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Hypothermic Coagulopathy in Trauma: Effect of Varying Levels of Hypothermia on Enzyme Speed, Platelet Function, and Fibrinolytic Activity

Watts, Dorraine Day PhD; Trask, Arthur MD; Soeken, Karen PhD; Perdue, Philip MD, MPH; Dols, Sheilah MT (ASCP); Kaufmann, Christoph MD, MPH

The Journal of Trauma: Injury, Infection, and Critical Care: May 1998 - Volume 44 - Issue 5 - p 846-854
Article: Presented At The 57Th Annual Meeting Of The American Association For The Surgery Of Trauma And The Japanese Association For Acute Medicine, September 24-27, 1997, Waikoloa, Hawaii
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Background The coagulopathy noted in hypothermic trauma patients has been variously theorized to be caused by either enzyme inhibition, platelet alteration, or fibrinolytic processes, but no study has examined the possibility that all three processes may simultaneously contribute to coagulopathy, but are perhaps triggered at different levels of hypothermia. The purpose of this study was to determine whether, at clinically common levels of hypothermia (33.0-36.9[degree sign]C), there are specific temperature levels at which coagulopathic alterations are seen in each of these processes.

Methods Of 232 consecutive adult trauma patients presenting to a Level I trauma center, 112 patients met the inclusion criteria of an Injury Severity Score of 9 or greater and time since injury of less than 2 hours. Of the included patients, 40 were normothermic and 72 were hypothermic (>or=to37[degree sign]C, n = 40; 36.9-36[degree sign]C, n = 29; 35.9-35[degree sign]C, n = 20; 34.9-34[degree sign]C, n = 16; 33.9-33[degree sign]C, n = 7). Included patients were prospectively studied with thrombelastography adjusted to core body temperature. Additionally, PT, aPTT, platelets, CO2, hemoglobin, hematocrit, and Injury Severity Score were measured.

Results Analysis by multivariate analysis of variance of the relationship between coagulation and temperature demonstrated that in hypothermic trauma patients, 34[degree sign]C was the critical point at which enzyme activity slowed significantly (p < 0.0001), and at which significant alteration in platelet activity was seen (p < 0.001). Fibrinolysis was not significantly affected at any of the measured temperatures (p > 0.25).

Conclusions Patients whose temperature was >or=to34.0[degree sign]C actually demonstrated a significant hypercoagulability. Enzyme activity slowing and decreased platelet function individually contributed to hypothermic coagulopathy in patients with core temperatures below 34.0[degree sign]C. All the coagulation measures affected are part of the polymerization process of platelets and fibrin, and this process may be the mechanism by which the alteration in coagulation occurs.

From the Department of Trauma Services (D.D.W., A.T., P.P., S.D., C.K.), Inova Regional Trauma Center, Falls Church, Virginia, University of Maryland at Baltimore (K.S.), Baltimore, Maryland, National Naval Medical Center (P.P.), Bethesda, Maryland, Division of Surgery for Trauma (C.K.) Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Nonmonetary support for this study was provided by Haemoscope Corporation, Skokie, Illinois, who loaned an additional thrombelastograph instrument for use as a back-up in this research.

Poster presentation at the 57th Annual Meeting of the American Association for the Surgery of Trauma and the Japanese Association for Acute Medicine, September 24-27, 1997, Waikola, Hawaii.

Address for reprints: Dorraine Day Watts, PhD, Inova Regional Trauma Center, Department of Trauma Services, 3300 Gallows Road, Falls Church, VA 22042-3300.

Key Words: Coagulation, Enzyme, Fibrinolysis, Hypothermia, Platelet, Thrombelastograph, Trauma.

Hemorrhage is superseded only by neurologic injury in the number of traumatic injury deaths it causes. [1] Even among those who do not die of their injuries, hemorrhage can be still be significant. Nearly all patients with multiple injuries have some degree of hemorrhage-induced hypovolemia, making hemorrhage an important contributor to morbidity as well as mortality. [2] It is imperative, therefore, that the trauma clinician have a complete understanding of the mechanisms of hemorrhage, so that adequate hemostasis can be achieved.

