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Changes in the Coagulation Mechanism Following Wounding and Resuscitation with Stored Blood

Chapter 8

Changes in the Coagulation Mechanism Following Wounding and Resuscitation with Stored Blood*

A Study of Battle Casualties in Korea

First Lieutenant Russell Scott, Jr., MC, USAR
Lieutenant Colonel William H. Crosby, MC, USA

During the summer and autumn of 1952 a study of hepatic function in battle casualties was carried out by the Surgical Research Team of the U. S. Army in Korea.11 The observations were made at a forward Surgical Hospital 1 to 4 hours after wounding, at the time of initial resuscitation and surgery and during the first days of convalescence. The one-stage prothrombin time was employed as one index of hepatic function. It was observed that following wounding and resuscitation with stored blood, prothrombin activity fell to about 50 per cent of normal. This was followed, within 4 days, by a return toward normal which persisted 1 to 3 days. Following this rise, prothrombin activity again fell. In some of the most severely wounded the "primary rise" toward normal was small or absent, and the "primary fall" and "secondary fall" blended into one period of decreased prothrombin activity before the late rise to normal began on about the tenth day. It was the purpose of the present study to define these changes in prothrombin activity.

Methods and Materials

During the winter of 1952-1953 a total of 11 moderately and severely wounded battle casualties were studied in detail, 7 from the immediate postoperative period, the remainder from the first postoperative day until evacuation 4 to 10 days later. These patients had received 6 to 16 pints of stored whole blood 10 to 15 days old. The daily tests consisted of clotting time, platelet count, plasma fibrinogen, and one-stage prothrombin time. On days that significant changes in prothrombin activity were noted three additional tests were carried out to determine the effect of the patients' plasma on the prothrombin time of stored plasma and to determine the effect of deprothrombinized plasma and heated serum on the patients' 


*Previously published in Blood, The Journal of Hematology 9: 609, 1954.


98

plasma. An additional 16 patients had prothrombin time determinations only. This group had received 5 to 30 units of blood.

Prothrombin time was determined by the one-stage method of Quick,9 adding calcium and then thromboplastin to 0.1 ml. of oxalated plasma. The determination was carried out in duplicate or triplicate. The variation between determinations on any given specimen was usually 0 to 0.1 second, rarely greater than 0.2 second, and 0.3 second was considered the maximal allowable variation. Meticulous care in every detail was employed in standardizing the test. All of the determinations were carried out by one of the authors (RS).

Thromboplastin was of human brain origin prepared by the standard acetone extraction technic.9 The prothrombin time of normal plasmas varied from 9.8 to 11 seconds with one lot of thromboplastin and from 11 to 12.6 seconds with another lot.

Calcium chloride, 0.015 M, was used in the volume that was found to give the shortest prothrombin time for each plasma tested. The volume of calcium chloride solution added was varied by 0.01 ml. until the optimal amount was determined. It was found that a patient with a low hematocrit usually required less calcium than a patient with a high hematocrit. The usual volume of calcium chloride solution required was 0.1 .02 ml.

Diluent for establishing the curve for normal prothrombin activity was prepared by incubating normal oxalated plasma with 0.008 M tricalcium phosphate gel.9 Residual prothrombin activity of this plasma was less than 1 per cent (Table 1, tube 12). Gel-treated plasma is free of prothrombin and stable factor but contains the original labile factor.2-4 It is referred to below as "deprothrombinized plasma."

Stored plasma was prepared by storing normal, sterile oxalated plasma at 4 C for 4 weeks in an unsealed container. It had a prothrombin time of about 26 seconds (Table 1, tube 9). Plasma so treated is deficient in labile factor.9 When one part of normal oxalated plasma was added to nine parts of stored plasma the deficiency was partially corrected and the prothrombin time decreased from 26 seconds to about 15 seconds (Table 1, tubes 9-10).


99

Table 1. Characterization of Reagents Prepared From Normal Blood
 

Tube

Oxalated Plasma (ml.)

Deprothrombinized Plasma (ml.)

Stored Plasma (ml.)

Heated Serum (ml.)

