A new treatment for traumatic shock and ARDS

Resuscitation, 19 (1990) 61-76 Elsevier Scientific Publishers Ireland Ltd.

A new treatment

61

for traumatic ARDS

shock and

Robert M. Hardaway and Charles H. Williams Department of Surgery, Texas Tech University Health Sciences Center, 4800 Albert Avenue, El Paso, TX 799051298 (U.S.A.) (Received December 27th, 1988; revision received June 18th. 1989; accepted August 14th, 1989) Trauma causes more years of lost life than any other cause of death. Traumatic shock and sepsis are the most common late causes of death following trauma. Traumatic shock and sepsis cause mutliple organ failure. The most common organ to fail is the lung, which develops Adult Respiratory Distress Syndrome (ARDS). ARDS can be caused by Disseminated Intravascular Coagulation (DIC) with microscopic clots in the lungs. Trauma causes hemolysis and the red cell stroma may initiate DIC. Plasminogen activators, which causes lysis of blood clot, can lyse pulmonary microthrombi and prevent the onset of ARDS even when given several hours after the trauma. Shock -Trauma - Traumatic shock - Adult Respiratory Distress Syndrome - Disseminated Intravascular Coagulation - Plasminogen - Plasminogen activator INTRODUCTION

Trauma is the number one cause of death of all Americans under the age of 45 years [1,2]. It is the number three cause of death of Americans of any age [l]. Trauma is the cause of more lost years of life than any other cause of death [31 (Fig. 1). Trauma touches over 60 million Americans every year. Major traumatic injury afflicts one in three persons in the U.S.A., resulting in 99 million physician contacts, 500 000 hospital admissions, 164 000 deaths and over 300 000 major disabilities [4]. The total cost of the U.S.A. is estimated to be over 100 billion dollars annually [5]. The National Academy of Sciences has called trauma ‘the principal public health problem in American today’. Approximately 30% of trauma victims die of treatable injuries. It is amazing that this number one cause of loss of productive life by young people has resulted in a microscopic level of research funding (Fig. 2) Ul. The most common causes of death ensuing from trauma are shock and sepsis. The most common cause of death after traumatic shock and sepsis is multiple organ failure. Perhaps the most common organ to fail is the lung. This condition is called Adult Respiratory Distress Syndrome (ARDS). ARDS affected 200 000 Americans last year of which two third (about 130 000) died [2]. ARDS is caused by trauma or sepsis or both. ARDS, formerly called shock lung, stiff lung, Da Nag lung, respirator lung, post traumatic pulmonary insufficiency, wet lung, pulmonary edema, and other names,

0300-9572/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

62

YEARS t-

Fig. 1. ease.

OF POTENTIAL

LIFE LOST

1 ?? cnRDIounSalLaR ?T ? IMUM

?? CnNcER

Trauma causes twice as many years of potential loss of life as either cancer or cardiovascular dis-

RESEARCH

EXPENDITURES

In Millions Of Dollars

1200 -j-

998

1000

1000 +

800 800

t-

m

TRAUMA

m

CARDIOVASCULAR

t::]

CANCER

m

AIDS (Projected)

Fig. 2. Research funding for trauma is miniscule compared to research funding for cardiovascular disease, cancer and AIDS.

63

has been treated empirically by oxygen, given by respirator and assisted by PEEP (positive and expiratory pressure) [3]. In spite of this supportive treatment mortality exceeds 70% [6]. During the past 25 years evidence has accumulated that this condition was associated with and caused by Disseminated Intravascular Coagulation (DIC) [7--151. The DIC may be brought on by hemolysis of red cells secondary to trauma [14,15]. The inner surface of the red cell membrane when exposed to the circulating blood is highly thrombogenic [ 161 and initiates DIC, especially if there is some hypovolemia at the same time, as there usually is. The thrombogenic substances on the inner surface of the red cell membrane are phosphatidyl-ethanolamine and phosphatidyl-serine [16]. The red cell membrane may also act as particulate matter to stimulate the onset of DIC [17]. ARDS follows either trauma or sepsis or both. DIC occurs after both trauma and sepsis. Bacterial toxins cause coagulation, DIC and ARDS [21,24,25]. Human septic shock with ARDS has been successfully treated with thrombolysin [26]. Hemolysis following trauma has been documented repeatedly [ 14,15,17,18] (Fig. 3). Trauma and hemolysis results in traumatic shock and lung lesions similar to clinical ARDS. Similar lesions can be produced by human septic shock, hemorrhagic

