Professional Documents
Culture Documents
Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres
a r t i c l e i n f o a b s t r a c t
Article history: Background: Patients with schizophrenia are at increased risk of venous thromboembolism. The mechanisms
Received 21 January 2014 underlying this association are poorly understood.
Received in revised form 4 December 2014 Aims: We investigated whether there is a global hypercoagulable state in patients with schizophrenia utilising the
Accepted 6 December 2014 overall haemostatic potential (OHP) assay which assesses overall coagulation potential (OCP), haemostatic
Available online xxxx
potential (OHP) and fibrinolytic potential (OFP).
Method: Citrated plasma was collected for OHP assays from patients with schizophrenia on long-term antipsy-
Keywords:
Schizophrenia
chotic treatment and compared with healthy age- and sex-matched controls. Time courses of fibrin formation
Blood coagulation test and degradation were measured by spectrophotometry (absorption of 405 nm) after the addition of tissue factor
Coagulation and tissue plasminogen activator to plasma.
Thrombosis Results: Ninety patients with schizophrenia (antipsychotic treatment-15.9 ± 9.7 years) and 30 controls were
Fibrinolysis recruited. Patients with schizophrenia had higher rates of smoking and levels of inflammatory markers (high-
sensitivity C-reactive protein and neutrophil-to-lymphocyte ratio) than controls. Whilst D-dimer, fibrinogen
and platelet count did not differ between patients with schizophrenia and controls, the OCP (54.0 ± 12.6 vs
45.9 ± 9.1, p = 0.002) and OHP (12.6 ± 5.8 vs 7.2 ± 3.7, p b 0.001) were higher, and OFP was lower (76.6 ±
9.8% vs 84.9 ± 6.4%, p b 0.001) in patients with schizophrenia, implying both a hypercoagulable and
hypofibrinolytic state in these patients. Importantly, abnormalities in overall coagulation were independently
predicted by levels of plasminogen-activator-inhibitor-1, fibrinogen, platelet count, inflammatory markers and
plasma triglycerides, suggesting a multifactorial aetiology.
Conclusion: Patients with schizophrenia have evidence of a global hypercoagulable and hypofibrinolytic state
which may contribute to their increased risk of venous thromboembolism.
© 2015 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.schres.2014.12.042
0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
2 V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx
been shown to increase the risk of VTE by 2–9 fold in the general popu- cardiac evaluation and screening of patients with schizophrenia receiv-
lation (Rogers et al., 2012; Authors/Task Force et al., 2014). ing antipsychotic treatment were recruited. The control groups com-
Appropriate risk stratification for VTE risk and development of prised of healthy volunteers of similar age and gender with no prior
prevention strategies requires a clear understanding of the mechanisms history of schizophrenia or VTE or ischaemic heart disease and those
involved, and very few studies have directly quantified or addressed the not receiving antipsychotic or long-term anticoagulation medications.
mechanisms of increased thrombotic risk in patients with schizophrenia Amongst the 90 patients with schizophrenia, there were no patients
receiving long-term antipsychotic treatment. Overall coagulation and receiving conventional neuroleptics. 68/90 (76%) of patients were
fibrinolysis are determined by the interplay between pro-coagulant receiving clozapine treatment, and the remaining 22 patients received
factors such as factor VIII (FVIII) and plasminogen activator inhibitor the following treatment: olanzapine (6), aripiprazole (4), quetiapine
type-1 (PAI-1), and anti-coagulant factors such as protein C and protein (4), paliperidone (4), risperidone (2), amisulpride (1) and zuclopenthixol
S. FVIII is an important component of the intrinsic coagulation pathway (1). Patients were excluded if they: 1) were prescribed an antipsychotic
and is responsible for the amplification of the coagulation cascade after medication for less than one year; 2) deemed noncompliant with
initial thrombin generation (Furie and Furie, 2008). PAI-1 is one of the antipsychotic medications based on psychiatry reviews and serum
most important inhibitors of the plasma fibrinolytic activity and is clozapine levels for patients receiving this drug; 3) had previous
raised in inflammatory states, atherosclerosis and obesity (Cesari et al., history of VTE (PE and/or deep vein thrombosis [DVT]); 4) had symp-
2010). Elevated levels of FVIII and PAI-1 have been shown to increase toms suggestive of ischaemic heart disease and/or were found to
the risk of VTE by 4.8-fold (Koster et al., 1995a; Jenkins et al., 2012b) have ischaemic heart disease on functional testing or 5) receiving
and 1.6-fold (Meltzer et al., 2010) respectively. Proteins C and S exert long-term oral anticoagulation. All patients with schizophrenia met
anticoagulant effects by inactivating coagulation factors V and VIII. DSM-IV diagnostic criteria for a schizophrenic disorder according
Patients with protein C and S deficiencies have a 7.3–8.5 fold lifetime to the guidelines of the American Psychiatric Association (1994).
increased risk of VTE (Koster et al., 1995b). This cross-sectional study was approved by the institutional Human
Previous studies have found inconsistent associations between FVIII Ethics Committees.
levels (Bank et al., 2007; Jenkins et al., 2012a), protein C and S levels
(Mahmoodi et al., 2010; Bucciarelli et al., 2012), PAI-1 levels
(Yukizawa et al., 2012), direct effects of antipsychotics (Carrizo et al., 2.2. Overall haemostatic potential (OHP) assay
2008) and VTE risk in these patients (Reitter-Pfoertner et al., 2013).