Prothrombin Time (Seconds)

1

0.10

     

12.0

2

0.08

0.02

   

13.1

3

0.05

0.05

   

15.0

4

0.03

0.07

   

18.8

5

0.02

0.08

   

22.2

6

0.09

0.01

   

12.4

7

0.09

   

0.01

12.4

8

 

0.05

 

0.05

No clot

9

   

0.10

 

26.4

10

0.01

 

0.09

 

15.4

11

   

0.09

0.01

27.5

12

 

0.10

   

90.0

13

0.1

(No brain thromboplastin added).

0.10

No clot

Note. In tubes 1 to 12 the prothrombin time was taken after adding first calcium and then thromboplastin.

Plasma free of stable factor (Factor VII) was prepared by filtering oxalated ox plasma through 30 per cent asbestos filter pads.7

Heated serum was prepared by adding 5.0 ml. of freshly drawn blood to 0.2 ml. of active thromboplastin solution. The blood coagulated instantly and was then incubated for 30 minutes at 37 C. This treatment was found to convert all prothrombin to thrombin and all labile factor to activated labile factor. The serum was decanted and 2.8 ml. were oxalated by adding 0.5 ml. of 0.1 M potassium oxalate. Finally it was incubated at 53 C. for 30 minutes. Heated serum used as a diluent prolonged the prothrombin time of normal plasma (Table 1, tubes 1 and 7). It did not cause deprothrombinized plasma to clot (Table 1, tube 8). These observations indicated that the heated serum contained no thrombin or prothrombin. Heated serum did not cause clotting of ox plasma that was free of stable factor. This indicated that heated serum did not contain stable factor. Heated serum prolonged the clotting time of stored plasma (Table 1, tubes 9 and 11). This indicated that heated serum did not contain labile factor. Heated serum when used in the place of thromboplastin in a one-stage test did not cause normal plasma to clot (Table 1, tube 13). This indicated that heated serum did not contain thromboplastin.


100

The serum at 56 C. did not form a coagulum. This indicated that no fibrinogen was present in heated serum.

Fibrinogen determinations were carried out using Quick's modification of the method of Cullen and Van Slyke.9 Twenty normal plasmas varied from 225 to 400 mg. per 100 ml.

Clotting time was carried out using a modification of the method of Lee and White.10 Siliconed (Desicote) tubes and syringes were used throughout. After venipuncture the syringe was changed to draw the blood, obviating contamination with tissue juices. A stop watch was started when blood appeared in the syringe. Clotting time of normal blood varied from 25 to 40 minutes.

Platelet counts were determined using the method of Brecher and Cronkite.1 The normal platelet count varied between 200,000 and 300,000 per cu. mm.

Calculation of Results

So that changes could be studied and presented graphically the following system was followed.

Prothrombin activity was stated as per cent of normal activity. By diluting normal plasma with normal deprothrominized plasma, the prothrombin time at several concentrations was established. Prothrombin time was plotted against concentration on logarithmic graph paper, and the patient's activity was calculated from this curve (Table 1, tubes 1-5).

The effect of heated serum and deprothrombinized plasma on patient's plasma was calculated as follows (for example, Patient DD, Table 2):

The deficit of prothrombin activity of undiluted plasma was determined.

Activity of normal undiluted plasma 100 per cent
Activity of patient's undiluted plasma -66 per cent

Per cent deficit of undiluted plasma 34 per cent (A)


101

Table 2. The Effect of Deprothrombinized Plasma on the Prothrombin Time of Patient's Plasma During the Primary Fall
 

Patient.*
Size of Transfusion.
Type of Wound.

Oxalated Plasma (ml.)**

Deprothrombinized Plasma (ml.)

