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Psychosomatic Medicine 68:598-604 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

Altered Blood Coagulation in Patients With Posttraumatic Stress Disorder

Roland von Känel, MD, Urs Hepp, MD, Claus Buddeberg, MD, Marius Keel, MD, Ladislav Mica, MD, Kirstin Aschbacher, BA and Ulrich Schnyder, MD

From the Department of General Internal Medicine, Division of Psychosomatic Medicine (R.v.K.) and Psychocardiology Unit, Cardiovascular Prevention and Rehabilitation, Swiss Cardiovascular Center (R.v.K.), University Hospital Berne, Berne, Switzerland; Department of Psychiatry (U.H., U.S.), Division of Psychosocial Medicine (C.B.), and Department of Trauma Surgery (M.K., L.M.), University Hospital Zurich, Zurich, Switzerland; Department of Psychiatry, University of California, San Diego, California (K.A.).

Address correspondence and reprint requests to Roland von Känel, MD, Professor of Medicine/Head, Division of Psychosomatic Medicine, Department of General Internal Medicine, Freiburgstrasse 4, University Hospital/INSELSPITAL, CH-3010 Berne, Switzerland. E-mail: roland.vonkaenel{at}insel.ch


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Posttraumatic stress disorder (PTSD) has been associated with an increased cardiovascular risk, though the pathophysiologic mechanisms involved are elusive. A hypercoagulable state before occurrence of coronary thrombosis contributes to atherosclerosis development. We investigated whether PTSD would be associated with increased coagulation activity.

Methods: We measured resting plasma levels of clotting factor VII activity (FVII:C), FVIII:C, FXII:C, fibrinogen, and D-dimer in 14 otherwise healthy patients with PTSD and in 14 age- and gender-matched, trauma-exposed non-PTSD controls. Categorical and dimensional diagnoses of PTSD were made using the Clinician-Administered PTSD Scale (CAPS) interview. We also investigated to what extent the relationship between PTSD and coagulation measures would be confounded by demographics, cardiovascular risk factors, lifestyle variables, time since trauma, and mood.

Results: Coagulation factor levels did not significantly differ between patients with a categorical diagnosis of PTSD and controls while controlling for covariates. In all subjects, FVIII:C was predicted by hyperarousal severity (ß = 0.46, p = .014) independent of covariates and by overall PTSD symptom severity (ß = 0.38, p = .045); the latter association was of borderline significance when separately controlling for gender, smoking, exercise, and anxiety (p values <.07). In patients, fibrinogen was predicted by hyperarousal severity (ß = 0.70, p = .005) and by overall PTSD symptom severity (ß = 0.61, p = .020), with mood partially affecting these associations. FVII:C, fibrinogen, and D-dimer showed no independent association with PTSD symptoms.

Conclusions: PTSD may elicit hypercoagulability, even at subthreshold levels, offering one psychobiological pathway by which posttraumatic stress might contribute to atherosclerosis progression and clinical cardiovascular disease.

Key Words: atherosclerosis • blood coagulation • posttraumatic stress disorder • risk factor

Abbreviations: BMI = body mass index; CAD = coronary artery disease; CAPS = Clinician-Administered PTSD Scale; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; FVII:C = clotting factor VII activity; FVIII:C = clotting factor VIII activity; FXII:C = clotting factor XII activity; MBP = mean arterial blood pressure; MI = myocardial infarction; PTSD = posttraumatic stress disorder; SNS = sympathetic nervous system; IL = interleukin; HADS = Hospital Anxiety and Depression Scale.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Posttraumatic stress disorder (PTSD) may develop in the aftermath of a trauma involving threat of injury or death (1). According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the diagnosis of PTSD requires three clusters of symptoms, namely, reexperiencing, avoidance, and hyperarousal in relation to the trauma (2). Increasing evidence suggests that PTSD is not only related to impairment in mental health (3) and social functioning (4) but also to a heightened risk of somatic disease (5) and overall mortality (6). The bulk of studies on poor physical health in chronically traumatized subjects investigated cardiovascular disease risk (7). For instance, in male veterans, PTSD symptom severity correlated with higher rate of physician-diagnosed arterial disease (8), and electrocardiographic signs of infarction were greater in veterans with PTSD than in those without (9). In prospective studies, PTSD predicted cardiovascular readmission rate in patients after myocardial infarction (MI) (10) and cardiovascular mortality in veterans many decades after military service (6). This research suggests that PTSD is an adverse condition in individuals without cardiovascular disease, but perhaps even more so in post-MI patients, who show an impressively high mean frequency of 15% of full-blown PTSD (11,12).