Conventional testing for thrombophilia involves screening for specific Blood samples were collected by venipuncture from the cubital vein
individual abnormalities in haemostasis which can be costly and with a 21 gauge butterfly needle. The tourniquet was removed and the
prone to misinterpretation (Jennings et al., 2005). Consequently, cur- first 3 ml of blood was discarded. Blood was collected into BD
rent guidelines do not recommend routine screening for heritable Vacutainer 0.109 M sodium citrate tubes (Becton-Dickinson, Franklin
thrombophilia in asymptomatic individuals (Baglin et al., 2010; Lakes, NJ, USA) then centrifuged for 10 minutes (min) at 23 °C and
Middeldorp, 2011a). 2500 g (Eppendorf 5804 R, USA). The plasma supernatant was centri-
As the underlying biological mechanisms by which patients with fuged under the same conditions to produce platelet-poor plasma. We
schizophrenia develop VTE are likely multifactorial, these may lend used a modified OHP assay based on that described by Blomback (He
themselves to investigation by global coagulation assays rather et al., 1999, 2001; Curnow et al., 2007). Fibrin time curves were gener-
than by measuring individual factors. The overall haemostatic ated in microtiter plate wells and plasmas were tested in duplicate.
potential (OHP) assay is a simple, validated and inexpensive global The OHP assay blank buffer consisted of Tris (tris(hydroxymethyl)
coagulation assay that detects both the dynamic coagulation and aminomethane), NaCl and CaCl2, and purified water was used to make
fibrinolytic potential of plasma samples. The underlying principle the buffer in the OHP assay. The concentrations of the reagents in the
of the OHP assay determines whether the hypercoagulable state is buffer were: Tris—66 mM, NaCl—130 mM and CaCl2—35 mM. The buffer
due to increased fibrin generation (hypercoagulability), reduced was adjusted to a pH of 7 and stored at 4 °C.
fibrinolysis (hypofibrinolysis), or a combination of these. Fibrinolysis The overall coagulation potential (OCP) microtiter wells contained
is the process of degradation of a fibrin blood clot and limits throm- 75 μl plasma and 75 μl OCP buffer, at pH 7.0 with final concentrations
bus extension beyond the site of endothelial damage. The fibrinolytic of Tris 33 mmol/l, NaCl 65 mmol/l, CaCl2 16.5 mmol/l and tissue factor
system is a complex cascade that controls the dissolution of the fibrin 0.85 pmol/l. OCP curves were generated from automated absorption
blood clot into soluble fibrin degradation products and consists of measurements at 405 nm taken every minute for 100 min for all
many factors including plasminogen, plasminogen activator, PAI-1 samples, an extension to the original 60 minute protocol to ensure the
(Van De Craen et al., 2012). The fibrinolytic potential as measured fibrinolysis curves in all samples had returned to zero (baseline) to
in the OHP assay measures the aggregate effect of these components. enable calculation of OHP assay parameters. OHP curves were gener-
It has been shown to be useful in identifying hypercoagulable states ated using a similar method, except that the added buffer also
in patients with acute coronary syndromes, autoimmune diseases contained rt-PA to give a final concentration of 300 ng/ml. Values
and following cardiac bypass surgery (Vedin et al., 2005; Curnow for OCP and OHP represent the area under the relevant fibrin time
et al., 2007; Reddel et al., 2013). curve calculated by summation of absorption values (He et al.,
The primary aim of this study was to investigate whether patients 1999, 2001). The overall fibrinolysis potential (OFP) value was calcu-
with schizophrenia taking long-term antipsychotics demonstrated a lated by (OCP − OHP) / OCP × 100% and represents the area under
global hypercoagulable state as determined by the OHP assay (He the fibrinolytic portion of the curve as a percentage of the total OCP
et al., 1999, 2001; Curnow et al., 2007). The secondary aim of the value. Additional data derived from the fibrin time curve included
study was to assess for clinical characteristics and laboratory markers maximum optical density (Max OD), maximum slope (Max slope)
associated with alterations in global coagulation and fibrinolysis. and delay in onset of fibrin generation (Delay). Because all assays
were performed in duplicate, Max OD is the mean of the maximum
2. Methods and materials OD reached in the two OCP curves. The slope was calculated progres-
sively for each OD reading on the OCP curve, using a minimum of
2.1. Study population three time points. The greatest increase in OD for these points repre-
sents the Max slope. Delay was defined as the time intercept
From January 2010 to December 2012, 90 consecutive patients with between the line of maximum slope on the OCP curve and the line
schizophrenia who attended a specialist clinic established for the of baseline absorbance at time zero.
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx 3
Peripheral venous blood sample biochemical analyses included Patients with schizophrenia Controls
fasting plasma lipid profile, electrolytes, and liver and thyroid function (n = 90) (n = 30)
tests. Measurements of systemic inflammation included full blood Age (years) 40 ± 13 43 ± 12
count and its differentials (neutrophil, lymphocyte and eosinophil Gender
counts) and high-sensitivity C-reactive protein (hsCRP). All measure- Male 61 (68) 17 (57)
Schizophrenia
ments of hsCRP were performed using an immuno-turbidimetric
Duration of illness (years) 15.9 ± 9.7 –
method, on an autoanalyser (IMMAGE CRPH; Beckman Coulter, Family history of mental illness 18 (20) 0
Villepinte, France). Glycosylated haemoglobin (HbA1c) was measured Clozapine therapy 68 (76) –
by high-pressure liquid chromatography (BioRad, Hercules, CA). Body mass index (kg/m2) 29.1 ± 6.5 27.6 ± 4.4
The standard clotting assays prothrombin time, activated partial Comorbidities
Alcohol excess 9 (10) 0
thromboplastin time, D-dimer and Clauss fibrinogen were performed Atrial fibrillation 0 0
on an automated coagulation analyser (STA-R, Diagnostica Stago). Heart failure
Reagents were from Dade-Behring Diagnostics (NSW, Australia) Previous history of heart failure 1 (1) 0
and Diagnostica Stago. Platelet count was obtained by optical and NYHA class N 1 1 (1) 0
Stroke 1 (1) 0
impedance methods (Abbott Diagnostics CELL-DYN Sapphire).
