- Email: [email protected]
Coagulation and platelet changes after thermal injury in man
370
Burns. 7.370-377
Printedin Great Britain
Coagulation and platelet changes after thermal injury in man Robert H. Bartlett, Wayne Anderson
Susie W. Fong, Greg
Marrujo,
James
Hardeman
and
University of California, Irvine Burn Center, California, USA INTRODUCTION BLEEDING
tendency in the early phase and hypercoagulability in the late phase of acute bum care are common clinical observations. Intravascular coagulation can be seen in small vessels on the surface of full-thickness bums. Progressive microvascular coagulation has been suggested to contribute to the depth of the initial injury (Zawacki, 1974). It has been proposed that anticoagulation with heparin prevents this phenomenon (Saliba et al., 1973). Despite the importance of these factors in the pathogenesis in the management of acute bum injury, relatively few detailed studies of the coagulation and platelet response to thermal injury have been reported (Curreri et al., 1970; Gehrke et al., 1971; Caprini et al., 1977; Hergt, 1972; Meyers, 1972; Curreri et al., 1975b; Simon et al., 1977; Gabilondo et al., 1977). Of the studies that have been reported, the major surface treatment technique was exposure, or not specified. In most of these studies the response to systemic sepsis or catabolism cannot be differentiated from the response to the bum itself. This study was undertaken to characterize coagulation and platelet changes in a selected group of bum patients treated with the same protocol which includes colloid resuscitation, Presented at Southern California Chapter, American College of Surgeons, Newport Beach, California I979 and in part at American Bum Association, 1974, Cincinnati, Ohio. Address for correspondence: Dr Bartlett, Department of Surgery, University of Michigan Medical Center. Ann Arbor, Michigan 48 105, USA.
occlusive dressings, thorough daily cleaning, vigorous debridement and maximal nutrition. The hypermetabolic state is matched with caloric administration, preventing catabolism and weight loss. The incidence of infection with this protocol is less than 2 per cent. In planning this study we hoped to exclude or at least identify separate effects due to sepsis, and prevents effects due to malnutrition. PATIENT
SERIES
AND
METHODS
The patient series is shown in Fig. 1. A full battery of coagulation studies was carried out in 11 patients age 2- 45, total surface bum 30- 68 per cent and full-thickness bum 5- 60 per cent. These patients were selected from 200 admissions to the University of California lrvine Bum Center in a 12-month period. Young patients with extensive bums but good prognosis were selected because we hoped to study the entire group through the full course ofacute care and recovery. All patients were treated according to the same protocol (Allyn and Bartlett, 1976). Initial resuscitation was with 5 per cent albumin in 0.8 per cent sodium chloride (Albumisol) infused at a rate sufficient to maintain adequate peripheral perfusion. (Blood pressure >80 mean, pulse < 120, no metabolic acidosis, urine >20 cc M-2 h-1, hematocrit 45-50 per cent.) This usually amounted to 10 per cent of the body weight over the first 48 hours (Allyn and Bartlett, 1976). Pulmonary insufficiency and smoke inhalation were managed with early endotracheal intubation, mechanical ventilation, and diuretic drugs (Achauer et al, 1973).
Bartlett et al.: Coagulation and Platelet Changes
F/K. I. Age and total surface bum in the coagulation study group.
Nutrition was based on replacing measured caloric expenditure daily and maintaining body weight with oral and gastric feeding (Bartlett et al., 1977). Intravenous hyperalimentation was not required to maintain positive caloric balance in these patients. The surface was managed by daily cleaning with Betadine in a tub containing dilute hypochlorite. Gentle dtbridement was carried out daily and tangential dtbridement under anesthesia carried out in the tub every 3-4 days. Activity and ambulation were encouraged; no specific isolation procedure was followed. Grafting was carried out as soon as healthy granulation tissues covered areas of fullthickness burn. Tight fitting elastic occlusive dressings impregnated with sodium sulphadiazine or silver sulphadiazine were placed on the surface after tubbing daily. Blood samples were taken for full coagulation studies as soon as possible aRer admission, at daily intervals for the first 7 days, then weekly intervals for the next 4 weeks. Blood was drawn from indwelling catheters or fresh punctures. The initial sample was discarded, and blood placed in citrate or EDTA anti-coagulant polypropylene tubes. Partial thromboplastin time (Proctor and Rapaport, 1961), prothrombin 1935), and thrombin time time (Quick, (Rapaport, 1957), were measured as screening tests. Factor V (Stormorken, 1957), Factor VIII (Langdell and Wagner, 1964), and Factor I (fibrinogen) (Blombach and Blombach, 1956) were assayed directly. Fibrin degradation products were measured by semiquantative immunoassay (Pitcher, 1972). Platelet counting was done by phase microscopy (Brecher and Cronkite, 1950), as automated methods of plate-
371
let counting may be inaccurate at low platelet counts. Platelet function studies were carried out on platelet rich plasma with actual platelet counts approximately twice whole blood levels. Platelet thromboplastic activity (platelet Factor III) was measured by the method of Husom (1961) in which platelet rich plasma is used as the activating agent in a Stypven reagent. Time to complete platelet aggregation following stimulation with ADP was measured under direct microscopic observation (Born and Cross, 1966). The results correlate well in our laboratory with the optical density-platelet aggregometer method but much less blood is required. Platelet adhesiveness was measured by a modification of Salzman’s method (1963), in which 3 cc of citrate anti-coagulated blood are injected at a constant rate through a column of carefully cleaned glass beads; inflow and outflow platelet counts are measured. The normal range shown in the figures represents mean t2 standard deviations for normal human pooled plasma or platelet function tests as measured in our laboratory. Normal pooled plasma controls are run with all screening and factor assays. RESULTS All patients
survived, with an average time from burn to grafting of 21 days and average total hospitalization time of 36 days. Four patients required intubation and mechanical ventilation for airway edema and/or smoke inhalation. There was no bum wound infection. Septicemia occurred in one patient-a 2-year-old child with 65 per cent total surface, 60 per cent fullthickness bum with Klehsiella thromhophlehitis in a cutdown site. There were no major bleeding or clotting complications although several patients with large bums had moderate bleeding from escharotomy sites during the second or third day post burn. Neither were there stress ulcers or other signs of gastrointestinal bleeding in any of the patients. Blood transfusion was required at the time ofdtbridement and grafting. I blood volume total averaging approximately transfusion during hospitalization. Results of coagulation studies are shown in Figs. 2 and 3. In these and subsequent figures the normal range is shown in the shaded area and the time scale shows the first day, first week, and first month in equal increments. It can be seen from the figures that partial thromboplastin time is prolonged for the first 2- 4 days, following a course similar to that of Factor V. All values return to normal by 5 days (except a
Burns Vol. ~/NO.