As demonstrated for a variety of other psychosocial risk factors for cardiovascular disease (13), one pathway explaining the link between PTSD and increased cardiovascular risk is the clustering of traditional cardiovascular risk factors and unhealthy lifestyle in traumatized persons. PTSD has been associated with elevated blood pressure (14), obesity (15), dyslipidemia (16), diabetes (17), heavy smoking (18), and low physical activity level (19). In addition, recent research suggests that chronic low-grade systemic inflammation playing a major role in atherosclerosis initiation and progression (20) could be one pathophysiologic mechanism contributing to poor vascular health in PTSD (12). For instance, plasma levels of the proinflammatory cytokines interleukin (IL)-1ß (21) and IL-6 (22) and of the acute phase reactant C-reactive protein (23) were higher in PTSD patients than in non-PTSD controls. Systemic coagulation activation on its own (24) or by cross-talking with inflammation (25) is another cornerstone in atherosclerosis progression. However, to the best of our knowledge, it is unknown whether PTSD confers a hypercoagulable state.

We therefore investigated plasma levels of clotting factor VII activity (FVII:C), clotting factor VIII activity (FVIII:C), clotting factor XII activity (FXII:C), fibrinogen and D-dimer in otherwise healthy patients with PTSD and in age- and gender-matched, trauma-exposed, non-PTSD controls. The rationale for selecting these coagulation measures was threefold. First, FVII and FXII hold key positions in the coagulation system in that they are involved in the primary step of initiating the extrinsic and intrinsic coagulation pathway, respectively (26). Further downstream in the coagulation cascade, FVIII is crucially involved in the formation of thrombin, which, in turn, converts fibrinogen to fibrin. Fibrin is the major component of an intravascular clot and is also found in the atherosclerotic vessel wall (27). The fibrinolytic system dissolves fibrin, thereby generating the cross-linked fibrin degradation product D-dimer (26). In contrast to the activity of individual clotting factors, D-dimer represents activity of the entire coagulation system. Second, meta-analyses have shown that fibrinogen (28) and D-dimer (29) are prospectively associated with an increased coronary risk in different populations, suggesting these factors reflect clinically useful surrogate markers of coronary artery disease (CAD) risk. FVII:C (30) and FVIII:C (31) have also been found to predict cardiovascular risk. Third, all coagulation factors investigated in the present study are responsive to acute mental stress (32), and FVIII:C is also highly responsive to catecholamine infusions (33). In addition, chronic psychosocial stress has been associated with increased plasma levels of FVII:C, fibrinogen, and D-dimer (26,34). In PTSD, the sympathetic nervous system (SNS) is permanently hyperactive and shows hyperreactivity to short-term stressors (1). For instance, patients with PTSD have elevated plasma catecholamine levels both at rest and in response to trauma-specific and trauma-nonspecific stimuli (35–37). This research suggests that PTSD symptom cluster B related to trauma intrusion triggering acute SNS activation and symptom cluster D of hyperarousal reflecting chronic SNS activation should be particularly related to procoagulant activity.

We hypothesized that FVII:C, FVIII:C, FXII:C, fibrinogen, and D-dimer would be higher in patients with a categorical diagnosis of PTSD than in trauma-exposed, non-PTSD controls and that the dimensional diagnosis of PTSD (i.e., overall PTSD symptom severity) and severity of PTSD symptom clusters would show a positive association with these coagulation measures. We expected that reexperiencing and hyperarousal would relate more strongly to coagulation measures than avoidance because the former two are supposed to be associated with comparably greater sympathetic activity (38). Demographic factors (39,40), classic cardiovascular risk factors (26), lifestyle variables (41), and mood (26) may all affect plasma levels of various coagulation molecules. Although our study was not designed to control for an extensive number of variables potentially confounding the PTSD-coagulation relationship, we explored if this relationship was affected by gender, age, body mass index (BMI), blood pressure, smoking, hyperglycemia, hypercholesterolemia, exercising, alcohol consumption, and symptoms of anxiety and depression.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Design and Participants
The ethics committee of the State of Zurich, Switzerland, formally approved the study protocol, and all participants provided written informed consent. All study participants were recruited between July 2002 and May 2005 at the University Hospital of Zurich. We recruited 14 patients with chronic PTSD according to DSM-IV criteria (2) from the Department of Psychiatry and 14 gender- and age-matched (±5 years) non-PTSD controls from the Department of Trauma Surgery. Recruitment of consecutive outpatients was rigorous in order to yield a highly selective sample in excellent health aside from PTSD. Data on subjects approached and eventually excluded were therefore not collected.