Thyroid dysfunction 1 (1) 0
Plasminogen-activator-inhibitor-1 (PAI-1) (TriniLIZE PAI-1 Antigen, Risk factors for ischaemic heart disease
Trinity Biotech, Bray, Ireland) antigen levels were measured by ELISA Diabetes 21 (24) 3 (10)
in accordance with the manufacturer's instructions (samples were Hypercholesterolemia 25 (28) 0
diluted 2 in 3 with sample buffer solution). Statin therapy 19 (21) 0
Hypertension 11 (12) 5 (17)
Smoking 35 (39) 2 (7)
2.4. Statistical analyses Cardiac observations
Systolic blood pressure (mm Hg) 124 ± 11 119 ± 11
Diastolic blood pressure (mm Hg) 77 ± 9 73 ± 8
Data were summarized as frequencies and percentages for categori- Resting heart rate (bpm) 88 ± 13 70 ± 7
cal variables. Continuous variables were presented as mean ± standard
Categorical variables are presented as numbers (%). Continuous values are presented as
deviation. Comparison between two groups was based on unpaired t mean ± SD.
test (parametric distribution) or Mann–Whitney test (non-parametric bpm, beats per minute; NYHA, New York Heart Association functional class.
distribution) for continuous variables and χ2 tests or the Fisher exact
test for dichotomous variables. A two-tailed p value of b0.05 was used
as a cut-off for statistical significance. Amongst patients with schizo-
3.2. Biochemical and OHP assay parameters
phrenia, multivariate backward selection linear regression analysis
was performed to identify independent associations of the OHP assay
Patients with schizophrenia had higher levels of inflammatory
parameters (OCP, OHP and OFP). All variables with a univariate p
markers including hsCRP (3.7 ± 5.3 vs 0.9 ± 0.8 mg/l, p b 0.001)
value of b0.10 were included in the multivariate modelling to ensure
and neutrophil-to-lymphocyte ratio (NLR) (2.5 ± 1.4 vs 1.7 ± 0.8,
capture of all independent predictors of the above parameters.
p = 0.03) compared to healthy controls. Triglyceride levels were
Multicollinearity between variables was tested using Variance Inflation
significantly higher (2.0 ± 1.4 vs 1.2 ± 0.6 mmol/l, p = 0.02) and
Factor calculation. Statistical analysis was performed using GraphPad
HDL levels were significantly lower (1.2 ± 0.4 vs 1.4 ± 0.3 mmol/l,
Prism 6.01 (GraphPad Software, San Diego, CA) and SPSS (Version
p = 0.01) in patients with schizophrenia.
16.0, SPSS Inc., Chicago, IL).
Whereas D-dimer, fibrinogen and platelet count did not differ be-
Based on previous published literature and in house data of OHP
tween the two groups, the OCP (54.0 ± 12.6 vs 45.9 ± 9.1, p = 0.002)
assay parameters and standard deviation values (Curnow et al., 2007;
and OHP (12.6 ± 5.8 vs 7.2 ± 3.7, p b 0.001) were both significantly
Edelman et al., 2013), a sample size of 30 subjects in each group could
higher, and OFP (76.6 ± 9.8% vs 84.9 ± 6.4%, p b 0.001) significantly
detect significance difference in OHP assay parameters between
lower, in patients with schizophrenia, indicating both a hypercoagula-
patients with schizophrenia and healthy controls with a two-sided
ble and hypofibrinolytic state, compared to the controls. There were
significance level of 0.05 and statistical power of at least 80%.
no observable differences in Max OD and Max slope in the two groups.
The delay in the onset of fibrin generation was significantly shorter in
3. Results healthy controls compared to patients with schizophrenia (13.5 ± 3.4
vs 16.0 ± 5.3 min, p = 0.02) (Fig. 1). The reduced OFP prompted inves-
3.1. Baseline characteristics tigation of PAI-1 levels in these patients. PAI-1 levels were significantly
higher in patients with schizophrenia than in the control group (29.0 ±
A total of 120 subjects participated in the study, 90 patients with 12.1 vs 21.8 ± 9.4, p = 0.006) (Table 2).
schizophrenia and 30 healthy controls matched for age, gender and Although D -dimer, fibrinogen and platelet count did not differ
body mass index (BMI). Table 1 summarizes the clinical characteristics significantly between controls and patients with schizophrenia,
of the subjects. For patients with schizophrenia, the mean duration of their levels did correlate with OHP assay values in the patients
antipsychotic treatment was 15.9 ± 9.7 years, with the majority with schizophrenia (Tables 3 and 4). In patients with schizophrenia,
receiving clozapine treatment. They had higher rates of smoking, family OCP values demonstrated significant univariate associations with
history of mental illness and hypercholesterolemia. No subjects had a raised D -dimer, fibrinogen, hsCRP, NLR and triglyceride levels. In
history of PE or DVT prior to recruitment. Following the initial recruit- multivariate analysis, elevated fibrinogen (β = 0.39, p = 0.001)
ment, one patient with schizophrenia was subsequently diagnosed and hsCRP (β = 0.26, p = 0.02) levels were independent predictors
with DVT and PE, and there were two subsequent sudden deaths in of OCP level in these patients.
the schizophrenia group. One of the deaths was presumed to be due Elevated OHP and decreased OFP levels indicate a hypofibrinolytic
to drug overdose whilst the other was due to an acute myocardial state. Significant univariate associations with higher OHP included
infarction (an incidental unilateral right lower limb DVT was found on higher BMI, fibrinogen, D-dimer, PAI-1, hsCRP levels and raised NLR. In
autopsy). multivariate analysis, raised fibrinogen (β = 0.43, p b 0.001), platelet
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
4 V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx
Fig. 1. OHP assay parameters between patients with schizophrenia and healthy controls. A) Overall coagulation potential (OCP); B) overall haemostatic potential (OHP); C) overall
fibrinolytic potential (OFP); D) maximum optical density (Max OD); E) Delay and F) Max slope. G) Reference sample of the OCP and OHP in a patient with schizophrenia and a
healthy control.