372
5
TT hd
Fig. 2. Coagulation screening tests in burned patients. PTT, partial thrombo-
plastin time; Pro T, prothrombin time; TT, thrombin time.
-
.e_e.
60-rn(B)AW W-45 (5) Av.
Fig. 3. Factor assays and fibrin degradation products (FDP) in burned patients.
slight prolongation of prothrombin time). Hypercoagulability characterized by shortened PTT and elevated fibrinogen, Factor V, and Factor VIII characterize the period between 1 and 4 weeks. In these subsequent figures, data for small bums (30-45 per cent) and larger burns (SO-70 per cent) are presented separately. No significant differences in coagulation measurements are seen between these groups. Fibrin degradation products were present in very small amounts. This observation was
supported by the normal measurements of the thrombin time which becomes abnormally prolonged if fibrin degradation products are present. Platelet count and function studies are shown in Figs. 4-7. Progressive thrombocytopenia occurs during the first 3 days after injury, with greater change occurring with increasing extent of burn. Thrombocytopenia reaches a maximum on the third day and gradually returns to normal, reaching baseline values by 1 week and rebounding to abnormally high levels during the
Bartlett et al.: Coagulation and Platelet Changes
04
P
373
,
.
.
6
I?.
I6
Pos~-bum
noun
:
.
.
,
.
.
:
.
.
.
,
,
.
.
:
24234661 Days
I
I
2
W.,h, ’
’
1
Fig. 4. Platelet count in burned patients from Allyn. P. A. and Bartlett R. H. (1976) Management of the critically ill bum patient. In: Zschocku (ed). Comprehensive Review of Critical Care. St Louis, Mosby.
‘0 4..
I
6
12
PoQ-burn
18 .
Hours
24 :..y..: 2
I
3
4
5
6
Days
Fig. 5. Platelet adhesiveness in burned patients.
remainder of the acute phase. Platelet function studies showed a wide range of responses. .Adhesion decreased in relation to platelet count, with the exception of 1 of 5 patients studied (JS). Aggregation and PF3 follow a similar course, with the exception of one patient (JAR). Subsequent studies have shown that similar changes in function testing are caused by dilution of normally functioning platelets. When the platelet counts were high, function tests were generally in the normal (but not super-normal) range. Debridement was begun 4-l days post burn. Bleeding was easily controlled. Transfusion was required for maintenance of blood volume and hematocrit, but specific components were not
required or given. Although the timing of weekly samples was randomly related to transfusion, we could not identify any effects on the measurements which could be related to transfusion of bank blood. The episode of Klebsiella septicemia in patient IY can be identified in Fig. 4 as a drop in platelet count occurring at 3 weeks post bum. A decrease in fibrinogen and increase in FDP also occurred at that time. DISCUSSION
This
study
individuals
patients
group with
developed
was composed of young burns. None of the wound infection or other
major
Burns Vol. ~/NO. 5
374
ss
-
JS O---Q EA o---o JARr...-r
45x 45 36 30
IY 6SY. JL o----m 66 JRO--060 HP*...d 50
1.. f
.!
PostL” “0:. ‘* 1 24
Fig.
seconds
.
.
.
.
.
.
2
3 DOYS4
5
6
I1
I 2
,.I
4
y
6. Platelet aggregation in response to ADP.
60
m
60
ss JS BA JAR
100 >I20
Seconds
= Normal D---Q c----o A.......
fy
-
JL D---Q JR o-.4 HP A.......
controls 45% 45 36 ?LJ
65% 66 60 50
>
I..
.
6 I2“2.
Post-burn
. . . . . . . 1
24
2
3 00p4
5
6
I
4
..1....