Hemorrhage after injury has two causes, mechanical damage and coagulopathy. Whereas mechanical damage may be surgically repaired, coagulopathy in the trauma patient is a more insidious process and may account for as many as half of all hemorrhagic deaths. [3] Coagulopathy in the trauma patient is usually caused by hypothermia, massive transfusion, or both. [2] Whereas the manner by which massive transfusion affects clotting is well documented, [4] the mechanism by which hypothermia affects clotting is not clearly understood and continues to be debated. [3,5,6]

Regardless of whether the phenomena is understood, the potential extent of the problem of hypothermia-induced coagulopathy is immense. It is estimated that as many as 66% of all trauma patients arrive at the hospital hypothermic (temperature < 36.0[degree sign]C), so the potential for hypothermia-induced coagulopathy may exist in nearly two thirds of the trauma population. [7] Hypothermia in conjunction with severe injury is particularly deadly, with predicted mortalities as high as 100% in patients presenting with both severe hypothermia and severe injury. [7,8] Even mild hypothermia of as little as 0.5[degree sign]C (a drop to 36.5[degree sign]C) has been demonstrated to significantly slow the clotting of blood. [9-11]

Hypothermia may cause coagulopathy over a range of temperatures in a dose-response type of relationship. The more hypothermic a patients is, the more likely she/he is to hemorrhage. [8,12] Despite the potential seriousness of the problem, this relationship of hypothermia and hemorrhage continues to be poorly understood. The underlying physiologic cause of hypothermic coagulopathy in trauma patients is unclear, as is the correlation between varying degrees of body temperature and coagulation. [3] At the present time, there are three distinct theories that have been advanced to explain this relationship: (1) platelet alteration, (2) enzyme inhibition, and (3) fibrinolysis. [5] Initially, it was believed that there was only one cause for hypothermic coagulopathy and hence only one of these was an accurate theory. Now it seems more likely that the theories are complementary, with two or more of them working together, with each one explaining part of the relationship between coagulation and hypothermia (I. Rubin et al., unpublished data, 1995). [3,5,11,12,14-19] The interrelationship of these theories has only begun to be explored and no published studies were identified that simultaneously looked at all three processes in trauma patients.

The purpose of this study was therefore to explore the effect of hypothermia and trauma on coagulation during the immediate postinjury time period and to explicate the exact relationship of temperature to coagulation in trauma patients to determine answers to the following research questions: (1) Was there a temperature level at which slowing of coagulation began (enzyme inhibition)? (2) Was there a temperature level at which clot strength became affected (platelet alteration)? (3) Was there a temperature level at which fibrinolysis occurred?

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MATERIALS AND METHODS

Sample

Before initiation of this study the protocol was reviewed and approved by the Institutional Review Board at the study site to ensure protection of human subjects.

All trauma patients 15 years of age and older who met the institutional criteria for trauma team activation were candidates for the study. Inclusion criteria were Injury Severity Score (ISS) >or=to9, and time since injury <2 hours. Because the purpose of this study was to examine hypothermic coagulopathy in the immediate time period after injury, patients presenting to the hospital more than 2 hours after injury were excluded as their physiologic condition might have compensated or decompensated in this extended time period. [3] Patients who had preexisting coagulopathic blood disorders, or who were on anticoagulant medications were also ineligible, because any preexisting alteration in coagulation would confound the results of the study. [3]

Data were collected from November 1, 1996, to March 1, 1997. Subjects were enrolled consecutively, 7 days a week, 24 hours a day for the duration of the study. Data collection procedures were strictly controlled and did not alter the routine care of the enrolled patients. Patients arrived in the trauma receiving area and had their blood drawn, blood pressure, heart rate, and respiratory rate measured. Temperature was measured by direct core method (Foley catheter temperature probe) or aurally, mathematically converted to core equivalent. All laboratory samples were obtained within 5 minutes of arrival and were processed immediately.