Typically, patients had developed PTSD in response to an accident. Controls had also experienced an accident requiring inpatient surgical treatment but had not developed PTSD. Aside from the diagnosis of PTSD and a positive history of an accident >1 month previously, all subjects were required to be healthy following a structured interview asking about their medical history. Specifically, subjects were excluded from the protocol if they indicated a positive history of heart, liver, or renal diseases or of any other severe somatic disease, surgery within the previous month, current respiratory infection or fever within the previous 7 days, venous thrombosis, pulmonary embolism, or use of oral anticoagulants within the previous 3 months, intake of aspirin within the previous 10 days, pregnancy, and hormone therapy (oral contraceptive use was disclosed by one female patient only after she had been included in the protocol). To exclude a major psychiatric disorder in controls, we used the Primary Care Evaluation of Mental Disorders (PRIME-MD) (42).

Assessment of Cardiovascular Risk and Lifestyle Factors
The medical history included information on current smoking status and whether subjects had ever been told by a physician that they had elevated cholesterol or high blood glucose levels. BMI was calculated as the ratio between weight in kilograms and height in square meters. Mean arterial blood pressure (MBP) was computed from the average of three seated sphygmomanometric measurements by the formula (2/3 x diastolic BP) + (1/3 x systolic BP). Subjects were also asked about their exercise habits and intake of alcohol.

Psychometric Assessment
PTSD was diagnosed following DSM-IV criteria (2) by means of the German version of the Clinician-Administered PTSD Scale (CAPS) (43). The structured interview allows for a categorical diagnosis (i.e., yes/no) and for a dimensional diagnosis of PTSD (i.e., severity) based on the frequency and intensity of different symptom clusters and of the overall symptom score. The German version of the CAPS shows good internal consistency with a Cronbach’s {alpha} of 0.88 to 0.92 for the severity score of all 17 items and of 0.73 to 0.88 for each of the three symptom clusters (43). Two medical doctors trained in the specifics of posttraumatic stress research and supervised by the senior author (U.S.) conducted the CAPS interviews. Previously, this training had led to an interrater reliability for PTSD diagnosis (no versus subsyndromal versus full-blown PTSD) of {kappa} = 0.61 (p < .001) and excellent correlations (all p values <.001) between CAPS scores for reexperiencing (r = 0.91), avoidance (r = 0.95), hyperarousal (r = 0.82), and overall symptoms (r = 0.93), respectively (Wittmann et al., unpublished data).

All patients fulfilled Criterion A for the diagnosis of PTSD; i.e., they had experienced an event that involved threatened death or serious injury to which they responded with intense fear, helplessness, or horror. In addition to the assessment of Criterion A for the diagnosis of PTSD, the CAPS asks into 17 specific symptoms of PTSD across the three symptom clusters reexperiencing (Cluster B), avoidance and numbing (Cluster C), and hyperarousal (Cluster D). Each symptom’s frequency and intensity is rated on a 5-point scale ranging between, e.g., "never" (0 points) to "almost always" (4 points). To be diagnosed, a particular symptom has to be present with a frequency of ≥1 point and with an intensity of ≥2 points. To fulfill the diagnostic criteria for a particular cluster, one of five symptoms must be given for Cluster B, three of seven symptoms for Cluster C, and two of five symptoms for Cluster D, respectively. Overall severity of PTSD is obtained by adding up the scores from Clusters B+C+D. In statistical analyses, we examined the severity of symptom clusters by aggregating frequency and intensity of symptoms into one measure in order to mitigate spurious findings due to multiple comparisons.

