platelet function, the platelets release adenosine diphosphate (ADP) , adenosine triphosphate (ATP) , calcium, serotonin, platelet factor 4, and other substances. These substances, especially ADP, cause the platelet plug to undergo irreversible aggregation which is followed by retraction of the plug, fibrin formation and the release of additional platelet material, a secondary release phenomena, and platelet lysis. It would appear most practical for surgeons to be aware of some of the recent findings that relate to the role of platelets in in viva thrombosis

DONALD

SILVER

: COAGULOPATHIES

and to the studies of agents that increase and inhibit the function of platelets. In the arterial system platelets adhere to exposed collagen and/or basement membranes in areas of vascular damage and initiate the sequence of events which can proceed to vascular occlusion and activation of the intrinsic coagulation mechanism. In the venous system, however, platelet aggregation usually occurs in areas of stasis when thrombin is generated. The thrombininduced platelet aggregation may result in the release of platelet factor 3 which increases the rate of generation of thrombin via the intrinsic coagulation system. After aggregation occurs and fibrin formation is begun, vessel occlusion (in either arterial or venous system) is determined by the velocity of blood flow, the inhibitors of coagulation, and the amount of fibrinolytic activity present. All platelet functions are dependent on a continuous synthesis of ATP by glycolosis and oxidative phosphorylation. Some substances induce platelet function (Table 2) through the interactions with specific platelet receptors, some induce function by altering the platelet membrane through proteolysis, and some induce platelet function by causing conformational changes to foreign surfaces. Some inducers, for example, serotonin and vasopressin, are weak inducers and their stimulus stops after the first release phenomenon. Others, such as thrombin, collagen, etc., are strong inducers and cause rapid and complete changes in platelets. Platelet function may be inhibited: by selectively inhibiting specific inducers, e.g., thrombin may be blocked with heparin, the alpha-adrenergic catecholamines with blockers, ADP by competitive inhibition from AMP, ATP, and adenosine; by such agents as ethylenediaminetetraacetic acid products, fibrin-degradation (EDTA) , prostaglandin E, (PGE,) , and dipyridamole, which inhibit primary aggregation; or by agents such as aspirin, sulfinpyrazone, or phenylbutazone which inhibit sec-

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SURGEONS

Table 2. Inclucers of Platelet Function Specific receptors

Proteolytic enzymes

ADP Adrenalin Noradrenalin Serotonin Vasopressors

Thrombin Trypsin Snake venoms Papain

-

Foreign “surfaces” Collagen Antigen-antibody Endotoxin Latex particles

ondary aggregation [34, 361. An increased concentration of cyclic AMP is the most potent inhibitor of every step of platelet function. Cyclic AMP may be increased by activators of adenyl cyclase (Fig. 3). These activators include PGE,, adenosine, and isuprel. Cyclic AMP may also be increased by inhibiting cyclic phosphodiesterase by papaverine, methylxanthines, or dipyridamole [34]. Drugs that interfere with platelet function have undergone experimental and clinical trials as agents for preventing arterial and venous thromboses. Dextran, aspirin, dipyridamole, and/or sulfinpyrazone have been utilized in most of the trials [20, 51, 631. Sulfinpyrazone and dipyridamole have been found to normalize platelet survival in those patients who have accelerated intravascular coagulation, but tend to have little effect on platelet function tests, while aspirin effects in vitro testing but does not prolong platelet survival [39,63], Clinical trials are underway to evaluate the effectiveness of aspirin and sulfinpyrazone in preventing transient cerebral ischemit attacks and amaurosis fugax in patients with cerebrovascular insufficiency

j. Adenyl AI-P L Cyclase

c& Cyclic

AMP

Phosphodiesterase I

Methylxanthines Dipyridamole

Fig, S. Cyclic

amp in Platelets.