2
Wwks 3
4
i
Fig. 7. Platelet Factor 3 in burned patients,
major complications. Hence the findings are those of burn injury per se. The initial decrease in clotting factors and associated prolongation of screening test times is correlated in time with the most rapid volume infusion. Plasma leaks out of capillaries, in the bum and systemically, and is replaced by non-plasma fluids. The result is a moderate dilution of some coagulation factors which is not sufftcient to produce a bleeding disorder. The fluid infusion is rapidly curtailed between 36 and 48 hours post bum and the coagulation factors returned to normal shortly
after. The fact that this does not correlate with the pattern of platelet loss and reconstitution, and the absence of fibrin degradation products, is evidence that these changes in coagulation factors are due primarily to dilution rather than progressive consumption. The decreased levels of fibrinogen and Factor V found on the first measurement are indicative of the amount of coagulation occuring in vessles in the area of the burn. Factor VIII is rapidly secreted in response to any stress, hence levels of this enzyme tend to run higher than that of other factors. This stress
375
Bartlett et al.: Coagulation and Platelet Changes
response may account for the abnormally high levels of coagulation factors including ftbrinogen, and the corresponding hypercoagulable screening tests, seen during the remainder of the acute phase. Other investigators (Curreri et al., 1970; Gehrke et al., 1971; Caprini et al., 1977; Simon et al., 1977; Gabilondo et al., 1977) have reported similar findings in burn patients without major complications, although the pattern was difftcult to discern because data for the first week were usually lumped together. The presence of a circulating anticoagulant (prolonged TT corrected by protamine sulphate) reported in 5 patients with large fatal burns (Gehrke et al., 1971) was not detected in our series. The low levels of fibrin degradation products throughout the course (with the exception of the episode of septicemia), combined with the normal levels of coagulation factors listed above, suggest that intravascular coagulation or consumption coagulopathy is not necessarily a part of normal reaction to burn inury. We used the tanned red cell hemagglutination inhibition immunoassay (TBRC) for FDP. Meyers (1972) using the same method, found similar results. Curreri, et al. (1975a, 1975b) reported normal or slightly elevated FDP measured by TRBC in 73 per cent of a series of bum patients, but grossly elevated FDP measured by staphylococci clumping in 93 per cent of the same series. He concluded that most of the FDP in burn patients is fibrin fragment D, which is detected by staphylococci clumping but not TRBC. Caprini (1977) also found high levels of FDP, using the staphylococci clumping test, particularly in high-risk patients. It remains to be determined whether differences between these series are due to measurement techniques, sepsis, or both. Further study of fibrinolysis is particularly important, since Curreri’s group has demonstrated that FDP fragment D can cause interstitial pulmonary edema and respiratory failure (Manwaring et al., 1978; Luterman et al., 1977). Platelet count decreased rapidly, partly due to dilution, but continued to drop after fluid replacement had been completed, indicating a continuing decrease of circulating platelets the first 3 or 4 days after injury. This decrease may be due to inadequate production from the bone marrow, consumption in thrombosed vessels, aggregation and reticula-endothelial filtration of circulating platelets, or any combination of these factors. The experimental study of Eurenius et al. (1972) indicates that both
consumption and decreased platelet survival are significant factors. Kinetic studies of labelled platelets, fibrinogen and plasminogen were reported by Simon et al, (1977). Disappearance and turnover times of platelet and fibrinogen were markedly accelerated in burn patients, and labelled platelets and fibrinogen were localized in the burn wound. The pattern of coagulation and platelet changes was similar to that found in this study. The decrease which we observed in platelet function could be an artifact of testing, or could represent decreased platelet function in rive. This could be determined by measurement of bleeding time which was not carried out routinely in this study. Experience with patients indicates that bleeding time is prolonged during the period of severe thrombocytopenia. Platelet count returns to normal by 7 days and rebounds to high levels, contributing to rapid clotting of wounds and donor sites observed at the time of grafting. Other investigators have reported a similar pattern of platelet count following burn injury (Gehrke et al., 1971; Caprini et al., 1977: Hergt, 1972). Only Gabilondo (1977) has reported no thrombocytopenia (in a series of 12 burn patients). IMPLICATIONS MANAGEMENT
IN CLINICAL
BURN
The findings of this study have significantly and favourably affected our management of burn patients. Patients with less than 40 per cent total surface burn will generally have only minor abnormalities in coagulation and do not require special handling. Patients with burns greater than 40 per cent total body surface will have a bleeding tendency, beginning on the second and proceeding to the fourth day after injury, which increases in severity with increasing extent of burn. This coagulopathy is due almost exclusively to thrombocyptopenia and thrombocytopathia. It does not result in spontaneous bleeding, but cut tissues will ooze incessantly during this time, resulting in transfusion of bank blood which may contribute to the thrombocytopenia resulting in more bleeding, therefore a vicious cycle is established. Hence, in patients with major burns, required operations (laparotomy, fracture stabilization, tracheostomy. escharotomy, pin placement, etc.) should be carried out during the first 24 hours after injury or delayed until the platelet count has reached its nadir and is rising. This will usually be on the fourth or fifth day after injury. In our experience surgical procedures carried out when the platelet
376
count is rising will not result in significant bleeding, even if the actual count is still relatively low. If operation must be carried out, or if significant bleeding occurs during the period of progressive thrombocytopenia, fresh platelet transfusions should be given, and will return the thrombotic sequence to normal. The period of thrombocytosis and hypercoagulability which exists between the seventh and thirtieth day post bum is teleologically useful. Skin grafting operations done during that time cause less bleeding than procedures during the thromboctyopenic phase. CONCLUSIONS
Significant changes occur in coagulation, platelet count, and platelet function after thermal injury. An initial moderate decrease in coagulation factors correlates with dilution by resuscitation fluid. Progressive thrombocytopenia may be partly explained by dilution but continues until the third or fourth day after injury. The best explanation for this thrombocytopenia is intravascular platelet aggregation, filtration and consumption in the injured tissue. All phases of coagulation return to normal by I week after injury and progress to a true hyper-coagulable state between she second and fourth week. The presence of fibrin degradation products or later decreases in platelet count are correlated with septicemia (McManus et al., 1973) and are not part of the normal response to bum injury in patients treated according to our protocol. Clinical implications of these findings are: a bleeding disorder in patients with major burns between the second and fourth day following injury which is due to thrombocytopenia and thrombocytopathy. If bleeding does occur it is usually related to thrombocytopenia and can be reversed wi-th platelet transfusions. Acknowledgements
This research was supported by the Orange County Burn Fund and the Heart Foundation.