To assess symptoms of depression and anxiety regularly accompanying PTSD (45,46), subjects also completed the German version of the 14-item self-report Hospital Anxiety and Depression Scale (HADS) (47). Each item is rated on a 4-point Likert scale ranging from 0 = "mostly" to 3 = "not at all." The seven-item subscales for anxiety and depression yield a score of 0 to 21 for the severity of a mood disturbance that is interpreted as normal (0–7), mild (8–10), moderate (11–14), or severe (15–21). Internal consistencies of both the English and German versions are 0.80 to 0.93 for the anxiety and 0.81 to 0.90 for the depression subscales (47). In medically ill patients, the HADS depression subscale yielded estimates for sensitivity between 56% and 100% and for specificity between 73% and 94% when compared with gold standard clinical assessment of depression (48,49).

Blood Sampling and Assays
Logistic reasons required blood sampling either in the morning or in the afternoon (p = n.s. between groups). Approximately 45 minutes after the CAPS interview, venous blood was drawn into glass tubes (BD Vacutainer Systems, Plymouth, UK) containing 3.8% sodium citrate by one-time venipuncture. Samples were then centrifuged at 4°C and 2,000g for 20 minutes, and obtained plasma was immediately aliquoted in polypropylene tubes (Nunc Cryo Tube Vials, Nunc, Roskilde, DK) and frozen at –80°C.

All analyses were performed in the Thrombosis Research Laboratory, University Hospital Berne, Berne, Switzerland (André Haeberli, PhD). As previously described (32), determination of FVII:C, FVIII:C, and FXII:C was conducted following standard coagulometric methods using factor-deficient standard human plasma and reagents (Dade Behring, Marburg, Germany). Fibrinogen was quantified in plasma by a modified Clauss method (Multifibren U, Dade Behring). Determination of plasma D-dimer levels was by use of a commercial enzyme-linked immunosorbent assay (Asserachrom Stago, Asnières, France). To prevent systematic measurement errors, patient and control samples were randomly distributed across different assay runs. Inter- and intraassay coefficients of variation were <10% for all measures.

Statistical Analyses
SPSS 13.0 statistical software package (Chicago, IL) was used for data analyses. Results were considered statistically significant at the p < .05 level, and all testing was two-tailed. Because of nonnormal distribution, all psychometric data were normalized by the Blom transformation, and D-dimer levels were logarithmically transformed. For clarity, we provide original data throughout. Student’s t test and {chi}2 test were used to compare differences between two continuous variables and between categorical variables, respectively. The association between two continuous variables was estimated by applying Pearson’s correlation analysis.

Multiple perspectives on the data are offered, including both categorical group comparison models and correlational analyses. In a first set of analyses, univariate analysis of covariance was used to compare potential differences in the coagulation measures between patients with a categorical diagnosis of PTSD and controls while controlling for significant correlates of coagulation measures identified by bivariate correlation analyses. Cohen’s d was used to characterize the effect size of these group differences (50).

In a second set of analyses, multiple regression models were utilized to investigate associations between continuous PTSD symptom scores and each of the coagulation outcomes. In a one-step model, we first explored the relationship between overall PTSD symptom severity scores (i.e., clusters B+C+D) and coagulation. Given our hypotheses also related to specific symptom clusters, the coagulation outcomes were also regressed separately on each PTSD symptom cluster severity score. Potential confounders of these relationships (i.e., gender, age, BMI, MBP, smoking status, regular exercise, regular alcohol consumption, time since trauma in months, and symptom levels of anxiety and depression) were then controlled for by entering them in the first block of a hierarchical regression model. Hyperglycemia and hypercholesterolemia were not considered as control variables, because no participant reported a positive history of elevated blood glucose and only one control subject reported a positive history of hypercholesterolemia. Because of our sample size of 28 subjects, we entered one control variable at a time to prevent model overfitting. This rather conventional approach nevertheless allows identifying potential confounders of the relationship between PTSD-related variables and coagulation measures. If the effect of the predictor is cancelled, it is concluded that the original relationship between predictor (e.g., overall PTSD symptom severity score) and dependent variable (e.g., FVIII:C level) was not independent of the control variable just added to the model (51). Collinearity between predictors was tested and found to be tolerable in all analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Subjects’ Characteristics
Table 1 demonstrates that health characteristics were not significantly different between groups. In addition, patients and controls indicated a negative history of liver disease, renal disease, or any other severe somatic disease, with one patient reporting nonspecific heart problems. Two patients and two controls reported use of nonsteroidal anti-inflammatory drugs. As expected, patients had higher PTSD symptom cluster scores and overall score and higher symptom levels of anxiety and depression than controls (Table 2). Time elapsed since the trauma was significantly longer in patients than in controls (48 ± 35 months; range, 6–102 versus 21 ± 18 months; range 2–59; p = .017).