count (β = 0.25, p = 0.01) and PAI-1 levels (β = 0.23, p = 0.02) (Supplementary Fig. 1). However, there were no significant differences
remained as significant independent predictors of a raised OHP. Signifi- in OHP, OCP and OFP values between patients receiving clozapine or
cant univariate associations with lower OFP included raised white cell non-clozapine medications. There were 36 patients receiving adjunct
count, BMI, fibrinogen, PAI-1, total cholesterol and triglyceride levels therapy in additional to neuroleptic drugs and these included: sertraline
and lower high-density lipoprotein (HDL) levels. In multivariate analy- (8), sodium valproate (6), citalopram (5), escitalopram (4), fluoxetine
sis, the independent predictors of a reduced OFP state included raised (4), lithium (3), lamotrigine (3), venlafaxine (2) and mirtazepine (1).
triglyceride (β = − 0.35, p = 0.001), PAI-1 (β = − 0.29, p = 0.002) On exploratory analysis, we found no associations between adjunct
and fibrinogen (β = −0.23, p = 0.03) levels. usage and OHP assay parameters (OCP: p = 0.55, OHP: p = 0.26, OFP:
We investigated the influence of antipsychotic medications on the p = 0.21).
coagulation status of patients with schizophrenia, specifically investi-
gating whether clozapine use affected these parameters given previous- 4. Discussion
ly reported increased VTE risks in these patients (Walker et al., 1997).
Patients with schizophrenia receiving clozapine or non-clozapine We have identified increased overall coagulation potential and
antipsychotic medications were significantly more hypercoagulable impaired overall fibrinolysis potential in patients with schizophrenia
(higher OHP, p = 0.006) and had impaired fibrinolysis (higher OCP, receiving long-term antipsychotics. These haemostatic abnormalities
p b 0.001 and lower OFP, p = 0.002) than did healthy controls were independently associated with abnormalities in PAI-1, fibrinogen,
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx 5
Table 2
Biochemical parameters.
Biochemical parameters
Haemoglobin (g/l) 143 ± 14 148 ± 10 0.19
White cell count (×109/l) 7.8 ± 2.5 6.5 ± 1.5 0.004⁎
Neutrophil count (×109/l) 4.9 ± 2.1 3.6 ± 1.0 b0.001⁎
Neutrophil:lymphocyte ratio 2.5 ± 1.4 1.7 ± 0.8 0.03⁎
Eosinophil count (×109/l) 0.17 ± 0.1 0.17 ± 0.1 0.82
hsCRP (mg/l) 3.7 ± 5.3 0.9 ± 0.8 b0.001⁎
HbA1c (%) 5.9 ± 1.1 5.6 ± 0.9 0.27
Total cholesterol (mmol/l) 5.0 ± 1.1 4.9 ± 0.7 0.63
Triglycerides (mmol/l) 2.0 ± 1.4 1.2 ± 0.6 0.02⁎
HDL (mmol/l) 1.2 ± 0.4 1.4 ± 0.3 0.01⁎
LDL (mmol/l) 3.0 ± 1.0 3.0 ± 0.7 0.95
Platelet count (×109/l) 261 ± 75 249 ± 53 0.48
Fibrinogen (g/l) 3.4 ± 0.7 3.1 ± 0.6 0.35
D-dimer (mg/l) 0.19 ± 0.11 0.22 ± 0.28 0.71
PAI-1 (ng/ml) 29.0 ± 12.1 21.8 ± 9.4 0.006⁎
OHP assay
OHP 12.6 ± 5.8 7.2 ± 3.7 b0.001⁎ 1.73 3.78
OCP 54.0 ± 12.6 45.9 ± 9.1 0.002⁎ 7.35 10.43
OFP (%) 76.6 ± 9.8 84.9 ± 6.4 b0.001⁎ 2.61 1.90
Max OD (units) 0.7 ± 0.1 0.7 ± 0.2 0.52 0.81 4.28
Max slope (units) 222.3 ± 58.9 227 ± 43.5 0.69 7.37 13.36
Delay (min) 16.0 ± 5.3 13.5 ± 3.4 0.02⁎ 3.37 8.18
platelet count, inflammatory markers and lipoprotein levels suggesting or venous thromboembolism, are often not detected by the traditional
these as contributing factors to the risk of VTE in these patients. panel of tests as part of thrombophilia screening (including deficiencies
Routine coagulation assays are based on the traditional cascade of antithrombin, proteins C and S, factor V Leiden and prothrombin
model of coagulation and detect hypercoagulable states due to inherited G20210A mutations). A negative thrombophilia test may lead to false
deficient or abnormal coagulation factors and acquired inhibitors. Unse- assurance as thrombophilia can only identify approximately 50% of all
lected screening for inherited thrombophilic states in asymptomatic patients presenting with venous thrombosis by utilising the above
patients is not recommended due to the low frequency, low penetrance tests (Whiteman and Hassouna, 2000; Middeldorp and van Hylckama
of symptomatic VTE amongst carriers of the most common Vlieg, 2008; Middeldorp, 2011b).
thrombophilic conditions and the high cost associated with testing The OHP assay is a simple and inexpensive global coagulation assay
(Machin, 2003; Middeldorp, 2011a). Furthermore, hypercoagulable that detects both the dynamic coagulation and fibrinolytic potential of
states, which are defined as those with the potential to develop arterial plasma samples. It has been shown to be useful in identifying
Table 3
Correlation analysis in patients with schizophrenia (n = 90).
