Thrombocytosis after trauma: incidence, aetiology, and clinical significance

N. Valade, F. Decailliot, Y. Rébufat, Y. Heurtematte, P. Duvaldestin and F. Stéphan*

Unité de Réanimation chirurgicale et traumatologique, Service d'Anesthésie-Réanimation, AP-HP Hôpital Henri Mondor, and Université Paris XII 94000, Créteil, France

* Corresponding author. E-mail: francois.stephan{at}hmn.ap-hop-paris.fr

Accepted for publication August 19, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Our aim was to assess the occurrence, aetiology, and clinical significance of a platelet count greater than 600x103/mm3 in trauma patients.

Methods. All trauma patients admitted to the intensive care unit (ICU) during a 13-month period were prospectively studied. Platelet counts were performed daily. We recorded the patient's age, sex, nature of trauma, severity of illness scores, episodes of infections in the ICU, acute lung injury, bleeding, and thromboembolic events. Patients with thrombocytosis were also followed during their hospital stay and 1 month after hospital discharge.

Results. A total of 176 patients were included. Thrombocytosis developed in 36 patients (20.4%) at a mean (SD) time of 14.0 (4.0) days and the platelet count normalized 35.0 (13.0) days after admission to the ICU. All patients with thrombocytosis had one or more possible predisposing conditions before the occurrence of thrombocytosis: nosocomial infection occurred in 30 patients (83%), acute lung injury in 17 (47%), bleeding in 27 (75%), and administration of cathecholamines in 24 (67%). Three venous thromboembolic complications occurred in the ICU (1.7%) and one during follow-up. Only one patient presented thrombocytosis at the time of diagnosis. Despite the fact that patients with thrombocytosis had a greater severity of illness, the ICU mortality was comparable among patients with and without thrombocytosis (8 vs 14%, P=0.34).

Conclusions. Reactive thrombocytosis is a common finding after severe trauma and was found to be associated with a better survival than predicted by severity of illness score. Unless additional risk factors are present, reactive thrombocytosis is not associated with an increased risk of thromboembolic events.

Keywords: blood, thrombocytosis ; complications, deep venous thrombosis ; complications, infection ; complications, trauma ; intensive care, mortality rate ; lung, acute injury


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The platelet count has become a variable of great interest for physicians working in the intensive care unit (ICU). Hitherto, most studies have focused on thrombocytopenia and the time course of changes in the platelet count in critically ill patients.13 In patients who survive after trauma the platelet count displays a bimodal response with an initial decrease below baseline values, followed by an increase above the normal range after 1 week.2 3 Thus, in retrospective studies, one-quarter of trauma patients developed a platelet count of more than 450x103/mm3.4 However, little is known about the aetiology and clinical significance of such elevated platelet counts in trauma patients.5 Secondary or reactive thrombocytosis has been linked to thrombotic complications in various settings68 and has been associated with lower ICU mortality.4 We therefore conducted a prospective study, in order to further assess the occurrence, aetiology, and clinical significance of a platelet count greater than 600x103/mm3 in trauma patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Data collection
All trauma patients admitted to our trauma ICU between January 2002 and January 2003 were included in the study. Trauma patients represented 60% of the admissions. Data were collected prospectively for each patient. The severity of illness was evaluated with the first-day new Simplified Acute Physiology Score (SAPS II),9 the Injury Severity Score,10 and the Organ Dysfunction and/or Infection (ODIN) score,11 based on the presence or absence of cardiac, respiratory, renal, hepatic, neurological, haematological dysfunction, and/or infection. Various other variables were recorded: age, sex, site of major injury and specific injury, need and duration of mechanical ventilation, duration of stay, and mortality in the ICU.

Information concerning ICU-acquired infections, episodes of acute bleeding, need for splenectomy, and prescription of epinephrine/norepinephrine were prospectively collected as they are conditions reported previously to predispose to reactive thrombocytosis.6 7 12 Episodes of acute lung acute injury (ALI)/acute respiratory distress syndrome (ARDS) were also prospectively recorded as a result of the associated inflammatory response.13 ICU-acquired infection was defined as an infection which began at least 48 h after ICU admission. In patients receiving mechanical ventilation of the lungs, the diagnosis of nosocomial pneumonia was considered when they developed a new and persistent lung infiltrate and had purulent tracheal secretions, confirmed by a bacterial culture of a blind protected telescoping catheter more than/equal to 103 CFU ml–1 of at least one pathogen.14 In patients breathing spontaneously, the diagnosis was considered when they had a compatible chest radiograph and purulent sputum with Gram stain and sputum culture documenting the presence of microorganisms. Diagnosis of central venous catheter-related infection was confirmed by a positive quantitative tip culture with a significant threshold of 103 CFU ml–1.15 Other nosocomial infections were prospectively surveyed and detected according to standard surveillance and definitions.16 Microorganisms isolated from various sources were recorded for microbiological analysis. Diagnosis of ALI and ARDS was made according to the American-European Consensus Conference definitions13 (acute onset, bilateral infiltrates on frontal chest radiograph, less than 300 for ALI and less than 200 for ARDS, and the absence of clinical evidence of left atrial hypertension). Acute bleeding was defined as bleeding requiring operative intervention, and/or the transfusion of 3 or more units of red blood cells.