> 5’ AMP

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[21, 221. The preliminary results are encouraging. Although dipyridamole is effect’ive in reducing the incidence of thrombosis associated with heart valves [58], it has not been beneficial in decreasing the incidence of venous thrombosis [ 11, 511, or suppressing the incidence of thrombosis associated with atherosclerotic disorders [ 1, 171. PROPHYLACTIC ANTICOAGULATION One should, by interfering with the mechanism(s) responsible for arterial or venous thrombosis, be able to reduce the incidence of clinical thrombosis. Inhibition of platelet function is most promising as a means of reducing the incidence of arterial thromboses. The clinical trials of aspirin and sulfinpyrazone have been mentioned. Heparin also is an effective agent for reducing arterial thromboses. The prothrombinopenic agents have minimal to no value in reducing the incidence of arterial thromboses and probably should not be used. Inhibitors of coagulation are important, in addition to the avoidance of stasis and intimal damage, in reducing the incidence of venous thromboembolism. Heparin is an excellent anticoagulant and has been found by several investigators to reduce the incidence of thromboembolism in surgical and medical patients [ 16, 25, 541. Heparin may be administered in a variety of ways. The 6- to 9-hr persistance of heparin that has been administered subcutaneously [ 91 suggests that giving heparin at 8-hr intervals should inhibit thrombosis. Gallus, Hirsh, and associates have reduced the incidence of thromboembolism from 21.5% to 3.6% in surgical and high-risk medical patients by giving 5000 units of heparin at 8-hr intervals [ 161. The prothrombinopenic agents have also reduced the incidence of postoperative thromboembolism [50]. Plateletinhibiting agents may be used to prevent venous thromboembolism. Salzman and associates have shown aspirin and dextran to appear to be as effective as warfarin in pre-

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venting thromboembolism, mole was ineffective [51]. DEFIBRINOGENATING

1974

while dipyridaAGENTS

Although there is great interest in defibrinogenating agents, the agent we know most about is Arvin, the coagulant fraction of the Malayan pit viper venom. Since the report by Reid and associates in 1963 [46], it has been found that Arvin acts like thrombin and clots fibrinogen but is not inhibited by heparin [14]. Arvin does not split off the fibrinopeptide B and, thus, interferes with the formation of the proper fibrin monomer and subsequently with fibrin polymerization. Also, factor 13 is not activated, and the stabilization of fibrin polymerization does not occur. The administration of 1 U/kg of Arvin intravenously or intramuscularly will produce defibrinogenation which can be maintained by repeat injections at 12-hr intervals [55]. The defibrinogenation is usually not associated with hemorrhage presumably because platelet function and other coagulation factors remain normal. The fibrin polymer is fragile and is dispersed throughout the circulation where it is lysed. Arvin is relatively nontoxic, the lethal dose being 500-1000 times the defibrinogenating dose in animals [55]. Spontaneous hemorrhage has not been observed during Arvin therapy, although bleeding from “recent” surgical wounds has occurred [55]. Arvin may be neutralized rapidly with specific antivenin. Arvin has been effective in the management of animal and clinical arterial and venous thromboses [4, 26, 551, and has been an effective form of therapy in experimental pulmonary embolism [3.7, 531. It has reduced the severity of any embolization and has accelerated the disappearance of the embolus. Its use in clinical pulmonary embolism is being planned. The procoagulant, anticoagulant, and fibrinolytic properties of other viper venoms are undergoing preliminary investigations [8].