Of 232 consecutive patients screened, 112 patients met the inclusion criteria and had useable test results. Patients were excluded for ISS<9 (n = 101), downtime >2 hour (n = 10), or unusable/no test results (n = 9). Of the included patients, 40 patients were normothermic (temperature >or=to 37.0[degree sign]C) and 72 were hypothermic (temperature < 37.0[degree sign]C) by core body temperature in the trauma receiving area. Included patients were prospectively studied with thrombelastography (TEG) adjusted to the patient's core body temperature to assess their coagulation status. In addition to the TEG parameters, the following supplemental variables were collected from the patient record for assistance in interpretation of findings: age, gender, mortality, Revised Trauma Score (RTS), Injury Severity Score (ISS), injury type, injury location(s), platelet count, carbon dioxide (CO2), prothrombin time (PT), activated partial thromboplastin time (aPTT), hematocrit, and transfusion amount and type before blood draw. Demographic data were obtained from the study institution trauma registry.

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Thrombelastography

TEG was first described by Hartnet in 1948. [20] Although it is a relatively unfamiliar test to most trauma surgeons, it has well-established reliability and validity and is in widespread current clinical use, particularly in the liver transplant and cardiovascular surgery arenas. [21] It uses the viscoelastic properties of the blood to derive information on platelet function, enzyme activity, and fibrinolysis. Initial results are available in less than 20 minutes if an activator is used. The TEG uses only 0.36 mL (360 [micro sign]L) of whole blood. The blood is pipetted into a heated cup on the instrument, a pin suspended from a torsion wire is lowered into the cup and the instrument activated. The cup rotates beneath the pin and as the fibrin forms it couples the pin to the cup. The rotational motion is transferred to the pin and wire and is recorded electronically through an electromagnetic transducer. The measurements are recorded and displayed graphically (Figure 1). Results are calculated by the computer and saved on disk. The signature of generated tracings gives information on the platelets, enzymes, and fibrinolysis of the sample. [20-22]

Figure 1

Figure 1

Whereas multiple tests could have been done to measure the outcome variables in this study (clotting time, factor levels, fibrin degradation products, etc.), TEG was chosen because it was felt to be a most rapid, simple, clinically available test that would answer the research questions. The advantage of the TEG is that it gives two discrete measures of each of the three aspects of coagulation under investigation with a single sample. Enzyme inhibition is manifested as a slowing of clotting on the TEG and is measured by the reaction time (R), which is when the first clotting is noted, and the angle (alpha), which is the rate of clot growth. A prolonged R time or a decreased alpha is indicative of factor deficiencies and/or enzyme inhibition. Platelet alteration is measured by the time to 20 mm of firmness (K time) and the maximal amplitude (MA), which are both measures of the strength of the clot. A strong clot depends on the interaction of platelets and fibrin. A prolonged K or decreased MA indicates that there is fibrin formation but insufficient platelet function to form an adequate clot. Fibrinolysis is measured by the fibrinolytic index at 30 minutes (ly30) and 60 minutes (ly60) after maximal amplitude is reached. This index looks at the degree of retraction/lysis by measuring the area under the clot curve. Additionally, the TEG includes an algorithm for calculating an overall measure of blood clotting or coagulopathy called the coagulation index from the R, K, MA, and alpha. TEG has well-documented reliability and validity, and its relationship to more direct measures of clotting are well documented. [9,11,13,20-22]

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Procedures

A total of 0.8 mL (800 [micro sign]L) of blood was collected from each patient in a sodium citrate tube (0.09 mL of 0.109 M sodium citrate/0.8 mL blood). The TEG was then performed at the patient's core body temperature according to standard protocol. The results of the TEG were calculated by the computer and recorded on the hard drive. All TEGs were run in duplicate, and the result used in analysis was the average of the two results obtained. The TEG parameters R, K, MA, alpha, ly30, ly60, and TEG coagulation index were collected on all patients.

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Statistical Analysis

Because the specific aim of this study was to determine whether there was a specific temperature level at which changes were noted, subjects were distributed into five groups for comparison based on their admission core body temperatures. The nonhypothermic control group (n = 40) was composed of patients meeting the inclusion criteria whose core body temperature was >or=to37[degree sign]C. Hypothermic patients were divided into groups based on 1[degree sign]C increments in body temperature (group 36, 36.9-36.0[degree sign]C; group 35, 35.9-35.0[degree sign]C; group 34, 34.9-34.0[degree sign]C; and group 33, 33.9-33.0[degree sign]C). On the TEG measures of coagulation, analysis was done using multivariate analysis of variance to look at differences in variables by group. Assessment of the homogeneity of the variance/covariance matrix was done using Boxes M and adjustments made to alpha if necessary. Pillia's test was used to assess multivariate significance, and univariate post hoc testing was done using a simple contrast comparing each hypothermic group to the nonhypothermic control group.