REFERENCES
Achau& B. M., Allyn P., Fumas D. W. et al. (1973) Pulmonary complications ofburns: the major threat to the burned patient. Ann. Sur.~. 177,3 I I. Allyn P. A. and Bartlett R. H. (1976) Management of the critically ill burn patient. In: Zschocke (ed.) Comorehensive Review of Critical Care. St Louis. Mosby. Bartlett R. H., Allyn P. A., Medley T. et al. (1977) Nutritional therapy based on positive caloric
Burns Vol. ~/NO. 5
balance in bum patients. Arch. Surg. 112,974. Blombach B. J. and Blombach M. (1956) Purification of human and bovine fibrinogen. Arkiv. Fiir. Kemi. 10,415. Born G. V. R. and Cross M. J. (I 966) The aggregation ofblood platelets. Br. J. Haematol. 12,764. Brecher G. and Cronkite E. P. (1950)Morphology and enumeration of human blood platelets. J. Appl. Physiol. 3,365. Caprini J. A., Lipp V., Zuckerman L. et al. (1977) Hematologic changes following bums. J. Surg. Res. 22,626. Curreri P. W., Katz A. J., Dotin L. N. et al. (1970) Coagulation abnormalities in the thermally injured patient. Curr. Top. Surg. Res. 2,401. 1970. Curreri P. W., Rayfield D. L., Vaught M. et al. (1975a) Extravascular fibrinogen degradation in experimental bum wounds: a source of fibrin split products. Surg. 77.86. Curreri P. W., Wilterdink M. E. and Baxter C. R. (1975b) Characterization of elevated fibrin split products following thermal injury. Ann. Surg. 181, 157. Eurenius K., Mortensen R. F., Mesero P. M. et al. (1972) Platelet and megakaryocyte kinetics following thermal injury. J. Lab. Cfin. Med. 79,247. Gabilondo F. J., Huerta E. H. and Jimenez M. C. (1977) Haemostasis in bums: a preliminary report. Burns 3,24. Gehrke C. F., Penner J. A. and Niederhuber J. et al. (197 1) Coagulation defects in burned patients. Surg. Gynecol. Obstet. 133,6 13. Hergt K. (1972) Blood levels of thrombocytes in burned patients: observations on their behaviour in relation to the clinical condition of the patient. J. Trauma 12,599. Husom 0. (196 I) A one stage method for the assay of platelet factor 3. Stand. J. Clin. Lab. Invest. 13,609. Langdell R. D. and Wagner R. H. (1964) Estimation on antihemophiliac activity by PTT techniques. In: Tocantins L. M. (ed.) Blood, Coagulation, Hemorrhage and Thrombosis. Grune and Stratton, New York, pp. 107-I 12. Luterman A., Manwaring B. A. and Curreri P. W. (I 977) The role of fibrinogen degradation products in the pathogenesis of the respiratory distress syndrome. Surgery 82,703. Manwaring D., Thoming D. and Curreri P. W. (1978) Mechanisms of acute pulmonary dysfunction induced by fibrinogen degradation product D. Surger.v84,45. McManus W. F., Eurenius K. and Pruitt B. A. (1973) Disseminated intravascular coagulation in burned patients. J. Trauma 13,416. Meyers A. (1972) Fibrin split products in the severely burned patient. Arch Surg. 105,404. Pitcher P. (I 972) The detection of fibrinogen degradation products (FDP) in serum and urine. Can. .I. Med. Technol. 34, 166. Proctor R. R. and Rapaport S. E. (196 I ) The partial thromboplastin time with koalin. Am. J. C/in. Path. 36.212.
Bartlett et al.: Coagulation and Platelet Changes
Quick A. J. (1935)A study of the coagulation defect in hemophilia and in jaundice. Am. J. Med. Sci. 190, 501. Rapaport S. 1. (1957) Clotting factor assays on plasma from patients receiving intramuscular subcutaneous heparin. Am. J. Med. Sri. 234,678. Saliba M. J., jun., Dempsey W. C. and Kruggel J. L. (1973) Large Bums in humans. JAMA 225,261. Salzman E. W. (1963) Measurement of platelet adhesiveness. A simple in vitro technique demonstrating abnormality in von Willebrand’s disease. J. Lab. Clin. Med. 62, 724.
377
Simon T. L., Curreri P. W. and Harker L. A. (1977) Kinetic characterization of hemostasis in thermal injury. J. Lab. Clin. Med. 89,70. Stormorken H. (1957) The preparation of proaccelerin difftcient plasma for the assay of proaccelerin. Stand. J. Clin. Lab. Invest. 9,273. Zawacki B. E. (1974) Reversal of capillary stasis and prevention ofnecrosis in bums. Ann. Surg 180,98.