Prothrombin Time (Seconds)

Prothrombin Activity
(Per Cent of Normal)

Correction of Coagulation Defect 
(Per Cent)

DD-15

         

Perforation of chest and lung

N-0.1
N-0.02
P-0.1
P-0.02

0
0.08
0
0.08

11.4
19.8
13.2
21.0

100
20
66
18

 
70

EE-9

 

       

Penetrating wounds of both legs; traumatic

N-0.1
N-0.01
P-0.1
P-0.01

0
0.09
0
0.09

10.6
27.0
12.8
33.6

100
10
80
8

 
0

M-6

 

       

Penetrating wound of chest, diaphragm and liver

N-0.1
N-0.02
P-0.1
P-0.02

0
0.08
0
0.08

12.0
20.4
14.6
25.5

100
20
62
12

 
0

FF-9

 

       

Penetrating wound of abdominal walls and back

N-0.1
N-0.01
P-0.1
P-0.01

0
0.09
0
0.09

12.0
26.8
13.2
28.5

100
10
80
8

 
0

X-16

 

       

Extensive injury of buttocks

N-0.1
N-0.09
P-0.1
P-0.09

0
0.01
0
0.01

10.4
11.0
13.7
13.6

100
90
48
48

 
10

GG-13

 

       

Penetrating wounds of extremities, large and small intestine

N-0.1
N-0.04
P-0.1
P-0.04

0
0.06
0
0.06

12.2
14.5
13.8
17.4

100
40
55
28

 
33

*The identifying letters are the same as those used in two other reports dealing with this same group of patients.3, 4 The number is volume of transfusion in pints of blood.
**N = Normal Plasma. P = Patient's Plasma.


102

Prothrombin activity of patient's and normal plasmas at a given dilution was determined after diluting the plasmas with heated serum or deprothrombinized plasma. The deficit of prothrombin activity at that dilution was then established (DD, Table 2).

At 20 per cent dilution normal plasma activity = 20 per cent.

At 20 per cent dilution patient's plasma activity = 18 per cent.

Activity of the patient's plasma in terms of normal at that dilution = 18/20 or 90 per cent activity.

The deficit at that dilution = 100 minus 90 or 10 per cent (B).

The correction of the coagulation defect by the diluent can be calculated: A=B/A x 100 = 34-10/34 = 70 per cent Correction

Effect on stored labile factor deficient plasma was calculated on a logarithmic curve constructed in a fashion similar to that used for the one-stage prothrombin time.

Results

A primary fall of prothrombin activity to about 50 per cent of normal was observed immediately after surgery and persisted 1 to 4 days. This is referred to as the "primary fall." In 70 per cent of 28 cases, the maximal depression had been found to occur immediately postoperatively and varied from 34 to 80 per cent of normal.11 This was followed by a "primary rise" to 90 per cent of normal activity or higher during the first 4 postoperative days. On the third to the fifth day there was "secondary fall" to 50 per cent of normal activity which persisted until the tenth postoperative day before a return to normal activity began. The maximal fall usually occurred about the seventh day and varied from 20 to 80 per cent of normal activity.

Observations During the Primary Fall

1. In three of six cases the addition of defibrinized plasma to patient's plasma caused some correction of coagulation defect in the one-stage test (Table 2). This occurred in the three patients who had the largest transfusions.

2. In all of four cases the patient's plasma had less than normal ability to correct the coagulation defect of stored plasma (Table 3). This defect of patient's plasma was most pronounced in the immediate postoperative period and was less pronounced as the one-stage prothrombin time rose to normal between the first and third days.


103

Table 3. The Effect of Patient's Plasma on the Prothrombin Time of Stored Plasma During the Primary Fall

dd align="right">
0.01

0.01

Patient.
Size of Transfusion.
Type of Injury.

Oxalated Plasma (ml.)*

Stored Plasma (ml.)

Prothrombin Time (Seconds)

Labile Factor Activity (Per Cent of Normal)

DD-15

 

 

   

Perforation of chest and lung

 


N-0.01
P-0.01

0.10
0.09
0.09

26.5
18.7
20.4

 


100
78

EE-9

 

 

 

 

Penetrating wounds of both legs; traumatic amputation of left leg

 


N-0.01
P-0.01

0.10
0.09
0.09

26.2
17.2
18.4

 


100
82

M-6

 

 

 

 

Penetrating wound of chest, diaphragm and liver

 


N-0.01
P-0.01

0.10
0.09
0.09

26.0
17.6
20.6

 


100
70

X-16

 

 

 

 

Extensive injury of buttocks

 


N-0.01
P-0.01

0.10
0.09
0.09

25.2
15.0
20.8

 


100
56

 

 

9.2
9.5
10.4
10.3

100
90
80
80

 


45

L-14

         
 