Fig. 3. Three spun down samples taken on the left (A) before trauma, center (B) 30 min after trauma, and right (C) 24 h after trauma. Note that hemolysis did not appear right away but rose steadily for 24 h. (Published with permission from R.M. Hardaway, Shock-The Reversible Stage of Dying, PSG Publishers 1988).

64

shock and endotoxin shock in animals (Figs. 4-6). All of the lesions appear to be caused by DIC and microclots in the lungs by the sieving action of the lung capillaries can cause a slowly accumulating dysfunction of lung gas exchange. A 5% dysfunction per hour due to microclots will seriously compromise lung gas exchange in 24 to 36 hours. The microclots in the lungs which cause the syndrome of ARDS, can be lysed by fibrinolytic enzymes [7,9,10-12,18,20,21]. REVIEW OF ANIMAL AND CLINICAL

STUDIES ON TRAUMATIC

AND HEMORRHAGIC

SHOCK AND TREATMENT WITH FIBRINOLYTIC ENZYMES

(I) In 1963, 28 dogs were subjected to ‘irreversible’ hemorrhagic shock of 30 mm mean arterial pressure for 2.5 h at which time the bled blood was retransfused [lo]. Fourteen dogs received no treatment. The other 14 dogs received 4000 MSD units/ kg in 25 ml saline of human fibrinolysin activated by streptokinase (MSD Thrombolysin) immediately following the bleed [lo]. Three (21%) of the control dogs survived 48 h whereas 11 (79%) of the fibronolysin-treated dogs survived 48 h. This was significant at P < 0.05.(It was our experience that animals which survived 48 h survived indefinitely).

Fig. 4. Lung of dog dying of endotoxin shock. Note large areas of dark blue color, consolidation, edema congestion and hemorrhage. (Published with permission from R.M. Hardaway, Shock-The Reversible Stage of Dying, PSG Publishers, 1988).

65

Fig. 5.

Photomicrograph of lung of human dying of ARDS and septic shock. (Published Hardaway, Shock-The Reversible Stage of Dying, PSG Publishers, 1988).

with permis-

sionfrom R.M.

(II) Also in 1963 in another experiment [20], 39 dogs were divided into 3 groups. Fifteen dogs were bled to a mean aortic pressure of 0.30 mHg and kept there for 2.5 h when the bled blood was returned to the animal. No treatment was given. Another fifteen dogs were similarly bled but was given 2000 MSD units of human fibrinolysin (Thrombolysin) immediately after the bleed. This was half the dose of fibrinolysin given in the previous series. Another nine dogs were not bled but were given fibrinolysin alone. In the untreated group, 11 (74%) died within 24 h while 4 (26% of the fibrinolysin group) died. This was significant at P > 0.05. All of the dogs given fibrinolysin alone survived. (III) In 1964 in another experiment [14], 121 dogs were divided into 10 groups. Group 1 was bled to 40 mHg for 3.5 h at which time the bled blood was returned to the animal. Group 2 was treated the same as group 1 except that prior to bleeding 20 ml of his own blood was withdrawn frozen in solid CO, thawed and immediately returned to the animal. Group 3 was treated as in group 2 except that 100 000 units of fibrinolysin was given at the end of the shock period. Group 4 had 100 ml of their own hemolyzed blood given but were not bled. Group 5 had 50 ml of their own blood hemolyzed. Group 6 had 20 ml of their own blood hemolyzed. Group 7 was given a purified hemoglobin without the stroma. Group 8 was given fibrinolysin but was not bled nor given hemolyzed blood. Group 9 was bled, given 20 ml of hemolyzed blood and was given separin (1 before and after shock). Group 10 was given

kcl+

B

100

20 ml Hem. El.

