Key-words:
D-dimer - disseminated intravascular coagulation - fibrinopeptide A - Glasgow Coma Score - traumatic brain injury
Introduction
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide which places a substantial economic burden on the health-care system.[[1]] These patients are prone to the early development of coagulopathy.[[1]],[[2]] Disseminated intravascular coagulation (DIC) is the most severe complication characterized by formation of microthrombi in the cerebral vessels and eventual ischemia.[[3]]
Levels of D-dimer, a marker of fibrinolysis, are elevated in patients with DIC.[[3]] Fibrinopeptide A (FPA) levels provide a sensitive marker of in vivo hypercoagulability.[[4]] Hypofibrinogenemia has also been observed in these patients.[[5]] Changes in levels of plasma fibrinogen and D-dimer occur soon after head trauma. In a study of 20 patients evaluated within 6 hours of isolated severe head injury and 4 controls, plasma fibrinogen was significantly (P < 0.005) lower and D-dimer significantly (P < 0.005) higher in patients as compared to controls.[[4]]
Elevated D-dimer levels and hypofibrinogenemia have both been associated with poor outcome.[[3]],[[5]],[[6]] However, only an occasional study has evaluated the role of FPA as a marker of fibrinolysis in patients with TBI.[[4]],[[7]] Measurement of these markers will help in early identification of patients at risk which will aid in better management and improved prognosis. The present study aimed to measure the levels of fibrinogen, D-dimer, and FPA in patients admitted within 12 h of isolated head trauma and correlate them with outcome.
Subjects and Methods
One hundred patients admitted within 12 h of isolated head trauma were included in the study. Patients with polytrauma/clinical evidence of infection/those on anticoagulants were excluded from the study. The severity of injury was assessed by Glasgow Coma Score (GCS).[[8]] A written informed consent was obtained from all patients. The study received clearance from the Institutional Ethics Committee for human research.
Complete blood counts with platelet count (automated hematology analyzer LH500) and tests of hemostasis including PT (Thromborel S, Siemens Healthcare Diagnostics Products), APTT (Siemens Healthcare Diagnostics Products), plasma fibrinogen (FIBROQUANT, Tulip Diagnostics), and markers of fibrinolysis: D-dimer (Biomedical Assay ELISA) and fibrinopeptide A (ZYMUTEST FPA, Hyphen BioMed ELISA) were measured. DIC score was calculated using standard criteria.[[9]] All patients were followed up till the time of discharge/death.
Statistical analysis
SPSS (20.2) software was used for mean, standard deviation, and median values of the quantitative parameters, and for all qualitative parameters, their frequencies were obtained. For comparison between survivors and nonsurvivors, Chi-square test/Fisher's exact test was employed for the qualitative parameters and unpaired t-test for the quantitative parameters. The parameters not following the Gaussian distribution were normalized by log transformation, and then, the appropriate statistical test was used to compare. P < 0.05 was considered as significant.
Results
The age of the patients ranged from 7 to 82 years with a mean ± standard deviation of 33.7 ± 13.6 years; majority (60%) of patients being in the age range of 21–40 years. The study included 78 (78%) males and 22 (22%) females. Road traffic accident was the most (74%) frequent cause of TBI, with fall from a height (13%) and physical assault (13%) contributing to the remaining cases. As assessed by GCS, mild, moderate, and severe injuries were seen in 45%, 28%, and 27% patients, respectively. The results of platelet count and screening tests of hemostasis and the abnormal result observed in each parameter are shown in [[Table 1]].
Table 1: Platelet count, prothrombin time, international normalized ratio, and activated partial thromboplastin time and abnormal results in each parameter
[[Table 2]] shows the levels of plasma fibrinogen, D-dimer, and FPA and the abnormality observed in each parameter. Hypofibrinogenemia (<150 mg/dl) was observed in 48% of patients. An elevated (>250 ng/ml) D-dimer was observed in 64% of patients. Of these patients, 36 (56.2%) showed moderate (251–500 ng/ml) and 28 (43.8%) showed marked (>500 ng/ml) elevation. Elevated (>3 ng/ml) FPA levels were observed in 41/45 (91.1%) patients. D-dimer and FPA were both elevated in 30/45 (66.6%) patients while only FPA was elevated in 11 (24.4%) patients.