Clinical variables
Age 0.08 0.45 −0.02 0.87 0.02 0.90
Body mass index 0.20 0.07 0.33 0.002⁎ −0.22 0.04⁎
Diabetes −0.07 0.51 0.02 0.85 −0.11 0.34
Hypercholesterolemia −0.07 0.53 0.09 0.41 −0.19 0.08
Smoking −0.03 0.77 0.04 0.74 −0.07 0.51
Clozapine treatment 0.07 0.56 −0.05 0.64 0.05 0.63
Laboratory markers
Platelet 0.13 0.23 0.31 0.004⁎ −0.26 0.02⁎
D-dimer 0.35 0.001⁎ 0.23 0.04⁎ −0.03 0.82
Fibrinogen 0.61 b0.001⁎ 0.50 b0.001⁎ −0.22 0.04⁎
PAI-1 −0.02 0.83 0.30 0.008⁎ −0.31 0.005⁎
hsCRP 0.49 b0.001⁎ 0.35 0.001⁎ −0.10 0.35
White cell count 0.25 0.02⁎ 0.41 b0.001⁎ −0.33 0.002⁎
Neutro:lymph ratio 0.39 b0.001⁎ 0.23 0.03⁎ −0.07 0.53
Cholesterol −0.19 0.11 0.17 0.11 −0.41 b0.001⁎
HDL 0.03 0.81 −0.17 0.10 0.23 0.03⁎
Triglyceride 0.34 0.002⁎ 0.12 0.28 −0.41 b0.001⁎
PAI-1, plasminogen-activator-inhibitor-1; hsCRP, high sensitivity C-reactive protein; HDL, high density lipoprotein; OCP, overall coagulation potential; OHP, overall haemostatic potential;
OFP, overall fibrinolysis potential. Pearson's and Spearman's correlations were performed for parametric and non-parametric variables respectively. Point biserial correlation was applied
to dichotomous and continuous variables.
⁎ p b 0.05.
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
6 V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx 7
In conclusion, we report for the first time that a hypercoagulable and Cellai, A.P., Lami, D., Antonucci, E., Fiorillo, C., Becatti, M., Olimpieri, B., Bani, D., Grifoni, E.,
Cenci, C., Marcucci, R., Mannini, L., Poli, D., Abbate, R., Prisco, D., 2013. Fibrinolytic
hypofibrinolytic state is present in patients with schizophrenia on long- inhibitors and fibrin characteristics determine a hypofibrinolytic state in patients
term antipsychotic medications. These data may help our understand- with pulmonary embolism. Thromb. Haemost. 109 (3), 565–567.
ing of the mechanisms underlying the increased risk for VTE in this Cesari, M., Pahor, M., Incalzi, R.A., 2010. Plasminogen activator inhibitor-1 (PAI-1): a key
factor linking fibrinolysis and age-related subclinical and clinical conditions.
patient population. Cardiovasc. Ther. 28 (5), e72–e91.
Supplementary data to this article can be found online at http://dx. Chamberlain, A.M., Folsom, A.R., Heckbert, S.R., Rosamond, W.D., Cushman, M., 2008.
doi.org/10.1016/j.schres.2014.12.042. High-density lipoprotein cholesterol and venous thromboembolism in the
Longitudinal Investigation of Thromboembolism Etiology (LITE). Blood 112 (7),
2675–2680.
Role of funding source Curnow, J.L., Morel-Kopp, M.C., Roddie, C., Aboud, M., Ward, C.M., 2007. Reduced
This study is supported by the Australian Postgraduate Awards Scholarship from the fibrinolysis and increased fibrin generation can be detected in hypercoagulable
University of Sydney [Postgraduate Medical Scholarship to V Chow] and a Program patients using the overall hemostatic potential assay. J. Thromb. Haemost. 5
Grant from the Australian Government National Health and Medical Research Council (L (3), 528–534.
Kritharides) Grant No: 1037903. The funders had no role in the study design, data collec- Davis, S., Kern, H.B., Asokan, R., 1994. Antiphospholipid antibodies associated with
tion, data analysis, data interpretation, writing of the report, or decision to submit the clozapine treatment. Am. J. Hematol. 46 (2), 166–167 (46(2), 166–167).
results. Edelman, J.J., Reddel, C.J., Kritharides, L., Bannon, P.G., Fraser, J.F., Curnow, J.L., Vallely,
M.P., 2013. Natural history of hypercoagulability in patients undergoing
coronary revascularization and effect of preoperative myocardial infarction.
Contributors J. Thorac. Cardiovasc. Surg. 148 (2), 536–543.
V. Chow, C. Reddel, G. Pennings, A. C. C. Ng, J. Curnow and L. Kritharides designed Eichinger, S., Pecheniuk, N.M., Hron, G., Deguchi, H., Schemper, M., Kyrle, P.A., Griffin, J.H.,
the study, analysed and interpreted the data. V. Chow, A. C. C. Ng and L. Kritharides drafted 2007. High-density lipoprotein and the risk of recurrent venous thromboembolism.
the manuscript. T. Yeoh, E. Scott, and T. Pasqualon contributed to the critical revision of the Circulation 115 (12), 1609–1614.
Everett, B.M., Glynn, R.J., Buring, J.E., Ridker, P.M., 2009. Lipid biomarkers, hormone
manuscript for important intellectual content. V. Chow and L. Kritharides are guarantors.
therapy and the risk of venous thromboembolism in women. J. Thromb. Haemost. 7
(4), 588–596.
Conflict of interest Fitzsimons, J., Berk, M., Lambert, T., Bourin, M., Dodd, S., 2005. A review of clozapine
J. Curnow is a consultant haematologist for Clozapine Patient Monitoring Service safety. Expert Opin. Drug Saf. 4 (4), 731–744.
(Norvatis), Australia. All other authors have no conflict of interest. Furie, B., Furie, B.C., 2008. Mechanisms of thrombus formation. N. Engl. J. Med. 359 (9),
938–949.
Glynn, R.J., Danielson, E., Fonseca, F.A., Genest, J., Gotto Jr., A.M., Kastelein, J.J., Koenig, W.,
Acknowledgements Libby, P., Lorenzatti, A.J., MacFadyen, J.G., Nordestgaard, B.G., Shepherd, J., Willerson,
None. J.T., Ridker, P.M., 2009. A randomized trial of rosuvastatin in the prevention of venous
thromboembolism. N. Engl. J. Med. 360 (18), 1851–1861.
Griffin, J.H., Kojima, K., Banka, C.L., Curtiss, L.K., Fernandez, J.A., 1999. High-density
References lipoprotein enhancement of anticoagulant activities of plasma protein S and activated
protein C. J. Clin. Invest. 103 (2), 219–227.