+ 20 ml.Hcm. 81. + Fibrinolysin

Shock

0

L

Fig. 6. (A) Lung of pig dying of traumatic shock. Note large areas of congestion, edema, hemorrhage and dark color. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator, Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, California, 1988). (B) Hemorrhage alone caused only a 13% mortality. Hemolyzed blood alone caused no mortality. However, the combination of hemorrhage and hemolysis caused a 91 Vo mortality. This could be reduced to 38% with fibrinolysin treatment.

67

fibrinolysin as in group 8 (no shock) but was given 100 ml hemolyzed blood after the fibrinolysin. Mortality was as follows (Fig. 6B): Group 1 2 3 4 5 6 7 8 9 10

Shock alone Shock and hemolyzed blood 20 ml Shock, hemolyzed blood (20 ml) and fibrinolysin Hemolyzed blood alone (100 ml) Hemolyzed blood alone (50 ml) Hemolyzed blood alone (20 ml) Shock and “purified” hemoglobin Fibrinolysin alone Shock, hemolyzed blood (20 ml) and heparin Hemolyzed blood (100 ml) and fibrinolysin

No. of dogs

No. Died

% Died

15 34 13 13 2 2 13 14 8 9

2 31 5 0 0 0 11 0 9 0

13 91 38 0 0 0 84 0 100 0

(IV) In 1967, a 30-year-old white woman was in Walter Reed Army Medical Center in severe septic shock with positive blood cultures of E. coli and Klebsiella aerobacter [12]. She suffered from severe ARDS with an arterial PO, of 37 mmHg on lOO@/o oxygen on a respirator with PEEP. Death seemed imminent. She was given 45 000 units of fibrinolysin, an activated plasminogen then commercially available. It was given intravenously over a 4-h period (Fig. 7). Within 6 h her arterial PO, was 155 mmHg and she was quickly weaned off 100% oxygen down to 40% 0, and within 4 days was taken off the respirator. There was no evidence of bleeding. She went on to recovery and discharge. (V) Picking up on the above experimental and clinical results, Harke and Rahman, in Germany in 1988 [21], treated 30 patients in severe traumatic or septic shock with ARDS with streptokinase. There was a mean rise of 217 mmHg in the arterial PO, as a result of the treatment (Table I). Forty-six percent of the patients survived even though the previous treatment with respirator and oxygen had failed. Two of the patients experienced a mild bleeding tendency which was not a problem. (VI) In 1988, animal experiment carried out at Texas Tech University Health Sciences Center in El Paso have dealt with traumatic shock in pigs 1181. The animals were anesthetized and kept under continuous anesthesia for 48 h. They were then sacrificed by an overdose of anesthesia. Each animal had received 60 blows with a padded mallet to each outer thigh. Care was taken not to break skin, bone, or major blood vessels. A contusion of the muscles of the outer thigh was produced. All procedures were conducted under aseptic conditions. Ventilation was maintained for 48 h with a volume cycled respirator with 40% 0, (Fig. 8). Adequate blood volume was assured by infusion of Ringers Lactate governed by central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, urine output and arterial pressure. Intravenous dextrose provided supplemental nutrition. Fifty three different parameters were measured periodically over the 48-h period including clotting studies, blood gases, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, left ventricular pressure, core temperature, cardiac output, femoral artery flow to the leg and many others. The animals were divided into three groups.

m

March

March

March

March

MmCh

MNCh

SEPTIC SHOCK

Mvcil

30 yr. old female, Septic Shock, Pt. 28 Fig. 7. Patient in severe septic shock and ARDS with an arterial PO, of 37 mmHg. After IV administration of fibrinolysin, PO, rose to 155 mmHg. (Published with permission from R.M. Hardaway, ShockThe Reversible Stage of Dying, PSG Publishers, 1988).