Platelet counts were performed daily on a Coulter counter Gen.STM (Beckman Coulter France SA, Villepinte, France) using EDTA anticoagulated fresh blood. Thrombocytosis was defined as a platelet count more than 600x103/mm3 occurring at least once during the ICU stay and was confirmed by repeat examinations and/or peripheral smear examination. Thrombocytosis was considered to have resolved when the platelet count fell below 450x103/mm3.

Thromboembolic complications
Low-molecular-weight heparin (LMWH) is the method used in our institution for antithrombotic prophylaxis in trauma.17 Patients received 40 mg of enoxaparin (Lovenox, Aventis, Paris, France) subcutaneously once daily. Administration of LMWH was delayed if patients had frank intracranial bleeding on computed tomographic scanning (patients with a cerebral contusion or diffuse axonal damage could receive LMWH), had bleeding that remained uncontrolled 36 h after the injury, had non-operative management of splenic or hepatic trauma, had incomplete spinal cord injury associated with perispinal haematoma, or had systemic coagulopathy (defined by a prothrombin time ratio below 50% or a platelet count of less than 50x103/mm3). Graded elastic compression stockings were used for these patients when possible.

Each patient's clinical status was assessed daily in the ICU and risk factors for venous thromboembolism after trauma were also recorded.17 18 Patients in whom deep-vein thrombosis was clinically suspected underwent venous ultrasonography to confirm the diagnosis. Patients with clinical features suggestive of pulmonary embolism underwent a computed tomographic scan and/or pulmonary angiography to confirm the diagnosis.

For patients with thrombocytosis, signs of venous thromboembolism were also recorded during the hospital stay and 1 month after hospital discharge. Attempts to determine the occurrence of such complications 1 month after hospital discharge were made in writing and by telephone contact. If a patient could not be contacted by telephone or mail, attempts were made to contact the next-of-kin.

According to French law (Law No. 88-1138, December 20, 1988), this study did not need Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale (CCPPRB) approval because, as an observational study, it did not modify current diagnostic or therapeutic strategies. Written or verbal informed consent was obtained from each patient or their relatives when they were contacted by mail or by telephone. All data used in subsequent analyses were anonymized.

Statistical analysis
Data were entered onto a computer and analysed using Statview 5.0 statistical packages (SAS Institute Inc., SAS Campus Drive, Cary, NC 27515, USA). We expressed continuous variables as the mean (SD) or as the median and 25th to 75th percentiles when appropriate. {chi}2-tests or Fisher's exact test were used to compare proportions and rates, while continuous variables were compared using the Student's t-test or Mann–Whitney U-test when appropriate. Statistical significance was defined as a P-value of 0.05 or less.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During the study period, 176 patients were admitted to the ICU after trauma. Thrombocytosis developed in 36 patients (20.4%) at a mean (SD) of 14.0 (0.4) days (range 8–22) after ICU admission. The characteristics of patients who developed thrombocytosis are reported in Table 1. The lowest and highest platelet counts and their dates of occurrence for all patients are reported in Table 2. The distribution of the highest platelet count observed during ICU stay for patients with thrombocytosis is reported in Figure 1. The platelet count rose to more than 1000x103/mm3 in 10 patients. Thrombocytosis persisted for 20.8 (13.8) days and the platelet count normalized 35.0 (13.0) days (range 17–73) after ICU admission for all patients.


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Table 1 Clinical characteristics of the patients with and without thrombocytosis.

 

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Table 2 Lowest and highest platelet count and date of occurrence after ICU admission in patients with and without thrombocytosis during ICU stay

 


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Fig 1 Distribution of the highest platelet count and related current anticoagulant therapy in patients with thrombocytosis. Elastic stockings were systematically used for patients without anticoagulant therapy. UH, unfractionated heparin.

 
Aetiology
The incidence of conditions associated with thrombocytosis in patients who did or did not develop thrombocytosis is shown in Table 3. All patients who developed thrombocytosis had one or more of these possible aetiologic conditions before the occurrence of thrombocytosis. Episodes of ALI/ARDS occurred at a median time of 5 days (2.5–8.0) after ICU admission for patients with thrombocytosis compared with a median time of 1 day (1.0–4.0) for patients without (P=0.01).


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Table 3 Aetiologic conditions associated to thrombocytosis during ICU stay.

 
Thirty patients with thrombocytosis (83%) acquired a nosocomial infection compared with 25 patients (17%) without (P<0.0001). The time between ICU admission and onset of first infection was 6.2 (3.3) days for patients with thrombocytosis and 5.3 (2.7) days for patients without (P=0.29). The type of infection is also reported in Table 3. Infection developed before thrombocytosis in 83.3% of cases. When considering all isolates from all sources identified, Enterobacteria species were reported in 53 cases (75.7%), Staphylococcus aureus in 27 cases (38.6%), non-fermenting Gram-negative bacilli (i.e. Pseudomonas aeruginosa, Acinetobacter baumanii, and Stenotrophomonas maltophilia) in 24 cases (34.3%), Haemophilus influenzae in 19 cases (27.1%), and other cocci in 13 cases (18.6%). Only one urinary tract infection was a result of Candida albicans. Polymicrobial infection occurred in 32 (45.7%) of the 70 episodes of nosocomial infections. There was no statistical difference between patients with and without thrombocytosis regarding the distribution of microorganisms.