Paper accepted 8 January 1980.
Burns. 7.370-377
Printedin Great Britain
Coagulation and platelet changes after thermal injury in man Robert H. Bartlett, Wayne Anderson
Susie W. Fong, Greg
Marrujo,
James
Hardeman
and
University of California, Irvine Burn Center, California, USA INTRODUCTION BLEEDING
tendency in the early phase and hypercoagulability in the late phase of acute bum care are common clinical observations. Intravascular coagulation can be seen in small vessels on the surface of full-thickness bums. Progressive microvascular coagulation has been suggested to contribute to the depth of the initial injury (Zawacki, 1974). It has been proposed that anticoagulation with heparin prevents this phenomenon (Saliba et al., 1973). Despite the importance of these factors in the pathogenesis in the management of acute bum injury, relatively few detailed studies of the coagulation and platelet response to thermal injury have been reported (Curreri et al., 1970; Gehrke et al., 1971; Caprini et al., 1977; Hergt, 1972; Meyers, 1972; Curreri et al., 1975b; Simon et al., 1977; Gabilondo et al., 1977). Of the studies that have been reported, the major surface treatment technique was exposure, or not specified. In most of these studies the response to systemic sepsis or catabolism cannot be differentiated from the response to the bum itself. This study was undertaken to characterize coagulation and platelet changes in a selected group of bum patients treated with the same protocol which includes colloid resuscitation, Presented at Southern California Chapter, American College of Surgeons, Newport Beach, California I979 and in part at American Bum Association, 1974, Cincinnati, Ohio. Address for correspondence: Dr Bartlett, Department of Surgery, University of Michigan Medical Center. Ann Arbor, Michigan 48 105, USA.
occlusive dressings, thorough daily cleaning, vigorous debridement and maximal nutrition. The hypermetabolic state is matched with caloric administration, preventing catabolism and weight loss. The incidence of infection with this protocol is less than 2 per cent. In planning this study we hoped to exclude or at least identify separate effects due to sepsis, and prevents effects due to malnutrition. PATIENT
SERIES
AND
METHODS
The patient series is shown in Fig. 1. A full battery of coagulation studies was carried out in 11 patients age 2- 45, total surface bum 30- 68 per cent and full-thickness bum 5- 60 per cent. These patients were selected from 200 admissions to the University of California lrvine Bum Center in a 12-month period. Young patients with extensive bums but good prognosis were selected because we hoped to study the entire group through the full course ofacute care and recovery. All patients were treated according to the same protocol (Allyn and Bartlett, 1976). Initial resuscitation was with 5 per cent albumin in 0.8 per cent sodium chloride (Albumisol) infused at a rate sufficient to maintain adequate peripheral perfusion. (Blood pressure >80 mean, pulse < 120, no metabolic acidosis, urine >20 cc M-2 h-1, hematocrit 45-50 per cent.) This usually amounted to 10 per cent of the body weight over the first 48 hours (Allyn and Bartlett, 1976). Pulmonary insufficiency and smoke inhalation were managed with early endotracheal intubation, mechanical ventilation, and diuretic drugs (Achauer et al, 1973).
Bartlett et al.: Coagulation and Platelet Changes
F/K. I. Age and total surface bum in the coagulation study group.
Nutrition was based on replacing measured caloric expenditure daily and maintaining body weight with oral and gastric feeding (Bartlett et al., 1977). Intravenous hyperalimentation was not required to maintain positive caloric balance in these patients. The surface was managed by daily cleaning with Betadine in a tub containing dilute hypochlorite. Gentle dtbridement was carried out daily and tangential dtbridement under anesthesia carried out in the tub every 3-4 days. Activity and ambulation were encouraged; no specific isolation procedure was followed. Grafting was carried out as soon as healthy granulation tissues covered areas of fullthickness burn. Tight fitting elastic occlusive dressings impregnated with sodium sulphadiazine or silver sulphadiazine were placed on the surface after tubbing daily. Blood samples were taken for full coagulation studies as soon as possible aRer admission, at daily intervals for the first 7 days, then weekly intervals for the next 4 weeks. Blood was drawn from indwelling catheters or fresh punctures. The initial sample was discarded, and blood placed in citrate or EDTA anti-coagulant polypropylene tubes. Partial thromboplastin time (Proctor and Rapaport, 1961), prothrombin 1935), and thrombin time time (Quick, (Rapaport, 1957), were measured as screening tests. Factor V (Stormorken, 1957), Factor VIII (Langdell and Wagner, 1964), and Factor I (fibrinogen) (Blombach and Blombach, 1956) were assayed directly. Fibrin degradation products were measured by semiquantative immunoassay (Pitcher, 1972). Platelet counting was done by phase microscopy (Brecher and Cronkite, 1950), as automated methods of plate-
371
let counting may be inaccurate at low platelet counts. Platelet function studies were carried out on platelet rich plasma with actual platelet counts approximately twice whole blood levels. Platelet thromboplastic activity (platelet Factor III) was measured by the method of Husom (1961) in which platelet rich plasma is used as the activating agent in a Stypven reagent. Time to complete platelet aggregation following stimulation with ADP was measured under direct microscopic observation (Born and Cross, 1966). The results correlate well in our laboratory with the optical density-platelet aggregometer method but much less blood is required. Platelet adhesiveness was measured by a modification of Salzman’s method (1963), in which 3 cc of citrate anti-coagulated blood are injected at a constant rate through a column of carefully cleaned glass beads; inflow and outflow platelet counts are measured. The normal range shown in the figures represents mean t2 standard deviations for normal human pooled plasma or platelet function tests as measured in our laboratory. Normal pooled plasma controls are run with all screening and factor assays. RESULTS All patients
survived, with an average time from burn to grafting of 21 days and average total hospitalization time of 36 days. Four patients required intubation and mechanical ventilation for airway edema and/or smoke inhalation. There was no bum wound infection. Septicemia occurred in one patient-a 2-year-old child with 65 per cent total surface, 60 per cent fullthickness bum with Klehsiella thromhophlehitis in a cutdown site. There were no major bleeding or clotting complications although several patients with large bums had moderate bleeding from escharotomy sites during the second or third day post burn. Neither were there stress ulcers or other signs of gastrointestinal bleeding in any of the patients. Blood transfusion was required at the time ofdtbridement and grafting. I blood volume total averaging approximately transfusion during hospitalization. Results of coagulation studies are shown in Figs. 2 and 3. In these and subsequent figures the normal range is shown in the shaded area and the time scale shows the first day, first week, and first month in equal increments. It can be seen from the figures that partial thromboplastin time is prolonged for the first 2- 4 days, following a course similar to that of Factor V. All values return to normal by 5 days (except a
Burns Vol. ~/NO.