Group A: (9 animals) received no medication. All nine died before 48 h (Fig. 9). The average initial PO, was 222 mmHg. Their average PO, at the end of observation was 39 mmHg (Fig 10). All animals showed massive lung involvement of both lungs with the lungs appearing hemorrhagic, endematous and stiff. Other data showed the onset of DIC starting between 4 and 8 h after trauma as indicated by the sudden rise in fibrin split products (Fig. 11). This coincided with the appearance of a severe hemolysis in the spun down serum (Fig. 12). Fibrinogen rose sharply from about 150

69

Fig. 8. Experimental design of pig experiments with traumatic shock. Animals were under anesthesia for entire 50-h period until sacrifice. Plasminogen activator infusion was started 4 hours after trauma. (From R.M. Hardaway. Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Reach, Calif., 1988).

--9 --0 --1 --6 --5 --4 --3 t2 1 0

Fig. 9. Nine untreated trauma pigs. All died within 48 h, all but one within 32 h. Ten trauma pigs treated with plasminogen activator survived 48 h and were sacrificed by overdose of anesthesia. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Reach, Calif., 1988).

mm% to 500 mg% over the 4 h (Fig. 13). PT, PTT and clotting time remained within normal limits. Platelets fell moderately. Blood loss into traumatized tissue was not significant. Central venous pressure, pulmonary artery pressure and pulmonary capillary wedge pressure remained within normal limits. Core temperature usually rose from about 37.7OC to around 40°C. Group B: (5 animals) received 500 000 units of Urokinase (Abbokinase) in 5% glucose solution overa 44-h period starting 4 h after the trauma. All pigs survived. The average PO, at the end of the 48-h period was 86 mmHg (Fig. 10). Other parameters remained within normal limits. There was moderate lung involvement at autopsy involving the lower and posterior parts of the lower lobes. Clotting parameters remained within normal limits. Blood loss into traumatized tissue was not significant. Group C: (5 animals) received 250 mg. TPA (tissue plasminogen activator) (Activase) over a 44-h period starting 4 h after the trauma. All pigs survived. The average PO, at the end of the 48-h period was 190 mmHg (Fig. 10). Lung lesions at autopsy were minimal, usually involving just the tips of both lower lobes (Figs. 14 and 15). Clotting and other parameters remained within normal limits. Blood loss into traumatized tissue was not significant. (YII) In 1989, a clinical study is under way using urokinase (abbokinase) in the treatment of ARDS following either trauma or sepsis or both. The protocol is as follows: If a patient. suffers from trauma or sepsis or both develops ARDS it is treated by all means possible including 100% oxygen by respirator and PEEP. If his arterial

250

TRAUMA 222

P-n.%

P=
200

!ia

a

Fig. 10. Nine untreated pigs (right) had an average 22 h PO, of 39 mmHg. A drop from an initial reading of 222 mgHg. This is significant at P < 0.00004. Two groups of plasminogen activator pigs showed insignificant falls in PO, after 48 h. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, Calif., 1988).

40 TRAUMA-FIBRINOGEN DEGRADATION PRODUCTS ,-

M 30 i 0 G

’

!z M s 10

0

1

4

7.5

18

24

TIME (hrs) Trauma Fig. 11. After trauma, no fibrin split products appeared in any of the pigs until 7 h when high levels of split products appeared. The level usually fell toward the 48 h time. Ail pigs, both controls and plasminogen activators treated, showed similar fibrin split products indicating DIC. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, Calif., 1988).

Fig. 12. Spun down blood samples taken at intervals after trauma. Note that hemolysis started with the 8-h sample, increased until the 24-h sample, and decreased so that it was absent in the 48-h sample. This was similar in all pigs, both untreated and those given plasminogen activator. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, Calif., 1988).

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SW

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36

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43

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Fig. 14. Lung of pig sacrificed after 48 h and treated by plasminogen activator. Note minimal lesions at tips of lower lobes. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, Calif., 1988).