Clinical significance of thrombocytosis
The anticoagulant treatment at the time of the highest platelet count in patients with thrombocytosis is shown in Figure 1. The four thromboembolic complications were of venous origin. Three occurred in the ICU (1.7%) and one during the follow-up. Even though such complications occurred in the group of patients with thrombocytosis, only one patient actually had thrombocytosis at the time of diagnosis (Table 4).


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Table 4 Characteristics of patients with thromboembolic complications. IVC, inferior vena cava; GCS, Glasgow coma score

 
Despite the fact that patients with thrombocytosis had a greater severity of illness, the ICU mortality rate was similar between patients with and without thrombocytosis (8 vs 14%, P=0.34). Patients with thrombocytosis stayed longer in the ICU (24.5 [16.5–39.0] vs 4.5 [3.0–9.0] days, P<0.0001).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We found that 20.4% of trauma patients developed thrombocytosis during their ICU stay. Such reactive thrombocytosis was associated with few thromboembolic complications, and appeared to be a good prognostic factor. Development of thrombocytosis is common after trauma as reported previously in a retrospective study in which 27% of patients had a platelet count above 450x103/mm3.4 The definition of thrombocytosis varies widely among authors.6 7 We chose the threshold of 600x103/mm3 as this is one of the criteria for essential thrombocythaemia.12

Thrombocytosis can be primary or secondary to a variety of illnesses.5 In the present study, thrombocytosis was encountered exclusively as a reactive phenomenon: all patients had one or more underlying disorders associated with secondary thrombocytosis and the platelet count normalized after resolution of the acute disease state in all patients. Although recent trauma may have a part to play in these patients, the most common cause of reactive thrombocytosis was an infectious process, as in other studies6 7 in which pneumonia was the main infection implicated.7 During the acute phase of ALI/ARDS, platelet sequestration in the lung has been described,19 20 and levels of IL-6 measured within the alveolar airspace indicate a profound pro-inflammatory cytokine response to traumatic injury.21 Interestingly, in our study, the peak platelet count occurred 11 days after the beginning of ALI/ARDS when the initial phase had resolved for the majority of patients.

In agreement with previous work,5 6 7 12 the present study confirms the infrequency of clinical consequences of reactive thrombocytosis per se. Fewer than 3% of our trauma patients with thrombocytosis (1/34) had clinical features of venous thromboembolism. A strong point of our study was the follow-up of patients with thrombocytosis. Only one patient presented a calf vein deep venous thrombosis 1 month after hospital discharge. We acknowledge that we did not determine the true incidence of venous thromboembolism as investigations were not performed routinely on all patients. While contrast venography remains the most sensitive and specific method of detecting deep venous thrombosis, it is impractical for use in a surveillance study.17 18 22 There is also considerable evidence that venous ultrasonography has substantially reduced sensitivity when used in asymptomatic patients.17 Thus, as routine screening for deep venous thrombosis cannot be justified in trauma patients,17 we performed ultrasonography once deep venous thrombosis was clinically suspected and after taking into account the presence of risk factors.17 18

In our study, thrombocytosis appeared to be a marker related to outcome. Trauma patients who subsequently developed thrombocytosis had, on average, a higher predicted risk of death at admission and presented more organ failures during their ICU stay than patients without thrombocytosis. Moreover, patients with thrombocytosis had the lowest nadir platelet count, and ICU mortality has been reported to be inversely proportional to the nadir platelet count.1 Surprisingly, the mortality rate of patients with thrombocytosis was similar to those without.

Changes in platelet count over time are related to outcome.14 A blunted rise in platelet count in critically ill patients was associated with a worse outcome.2 3 On the other hand, correction of thrombocytopenia has been reported to be an independent protective factor of death for surgical patients1 and outcome was also more favourable in trauma patients who developed a reactive thrombocytosis.4 The reason why only some of the most severely ill patients developed thrombocytosis and survived is still speculative. A reactive increase in platelet count is probably caused by an increment in circulating thrombopoietin.23 IL-6 also plays a prominent role by stimulating thrombopoiesis primarily through thrombopoietin,23 24 although IL-6 is able to support megakaryopoiesis.25 Interestingly, patients with the most severe injuries have the highest plasma levels of this long-lived cytokine.26 Reactive thrombocytosis could be the result of the intense stimulation of thrombopoiesis by IL-6 during the acute phase of injury and the absence of concomitant platelet consumption thereafter.

In conclusion, reactive thrombocytosis is a common finding after severe trauma and was found to be associated with a better survival than predicted by severity of illness score. Unless additional risk factors are present, reactive thrombocytosis is not associated with an increased risk of thromboembolic events.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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