Analysis of variance with Tukey post hoc testing was used to make comparisons of univariate demographic and related variables. Pearson's r test was used as a measure of association where appropriate. A p value of <0.05 was used as the level of significance unless a lower value was substituted for statistical stringency.

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RESULTS

TEG Coagulation

For the two measures of speed of blood clotting, the results show that hypothermic trauma patients and nonhypothermic trauma patients do not differ on the time to initial clot formation (r time) at the levels of hypothermia tested. On the speed of clot growth (angle), only the very coldest group (33[degree sign]C) differed from the nonhypothermic control group (37[degree sign]C) (p < 0.001). The mean values for r time and angle, with the standard error of measurement are given in Figure 2 and Figure 3.

Figure 2

Figure 2

Figure 3

Figure 3

On the measures of platelet activity, hypothermic trauma patients and nonhypothermic trauma patients differed on both measures (K time and MA), but at only the coldest temperature tested (group 33[degree sign]C vs. group 37[degree sign]C). The K time was significantly slower and MA was significantly weaker if the patient's temperature was below 34[degree sign]C (p < 0.001). The mean values for K time and MA, with the standard error of measurement are given in Figure 4 and Figure 5.

Figure 4

Figure 4

Figure 5

Figure 5

For the measures of fibrinolysis, hypothermic trauma patients and nonhypothermic trauma patients did not differ significantly on either the amount of fibrinolysis at 30 minutes after maximal amplitude is reached, or the amount of fibrinolysis present 60 minutes after maximal amplitude is reached for any of the temperature groups. The mean values for ly30 and ly60, with the SEM are given in Figure 6 and Figure 7.

Figure 6

Figure 6

Figure 7

Figure 7

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Demographics and Injury Patterns

The mean age for the study group was 36.4 years. The means for the individual temperature groups ranged from 33 to 43, but the differences were not statistically significant (p > 0.72). Likewise there were no statistically significant differences between the temperature groups on gender or mechanism of injury. The vast majority of the included patients suffered from blunt injury (87%), which is typical of the population at the study institution.

Downtime for this study was calculated as the time from injury until the time blood was drawn. The mean downtime for the entire group was 54 minutes. The groups did not differ significantly, and the range for each of the groups was similar as well (Table 1).

Table 1

Table 1

Patients were classified as to the presence or absence of head, chest, abdominal, or extremity injury by examining ICD-9 code diagnosis. The percentage of patients in each temperature group with the injury present is given in Table 1. Whereas there are slightly more head injuries in the hypothermic groups, there were no statistically significant differences between any of the hypothermic groups and the nonhypothermic control group on the percentage of injuries for head, chest, abdomen, or extremities (p > 0.72).

The ISS was significantly higher in the temperature group 34.0 to 34.9[degree sign]C when compared with the nonhypothermic (temperature >or=to 37.0[degree sign]C) control group (p < 0.05). A progressive increase in ISS could also be seen across the temperature groups, with the colder patients tending to have a higher ISS.

The two coldest groups (34.0-34.9[degree sign]C and 33.0-33.9[degree sign]C) had significantly lower Glasgow Coma Scale scores than the nonhypothermic (<or=to37.0[degree sign]C) control group (p < 0.001). A linear decrease in Glasgow Coma Scale scores could also be seen as temperature fell.

The mean RTS for the two coldest groups [23,24] were significantly lower than the nonhypothermic control group (p < 0.001), and a linear decrease in RTS was noted as temperature fell. There were no significant differences in vitals signs (heart rate, blood pressure) between the groups on admission to the trauma receiving area (p > 0.38).

The coldest group (group 33) had a total hospital length of stay that was more than double the control group (11.3 vs. 4.8; p < 0.037), and their overall mortality rate was 43% compared with 5% in the nonhypothermic control group (p < 0.001).