Perforation of iliac artery

N-0.10
N-0.09
P-0.10
P-0.09

 
0.01

0.01

12.6
12.9
15.0
14.0

100
90
47
57

 
30

GG-13 

         

Penetrating wounds of extremities, large and small intestine

 N-0.10
N-0.09
P-0.10
P-0.09

 
0.01

0.01

10.1
10.6
12.0
12.1

 100
90
60
60

 
17

LL-9

         

Penetrating wounds of kidney, colon, bladder and extremity

N-0.10
N-0.09
P-0.10
P-0.09

0.01

0.01

10.4
11.0
11.8
11.6

100
90
72
74

 
36

*N = Normal Plasma. P = Patient's Plasma.


105

Table 5. Effect of Patient's Plasma of the Prothrombin in Time of Stored Plasma During the Secondary Fall

Patient.
Size of Transfusion.
Type of Wound.

Oxalated Plasma** (ml.)

Stored Plasma (ml.)

Prothrombin Time (Seconds)

Labile Factor Activity (Per Cent of Normal)

DD-15

       

Perforation of chest and lung

 


N-0.01
P-0.01

0.10
0.09
0.09

25.0
17.2
16.2

 


100
113

EE-9

       

Penetrating wounds of both legs; traumatic amputation of left leg

 


N-0.01
P-0.01

0.10
0.09
0.09

25.0
17.8
15.8

 


100
128

M-6

       

Penetrating wound of chest, diaphragm and liver

 


N-0.01
P-0.01

0.10
0.09
0.09

25.0
17.8
14.8

 


100
141

FF-9

 

 

 

 

Penetrating wound of abdominal walls and back

 


N-0.01
P-0.01

0.10
0.09
0.09

26.4
16.9
13.6

 


100
135

X-16*

 

 

 

 

Extensive injury of buttocks

 


N-0.01
P-0.01

0.10
0.09
0.09

28.0
14.2
15.4

 


100
92

L-14

 

 

 

 

Perforation of iliac artery

 


N-0.01
P-0.01

0.10
0.09
0.09

24.0
17.8
17.8

 


100
100

GG-13*

 

 

 

 

Penetrating wounds of extremities, large and small

 


N-0.01
P-0.01

0.10
0.09
0.09

28.0
14.2
17.0

 


100
80

**N = Normal plasma. P = Patient's plasma.
*Severely wounded with complicated recovery.

3. The addition of deprothrombinized plasma to patient's plasma failed to cause the anticipated prolongation of the patient's prothrombin time. In all six of the patients tested (Table 6) there was


106

evidence to indicate that normal deprothrombinized plasma tended to correct the coagulation defect of the patient's plasma in the one-stage test. When normal deprothrombinized plasma was used to dilute normal plasma and the plasma of patients in the secondary fall, the two dilution curves crossed, so that in some cases the prothrombin time of the patient's plasma at high dilutions was actually shorter than that of normal plasma at the same dilution (Table 6, L-14).

Fibrinogen (Fig. 1). Only one patient in the study group had an abnormally low fibrinogen, but the value was not low enough to affect coagulation (182 mg. per 100 ml.). This occurred after operation and had corrected itself by the first postoperative day. The average postoperative value was 233 mg. per 100 ml. and rose to an average of 423 mg. per 100 ml. by the first day. The average maximum value, 653 mg. per 100 ml., occurred between the third and eighth days.

Clotting Time in Silicone (Fig. 1). Six of seven patients studied in the immediate postoperative period had clotting times of 13 to 20 minutes which were more rapid than normal. Six of ten patients had a normal clotting time by the first postoperative day. In four the clotting became abnormally prolonged. Of these, two returned to normal on the third and fifth days. The other two remained abnormal during their entire hospital stay of 4 and 6 days respectively. One of the latter developed lower nephron nephrosis and demonstrated a bleeding tendency on the third and fourth day, but with no abnormality of platelet count, fibrinogen, or prothrombin activity that would account for the prolonged clotting time. In general, clot reaction was normal. Some patients who had been overtransfused and had a high hematocrit appeared to have poor clot retraction.


107

Table 6. The Effect of Deprothrombinized Plasma on the Prothrombin Time of Patient's Plasma During the Secondary Fall

Patient.
Size of Transfusion.
Type of Wound.

