PREVENTION OF VENOUS THROMBOEMBOLIC COMPLICATIONS IN ABDOMINAL AND PELVIC GUNSHOT WOUNDS
Main Clinical Hospital of Ministry of Internal Affairs of the Russian Federation,
Moscow, Russia
Main Military Clinical Hospital of Internal Troops of Ministry of Internal Affairs of the Russian Federation,
Balashikha, Moscow region, Russia
Russian Scientific Research Institute of Hematology and Transfusiology,
Saint Petersburg, Russia
Russian Medical Academy of Postgraduate Education,
Moscow, Russia
Kirov Military Medical Academy,
Saint Petersburg, Russia
During the wars of the 20th century the rates of penetrating abdominal injuries varied from 4.5 % to 8.2 % [1, 2]. Up to the present time, gunshot abdominal injuries are difficult for diagnostics and treatment and are accompanied by high rate of complications (about 70 % of cases) [3, 4, 5].
Venous thromboembolic complications (VTEC) are one of the most dangerous and catastrophic complications in surgical patients. They develop in 19-58 % in abdominal surgery [6, 7] and in 42.5 % in pelvic fractures [8]. The current methods for diagnostics of pathologic changes in venous system are characterized by various diagnostic accuracy. They often do not show a degree of available injuries that leads to incorrect estimation of actual hidden threat of development of thromboembolic complications [9].
VTEC are identified in 10 % of patients with polytrauma including 75 % of symptomless cases [10, 11]. VTEC are identified 6 times more often in gunshot injuries during warfare as compared with peace time. The statistically reliable factors of risk of VTEC are injuries to the head, the neck and the upper region of the abdomen, wounds and amputation of the lower extremities [12].
During the Great Patriotic War thromboembolic complications were not separated as an individual category and were the direct cause of death in 1.5-2.2 % of victims with abdominal injuries, as well as in 3.7 % in the post-war period [13, 14]. The last studies showed that VTEC were one of the main causes of death in patients who survived after severe associated injury [15, 16]. 36.4 % of patients die within a year after development of VTEC, 52.3 % – after an event of pulmonary embolism [17].
The issues of correction of coagulopathy were studied by the military surgeons in the second half of the 20th century. Then the main preventive agent was unfractionated heparin (UFH). For the first time it was used in 1938 [18], but its use for prevention of clot formation in extensive gunshot abdominal and retroperitoneal injuries was limited by the high risk of profuse bleeding [19], and low molecular heparins (developed in early 1990s) were not available for general practice.
The standards and the guidelines for venous thrombosis prevention were developed on the basis of the experience of administration of anticoagulant agents [20-23]. However in USA the attending physicians adhere to the guidelines for prevention and treatment of VTEC in only 33.9-55 % of cases [24, 25, 26], in Russia – in 25.9 % [27].
Despite of long term and comprehensive researching of the issues of VTEC prevention by the physicians of various specialties, a group of patients still exists for whom anticoagulants only slightly decrease the amount of cases of deep venous thrombosis, and the dosages, which are common for the high risk group, do not prevent development of venous thrombosis [28]. Such patients are separated into the group of very high risk of VTEC [29, 30].
According to the data of the pharmacoeconomic analysis, the costs for treatment of VTEC in USA are 13.5-69.3 billion dollars per year. Pharmacological and other types of prevention allow saving about 4.5-39.3 billion dollars [31, 32].
Objective – to improve the methods of prevention of venous thromboembolic events (VTE) in persons with gunshot abdominal and pelvic wounds at the stages of evacuation.
MATERIALS AND METHODS
The analysis included the results of treatment of 311 patients with gunshot abdominal, retroperitoneal and pelvic injuries who were treated in Main Clinical Hospital of Ministry of Internal Affairs of the Russian Federation and Main Military Clinical Hospital of Internal Troops of Ministry of Internal Affairs of the Russian Federation during 2000-2015. All patients were men, the mean age of 31.9 ± 7.3. Mine-explosive injuries were in 121 (38.9 %), gunshot wounds – in 190 (61.1 %) patients.
Medical evacuation from the accident site was realized in 2 stages: the first stage included transportation to the special medical detachment, the separate medical battalion of internal troops of Ministry of Internal Affairs of the Russian Federation or to the nearest hospital, where qualified or specialized medical aid was given. The second stage included evacuation to the central hospitals. At the first stage qualified and specialized medical aid was realized from 20 minutes to 2 days after an injury.