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Fluid Resuscitation

There was no significant correlation between vital signs and fluid administered and there were no groupwise differences on amount of fluid administered. Even though groupwise differences were not found, there remained a strong correlation between temperature and the amount of fluid infused (r = -0.30; p = 0.002), and temperature and amount of blood infused (r = -0.26; p = 0.005). There was a similar correlation between injury severity and fluid infused (r = 0.31; p = 0.002). As suspected, there was also a correlation between downtime and the amount of fluid received (r = 0.32; p = 0.006). To attempt to sort out the differential contributions to coagulation, the correlations were repeated, controlling for (partialing out) the contribution of the intercorrelated factors (fluid and temperature). When the contribution of temperature is controlled for in the correlation of fluid and coagulation, the correlation becomes nonsignificant. However when fluid is controlled for in the correlation of temperature and coagulation, the r decreases slightly but remains significant. This finding indicates that for this sample, temperature has independent effects on coagulation not mediated by fluid infused, whereas the effects of fluid infused on coagulation seem to be significant only when mediated by temperature.

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Laboratory Data

PT and aPTT did not differ among the temperature groups (p > 0.58), and all means were within normal limits. This finding is not unexpected, because on average it takes a 30 to 40% drop in factor activity for the aPTT/PT to become abnormal. [25] This finding is in contrast to the TEG coagulation index which is extremely sensitive to even small changes. Results of the TEG coagulation index test indicated that in fact, on average, all of the groups were hypercoagulable overall except for the coldest group (33.0-33.9[degree sign]C). The coldest group was on the hypocoagulable side of normal and was significantly different from the nonhypothermic control group (temperature >or=to 37.0[degree sign]C) (p < 0.001).

All groups had mean platelet counts within normal limits (reference range, 140-400 for the study institution) and none of the hypothermic groups differed significantly from the nonhypothermic control group (p > 0.18). A downward trend in number of platelets was noted as the mean group temperature decreased, however.

Mean hemoglobin and hematocrit levels were within normal limits for both men and women for all groups except the 34.0-34.9[degree sign]C group (group 34). Group 34 had a large number of patients with very low hemoglobin and hematocrit levels.

Systemic acidosis by itself may also alter coagulation. Serum carbon dioxide (CO2) correlates highly with arterial pH and is an accurate indication of acid-base balance. [25-27] The reference range for normal serum CO2 for the study institution is 21 to 30 mEq/L. In this study, the two coldest groups (34.0-34.9[degree sign]C and 33.0-33.9[degree sign]C) had below normal CO2 levels, and were significantly lower than the normothermic control group (p < 0.001). This finding infers that the two coldest groups had a serum pH that was more acidotic than the nonhypothermic (temperature >or=to 37.0[degree sign]C) control group. Acidosis, however, did not correlate significantly with injury severity (r = -0.15; p = 0.11) but did correlate significantly with temperature (r = 0.44; p < 0.001). When injury severity was controlled for (partialed out) in the correlation of CO2 and temperature, there was still an r of 0.39 of temperature with CO2 (p < 0.001). Temperature therefore accounted for six times more of the variation in acidosis as did injury severity. So for this sample, acidosis seems more likely to be a sequelae to hypothermia, compared with injury severity. Therefore in this study, acidosis most likely contributes to coagulopathy primarily as a result of hypothermia, not independent of it.

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DISCUSSION

The results of this study demonstrate that only the very coldest trauma patients (33.0-33.9[degree sign]C) are significantly different from the nonhypothermic patients (>or=to37.0[degree sign]C) on any of the study variables. These patients had significant alterations in measures of platelet function (K time and MA) and in the enzyme function (angle). None of the groups differed significantly on either of the measures of fibrinolysis.

According to some sources, hemorrhage alone can lead to hypothermia. [28] In this study, however, there was no significant correlation between hemorrhage and hypothermia (r < 0.17; p > 0.07). This is similar to the findings of Luna et al. (1987), who found no difference in admission temperature between those patients who had severe hemorrhage requiring transfusion of 1 to 10 units of blood and patients who did not have severe hemorrhage. [7] Sori et al. (1987), using a rat model, also found no significant drop in temperature related to blood volume loss alone until there was a >50% blood loss accompanied by shock. [29] Multiple other studies confirm this finding that whereas hemorrhage may lead to hypothermia, hypothermia seems to be related to the resultant shock state rather than merely a volume loss. [8,28,30,31] In this study as well, hemorrhage did not seem to be an independent contributor to hypothermia.