DONALD

SILVER

: COAGULOPATHIES

SUMMARY The certain mortality from uncontrolled bleeding and the high morbidity and mortality associated with arterial and venous thromboses make it mandatory that the surgeon be knowledgeable about coagulopathies and about mechanisms for reducing the incidence and sequelae of venous and arterial thromboses. It is hoped that this exposure to coagulation and coagulationrelated research will help some surgeons in their practice of surgery, some in their research-related efforts, and, perhaps, entice a few surgeons to become involved in this exciting area of biological investigations. REFERENCES 1. Acheson, J., Danta, G., and Hutchinson, E. C. Controlled trial of dipyridamole in cerebral vascular disease. Br. Med. J. 1:614, 1969. 2. Acinapura, A. J., Porter, J. M., Futrell, W., and Silver, D. The effect of local vascular trauma on fibrinolysis. Am. Surg. 32:762, 1966. 3. Aoki, N., and VonKaulla, K. N. Dissimilarity of human vascular plasminogen activator and human urokinase. J. Lab. Clin. Med. 78:354, 1971. 4. Bell, W. R., Pitney, W. R., Oakley, C. M., and Goodwin, J. F. Therapeutic defibrination in the treatment of thrombotic disease. Lancet 1:490, 1968. 5. Bennett, B., and Ogston, D.: Natural and drug-induced inhibition of fibrinolysis. Clin. Hematol. 2:135, 1973. 6. Bernik, M. B., and Kwaan, H. C.: Plasminogen activator activity in cultures from human tissues. An immunological and histochemical study. .I. Clin. Invest. 48:1740, 1969. 7. Biggs, R., Macfarlane, R. G., and Pilling, J.: Observations on fibrinolysis. Experimental activity produced by exercise or adrenaline. Lancet 1:402, 1947. 8. Boffa, M. C., Josso, F., and Boffa, G. A.: The action of vipera aspis venom on blood clotting factors and platelets. Thromb. Diath. Haemorrh. 27:8, 1972. 9. Bonnar, J., Denson, K. W. E., and Biggs, R.: Subcutaneous heparin and prevention of thrombosis. Lancet 2:539,1972. 10. Breen, F. A., Jr., and Tullis, J. L. Ethanol gelation: A rapid screening test for intravascular coagulation. Ann. Intern. Med. 69:11197, 1968. 11. Browse, N. L., and Hall, J. H. Effect of dipy-

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ridamole on the incidence of clinically detectable deep-vein thrombosis. Lancet 2:718, 1969. 12. Bull, B. S., Rubenberg, M. L., Dacie, J. V., and Brain, M. C. Microangiopathic haemolytic anemia: Mechanisms of red cell fragmentation: In vivo studies. Br. J. Haematol. 14:643, 1968. 13. Dubber, A. H. C., McNicol, G. P., and Douglas, A. S. Amino methyl cyclohexane carboxylic acid (AMCHA), a new synthetic fibrinolytic inhibitor. Br. J. Haematol. 11:237, 1965. 14. Esnouf, M. P., and Tunnah, G. W. The isolation and properties of the thrombin-like activity from Ancistrodon rhodostoma venom. Br. J. Haematol. 13:581, 1967. 15. Forbes, C. D., Pensky, J., and Ratnoff, 0. D. Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified (Cl inactivator. J. Lab. Clin. Med. 76:809, 1970. 16. Gallus, A. S., Hirsh, J., Tuttle, R. J., Trebilcock, R., O’Brien, S. E., Carroll, J. J., Minden, J. H., and Hudecki, S. M. Small subcutaneous doses of heparin in prevention of venous thrombosis. N. Engl. J. Med. 288:545, 1973. 17. Gent, A. E., Brook, C. G. D., Foley, T. H., and Miller, T. N. Dipyridamole: A controlled trial of its effect in acute myozardial infarction. Br. Med. J. 4:366, 1968. 18. Gurewich, V., and Hutchinson, E. Detection of intravascular coagulation by a serial-dilution protamine sulfate test. Ann. Intern. Med. 75895, 1971. 19. Hardaway, R. M. Syndromes of disseminated intravascular coagulation with special reference to shock and hemorrhage. Thomas, Springfield, Ill., 1966. 20. Harker, L. A., and Slichter, a. J. Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. N. Engl. J. Med. 283:1302, 1970. 21. Harrison, M. J. G., Marshall, J., Meadows, J. C., and Russell, R. W. R. Effect of aspirin in amaurosis fugax. Lancet 2:743, 1971. 22. Hirsh, J. Platelets. Can. Med. Assoc. J. 108:416, 1973. 23. Hocking, E. D., Chakrabarti, R., Evans, J., and Fearnley, G. R. Effect of biguanides and atromid on fibrinolysis. J. Atheroscler. Res. 7:121, 1967. 24. Hunter, J.: A treatise on blood, inflammation, and gun-shot wounds. Nicol, London, 1794. 25. Kakkar, V. V., Field, E. S., Nicolaides, A. N., and Flute, P. T. Low doses of heparin in prevention of deep-vein thrombosis. Lancet 2:669, 1971. 26. Kakkar, V. V., Flanc, C., Howe, C. T., O’Shea, M., and Flute, P. T. Treatment of deep vein

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