Traumatic shock was diagnosed in 277 (89.1 %) patients at the moment of admission. Shock of degree 1 was identified in 16 (5.1 %) patients, of degree 2 – in 44 (14.2 %), of degree 3 – in 242 (77.8 %), of degree 4 – in 9 (2.9 %) patients. Abdominal wounds were identified in 279 (89.7 %), retroperitoneal injuries – in 8 (2.6 %), pelvic injuries – in 63 (20.3 %). Single injuries to the abdomen were in 8 (2.6 %), to the pelvis – in 3 (1 %), combination of wounds of the abdomen and the pelvis with wounds of single anatomic region was identified in 56 (18 %), 2 regions – in 82 (26.4 %), 3 regions – in 150 (48.2 %), 4 regions – in 23 (7.4 %).
Injuries to the lower extremities (141 patients, 45.3 %) and the chest (94 patients, 30.2 %) prevailed among associated injuries to the abdomen and the pelvis.
The stage of emergency medical aid lasted for 57.3 ± 11.5 days.
A degree of development of VTEC was estimated on the basis of the Russian clinical guidelines for diagnostics, treatment and prevention of VTEC [21]. All patients were considered as the high risk group and they demonstrated 3-4 factors of development of VTEC.
The study used the method of stratification randomization with separation of two groups of the patients in dependence on received prevention of VTEC. The signs of homogeneity of the groups are presented in the table 1.
Table 1
| The characteristics of the signs of homogeneity in the main and control groups |
| A sign | Main group | Control group |
| Number of victims | 171 (55 %) | 140 (45.%) |
| Sex | men | men |
| Age | 28.1 ± 4.6 | 27. 1 ± 5.1 |
| Body weight | 81.5 ± 6.3 | 82.7 ± 5.1 |
| Injury severity according to MFS-I (GSW) | 5.4 ± 2.9 | 4.8 ± 3.9 |
| Injury severity according to abdominal AIS | 3.2 ± 0.2 | 3.3 ± 0.5 |
| Injury severity according to ISS | 22.6 ± 5.1 | 23.3 ± 4.1 |
On the basis of Lehmann-Roseblatt and Smirnov tests the groups were considered as homogenous.
At the stage of qualified medical aid the patients of the main group received pharmacological prevention with unfractioned heparin, 2,500-5,000 IU 3-4 times per day, in 6 hours after surgery within 1-5 days from the moment of evacuation with continuing prevention after arrival. At the stage of specialized medical aid the complex of preventive measures included mechanical (elastic dressing, compression knitwear, intermittent pneumocompression) and pharmacological methods: heparins with various molecular weight for the whole period of hospital stay – UFH (5,000 IU subcutaneously 4 times per day) or LMWH (nadroparin calcium [fraxiparine], 5,700 IU [0.6 ml]) or enoxaparin sodium (Klexan, 6,000 IU [0.6 ml]) or dalteparin sodium (fragmin, 7,500 IU [0.3 ml] 1 time per day).
The patients of the control group did not receive prevention of VTEC at the stage of qualified medical aid. At the stage of specialized medical aid they received UFH (2,500 IU subcutaneously 4 times per day) or LMWH (nodraparin calcium [Fraxiparine], 2,850 IU [0.3 ml]) or enoxaparin sodium (Klexan, 4,000 IU [0.4 ml]) or dalteparin sodium (fragmin, 2,500 IU [0.2 ml] 1 time per day for 16-20 days from the moment of admission).
The estimation of the venous system and visualization of venous clots were conducted with ultrasonic angioscanning with the expert devices and the linear transducers (5-12 MHz). Also the mobile ultrasonic scanner MicroMaxx (Sonosite, USA) was used. Ultrasonic angioscanning was conducted within 24 hours after admission and after 5-7 days, as well as before surgical intervention and in the postsurgical period. If venous clots were found, ultrasonic angioscanning was conducted 1 time in 2-3 days.