Severe trauma is invariably accompanied by large amounts of soft-tissue damage, and the resulting release of tissue thromboplastin may lead to hypercoagulability and tissue hypoxia. Hypercoagulability is a common finding in trauma patients. [23,24,32-35] Reported rates range from 65% to 97% of severely injured patients presenting with some degree of hypercoagulability. [10,23,35,36] In this study, 68% of the patients had a TEG coagulation index indicating hypercoagulability (TEG coagulation index >2.0).and every temperature group except for the 33.0-33.9[degree sign]C group actually had a hypercoagulable group mean (>2.0) on the coagulation index (Table 1).

Resuscitation volume in this study was measured as amount of fluid (crystalloid, colloid, and blood) infused before the blood being drawn. Fluids may cause or exacerbate hypothermia if they are not sufficiently warmed, and may cause coagulopathy through dilution of clotting factors. [37-45] For this sample, temperature had independent effects on coagulation not mediated by fluid infused, whereas the effects of fluid infused on coagulation seem to be significant only when mediated by temperature.

The result obtained in this study is somewhat different from that commonly reported in the literature. It has generally been reported that the more fluid a patient receives, the colder they will become. [46] This finding is, however, dependent on many factors such as age, injury type, and shock state. [47] The difference found in this study may be attributable to several reasons. First of all, most studies of resuscitative fluid looked at patients in shock. [39,47-49] In this study, few patients (n = 4) met the criteria for shock upon hospital arrival and so were not aggressively resuscitated. Second, the study sample had very conservative fluid resuscitation in general, because patient temperature and fluid amount were assessed upon arrival to the trauma receiving area and fluid infused was only calculated to the point when blood was drawn. [50,51] At the point TEG bloods were drawn, most patients had received fluids only from the prehospital paramedics. Because the transport times were very short (mean, <20 minutes), the opportunity to receive fluids was very brief for patients in this study, unlike studies that examined patients through several hours of resuscitation. [47,51-55] Only 5% of the patients received over 1,000 mL of fluid. The finding of no independent effect of fluid, whereas correct for this study, are probably not representative of the effects of fluid resuscitation at higher volumes over longer time periods.

To summarize, although hemorrhage can affect hypothermia, in this sample, it seems to be a minor contributor. Mild intravascular coagulation in the form of hypercoagulability may be present in all but the coldest patients, yet its independent contribution to acidosis by means of tissue hypoxia is small compared with the contribution of hypothermia alone. Acidosis in the sample contributes to coagulopathy mainly as a result of hypothermia, not independent of it. The amount of fluid transfused is significantly related to coagulation, but primarily as mediated by temperature, not independent of it. It is clear for the sample that, although many factors may affect coagulation, temperature is clearly the major independent contributor to coagulation alteration.

The last area of discussion then, is the relationship of hypothermia to coagulopathy, which was the target of this study. On the first research question, there were no significant differences between temperature groups on the r time. This is despite that the coldest group (33.0-33.9[degree sign]C) had a mean r time that was nearly 2 mm (60 seconds) different from the control group. In fact, all groups had mean r times that were shorter than the stated reference range of 10 to 14 mm (5-7 minutes), indicating a hypercoagulable status in general. This is consistent with the general findings of hypercoagulability in trauma patients discussed earlier. [23,35,36]

Although the r time was shortened, once clotting had been initiated, the clots of the coldest group of patients (33.0-33.9[degree sign]C) grew at a significantly slower rate than the clots of the nonhypothermic control group (>or=to37[degree sign]C), as evidenced by a much smaller mean angle (55.5 degrees vs. 69.4 degrees). Although these findings support in part the theory of enzyme inhibition, but one must wonder why the angle was significantly different, while the r time was not. Part of the reason may be simply due to a lack of power for the comparison. With seven patients in the group, sample size is small, and combined with a small effect size (0.048), power is low at 0.41. Previous studies who found that r time was decreased used a paired t test using the patients as their own controls. [9,10,12,13] In this way they were able to control more of the variance. This idea is supported by the fact that the means for this study are consistent with those obtained by the other research groups. In addition, even though the difference is not statistically significant, there is some effect for temperature, as the coldest group (33.0-33.9[degree sign]C) had the longest r time by far, consistent with the literature. An alternative explanation as to why angle was significant and r time was not may be that because r time measures the time to initial clot formation, the large amount of tissue thromboplastin available secondary to the trauma ensures prompt initiation of clotting in these patients despite depression of enzyme function. However, because there is no surplus of the other factors in the cascade, the enzymatic reactions necessary for continued growth are slowed by the colder temperatures. It is clear that once patient temperature drops below 34[degree sign]C that the blood clot grows at a much slower rate than for patients whose temperature is normal.