Agarwal, V., Phung, O.J., Tongbram, V., Bhardwaj, A., Coleman, C.I., 2010. Statin use and the Guimaraes, A.H., de Bruijne, E.L., Lisman, T., Dippel, D.W., Deckers, J.W., Poldermans, D.,
prevention of venous thromboembolism: a meta-analysis. Int. J. Clin. Pract. 64 (10), Rijken, D.C., Leebeek, F.W., 2009. Hypofibrinolysis is a risk factor for arterial thrombo-
1375–1383. sis at young age. Br. J. Haematol. 145 (1), 115–120.
Ageno, W., Squizzato, A., Garcia, D., Imberti, D., 2006. Epidemiology and risk factors of Hagg, S., Jonsson, A.K., Spigset, O., 2009. Risk of venous thromboembolism due to antipsy-
venous thromboembolism. Semin. Thromb. Hemost. 36, 772–779 (32(7), 651–658). chotic drug therapy. Expert Opin. Drug Saf. 8 (5), 537–547.
Ageno, W., Becattini, C., Brighton, T., Selby, R., Kamphuisen, P.W., 2008. Cardiovascular He, S., Bremme, K., Blomback, M., 1999. A laboratory method for determination of overall
risk factors and venous thromboembolism: a meta-analysis. Circulation 117 (1), haemostatic potential in plasma. I. Method design and preliminary results. Thromb.
93–102. Res. 96 (2), 145–156.
Albert, M.A., Danielson, E., Rifai, N., Ridker, P.M., 2001. Effect of statin therapy on C- He, S., Antovic, A., Blomback, M., 2001. A simple and rapid laboratory method for
reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a determination of haemostasis potential in plasma. II. Modifications for use in routine
randomized trial and cohort study. JAMA 286 (1), 64–70. laboratories and research work. Thromb. Res. 103 (5), 355–361.
American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Hu, Q., Zhang, C., Zhu, S., 2013. Fatal multisystem venous thrombosis associated with
Disorders. 4th edition (Washington, DC). clozapine. J. Clin. Psychopharmacol. 33 (2), 256–258.
Anderson Jr., F.A., Spencer, F.A., 2003. Risk factors for venous thromboembolism. Circula- Iwata, Y., Suzuki, K., Nakamura, K., Matsuzaki, H., Sekine, Y., Tsuchiya, K.J., Sugihara, G., Kawai,
tion 107 (23 Suppl. 1), I9–I16. M., Minabe, Y., Takei, N., Mori, N., 2007. Increased levels of serum soluble L-selectin in
Authors/Task Force, Konstantinides, M., Torbicki, S.V., Agnelli, A., Danchin, G., Fitzmaurice, unmedicated patients with schizophrenia. Schizophr. Res. 89 (1–3), 154–160.
N., Galie, D., Gibbs, N., Huisman, J.S., Humbert, M.V., Kucher, M., Lang, N., Lankeit, I., Jenkins, P.V., Rawley, O., Smith, O.P., O'Donnell, J.S., 2012a. Elevated factor VIII levels and
Lekakis, M., Maack, J., Mayer, C., Meneveau, E., Perrier, N., Pruszczyk, A., Rasmussen, risk of venous thrombosis. Br. J. Haematol. 157 (6), 653–663.
P., Schindler, L.H., Svitil, T.H., Vonk Noordegraaf, P., Zamorano, A., Zompatori, J.L., Jenkins, P.V., Rawley, O., Smith, O.P., O'Donnell, J.S., 2012b. Elevated factor VIII levels and
Authors/Task Force, 2014. 2014 ESC guidelines on the diagnosis and management risk of venous thrombosis. Br. J. Haematol. 157 (6), 653–663 (157(6), 653–663).
of acute pulmonary embolism: the Task Force for the Diagnosis and Management Jennings, I., Kitchen, S., Woods, T.A., Preston, F.E., 2005. Multilaboratory testing in
of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed thrombophilia through the United Kingdom National External Quality Assessment
by the European Respiratory Society (ERS). Eur. Heart J. 35 (43), 3033–3069. Scheme (Blood Coagulation) Quality Assurance Program. Semin. Thromb. Hemost.
Axelsson, S., Hagg, S., Eriksson, A.C., Lindahl, T.L., Whiss, P.A., 2007. In vitro effects of 31 (1), 66–72.
antipsychotics on human platelet adhesion and aggregation and plasma coagulation. Koster, T., Blann, A.D., Briet, E., Vandenbroucke, J.P., Rosendaal, F.R., 1995a. Role of clotting
Clin. Exp. Pharmacol. Physiol. 34 (8), 775–780 (34(8), 775–780). factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.
Baglin, T., Gray, E., Greaves, M., Hunt, B.J., Keeling, D., Machin, S., Mackie, I., Makris, M., Lancet 345 (8943), 152–155.
Nokes, T., Perry, D., Tait, R.C., Walker, I., Watson, H., 2010. Clinical guidelines for test- Koster, T., Rosendaal, F.R., Briet, E., van der Meer, F.J., Colly, L.P., Trienekens, P.H., Poort,
ing for heritable thrombophilia. Br. J. Haematol. 149 (2), 209–220. S.R., Reitsma, P.H., Vandenbroucke, J.P., 1995b. Protein C deficiency in a controlled
Bank, I., van de Poel, M.H., Coppens, M., Hamulyak, K., Prins, M.H., van der Meer, J., series of unselected outpatients: an infrequent but clear risk factor for venous throm-
Veeger, N.J., Buller, H.R., Middeldorp, S., 2007. Absolute annual incidences of bosis (Leiden Thrombophilia Study). Blood 85 (10), 2756–2761.
first events of venous thromboembolism and arterial vascular events in Li, L., Sun, T., Zhang, P., Tian, J., Yang, K., 2011. Statins for primary prevention of venous
individuals with elevated FVIII:c. A prospective family cohort study. Thromb. thromboembolism. Cochrane Database Syst. Rev. 12, (CD008203).
