HYPERCOAGULATION IN BURN PATIENTS - EFFICACY OF THROMBOEMBOLIC PROPHYLAXIS

Arevalo Velasco A., Del Campo Balsa T, Gomez Bajo G.,* Cuesta Garcia V., Garcia Muhoz S., Lopez Pastor A., Fernandez-Chacon J.L., Fernandez-Pavon A., Garcia Torres V.*

Analytic Haemotology Department, La Paz Hospital, Madrid, Spain
* Burn Unit

SUMMARY. Sixty-nine patients admitted to our hospital with bums, most commonly deep-dermal, of different extent and production mechanism were studied. Heparin prophylaxis was administered to all these patients, 18% with non-fractionated heparin (one dose every 12 hours) and 82% with low molecular weight heparin (Tedelparine-BoxoF). A coagulation study was performed on admission and 5, 10 and 30 days later. The results obtained support the existence of a state of hypercoagulation, due mainly to a decrease of antithrombin III to thrombogenic limits which tends to become normal as it evolves. We consider that this prophylaxis, administered even in the absence of thromboembolic disease, is positive.

Thromboembolic venous disease (TVD) is today one of the most important causes of morbidity and mortality. Pathology related to burn injuries is outstanding among TV13 risk factors in non-surgical patients. The incidence of pulmonary embolism, the most severe complication of TVD, ranges from 5% to 7% in bum patients (1). The activation of haemostatic factors, the appearance of disseminated intravascular coagulation (DIC) and long stays in bed have been considered pathogenic factors of this complication (2). In a previous study (3), we described the decrease of antithrombin Ill (AT 111), the most important inhibitor of thrombin production, in this pathology. This decrease is considered to be one of the basic aetiologies of the thrombotic phenomenon; for this reason, considering the certainty of the risk, we propose in this pathology prophylactic therapy with subcutaneous heparin. The objectives of this study were thus to evaluate the efficiency of heparin prophylaxis, to analyse the behaviour of AT Ill and to study how basic coagulation parameters evolve with this treatment.

Sixty-nine patients admitted to the Bum Unit of our hospital, mostly with deep-dermal burns (age range 10 to 92 yr, average: 43 ± 21 yr; 19 females and 50 males) were studied.
Burn wound extent ranged from I to 90% (average: 34.5 ± 22.8%). 52.8% of the patients had a TBSA between I and 30%, 34.7% between 31 and 60% and 12.5% over 60%. Regarding the burn mechanism, in 59 cases the lesions were produced by flame, in three by scalds and six by electricity.
Prophylaxis with subcutaneous heparin was administered to all the patients: non-fractionated calcium heparin (NFH) every 12 h to 18% and low molecular weight heparin (LMWH) (TedelparineBoxol', at high-risk dose: 5000 Ul) every 24 hours to the other 82%. This prophylaxis was administered from admission until the risk had disappeared.
The study was performed on admission and 5, 10 and 30 days later.
Blood samples were obtained by venous puncture and distributed in various tubes: one with EDTA for platelet count, another with fibrinolysis inhibitors to determine serum fibrinogen degradation products (FDP), and two others with sodium citrate in a proportion of one to nine for the other parameters.
The following measures were made: platelet count (in a HI device, Technicon); prothrombin activity, APTT and fibrinogen, according to Caen et al., with an automatic technique (Electra 900, MLA); FDP with the latex technique; and AT III using a chromogenic substrate method in ACL 300.
The statistical analysis was performed using linear regressions, analysis of variance (ANOVA) and Student's t test.
Sixteen patients died during the study: one of DIC, one of a haemorrhagic disease and the other fourteen of non-haematological causes. All the other patients recovered.

The clinical evolution, as already said, was good in 53 patients (76.81%), with 16 deaths (23.18%). Analysis of the causes of death shows (Fig. 1) only two cases related to the coagulation system, one patient dying of DIC and the other after a haemorrhage. Both patients were young, with deepdermal 80% TI1SA bums. The blood disease appeared after admission and did not respond to substitutive therapy. The rapid evolution prevented the use of thromboembolic prophylaxis and for this reason the clinical pictures cannot be related to this therapy. A haemostatic study was performed on the admission of the two patients but the mortal evolution prevented further studies. The death of these patients supports the thesis of the importance of coagulation abnormalities in critically injured bum patients, and underlines the necessity of their control and treatment.