The second research question examined platelet function, and both measures of platelet function (K and MA) were significantly lower for the patients whose temperature was below 34[degree sign]C (group 33). They had decreased platelet function in the polymerization phase (K time) and also had decreased MA or strength of their clots. The theory of platelet alteration and sequestration as originally proposed, and later replicated, is that platelets are sequestered in the liver and spleen during hypothermia. [17,56] Others found that along with sequestration, multiple morphologic changes in the platelets were present. [18] These theories indicate that, for the platelet variance component to be altered fully, there needs to be "in vivo" hypothermia, not just the cooling of blood from a healthy sample. This theory would explain the mixed results obtained from those who used in vitro cooling or warming methods. [9,11-13,57,58]

It is difficult to determine from this study whether hypothermia produces a (relative) quantitative platelet deficiency or whether there is a qualitative deficiency as well. Although the mean platelet count for all of the groups was quantitatively adequate by the reference range for the study institution (range, 140-400 cells), there was a strong correlation between the patients absolute platelet count and both the K time (r > 0.47; p < 0.001) and MA (r > -0.42; p < 0.001). This finding implies that although the platelets were within "normal limits," their absolute numbers might still play a role in clotting. Indeed, platelet count was trending downward in the colder groups, even though the difference was not significant (Table 1). Although there is clearly an alteration in platelets for the coldest group, there is no way to determine definitively from the thrombelastogram whether it is a quantitative or qualitative deficiency, or if it is caused by platelet alteration or sequestration.

The third and final research question dealt with fibrinolysis. No significant differences were found between any of the temperature groups on either of the fibrinolytic measures (ly30, ly60). Again, part of the reason for no significance might be attributed to a lack of statistical power for the multivariate test. There is also a great deal of within-group variation, particularly in the coldest group, which would make it more difficult to obtain significant statistical differences. The most simple alternative explanation may be that because all of the measures of fibrinolysis were well within normal limits (ly30 < 7.5; ly60 < 15.0), and because the thrombelastogram studies agree, that fibrinolysis is simply not an important variable in coagulation at these temperatures for these patients. Indeed this theory is supported by the fact that Kearney et al. (1992) found fibrinolysis only in the patient with severe head injury without regard to temperature, and Gando et al. (1992) found no evidence for a fibrinolytic activity in any trauma patients, including those patients with head injuries. [32,33] There remains some evidence in the literature that fibrinolysis plays a role, and more study is warranted. [59-61]

It is easy to try to attribute coagulation alterations to the magnitude of injury, because there is somewhat of a reciprocal relationship between temperature and injury severity. However, that temperature group 34.0 to 34.9[degree sign]C had the highest injury severity, yet did not differ significantly from the nonhypothermic control group is evidence that injury severity alone is not the answer. Several other studies have also found that coagulation alterations are indeed independent of injury severity. [4,32,41]

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CONCLUSIONS

Enzyme activity slowing and decreased platelet function individually contribute to hypothermic coagulopathy in trauma patients, particularly below 34.0[degree sign]C. All the coagulation measures affected are part of the polymerization process of platelets and fibrin, and this may be the mechanism by which the alteration in coagulation occurs.

In the sample, while there were significant differences on measures of coagulation for the coldest group (33.0-33.9[degree sign]C), only one measure (MA) was outside of the "normal" reference range. All of the subjects in the other temperature group exhibited hypercoagulable test results. So while hypothermia does affect coagulation, the hypercoagulability that is the result of severe trauma seems to allow the body to compensate for some of this hypothermic alteration.

Hypothermia and coagulation are complicated variables, potentially affected by injury severity, hemorrhage, and environment. Further research is required to look at a broader range of temperatures in a multicenter trial to obtain larger numbers in the coldest groups and to more completely evaluate this vital area of trauma care.

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