372
5
TT hd
Fig. 2. Coagulation screening tests in burned patients. PTT, partial thrombo-
plastin time; Pro T, prothrombin time; TT, thrombin time.
-
.e_e.
60-rn(B)AW W-45 (5) Av.
Fig. 3. Factor assays and fibrin degradation products (FDP) in burned patients.
slight prolongation of prothrombin time). Hypercoagulability characterized by shortened PTT and elevated fibrinogen, Factor V, and Factor VIII characterize the period between 1 and 4 weeks. In these subsequent figures, data for small bums (30-45 per cent) and larger burns (SO-70 per cent) are presented separately. No significant differences in coagulation measurements are seen between these groups. Fibrin degradation products were present in very small amounts. This observation was
supported by the normal measurements of the thrombin time which becomes abnormally prolonged if fibrin degradation products are present. Platelet count and function studies are shown in Figs. 4-7. Progressive thrombocytopenia occurs during the first 3 days after injury, with greater change occurring with increasing extent of burn. Thrombocytopenia reaches a maximum on the third day and gradually returns to normal, reaching baseline values by 1 week and rebounding to abnormally high levels during the
Bartlett et al.: Coagulation and Platelet Changes
04
P
373
,
.
.
6
I?.
I6
Pos~-bum
noun
:
.
.
,
.
.
:
.
.
.
,
,
.
.
:
24234661 Days
I
I
2
W.,h, ’
’
1
Fig. 4. Platelet count in burned patients from Allyn. P. A. and Bartlett R. H. (1976) Management of the critically ill bum patient. In: Zschocku (ed). Comprehensive Review of Critical Care. St Louis, Mosby.
‘0 4..
I
6
12
PoQ-burn
18 .
Hours
24 :..y..: 2
I
3
4
5
6
Days
Fig. 5. Platelet adhesiveness in burned patients.
remainder of the acute phase. Platelet function studies showed a wide range of responses. .Adhesion decreased in relation to platelet count, with the exception of 1 of 5 patients studied (JS). Aggregation and PF3 follow a similar course, with the exception of one patient (JAR). Subsequent studies have shown that similar changes in function testing are caused by dilution of normally functioning platelets. When the platelet counts were high, function tests were generally in the normal (but not super-normal) range. Debridement was begun 4-l days post burn. Bleeding was easily controlled. Transfusion was required for maintenance of blood volume and hematocrit, but specific components were not
required or given. Although the timing of weekly samples was randomly related to transfusion, we could not identify any effects on the measurements which could be related to transfusion of bank blood. The episode of Klebsiella septicemia in patient IY can be identified in Fig. 4 as a drop in platelet count occurring at 3 weeks post bum. A decrease in fibrinogen and increase in FDP also occurred at that time. DISCUSSION
This
study
individuals
patients
group with
developed
was composed of young burns. None of the wound infection or other
major
Burns Vol. ~/NO. 5
374
ss
-
JS O---Q EA o---o JARr...-r
45x 45 36 30
IY 6SY. JL o----m 66 JRO--060 HP*...d 50
1.. f
.!
PostL” “0:. ‘* 1 24
Fig.
seconds
.
.
.
.
.
.
2
3 DOYS4
5
6
I1
I 2
,.I
4
y
6. Platelet aggregation in response to ADP.
60
m
60
ss JS BA JAR
100 >I20
Seconds
= Normal D---Q c----o A.......
fy
-
JL D---Q JR o-.4 HP A.......
controls 45% 45 36 ?LJ
65% 66 60 50
>
I..
.
6 I2“2.
Post-burn
. . . . . . . 1
24
2
3 00p4
5
6
I
4
..1....