Oxalated Plasma*
(ml.)

Deprothrombinized Plasma (ml.)

Prothrombin Time (Seconds)

Prothrombin Activity (Per Cent of Normal)

Correction of Coagulation Defect (Per Cent)

M-6

 

 

     

Penetrating wound of chest, diaphragm and liver.

N-0.1
N-0.09
P-0.01
P-0.09

 


0.01

0.01

12.8
13.4
13.7
13.2

100
90
85
90

 


100

FF-9

 

 

   

 

Penetrating wound of abdominal walls and back.

N-0.1
N-0.09
P-0.1
P-0.09

 


0.01

11.9
12.2
12.2
12.2

100
90
90
90

 


100

L-14

 

 

   

 

Perforation of iliac artery.

N-0.1
P-0.1
N-0.08
P-0.08
N-0.02
P-0.02

0.02
0.02
0.08
0.08

12.0
13.1
13.1
13.1
22.2
19.0

100
80
80
80
20
27

 


100

100+

GG-13

 

 

   

 

Penetrating wounds of extremities, large and small intestine.

N-0.1
N-0.09
P-0.1
P-0.09

 


0.01

0.01

9.8
10.2
12.0
11.8

100
90
60
63

 


25

LL-9

 

 

     

Penetrating wounds of kidney, colon, bladder, and extremity.

N-0.1
N-0.09
P-0.1
P-0.09

 


0.01

0.01

10.4
11.0
11.8
11.6

100
90
78
76

 


33

*N = Normal plasma. P = Patient's plasma.


108

FIGURE 1. Daily changes in clotting time, plasma fibrinogen and platelet count in 11 casualties who were severely wounded. Two platelet counts on the fourth and fifth days have been omitted. One was 4.2 million, the other 3.2 million per cu. mm.

Platelets (Fig. 1). No patients in this group had a fall in platelets that could cause a hemorrhagic tendency. Only one patient had low platelet count immediately postoperatively (190,000 per cu. mm.), and this was corrected by the second postoperative day. One other patient had a low count (170,000 per cu. mm.) on the first day postoperatively, following continued transfusion of stored blood. It became normal the next day. In most of the patients after operation the platelet count rose well above normal and reached a peak between the third and ninth day. The maximum counts varied from 0.48 to 4.2 million per cu. mm.

109

Discussion

The changes in one-stage prothrombin activity observed in these patients are small, but the method was carefully controlled. It is believed that the changes are significant. Alteration of prothrombin activity after surgical operations has been described by Stefanini12 and by Warren and Belko.13 Stefanini ascribed the fault to a lack of labile factor. Warren and Belko indicated that it was due to a lack of "coagulation accelerators." Our own observations indicate that the primary fall was caused, in part at least, by a lack of labile factor. The secondary was due to lack of something else. Many factors can modify the one-stage prothrombin time. Some are known, and these include prothrombin, labile factor (labile component, Factor V, proaccelerin, plasma Ac-globulin), stable factor (proconvertin, Factor VII), antihemophilic globulin and similar factors, the platelet factors, anti-thrombin and heparin.12 There may be others that are still unknown.

It seems improbable that the coagulation defect in the severely wounded was due to an anticoagulant. Six of ten patients studied had a normal clotting time by the first postoperative day and it is safe to assume that no anticoagulant was present in these patients. Previous authors have reported a fall in clotting time after stress.2 Four of the ten patients did have abnormally prolonged clotting times past the first day. These patients had changes of prothrombin activity of the same degree as did patients with normal clotting times. The abnormal clotting time in these four patients could have been on the basis of some inhibitor but this was not proven. However, it was shown that these patients had, in addition, the same abnormality of prothrombin conversion that was possessed by the other six patients who had a normal clotting time.

There was no lack of fibrinogen to account for the coagulation defect. A rise in plasma fibrinogen following injury has been reported previously.5 It is interesting to note that this response does occur in a severely wounded casualty who is in a state of severe negative nitrogen balance. Two of the casualties were polycythemic from "overtransfusion"; neither of these patients demonstrated depression of the fibrinogen associated with polycythemia vera.