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  		TABLE 1. Demographic and Medical Data of PTSD Patients and Controls

 

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  		TABLE 2. Psychometric Data of Patients and Controls

 

Correlations With Coagulation Measures
In all subjects, FVII:C correlated with FXII:C (r = 0.61, p = .001) and fibrinogen correlated with D-dimer (r = 0.50, p = .007). FVII:C (r = 0.44, p = .021) and FXII:C (r = 0.48, p = .010) correlated with mean arterial BP. FVIII:C correlated with age (r = 0.47, p = .011), and fibrinogen was lower in those who exercised regularly than in those who did not (2.80 ± 0.35 g/l versus 3.38 ± 0.77 g/l, p = .043). Symptoms of depression and of anxiety showed no significant correlation with any coagulation measure. The number of months since the trauma was inversely related to FVII:C (r = –0.38, p = .046) and FXII:C (r = –0.50, p = .007).

Categorical PTSD Diagnosis and Coagulation Measures
Table 3 shows that coagulation factor levels were not significantly different between PTSD patients and controls even after adjustment for covariates delineated in the legend to Table 3. Crude differences in coagulation levels between groups showed a medium effect size (Cohen’s d) for FVII:C (0.63), FVIII:C (0.44), and FXII:C (0.44), and a negligible effect size for fibrinogen (0.14) and D-dimer (0.07). The required sample size to detect a significant difference in coagulation levels between groups with a statistical power of 0.80 and {alpha} error level of 0.05 was n = 88 for FVII:C, n = 173 for FVIII:C, and n = 171 for FXII:C. These analyses suggest that, in spite of some coagulation factor differences showing medium effect sizes, the sample size was too small to render crude differences between groups significant.


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  		TABLE 3. Coagulation Measures in PTSD Patients Compared to Controls

 

Association of PTSD Symptom Clusters With Coagulation Measures
Factor VII Clotting Activity
Reexperiencing severity was a significant predictor of FVII:C in all subjects (adjusted R2 = 0.101, standardized ß = –0.38, t = –2.08, p = .048) but not in either group alone. This relationship stayed significant when separately controlling for gender, BMI, MBP, smoking, regular exercise, regular alcohol consumption, and anxiety (p values <.05) but became of borderline significance when controlling for age (p < .06) and nonsignificant when controlling for time since trauma (p > .20) and depression (p > .20).

Factor VIII Clotting Activity
Overall PTSD symptom severity (adjusted R2 = 0.113; ß = 0.38, t = 2.11, p = .045) and hyperarousal severity (adjusted R2 = 0.181; ß = 0.46, t = 2.64, p = .014) both predicted FVIII:C in all subjects. The predictive value of overall PTSD symptom severity for FVIII:C remained significant when controlling for age, BMI, MBP, alcohol, time since trauma and depression (p values <.05) and became of borderline significance when controlling for gender, smoking, exercise, and anxiety (p values <.07). Hyperarousal severity remained a significant predictor of FVIII:C when controlling for gender, age, BMI, MBP, smoking, exercise, alcohol, time since the trauma, anxiety, and depression (p values <.04). Crude subgroup analysis showed significant correlations between hyperarousal severity in patients (r = 0.63, p = .017) and controls (r = 0.57, p = .034) and between overall PTSD symptom severity and FVIII:C in patients (r = 0.54, p = .048) but not in controls.

Factor XII Clotting Activity and D-dimer
There was no significant relationship between any PTSD-related variable and FXII:C and D-dimer in all subjects either with or without controlling for gender, age, BMI, MBP, smoking, exercise, alcohol, time since trauma, anxiety, and depression. Also, crude correlations between PTSD-related variables and FXII:C and D-dimer were not significant in either the patient or control group.