2
Wwks 3
4
i
Fig. 7. Platelet Factor 3 in burned patients,
major complications. Hence the findings are those of burn injury per se. The initial decrease in clotting factors and associated prolongation of screening test times is correlated in time with the most rapid volume infusion. Plasma leaks out of capillaries, in the bum and systemically, and is replaced by non-plasma fluids. The result is a moderate dilution of some coagulation factors which is not sufftcient to produce a bleeding disorder. The fluid infusion is rapidly curtailed between 36 and 48 hours post bum and the coagulation factors returned to normal shortly
after. The fact that this does not correlate with the pattern of platelet loss and reconstitution, and the absence of fibrin degradation products, is evidence that these changes in coagulation factors are due primarily to dilution rather than progressive consumption. The decreased levels of fibrinogen and Factor V found on the first measurement are indicative of the amount of coagulation occuring in vessles in the area of the burn. Factor VIII is rapidly secreted in response to any stress, hence levels of this enzyme tend to run higher than that of other factors. This stress
375
Bartlett et al.: Coagulation and Platelet Changes
response may account for the abnormally high levels of coagulation factors including ftbrinogen, and the corresponding hypercoagulable screening tests, seen during the remainder of the acute phase. Other investigators (Curreri et al., 1970; Gehrke et al., 1971; Caprini et al., 1977; Simon et al., 1977; Gabilondo et al., 1977) have reported similar findings in burn patients without major complications, although the pattern was difftcult to discern because data for the first week were usually lumped together. The presence of a circulating anticoagulant (prolonged TT corrected by protamine sulphate) reported in 5 patients with large fatal burns (Gehrke et al., 1971) was not detected in our series. The low levels of fibrin degradation products throughout the course (with the exception of the episode of septicemia), combined with the normal levels of coagulation factors listed above, suggest that intravascular coagulation or consumption coagulopathy is not necessarily a part of normal reaction to burn inury. We used the tanned red cell hemagglutination inhibition immunoassay (TBRC) for FDP. Meyers (1972) using the same method, found similar results. Curreri, et al. (1975a, 1975b) reported normal or slightly elevated FDP measured by TRBC in 73 per cent of a series of bum patients, but grossly elevated FDP measured by staphylococci clumping in 93 per cent of the same series. He concluded that most of the FDP in burn patients is fibrin fragment D, which is detected by staphylococci clumping but not TRBC. Caprini (1977) also found high levels of FDP, using the staphylococci clumping test, particularly in high-risk patients. It remains to be determined whether differences between these series are due to measurement techniques, sepsis, or both. Further study of fibrinolysis is particularly important, since Curreri’s group has demonstrated that FDP fragment D can cause interstitial pulmonary edema and respiratory failure (Manwaring et al., 1978; Luterman et al., 1977). Platelet count decreased rapidly, partly due to dilution, but continued to drop after fluid replacement had been completed, indicating a continuing decrease of circulating platelets the first 3 or 4 days after injury. This decrease may be due to inadequate production from the bone marrow, consumption in thrombosed vessels, aggregation and reticula-endothelial filtration of circulating platelets, or any combination of these factors. The experimental study of Eurenius et al. (1972) indicates that both
consumption and decreased platelet survival are significant factors. Kinetic studies of labelled platelets, fibrinogen and plasminogen were reported by Simon et al, (1977). Disappearance and turnover times of platelet and fibrinogen were markedly accelerated in burn patients, and labelled platelets and fibrinogen were localized in the burn wound. The pattern of coagulation and platelet changes was similar to that found in this study. The decrease which we observed in platelet function could be an artifact of testing, or could represent decreased platelet function in rive. This could be determined by measurement of bleeding time which was not carried out routinely in this study. Experience with patients indicates that bleeding time is prolonged during the period of severe thrombocytopenia. Platelet count returns to normal by 7 days and rebounds to high levels, contributing to rapid clotting of wounds and donor sites observed at the time of grafting. Other investigators have reported a similar pattern of platelet count following burn injury (Gehrke et al., 1971; Caprini et al., 1977: Hergt, 1972). Only Gabilondo (1977) has reported no thrombocytopenia (in a series of 12 burn patients). IMPLICATIONS MANAGEMENT
IN CLINICAL
BURN
The findings of this study have significantly and favourably affected our management of burn patients. Patients with less than 40 per cent total surface burn will generally have only minor abnormalities in coagulation and do not require special handling. Patients with burns greater than 40 per cent total body surface will have a bleeding tendency, beginning on the second and proceeding to the fourth day after injury, which increases in severity with increasing extent of burn. This coagulopathy is due almost exclusively to thrombocyptopenia and thrombocytopathia. It does not result in spontaneous bleeding, but cut tissues will ooze incessantly during this time, resulting in transfusion of bank blood which may contribute to the thrombocytopenia resulting in more bleeding, therefore a vicious cycle is established. Hence, in patients with major burns, required operations (laparotomy, fracture stabilization, tracheostomy. escharotomy, pin placement, etc.) should be carried out during the first 24 hours after injury or delayed until the platelet count has reached its nadir and is rising. This will usually be on the fourth or fifth day after injury. In our experience surgical procedures carried out when the platelet
376
count is rising will not result in significant bleeding, even if the actual count is still relatively low. If operation must be carried out, or if significant bleeding occurs during the period of progressive thrombocytopenia, fresh platelet transfusions should be given, and will return the thrombotic sequence to normal. The period of thrombocytosis and hypercoagulability which exists between the seventh and thirtieth day post bum is teleologically useful. Skin grafting operations done during that time cause less bleeding than procedures during the thromboctyopenic phase. CONCLUSIONS
Significant changes occur in coagulation, platelet count, and platelet function after thermal injury. An initial moderate decrease in coagulation factors correlates with dilution by resuscitation fluid. Progressive thrombocytopenia may be partly explained by dilution but continues until the third or fourth day after injury. The best explanation for this thrombocytopenia is intravascular platelet aggregation, filtration and consumption in the injured tissue. All phases of coagulation return to normal by I week after injury and progress to a true hyper-coagulable state between she second and fourth week. The presence of fibrin degradation products or later decreases in platelet count are correlated with septicemia (McManus et al., 1973) and are not part of the normal response to bum injury in patients treated according to our protocol. Clinical implications of these findings are: a bleeding disorder in patients with major burns between the second and fourth day following injury which is due to thrombocytopenia and thrombocytopathy. If bleeding does occur it is usually related to thrombocytopenia and can be reversed wi-th platelet transfusions. Acknowledgements
This research was supported by the Orange County Burn Fund and the Heart Foundation.