Haemost. 98 (5), 1040–1044. Lisman, T., de Groot, P.G., Meijers, J.C., Rosendaal, F.R., 2005. Reduced plasma fibrinolytic
Boullin, D.J., Know, J.M., Peters, J.R., Orr, M.W., Gelder, M.G., Grahame-Smith, D.G., 1978. potential is a risk factor for venous thrombosis. Blood 105 (3), 1102–1105.
Platelet aggregation and chlorpromazine therapy. Br. J. Clin. Pharmacol. 6 (6), Machin, S.J., 2003. Pros and cons of thrombophilia testing: cons. J. Thromb. Haemost. 1
538–540. (3), 412–413.
Braekkan, S.K., Borch, K.H., Mathiesen, E.B., Njolstad, I., Hansen, J.B., 2009. HDL-cholesterol Mahmoodi, B.K., Brouwer, J.L., Ten Kate, M.K., Lijfering, W.M., Veeger, N.J., Mulder,
and future risk of venous thromboembolism: the Tromso Study. J. Thromb. Haemost. A.B., Kluin-Nelemans, H.C., Van Der Meer, J., 2010. A prospective cohort study
7 (8), 1428–1430. on the absolute risks of venous thromboembolism and predictive value of
Bucciarelli, P., Passamonti, S.M., Biguzzi, E., Gianniello, F., Franchi, F., Mannucci, P.M., screening asymptomatic relatives of patients with hereditary deficiencies of pro-
Martinelli, I., 2012. Low borderline plasma levels of antithrombin, protein C and tein S, protein C or antithrombin. J. Thromb. Haemost. 8 (6), 1193–1200.
protein S are risk factors for venous thromboembolism. J. Thromb. Haemost. 10 (9), Masopust, J., Maly, R., Andrys, C., Valis, M., Bazant, J., Hosak, L., 2011. Markers of
1783–1791. thrombogenesis are activated in unmedicated patients with acute psychosis: a
Carrizo, E., Fernandez, V., Quintero, J., Connell, L., Rodriguez, Z., Mosquera, M., Acosta, A., matched case control study. BMC Psychiatry 11, 2.
Baptista, T., 2008. Coagulation and inflammation markers during atypical or typical Meltzer, M.E., Lisman, T., Doggen, C.J., de Groot, P.G., Rosendaal, F.R., 2008. Synergistic
antipsychotic treatment in schizophrenia patients and drug-free first-degree effects of hypofibrinolysis and genetic and acquired risk factors on the risk of a first
relatives. Schizophr. Res. 103 (1–3), 83–93. venous thrombosis. PLoS Med. 5 (5), e97.
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042
8 V. Chow et al. / Schizophrenia Research xxx (2015) xxx–xxx
Meltzer, M.E., Doggen, C.J., de Groot, P.G., Rosendaal, F.R., Lisman, T., 2009. Reduced plas- Rogers, M.A., Levine, D.A., Blumberg, N., Flanders, S.A., Chopra, V., Langa, K.M., 2012.
ma fibrinolytic capacity as a potential risk factor for a first myocardial infarction in Triggers of hospitalization for venous thromboembolism. Circulation 125 (17),
young men. Br. J. Haematol. 145 (1), 121–127. 2092–2099.
Meltzer, M.E., Lisman, T., de Groot, P.G., Meijers, J.C., le Cessie, S., Doggen, C.J., Rosenson, R.S., Tangney, C.C., 1998. Antiatherothrombotic properties of statins: implica-
Rosendaal, F.R., 2010. Venous thrombosis risk associated with plasma tions for cardiovascular event reduction. JAMA 279 (20), 1643–1650.
hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Squizzato, A., Galli, M., Romualdi, E., Dentali, F., Kamphuisen, P.W., Guasti, L., Venco, A.,
Blood 116 (1), 113–121. Ageno, W., 2010. Statins, fibrates, and venous thromboembolism: a meta-analysis.
Middeldorp, S., 2011a. Evidence-based approach to thrombophilia testing. J. Thromb. Eur. Heart J. 31 (10), 1248–1256.
Thrombolysis 31 (3), 275–281. Stein, P.D., Kayali, F., Olson, R.E., 2004. Estimated case fatality rate of pulmonary
Middeldorp, S., 2011b. Is thrombophilia testing useful? Hematol. Am. Soc. Hematol. Educ. embolism, 1979 to 1998. Am. J. Cardiol. 93 (9), 1197–1199.
Prog. 2011, 150–155. Torbicki, A., Perrier, A., Konstantinides, S., Agnelli, G., Galie, N., Pruszczyk, P., Bengel, F.,
Middeldorp, S., van Hylckama Vlieg, A., 2008. Does thrombophilia testing help in the Brady, A.J., Ferreira, D., Janssens, U., Klepetko, W., Mayer, E., Remy-Jardin, M.,
clinical management of patients? Br. J. Haematol. 143 (3), 321–335. Bassand, J.P., Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K.,
Mineo, C., Deguchi, H., Griffin, J.H., Shaul, P.W., 2006. Endothelial and antithrombotic Filippatos, G., Funck-Brentano, C., Hellemans, I., Kristensen, S.D., McGregor, K.,
actions of HDL. Circ. Res. 98 (11), 1352–1364. Sechtem, U., Silber, S., Tendera, M., Widimsky, P., Zamorano, J.L., Andreotti, F.,
Ng, A.C., Chung, T., Yong, A.S., Wong, H.S., Chow, V., Celermajer, D.S., Kritharides, L., 2011. Ascherman, M., Athanassopoulos, G., De Sutter, J., Fitzmaurice, D., Forster, T., Heras,
Long-term cardiovascular and noncardiovascular mortality of 1023 patients with M., Jondeau, G., Kjeldsen, K., Knuuti, J., Lang, I., Lenzen, M., Lopez-Sendon, J.,
confirmed acute pulmonary embolism. Circ. Cardiovasc. Qual. Outcomes 4 (1), Nihoyannopoulos, P., Perez Isla, L., Schwehr, U., Torraca, L., Vachiery, J.L., 2008.