Fig. 1

The evolutionary results of the haemostatic parameters are show in Table 1. Prothrombin time (PT) and APTT did not change significantly in time. PT levels were normal after the first test, with a slight nonsignificant decrease on day 10. Considering the results obtained with APTT, a shortening was observed after admission and throughout the month of study.
The blood platelet (PIT) count was normal, showing a slight decrease with a subsequent increase. These variations were significant but always remained within normal values, except for the increase on day 10.
The fibrinogen plasmatic levels significantly increased from normal values after the first test. These levels decreased gradually until day 30, but were still above normal values at that time.
The FDP level showed a slight significant increase above normal values between the first test and day 30. This increase, as we explain in the Discussion, reflects the tendency towards hypercoagulation in these patients; this datum also suggests the presence of DIC.
The testing of AT 111 was intended to show whether this coagulation inhibitor plays an important role in the thrombotic tendency observed in bum patients and how it evolves. Considering all the patients, we found (Table I) a significant decrease in the AT 111 level at the first measurement. This level, which appeared in 70% of the cases, is an important risk factor in thrombosis. When AT 111 levels range from 70 to 80% the thrombotic risk is important, and when they go from 60 to 70% it is alarming. From day 5 onwards, AT 111 levels became normal in all patients. These data are shown in Fig. 2. In many patients (66%) this level is below 80%, and more importantly 36% have levels below 60%. We can also see that AT III slowly became nomial after day 5 in all patients but four.
Relating AT 111 levels to T13SA (especially when this area is >50%) we can notice in the first test an inverse relation between AT 111 levels and T13SA.

We noticed in our study an initial increase in platelets and fibrinogen followed by a decrease. The behaviour of these two parameters is compatible with their expression as acute phase reactants. The findings in the literature are similar, considering the different chronology employed (4, 5).
An activation of the coagulation cascade also occurs at the same time. This is measured by a shortening of APTT. This activation continued throughout the 30 days. This is an important consideration to justify the administration of thromboembolic prophylaxis for a long period. This prophylaxis must be administered, in our opinion, until patients achieve two aims: active mobilization and the tendency of APTT to become normal. We consider this non-specific test so important because clinical experience (6) shows that the prevention of post-surgical deep venous thrombosis, in high-risk pathologies such as hip surgery, is not achieved until the shortening of APTT is corrected through adjusted doses of heparin. The standardized administration of this prophylaxis was effective in our study.
Prothrombin activity was kept within normal range after admission, which supports the existence of a previously normal hepatic function.
There was no significant increase in FDR This fact, together with the increase in the platelet count and fibrinogen, supports the absence of consumptive coagulation (DIC) in our group, apart from the patient who died of DIC in the first hours of its evolution.
The initial decrease of AT III down to thrombogenic limits became normal as it evolved. If the hepatic function is normal, we can assume that the decrease is due to consumption. The inverse relation between AT III levels and TBSA has been discussed in a previous work (3). Some studies try to relate AT III decrease in burn patients to alterations in granulocyte enzymes (4-7). Heparin prophylaxis was administered in view of the thrombogenic risk in these critically injured patients. In the first phase prophylaxis was performed with NFH (8, 9) twice daily, because at this dosage it causes fewer haernorrhagic complications but has the same antithrombotic efficacy (10). Some authors prefer to select patients in order to avoid secondary effects, especially haemorrhage (1-11). Our experience supports the principle of not excluding critically injured burn patients from this group of prophylaxis, as they have an important thrombogenic risk and do not suffer haemorrhagic complications when given this dose of NF14 (10).
We performed this study when low molecular weight heparins (LMWH) were beginning to be used as prophylaxis (12, 13), and for this reason we used one of these products (Tedelparine-Boxol') in almost all our patients. L~ owe their prophylactic use to their condition as a main inhibitor of factor X. and to their better bioavailability, which explains why they are an ideal antithrombotic agent. Clinical results in the literature (14, 15) show a similar level of protection to NFH with a subcutaneous single dose every day. This is an advantage that helps patients to manage long-time medication.
The evaluation of thrombotic incidence in our patients was clinical, as it was not possible to perform methods for detection of deep venous thrombosis, owing to the great extent of the burns.
The absence of thrombotic phenomena and haemorrhagic complications convinces us that this prophylaxis administered to critically injured burn patients is positive.

Fig. 2

 

Fig. 3

 

Fig. 4

RESUME. Les auteurs présentent les résultats d'une étude sur 69 patients hospitalisés dans leur centre atteints de brûlures, pour la plupart dermique-profondes, d'étendue et étiologie diverses. La prophylaxie avec l'héparine a été administrée à tous les patients, 18% avec l'héparine non fractionnée (une dose toutes les 12 heures) et 82% avec des héparines de poids moléculaire bas (Tedelparine-Boxoll). Une étude de la coagulation a été effectuée au moment de l'hospitalisation et après 5, 10 et 30 jours. Les résultats de la recherche confirment l'existence d'une condition d'hypercoagulation due principalement à la diminution de l'antithrombine III aux niveaux thrombogènes qui tend vers la normalité comme elle évolue. Nous considérons que cette prophylaxie, adininistrée même en absence d'une pathologie thromboembolique, est positive.

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