Table 2: Levels of plasma fibrinogen, D-dimer, and fibrinopeptide A and abnormal results in each
DIC score calculated using standard criteria [[9]] was ≥5 in 28% patients indicating overt DIC. None of these patients had any clinical feature of DIC and scores were not repeated subsequently.
Hypofibrinogenemia and elevated D-dimer and FPA were seen in patients irrespective of the severity of injury and even in those with mild injury. The mortality in this study was 26%. Plasma fibrinogen was significantly (P < 0.001) lower and D-dimer and FPA significantly (P < 0.001) higher in nonsurvivors as compared to survivors [[Table 3]]. Mortality was significantly (P < 0.001) higher in patients with hypofibrinogenemia and elevated D-dimer and FPA as compared to patients in whom these parameters were normal [[Table 4]].
Table 3: Plasma fibrinogen, D-dimer, and fibrinopeptide A levels in survivors and nonsurvivors
Table 4: Mortality in patients with and without changes in plasma fibrinogen, D-dimer, and fibrinopeptide A
Discussion
TBI is an acute brain injury arising from an external physical force to the head. The final injury to the brain results from a combination of primary and secondary insults. Coagulopathy which is frequently observed in these patients contributes to secondary brain injury and is associated with an adverse outcome.[[10]] DIC remains the most severe complication of TBI [[3]] in which there is depletion of coagulation factors and activation of coagulation. This study aimed to correlate the levels of plasma fibrinogen, D-dimer, and FPA with outcome in patients with isolated head trauma.
Hypofibrinogenemia was observed in 48% of patients in this study. In a previous study on 100 patients with isolated TBI, hypofibrinogenemia was reported in 7% of patients. The authors attributed the low incidence to genetic variation of the Indian population.[[5]] Kuo et al. observed hypofibrinogenemia in 23% of patients.[[11]]
The present study observed elevated levels of D-dimer and FPA in 64% and 91.1% of patients, respectively. Elevated levels denote increased thrombotic activity with consequent secondary fibrinolysis and have been commonly observed after TBI.[[4]],[[6]],[[10]],[[11]] In a study on 42 patients with head injury, elevated D-dimer was the most frequent coagulation abnormality seen in 48.5% of patients with severe injury. Even in patients with normal coagulation profile at admission, levels of D-dimer were elevated. The authors concluded that these levels must be measured at admission as early transfusion of Fresh Frozen Plasma (FFP) and platelets to these patients improved the prognosis.[[12]]
Levels of D-dimer rise soon after head trauma.[[4]],[[11]] Gando et al. studied 40 patients with trauma; 15 with and 25 without DIC. FPA and D-dimer were measured at days 0, 3, and 6. Both markers were elevated immediately after trauma, and though the levels decreased after the initial phase, the activity was higher than normal.[[13]]
Although not many studies have measured FPA in patients with head injury, increased levels have been observed following isolated head injury.[[4]],[[13]] In this study, FPA was elevated in a greater number (91.1%) of patients than D-dimer (64%), and 24.4% of patients had only elevation of FPA. The high levels are in agreement with those reported by Risberg et al.[[7]] The increased levels result from thrombin production which occurs after trauma.
DIC score was ≥5 in 28% of patients indicating overt DIC. None of these patients had any clinical feature of DIC and scores were not repeated subsequently. Similar results have been reported by other authors.[[3]],[[14]] Even though manifestations of DIC are not present initially, studies have shown that if fibrinolytic markers are elevated, early administration of heparin provides additional protection against cerebral ischemia as fibrinolytic turnover may spark DIC.[[14]]
The present study observed that hypofibrinogenemia and elevated D-dimer and FPA were associated with a worse outcome. Similar results have been reported by other authors.[[5]],[[11]],[[12]],[[15]]
Hypofibrinogenemia and elevated D-dimer and FPA were seen in patients irrespective of the severity of injury and even in those with mild injury. Measurement of these parameters in all patients with TBI irrespective of severity of injury at admission will help identify patients in need of additional therapy. Gando et al. treated patients of head trauma with DIC and elevated FPA levels with gabexate mesilate. There was no difference in the level from the non-DIC group.[[13]] This will help reduce morbidity and mortality.