PO, falls below 60 mmHg and fails to respond to the above treatment for 12 h, he is put on the protocol. Mortality for such patients approaches 100%. He is then given 1000 units of urokinase per pound of body weight in saline over 10 min. After this he is given 1000 units of urokinase per pound of body weight per hour for 24 h. A control group is not given the medication. Although the study is just starting results are interesting. A lady weighing 200 lb was hit by a truck and sustained multiple fractures and a ruptured liver. She developed ARDS with an arterial PO, of 40 mmHg on 100% 0, and 22 in PEEP. She also developed acute renal failure and acute liver failure (hepatorenal syndrome) and was deeply jaundiced. She was given urokinase and her PO, rose to 120 mmHg and remained there for 8 days when she died of renal and liver failure. Two control patients died with a continuing fall in PO, despite 0, therapy and PEEP. Fig. 13.

Fibrinogen levels spite of increased utilization manufacture stimulated by with Plasminogen Activator. of Trauma, Newport Beach,

consistently rose in all pigs (treated and untreated) over the 48-h period in and digestion. This is because of the tremendous stimulation to fibrinogen trauma (or any stress) [17]. (From R.M. Hardaway, Prevention of ARDS Presented at 48th Annual Meeting of American Association for the Surgery Calif., 1988).

Fig. 15. Lung of pig sacrificed after 48 h and treated by plasminogen activator. Note minimal lesions at tips of lower lobes. (From R.M. Hardaway, Prevention of ARDS with Plasminogen Activator. Presented at 48th Annual Meeting of American Association for the Surgery of Trauma, Newport Beach, Calif., 1988).

DISCUSSION

The cause of death in all of these animal and human studies of hemorrhagic and traumatic shock seem to be related to the onset of DIC. Proof of the presence of DIC is sometimes lacking but usually consists of the onset of a clotting defect secondary to a consumptive coagulopathy and the development of focal tissue infarction of vital organs. Microthrombi are usually not found, probably because the endogenous activation of plasminogen always accompanies DIC and causes rapid lysis of the microclots. If epsilon amino caproic acid is given to experimental animals before DIC is produced, microthrombi are always numerous [27-321. Further proof of the presence of DIC is the therapeutic effect of clot lysing substances. These can be in the form of already activated plasmin such as thrombolysin or as plasminogen activators such as urokinase, streptokinase or tissue plasminogen activator (TPA).

75

CONCLUSIONS

(1) Trauma is the most important cause of loss of productive years of life in America. (2) The most treatable causes of death after trauma are traumatic shock and sepsis. (3) Trauma causes hemolysis. Red cell stroma may initiate DIC. (4) DIC causes ARDS. (5) DIC can cause ARDS by causing small clots in the pulmonary capillaries. (6) ARDS is often fatal when treated only by 0, and respirator and PEEP. (7) ARDS can be successfully treated by plasminogen activator given several hours after trauma. (8) Bleeding, although a theoretical complication in trauma patients has not been a significant problem in plasminogen activator treated animals or streptokinase treated human patients. REFERENCES 1