Fibrinogen
PTSD-related variables did not significantly predict fibrinogen in all subjects either with or without controlling for gender, age, BMI, MBP, smoking, exercise, alcohol, time since trauma, anxiety, and depression. In subgroup analysis, overall PTSD symptom severity (adjusted R2 = 0.320; ß = 0.61, t = 2.67, p = .020) and hyperarousal severity (adjusted R2 = 0.449; ß = 0.70, t = 3.40, p = .005) were both predictors of fibrinogen in patients but not in controls. These relationships maintained significance when controlling for gender, age, BMI, MBP, smoking, exercise, alcohol, and time since trauma (p values ≤.04). The association between overall PTSD symptom severity and fibrinogen became nonsignificant when controlling for anxiety (p = .23) and depression (p = .12). The relationship between hyperarousal severity and fibrinogen became of borderline significance when controlling for anxiety (p < .08) but stayed significant when controlling for depression (p < .04).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
We found a positive and partially independent association between dimensional aspects of PTSD and plasma levels of both FVIII:C and fibrinogen, suggesting the more severe the PTSD symptomatology, the greater the concentration of these procoagulant factors. More precisely, overall PTSD symptom severity and hyperarousal severity showed a relationship with FVIII:C in all subjects and with fibrinogen in PTSD patients. We controlled for a set of demographic, biological, and psychological variables commonly shown in epidemiologic research to affect coagulation factors (26,39–41) and found that relationships between PTSD-related variables and FVIII:C and fibrinogen were largely independent of potential confounders of hemostasis and time since the trauma occurred. Notably, mood affected some of the relationship between PTSD symptomatology and fibrinogen in patients.

After a trauma, a substantial proportion of victims develop subthreshold PTSD that does not fulfill the criteria for a categorical diagnosis of PTSD (52). Currently, we lack studies investigating whether the risk of cardiovascular disease related to PTSD shows a steady relationship with overall PTSD symptom severity or is more related to one symptom cluster than to any other. However, our data suggest that posttraumatic stress could elicit FVIII:C increase and accompanying cardiovascular risk along a continuum of severity, i.e., even in trauma-exposed, non-PTSD controls with minor levels of stress symptoms. Such reasoning is supported by findings from the Northwick Park Heart Study showing that an increase of 1 SD in FVIII:C raised the risk of fatal CAD by almost 30% (31).

In contrast to FVIII:C, a level of posttraumatic stress meeting diagnostic criteria for full-blown PTSD seems necessary to elicit fibrinogen increase, given that we found no significant association between PTSD symptomatology and fibrinogen in controls. A meta-analysis showed that even modest increases in fibrinogen of 10% were prospectively associated with CAD endpoints, with an odds ratio of almost 2.0, if the top tertile of the fibrinogen distribution was compared with the bottom tertile (53). The Fibrinogen Studies Collaboration most recently performed a comprehensive meta-analysis of 31 prospective studies accumulating 1.38 million person-years of follow-up (54). Results from this meta-analysis provide the most reliable evidence to date for a moderately strong association of usual plasma fibrinogen levels and the risks of CAD, stroke, other vascular mortality, and nonvascular mortality in healthy, middle-aged adults. Therefore, relatively elevated plasma fibrinogen levels in our otherwise healthy patients with PTSD could be of particular clinical importance in terms of an elevated cardiovascular risk and overall mortality several years down the line (6,11,12).