122–128. Guidelines on the diagnosis and management of acute pulmonary embolism: the
Nishino, M., Hoshida, S., Kato, H., Egami, Y., Shutta, R., Yamaguchi, H., Tanaka, K., Tanouchi, Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the
J., Hori, M., Yamada, Y., 2008. Preprocedural statin administration can reduce European Society of Cardiology (ESC). Eur. Heart J. 29 (18), 2276–2315.
thrombotic reaction after stent implantation. Circ. J. 75 (6), 1472–1475 (72(2), Undas, A., Brozek, J., Musial, J., 2002. Anti-inflammatory and antithrombotic effects of
232–237). statins in the management of coronary artery disease. Clin. Lab. 48 (5–6), 287–296
Pai, M., Evans, N.S., Shah, S.J., Green, D., Cook, D., Crowther, M.A., 2011. Statins in the (48(5-6), 287–296).
prevention of venous thromboembolism: a meta-analysis of observational studies. Undas, A., Brummel-Ziedins, K.E., Mann, K.G., 2005. Statins and blood coagulation.
Thromb. Res. 122 (1), 21–25 (128(5), 422–430). Arterioscler. Thromb. Vasc. Biol. 23 (10), 1881–1888 (25(2), 287–294).
Parker, C., Coupland, C., Hippisley-Cox, J., 2010. Antipsychotic drugs and risk of venous Van De Craen, B., Declerck, P.J., Gils, A., 2012. The biochemistry, physiology and patholog-
thromboembolism: nested case–control study. BMJ 341, c4245. ical roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb. Res. 122
Parkin, L., Skegg, D.C., Herbison, G.P., Paul, C., 2003. Psychotropic drugs and fatal (1), 21–25 (130(4), 576–585).
pulmonary embolism. Pharmacoepidemiol. Drug Saf. 12 (8), 647–652 (12(8), 647– Varia, I., Krishnan, R.R., Davidson, J., 1983. Deep-vein thrombosis with antipsychotic
652). drugs. Psychosomatics 24 (12), 1097–1098.
Perez, A., Bartholomew, J.R., 2010. Interpreting the JUPITER trial: statins can Vedin, J., Antovic, A., Ericsson, A., Vaage, J., 2005. Hemostasis in off-pump compared to on-
prevent VTE, but more study is needed. Cleve. Clin. J. Med. 74 (3), 199–202 pump coronary artery bypass grafting: a prospective, randomized study. Ann. Thorac.
(77(3), 191–194). Surg. 80 (2), 586–593.
Reddel, C.J., Curnow, J.L., Voitl, J., Rosenov, A., Pennings, G.J., Morel-Kopp, M.-C., Brieger, Waldman, A., Kritharides, L., 2003. The pleiotropic effects of HMG-CoA reductase inhibi-
D.B., 2013. Detection of hypofibrinolysis in stable coronary artery disease using the tors: their role in osteoporosis and dementia. Drugs 63 (2), 139–152.
overall haemostatic potential assay. Thromb. Res. 122 (1), 21–25 (131(5), 457–462). Walker, A.M., Lanza, L.L., Arellano, F., Rothman, K.J., 1997. Mortality in current and former
Reitter-Pfoertner, S., Waldhoer, T., Mayerhofer, M., Eigenbauer, E., Ay, C., Mannhalter, C., users of clozapine. Epidemiology 8 (6), 671–677.
Kyrle, P.A., Pabinger, I., 2013. The influence of thrombophilia on the long-term surviv- Walsh, M.T., Ryan, M., Hillmann, A., Condren, R., Kenny, D., Dinan, T., Thakore, J.H., 2002.
al of patients with a history of venous thromboembolism. Thromb. Haemost. 109 (1), Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naive, first-episode
79–84. schizophrenic patients. Biol. Psychiatry 52 (9), 874–879 (52(9), 874–879).
Rezaie-Majd, A., Maca, T., Bucek, R.A., Valent, P., Muller, M.R., Husslein, P., Kashanipour, A., Wang, Y., Wang, P., Li, H., 2010. Correlation study of pulmonary embolism and high-
Minar, E., Baghestanian, M., 2002. Simvastatin reduces expression of cytokines density lipoprotein cholesterol. Clin. Cardiol. 33 (2), 72–76.
interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating Whiteman, T., Hassouna, H.I., 2000. Hypercoagulable states. Hematol. Oncol. Clin. North
monocytes from hypercholesterolemic patients. Arterioscler. Thromb. Vasc. Biol. 22 Am. 14 (2), 355–377 (viii).
(7), 1194–1199. Yukizawa, Y., Inaba, Y., Watanabe, S., Yajima, S., Kobayashi, N., Ishida, T., Iwamoto, N.,
Roche-Bayard, P., Rossi, R., Mann, J.M., Cordier, J.F., Delahaye, J.P., 1990. Left pulmonary Choe, H., Saito, T., 2012. Association between venous thromboembolism and plasma
artery thrombosis in chlorpromazine-induced lupus. Chest 98 (6), 1545. levels of both soluble fibrin and plasminogen-activator inhibitor 1 in 170 patients
Rodriguez, A.L., Wojcik, B.M., Wrobleski, S.K., Myers Jr., D.D., Wakefield, T.W., Diaz, J.A., undergoing total hip arthroplasty. Acta Orthop. 83 (1), 14–21 (83(1), 14–21).
2012. Statins, inflammation and deep vein thrombosis: a systematic review. Zornberg, G.L., Jick, H., 2000. Antipsychotic drug use and risk of first-time idiopathic
J. Thromb. Thrombolysis 33 (4), 371–382 (33(4), 371–382). venous thromboembolism: a case–control study. Lancet 356 (9237), 1219–1223.
Please cite this article as: Chow, V., et al., Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy,
Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2014.12.042