The efficiency of the preventive measures at the stages of treatment was conducted by means of estimation of changes in hemostasis system with assessment of thrombocytic link and coagulation activity. The first stage included the days 1-2 after an injury, the second one – the days 4-5 (in most cases it corresponded to initiation of the stage of specialized medical aid), the third stage – the days 9-10, the fourth stage – the days 14-15, the fifth stage – the days 19-20, the sixth stage – the days 29-30, the seventh stage – the day 35 and more after initiation of hospital treatment. The protocol of hemostasiological examination included activated partial thromboplastin time (APTT), prothrombin time in view of the international normalized ratio (INR), thrombin clotting time, fibrinogen concentration, the level of soluble fibrin monomer complexes, the level of D-dimers, the level of antithrombin III (AT-III), protein C, XIIa-dependent fibrinolysis, aggregative activity of platelets (estimated with the turbidimetric technique with ristocetin and ADP as inducers), ethanol gelation test. The investigation of allelic DNA polymorphism of the genes relating to the process of clot formation was performed on the basis of technology of polymerase chain reaction (PCR) of polymorphism of length of restriction fragments of PCR-product. The allelic polymorphism of the genes with conventional distribution into 3 groups was examined:
1) the genes coding the components of the plasma link of hemostasis: the factors I, II, V, XII of blood clotting, plasminogen activator inhibitor of type I – PAI-1;
2) the genes coding the components of thrombocytic receptors mediating the processes of adhesion and aggregation of blood plates: HPA-1, HPA-2, the thrombocytic receptor ADP P2Y12;
3) the genes of the components involved in the pathogenesis of endothelial dysfunction: GpIa C677T (MTHFR).
The composition of the studied hemostasiological tests was determined in dependence on the indications. The combined prevention of VTEC included early activation of patients, mechanical and pharmacological methods.
The mean terms of initiation of independent movement were 35.1 ± 12.5 days.
The mechanical methods of prevention included elastic dressing and compression knitwear. Hardware intermittent pneumocompression was conducted for 10 (3.2 %) patients. Presence of skin defects and pain syndrome in associated injuries to the extremities limited use of mechanical methods of VTEC prevention.
Electric stimulation of the legs was conducted for 17 (5.5 %) patients for decreasing pathological venous capacity, improving function and increasing the efficiency of muscular venous pump by means of Veinoplus DVT 180 minutes each day.
All data were statistically analyzed with Excel 2010, Statistica 7.0 and Biostat for Windows. Reliability of the data was estimated with Student’s test and non-parametrical statistical methods. The study was conducted in concordance with the requirements of the ethical committee of the hospital.
RESULTS AND DISCUSSION
According to the medical documents, the patients had not any vascular diseases or injuries before the accidents. According to ultrasonic angioscanning data, venous thrombosis was found in 33 (10.6 %) of the patients (the table 2).
Table 2
| The rate of venous thrombosis in gunshot wounds to the abdomen and the pelvis |
| Location | Number of victims, n = 311 | |||
| Main group | Control group | |||
| (n = 171) | (n = 140) | |||
| Abs. | % | Abs. | % | |
| Associated abdominal and lower limb injuries | 3 | 1.8 | 8 | 5.7 |
| Associated injuries to more than 3 regions | 2 | 1.2 | 8 | 5.7 |
| Associated abdominal and thoracic injuries | 2 | 1.2 | 6 | 4.3 |
| Single abdominal and pelvic injuries | 1 | 0.6 | 3 | 2.1 |
| Total: | 8* | 4.8 | 25* | 17.8 |
| Note: * - reliable differences, p < 0.05 |
All cases of thrombosis were found in the basin of the inferior vena cava. The level of thrombotic lesion of the veins in the patients of both groups did not show any statistical differences during the follow-up. The prevailing states were occlusive thrombosis of the leg (21 patients, 63.6 %) and the femur (8 patients, 24.2 %), proximal occlusive thrombosis was found in 3 (9.1 %) patients, mural thrombosis – in 1 (3 %) patient. Ultrasonic scanning did not identify any floating clots.
The examination of blood clotting system identified some disorders in platelet and coagulation hemostasis in 69 (40.4 %) patients in the main group and in 109 (77.9 %) patients of the control group at all stages of the follow-up. APPT was determined in the patients who received UFH; its average value was 43.82 ± 3.27 in the patients of the main group and 39.75 ± 3.91 in the patients of the control group (p < 0.05). The received results of APPT testify the blood level of heparin, which is insufficient for VTEC prevention in both groups [33]. Absence of increasing values of APPT at the background of heparin prevention can be associated with resistance to heparin determined by deficiency of AT-III and rapid excretion of heparin, increasing levels of fibrinogen or resistance caused by pharmaceuticals [34]. Moreover, the method of estimation of APPT is characterized by low sensitivity to hypercoagulation states of blood clotting system and it estimates the activity of individual links of hemostasis system only in intense change of the amount of the factors (by 40 % and more) [35].
The average INR was 1.31 ± 0.29 in the main group and 1.17 ± 0.21 in the control group (p > 0.05). In case of identification of deep venous thrombosis in the lower extremities and realization of medical procedures the values of INR were 1.8 ± 0.21 in the main group and 1.4 ± 0.28 in the control group (p < 0.05).