Pathophysiologically, FVIII:C exerts its procoagulant function by protecting circulating von Willebrand factor that is important in mediating platelet adherence to endothelial lesions (26). Fibrinogen is a substrate for thrombin in the coagulation cascade and also promotes platelet aggregation and smooth muscle cell proliferation (55). In PTSD, the SNS exhibits both chronic hyperactivity (i.e., increased levels of circulating catecholamines) and hyperactivity in response to short-term sympathetic challenges (35–37). Numerous studies have shown that plasma FVIII:C increases in a dose-response manner to epinephrine and norepinephrine infusion (33). This effect is achieved when catecholamines recruit functionally active FVIII from the spleen (56) and bind to vascular ß2-adrenergic receptors, resulting in rapid release of preformed FVIII from endothelial cells into the circulation (33). In addition, a number of studies found a fairly consistent increase in plasma fibrinogen in response to acute and chronic mental stress though the adrenergic mechanisms involved are unresolved (26). Hence, the predominantly observed relationship between hyperarousal and both FVIII:C and fibrinogen was expected. Because blood was drawn within 1 hour of the CAPS interview, observed coagulation changes could reflect an acute response to the stress of being interviewed. The interview could then be understood as a trauma-specific stimulus whereby subjects with relatively more severe PTSD and hyperarousal would show greater increase in FVIII:C and fibrinogen, respectively. Further studies may want to investigate the relationship between catecholamine discharge as elicited by trauma- and nontrauma-related stimuli in PTSD patients versus controls and concomitant coagulation changes. In addition to or as a consequence of an overactive SNS (57), the proinflammatory state observed in PTSD (12) could also contribute to enhanced coagulation activity. In a previous study, symptoms of trauma intrusion correlated positively with CRP (23), which, in turn, is associated with fibrinogen during the acute phase of an inflammatory response (55). Similarly, compared with non-PTSD controls, PTSD patients had elevated IL-6 (22), which, in turn, promotes the transcription of the FVIII gene in the liver (58). Therefore, elevated FVIII:C and fibrinogen levels with PTSD symptoms and hyperarousal in particular could also reflect an inflammatory response elicited by posttraumatic stress (59). Opposite to our hypothesis, we found that more reexperiencing severity predicted lower levels of FVII:C. Interestingly, this relationship became nonsignificant when covarying for time since the trauma. Down-regulation of the hypothalamic-pituitary-adrenal axis is typically thought to occur with longer duration of PTSD (1). Although speculative because we did not measure stress hormones, lower cortisol levels with more sustained PTSD symptomatology, in this case, intrusive reexperiencing of the trauma, could result in suppression of FVII synthesis by the liver. Indeed, in Addison’s disease that is characterized by endogenous hypocortisolism, reduced plasma FVII levels returned to near-normal values after 4 months of treatment with hydrocortisone (60).

We mention three limitations of our study. First, in contrast to dimensional facets of PTSD, the categorical diagnosis of PTSD was unrelated to any coagulation measure in analysis of variance, even when controlling for a reasonable set of common correlates of coagulation activity. Also, PTSD symptom clusters and overall severity were not independently associated with FVII:C, FXII:C and D-dimer. However, care must be taken not to overinterpret these nonsignificant findings because our study had apparently limited statistical power to reliably detect significant differences in coagulation measures between groups. Second, we included a highly selected sample in apparently good health aside from PTSD, which prevents us from generalizing our observations to the elderly and populations with cardiovascular disease, for whom our findings likely have the most clinical importance. Third, measuring the association between a number of PTSD scores and coagulation factors raises the issue of multiple comparisons. However, our study was to some extent exploratory and aimed to generate hypotheses for future research on the psychobiological links between PTSD and CAD. Moreover, the different PTSD symptom cluster scores tap into different domains of the posttraumatic stress experience (1). Also, the five coagulation factors are quite different in their role and function in the blood coagulation pathways and are therefore not interchangeable (26). Therefore, one parsimonious interpretation of our findings could be that our sample size allowed us to demonstrate that FVIII:C and fibrinogen, two clotting factors known to be responsive to psychosocial stress, are associated with PTSD. An alternative interpretation could be that the categorical diagnosis of PTSD counts a whole range of different symptoms, some of which (e.g., avoidance) are not unequivocally associated with heightened SNS activity. If subjects score, e.g., comparably high on avoidance but low on hyperarousal, the categorical diagnosis of PTSD may fail to yield a significant difference in coagulation activity between PTSD patients and controls. Future studies in larger samples need to clarify whether the categorical or the dimensional diagnosis of PTSD is a better predictor of the different components of the coagulation system.

Taken together, our study is the first to suggest that PTSD could be associated with a hypercoagulable state. In a small sample of carefully selected and matched patients with PTSD, we showed a relationship between plasma levels of FVIII:C and fibrinogen along a continuum with overall PTSD symptom severity and hyperarousal symptomatology. Fibrinogen and FVIII:C are both independent predictors of CAD. Therefore, pending replication in larger study samples, our findings suggest one psychobiological pathway by which posttraumatic stress could promote atherosclerosis and, thereby, contribute to the increased risk of cardiovascular diseases.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

This research was supported by a grant of the University of Berne, Switzerland (to R.v.K.).

DOI:10.1097/01.psy.0000221229.43272.9d


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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Another Connection Between Post-Traumatic Stress Disorder and Risk for Cardiovascular Disease?
Journal Watch Psychiatry, August 28, 2006; 2006(828): 2 - 2.
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