REFERENCES
Achau& B. M., Allyn P., Fumas D. W. et al. (1973) Pulmonary complications ofburns: the major threat to the burned patient. Ann. Sur.~. 177,3 I I. Allyn P. A. and Bartlett R. H. (1976) Management of the critically ill burn patient. In: Zschocke (ed.) Comorehensive Review of Critical Care. St Louis. Mosby. Bartlett R. H., Allyn P. A., Medley T. et al. (1977) Nutritional therapy based on positive caloric
Burns Vol. ~/NO. 5
balance in bum patients. Arch. Surg. 112,974. Blombach B. J. and Blombach M. (1956) Purification of human and bovine fibrinogen. Arkiv. Fiir. Kemi. 10,415. Born G. V. R. and Cross M. J. (I 966) The aggregation ofblood platelets. Br. J. Haematol. 12,764. Brecher G. and Cronkite E. P. (1950)Morphology and enumeration of human blood platelets. J. Appl. Physiol. 3,365. Caprini J. A., Lipp V., Zuckerman L. et al. (1977) Hematologic changes following bums. J. Surg. Res. 22,626. Curreri P. W., Katz A. J., Dotin L. N. et al. (1970) Coagulation abnormalities in the thermally injured patient. Curr. Top. Surg. Res. 2,401. 1970. Curreri P. W., Rayfield D. L., Vaught M. et al. (1975a) Extravascular fibrinogen degradation in experimental bum wounds: a source of fibrin split products. Surg. 77.86. Curreri P. W., Wilterdink M. E. and Baxter C. R. (1975b) Characterization of elevated fibrin split products following thermal injury. Ann. Surg. 181, 157. Eurenius K., Mortensen R. F., Mesero P. M. et al. (1972) Platelet and megakaryocyte kinetics following thermal injury. J. Lab. Cfin. Med. 79,247. Gabilondo F. J., Huerta E. H. and Jimenez M. C. (1977) Haemostasis in bums: a preliminary report. Burns 3,24. Gehrke C. F., Penner J. A. and Niederhuber J. et al. (197 1) Coagulation defects in burned patients. Surg. Gynecol. Obstet. 133,6 13. Hergt K. (1972) Blood levels of thrombocytes in burned patients: observations on their behaviour in relation to the clinical condition of the patient. J. Trauma 12,599. Husom 0. (196 I) A one stage method for the assay of platelet factor 3. Stand. J. Clin. Lab. Invest. 13,609. Langdell R. D. and Wagner R. H. (1964) Estimation on antihemophiliac activity by PTT techniques. In: Tocantins L. M. (ed.) Blood, Coagulation, Hemorrhage and Thrombosis. Grune and Stratton, New York, pp. 107-I 12. Luterman A., Manwaring B. A. and Curreri P. W. (I 977) The role of fibrinogen degradation products in the pathogenesis of the respiratory distress syndrome. Surgery 82,703. Manwaring D., Thoming D. and Curreri P. W. (1978) Mechanisms of acute pulmonary dysfunction induced by fibrinogen degradation product D. Surger.v84,45. McManus W. F., Eurenius K. and Pruitt B. A. (1973) Disseminated intravascular coagulation in burned patients. J. Trauma 13,416. Meyers A. (1972) Fibrin split products in the severely burned patient. Arch Surg. 105,404. Pitcher P. (I 972) The detection of fibrinogen degradation products (FDP) in serum and urine. Can. .I. Med. Technol. 34, 166. Proctor R. R. and Rapaport S. E. (196 I ) The partial thromboplastin time with koalin. Am. J. C/in. Path. 36.212.
Bartlett et al.: Coagulation and Platelet Changes
Quick A. J. (1935)A study of the coagulation defect in hemophilia and in jaundice. Am. J. Med. Sci. 190, 501. Rapaport S. 1. (1957) Clotting factor assays on plasma from patients receiving intramuscular subcutaneous heparin. Am. J. Med. Sri. 234,678. Saliba M. J., jun., Dempsey W. C. and Kruggel J. L. (1973) Large Bums in humans. JAMA 225,261. Salzman E. W. (1963) Measurement of platelet adhesiveness. A simple in vitro technique demonstrating abnormality in von Willebrand’s disease. J. Lab. Clin. Med. 62, 724.
377
Simon T. L., Curreri P. W. and Harker L. A. (1977) Kinetic characterization of hemostasis in thermal injury. J. Lab. Clin. Med. 89,70. Stormorken H. (1957) The preparation of proaccelerin difftcient plasma for the assay of proaccelerin. Stand. J. Clin. Lab. Invest. 9,273. Zawacki B. E. (1974) Reversal of capillary stasis and prevention ofnecrosis in bums. Ann. Surg 180,98.
Paper accepted 8 January 1980.