2

8 9 10 11 12 13 14 15 16 17 18

19 20

I.K. Cohen, Chairman of Division of Plastic and Reconstructive Surgery. Medical College of Virginia; quoting figures supplied by the American Trauma Association in Emergency Medicine and Ambulatory Care, 1988, Vol. X, No. 6, p. 1. D. Langunoff, Chairman, Department of Pathology. St. Louis University School of Medicine in Parameters in Health Care, Winter, 1989. Centers for Disease Control, Premature Mortality in the United States MMWR Suppl. 35 (1986) 1s -11s. D.D. Trunky, Value of trauma centers, Bull. Am. COB. Surg., Oct. 1982. S.R. Shackford and A. Perol, Forword to Trauma, Probl. Crit Care, No. 1. 1987. Multisystem Organ Failure, J. Am. Med. Assoc., 260 (1988) 22-29. R.M. Hardaway, Pulmonary Microthrombi in Pulmonary Embolic disease. Editor: A.-A. Sasahara, Grune and Stratton, New York, 1965, pp. 65-72. R.M. Hardaway, P.M. James, R.W. Anderson, C.E. Bredenberg and R.C. West, Intensive study and treatment of shock in man, J. Am. Med. Assoc., 199 (1967) 779-790. R.W. Hardaway and D.G. Johnson, Influence of fibrinolysin on shock, J. Am. Med. Assoc., 183 (1963) 597-599. R.M. Hardaway and J.W. Burns, Mechanism of action of fibrinolysin in the prevention of irreversible hemorrhagic shock, Ann. Surg., 157 (1963) 305-309. R.M. Hardaway, Pulmonary pathology in shock states, International Shock Symposium, Utrecht, Holland, March, 1977. R.M. Hardaway, Acute respiratory distress syndrome and DIC, Southern Med. J., 71 (1978) 596598. R.M. Hardaway, Mechanism of traumatic shock, Surg., Gynecol. Obstet. 151 (1980) 65-69. R.M. Hardaway, D.O. Jonson and M.J. Elovitz, Influence of trauma and hemolysis on hemorrhagic shock in dogs, J. Trauma, 4 (1964) 624. R.M. Hardaway, Tissue injury and activation of the coagulation system in Dynamics of thrombus formation and dissolution. Editors: S.A. Johnson and M.M. Guert, Lippincott, 1969. M. Feola, J. Simoni, P.C. Canizaro, R. Tran, G. Raschbaum and F.J. Behal, Toxicity of polymerized hemoglobin solutions, Surg., Gynecol. Obstet., 166 (1988) 21 l-222. R.M. Hardaway, R. Dumke, T. Gee, T. Meyers, J. Joyner and J. Graf, The danger of hemolysis in shock, Ann. Surg., 189 (1979) 373-376. R.M. Hardaway, C.H. Williams, M. Marvasti, M. Farias, A. Tseng et al., Treatment of ARDS with urokinase, Presented at the 48th Annual Meeting of the American Association for the Surgery of Trauma, 1988. R.M. Hardaway and D.G. Johnson, Clotting mechanism in endotoxin shock, Arch. Int. Med., 112 (1963), 775-782. R.M. Hardaway and P.C. Drake, Prevention of “Irreversible” hemorrhagic shock with fibrinolysin, Ann. Surg., 157 (1963) 37-47.

76 21 22 23 24 25 26 27 28

29

30 31 32

H. Harke and S. Rahman, Fibrinolytic enzymes in shock treatment. In Shock - The Reversible Stage of Dying. Editor: R.M. Hardaway, PSG Publishers, Littleton, MA, 1988. R.M. Hardaway, D.G. Johnson, D.N. Houchin, E.B. Jenkins, J.W. Burns and D.R. Jackson, Influence of stress on fibrinogen, J. Trauma, 4 (1964) 673-676. R.M. Hardaway, E.A. Husni, E.F. Geever et al., Endotoxin shock, a manifestation of intravascular clotting, Ann. Surg., 154 (1961) 791-802. R.M. Hardaway and D. Johnson, Clotting mechanism in endotoxin shock, Arch. Int. Med., 112 (1963) 775-782. R.L. West, M.J. Elovitz and R.M. Hardaway, Blood coagulation factor activity in experimental endotoxin, Ann. Surg., 163 (1966) 567-572. R.M. Hardaway, Acute respiratory distress syndrome and DIG, Southern Med. J., 71 (1978) 5%598. R.M. Hardaway, Clinical Management of Shock, Charles Thomas, Springfield, IL, 1968, p. 65. I.M. Nilsson, H. Krosh, N. Sternby et al., Severe thrombotic disease in a young man with bone marrow and skeletal changes and with a high context of an inhibitor in the fibrinolytic system, Acta Med. Stand., 169 (1961) 323. S. Golieb, Bleeding in the surgical patient, Ann. NY Acad. Sci., 115 (Art. 1) (1964) 299. S. Shery, A.P. Fletcher and N. Alkjaersig, Fibrinolytic bleeding and its management, Ann. NY Acad. Sci., 115 (Art. 1)(1964)421. R.L. Naeye, Thrombotic state after a hemorrhagic diathesis, A possible complication of therapy with epsilon caproic acid blood, XIX (1962) 694. A.P. Fletcher, N. Alkjaersig and S. Shery, Fibrinolytic mechanism and the development of thrombolytic therapy, Am. J. Med., 33 (1962) 738.