The status of prothrombin itself is open to question. In some patients it was possible to correct the prothrombin time to normal (or even better) by the addition of deprothrombinized plasma or heated serum that contained no prothrombin. This suggested that there was little or no lack of prothrombin in these patients. In other patients, where the use of prothrombin-free reagents improved but did not correct completely the defect in coagulation, there may have been


110

some deficiency of prothrombin. It is noteworthy that the use of vitamin K (100 mg. daily, intramuscularly) on five patients did not correct the defect in either the primary or secondary fall of prothrombin activity. Vitamin K-1 oxide was not tested.

The optimal concentration of calcium required for the one-stage prothrombin time was established each day for each patient. Immediately after large transfusions of citrated blood the amount of calcium required was no greater than was required for the normal control and no greater than was required for the same patient on the succeeding days, provided the hematocrit remained the same. This suggested that the citrate did not produce any great alteration of physiologically available calcium in the plasma of these patients. Clinical observation suggested the same, because hypocalcemic tetany was not encountered in these patients.

Labile factor appears to have been deficient during the primary fall. The labile factor deficiency of stored plasma was not well corrected by the addition of patient's plasma to stored plasma. At the same time the coagulation defect in three of the six patients could be corrected by adding deprothrombinized plasma which contains labile factor but not stable factor or prothrombin. The lack of labile factor, in the postoperative period, may have been due to the large transfusions of bank blood which these patients received. All of the blood was more than 10 days old, and it has been shown that blood stored in ACD solution becomes relatively deficient in labile factor.8 It should be stated, however, that the coagulation defect was not so great as to cause a serious fault of hemostasis. The slight oozing tendency that occurred among battle casualties after transfusion of 20 pints of blood or more was probably not on the basis of the labile factor deficiency of the degree demonstrated. We also found that it was not due to fibrinolysis or a deficient number of platelets. It may have been caused by some vascular phenomenon or plethora but not all patients with the oozing tendency were polycythemic. The phenomenon was observed in patients who were shown to be anemic from blood loss. The platelet factor, "serotonin,"6 acts upon capillaries to cause vasoconstriction at the site of the capillary damage. It should be pointed out that these severely wounded patients had received a virtual replacement transfusion with blood containing nonviable platelets. Since their platelet counts did not fall they must have produced large numbers of platelets in a relatively short time. It is possible that the immature platelets were deficient in "serotonin," or some other platelet factor of hemostatic importance. Such a deficiency could predispose to oozing. The oozing was of no clinical importance.


111

The "secondary fall" of prothrombin activity presents a problem we cannot explain. At this stage of recovery the coagulation defect of the one-stage prothrombin test was corrected by the addition of heated serum that was free of fibrinogen, labile factor, stable factor, prothrombin and thrombin. The defect was also corrected by deprothrombinized plasma, which indicates that the deficient factor was not absorbed by tricalcium phosphate gel. The factor or factors that corrected the "secondary" coagulation defect were stable in oxalated serum heated to 53 C for 30 minutes. It was found to withstand a temperature of 56 C for the same period of time. Its heat stability and its failure to be absorbed by tricalcium phosphate gel are two characteristics that eliminate all of the known clotting factors excepting the Platelet Factor 3.12 It should be mentioned that at this phase of recovery the patients were producing excessive numbers of platelets (Fig. 1), many of which were large and immature. It is possible that, because of rapid production of platelets, a deficiency of Platelet Factor 3 could exist. This deficiency may not have been apparent earlier, immediately after the transfusion, because of the contribution of platelet materials from the large numbers of nonviable platelets in the transfused blood or because the production mechanism of this factor had not as yet failed. There appeared to be no lack of labile factor during the secondary fall. The patient's plasma was usually more than adequate to correct the coagulation defect of stored plasma (Table 5). There appeared to be no lack of prothrombin in the patient's plasma. The addition of heated serum or deprothrombinized plasma restored the prothrombin times that were prolonged more quickly than normal (Tables 4 and 6). It is not assumed that a deficiency of Platelet Factor 3 has been demonstrated in these patients. The fault in the coagulation mechanism may have been due to lack of a heat-stable plasma factor (Toch'on-ni factor) that has not yet been described.