The values of thrombin clotting time and fibrinogenesis were without statistically significant differences in the main and the control groups. The results of XIIa-dependent fibrinolysis were 12.9 ± 2.13 minutes in the main group and 14.01 ± 2.73 minutes in the control group (p > 0.05).
Increasing aggregative activity of platelets with presence of hyperaggregation was found in 91 (53.2 %) patients in the main group and in 108 (77.1 %) patients in the control group (p < 0.05).
The analysis of the results of the examination of AT-III and protein C identified the decreasing level of AT-III in the main group in 11.1 % of the cases, decreasing protein C in 7 %. The control group showed the decrease in AT-III in 26.4 % and decreasing protein C in 12.9 %. The time course of AT-III and protein C is presented in the figures 1 and 2.
|
Figure 1 The comparative time trends of AT-III at the follow-up stages (*- ð < 0.05) |
Figure 2 The comparative time trends of protein C at the follow-up stages (*- ð < 0.05)
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1 |
2 |
The difference in the values of AT-III and protein C, which were found at the 2nd stage of the follow-up, could be associated with excessive consumption relating to the process of clot formation. The cause of development of differences in the values at 5th stage was termination of anticoagulant therapy in the control group.
The figure 3 demonstrates the results of the examination of soluble fibrin monomer complexes.
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Figure 3 The comparative time trends of SFMC at the follow-up stages (*- ð < 0.05)
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Figure 4 The comparative time trends of D-dimer at the follow-up stages
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The analysis of the results of the examination of soluble fibrin monomer complexes showed that thrombinemia developed in 24 hours after an injury and persisted for 35 days and more. The maximal values of soluble fibrin monomer complexes were found in both groups at 2nd stage of the follow-up: 11.4 ± 3.1 mg% in the main group and 15.1 ± 2.8 mg% in the control group. The trend to decreasing the values at the stages 3-5 of the follow-up is associated with realization of complex prevention of venous thrombosis. The increasing values of soluble fibrin monomer complexes at the stages 6-7 of the follow-up in the control group can be associated with termination of preventive measures. The results of ethanol gelation test correlate with the values of soluble fibrin monomer complexes in both groups.
The analysis of the results of the examination of D-dimer did not find any statistically significant differences in the main and control groups (Fig. 4).
The examination of blood D-dimers is a high sensitive test. Its negative result excludes presence of venous thrombosis, but it is characterized by low specificity and increasing values in clot formation, as well as in muscular injuries and necrosis, presence of inflammation, progression of infectious complications [36, 37, 38].
The maximal values of D-dimers were identified at 3rd stage of the follow-up: 3,214.8 ± 218.1 ng/ml in the main group, 3,358.1 ± 329.7 ng/ml in the control group (p > 0.05).
The examination of allelic polymorphism of the genes was conducted in 10 patients. 9 patients demonstrated 1-4 genetic mutations in the components coding the hemostasis system with increasing risk of VTEC (the table 3).
Table 3
|
Genetic allelic polymorphism in the victims |
| Examined genes | HPA-1 | HPA-2 |
Fibrinogen |
PAI-1 | Gpla C-677T | Factor XII (Hag) | P2Y12 ins 801A |
|
G/A-455 |
|||||||
| Number of mutations: | 2 | 2 | 3 | 2 | 1 | 1 | 2 |
Deep venous thrombosis in the lower extremities was found in 6 (60 %) patients with some genetic defects in the blood clotting system. The highest incidence of polymorphism was found for the gene Fibrinogen G/A-455.
Lethal outcomes were identified in 2 (1.4 %) patients in the control group. The postmortem examination identified some evident hematocirculatory disorders in the internal organs with presence of multiple mixed, red and fibrin clots in 1 patient.
CONCLUSION
1. The incidence of deep venous thrombosis is 10.6 % in patients with abdominal and pelvic gunshot wounds.
2. The complex scheme of VTEC prevention with mechanical and pharmacological methods for the whole period of treatment (57.3 ± 11.5 days) at the stages of evacuation allowed reducing the amount of venous thrombosis from 17.8 % in the control group to 4.8 % in the main group.
3. The condition of the hemostasis system is characterized by development of thrombinemia from the first day after an injury. Thrombinemia persists more than 35 days of treatment and requires prolonged correction of disorders for prevention of VTEC.
4. Identification of the genetic defects in the hemostasis system in 60 % of the patients with deep venous thrombosis showed the potential of the method for estimation of genetic thrombophilia in prediction of VTEC.