Summary and Conclusion

1. The coagulation system was studied in 11 battle casualties immediately after they had been wounded and resuscitated and during the first days of their convalescence.

2. In general the clotting time was shorter than normal and the platelet count and fibrinogen concentration were greater than normal. Prothrombin activity as measured by the one-stage test averaged 50 per cent of normal immediately after resuscitation with large transfusions of stored blood. This defect corrected itself within 1 to 3 days, but about the fourth day prothrombin activity again was reduced to about 50 per cent of normal and thereafter recovered gradually.


112

3. The primary fall of prothrombin activity was not proved to be caused by a lack of prothrombin but appeared in some cases to be related to a lack of labile factor which may have been a consequence of large transfusions of stored blood deficient in the labile factor. The prothrombin time was not always corrected by addition of labile factor. The defect of the coagulation mechanism was never great enough to cause serious hemorrhage. A tendency to ooze was noted in patients who had received over 20 pints of blood in a short time. It is suggested that this may have been due to the presence of a great number of immature platelets in the circulation. No fibrinolytic reactions were observed.

4. The secondary fall of prothrombin activity was not due to the lack of prothrombin. The defect of the coagulation mechanism could be corrected by the addition of heated serum that was free of prothrombin, thrombin, labile factor, stable factor, and thromboplastic activity. The factor responsible for the correction of the coagulation defect was heat stable (56 C. for 30 minutes in the presence of oxalate) and was not absorbed by tricalcium phosphate gel. Of the known factors involved in the coagulation system, these two characteristics eliminate all except the Platelet Factor 3. This fall in prothrombin activity was not associated with any clinical hemorrhagic tendency.

References

1. Brecher, G., and Cronkite, E. P.: Morphology and Enumeration of Human Blood Platelets. J. Appl. Physiol. 3: 365, 1950.

2. Cannon, W. B., and Gray, H.: Factors Affecting the Coagulation Time of Blood. Am. J. Physiol. 34: 232, 1914.

3. Crosby, W. H., and Akeroyd, J. H.: Some Immunohematologic Results of Large Transfusions of Group O Blood in Recipients of Other Blood Groups. A Study of Battle Casualties in Korea. Blood 9: 103, 1954. (Chapter 7, this volume.)

4. Crosby, W. H., and Howard, J. M.: The Hematologic Response to Wounding and to Resuscitation Accomplished by Large Transfusions of Stored Blood. A Study of Battle Casualties in Korea. Blood 9: 439, 1954. (Chapter 6, this volume.)

5. Ham, T. H., and Curtis, F. C.: Plasma Fibrinogen Response in Man, the Influence of Nutritional State, Induced Hyperpyrexia, Infectious Disease, and Liver Damage. Medicine 17: 413, 1938.

6. Janeway, T. C., Richardson, H. B., and Park, E. A.: Experiments on the Vasoconstrictor Action of Blood Serum. Arch. Int. Med. 21: 565, 1918.

7. Koller, F., Loeliger, A., and Duckert, F.: Experiments on a New Clotting Factor (Clotting Factor VII). Acta. haemat. 6: 1, 1951.

8. Lahey, J. L., Wone, A. S., and Seegers, W. H.: Stability of Prothrombin and Ac-globulin in Stored Human Plasma as Influenced by Conditions of Storage. Am. J. Physiol. 154: 122, 1948.

9. Quick, A. J.: The Physiology and Pathology of Hemostasis. Lea & Febiger, Philadelphia, 1951.


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10. Quick, A. J., Honorato, C. R., and Stefanini, M.: The Value and the Limitations of the Coagulation Time in the Study of the Hemorrhagic Diseases. Blood 3: 1120, 1948.

11. Scott, R., Jr., Howard, J. M., and Olney, J. M.: Hepatic Function in the Battle Casualty. (Chapter 8 in Volume I of this series.)

12. Stefanini, M.: Mechanism of Blood Coagulation in Normal and Pathologic Conditions. Am. J. Med. 14: 64, 1953.

13. Warren, R., and Belko, J. S.: Deficiency of Plasma Prothrombin Conversion Accelerators in the Postoperative State with a Description of a Simple Method of Assay. Blood 6: 544, 1951.

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