Influence of mental stress on platelet bioactivity

Table 1 Effects of acute mental stress and chronic care-giving strain on platelet reactivity

Author	Study design	Comorbidities	Medication allowed and health behavior	Stress task and assessment inventory	Sampling and Analysis	Platelet reactivity	Result
Patterson et al[86] 1995	Acute mental stress and cold pressor test on platelet activity in healthy stress (22) vs no-stress group (5)	None		Rest 1 10 min mental arithmetics	Rest 1 mental task	PF-4	Mental arithmetics : ↑PF-4 (P < 0.001) and β-TG (P < 0.001) vs baseline
					Rest 2 cold pressor task	β-TG
				Rest 2 2.5 min cold pressor test			Cold pressor test: ↑PF-4 (P < 0.001) and β-TG (P < 0.001) vs baseline
Hamer et al[87] 2006	Acute mental stress in full-time employees	None		3 min role speech task	Baseline	% PLA	↑PLA and ↑PMA by trial (P < 0.001) and session (P = 0.020) vs baseline
				5 min mirror tracing task	10 min post-stress	% PMA
	Longitudinal design				FACS
	91 non-smoking men (33.2 yr average)
Steptoe et al[88] 2003	Acute mental stress in men regarding socioeconomic status, cross sectional design	None	No aspirin allowed	Stroop Colour Word Interference Test	Baseline	% PLA	↑PLA (P < 0.009), ↑PMA (P < 0.037), ↑Plt-ne-agg (P < 0.045) over trial vs baseline, greater number of overall PLA (P = 0.031) in lower social status vs higher, ↑PLA (P < 0.001) and Plt-ne-agg (P = 0.003) in both groups in stress vs baseline
			No coffein		imm post-stress	% Plt-mo agg
			No caffeinated beverages	Mirror tracing task	30 min post-stress	% Plt-ly agg
	15 men with higher socioeconomic status vs 20 lower socioeconomic status		No alcohol		75 min post-stress	% Plt-ne agg
			No exercise before testing		FACS
Aschbacher et al[92] 2009	Acute mental stress in CG +/- persistent depressive symptoms, longitudinal design	Myocardial infarction	Aspirin	3 min impromptu speech	Baseline	% P-sel exp	Persistent DEP predicted P-sel reactivity and recovery (P < 0.01) vs transient DEP
		Others not specified	Antidepressants after enrollment: β-blocker		imm post-stress (reactivity)
				Brief Symptom Inventory	14 min post-stress (recovery)
	99 CG (73 yr average, 68% female, 93% Caucasian)				FACS
Aschbacher et al[91] 2009	Acute mental stress in elderly persons, longitudinal design	Myocardial infraction	Aspirin, antidepressants, statins, NSAIDs, anti-hypertensives, β-blockers, HRT, anti-aggregation drugs, anti-platelet drugs	3 min impromptu speech	Baseline	% plt agg	↑All platelet (P < 0.001) outcome measures in stress vs rest
		Diabetes			imm post-stress	% FbR exp
	149 elderly participants (mean age 71 yr, 30% male, 93% Caucasian)	Hypertension			FACS	% P-sel exp
		Hypercholesterolemia
		Cerebrovascular incident
Aschbacher et al[89] 2008	Acute mental stress in CG +/- negative effect	Cerebrovascular disease	Aspirin, antidepressants, α blockers, after enrollment: β-blocker	3 min impromptu speech	Baseline	% plt agg	↑P-selectin reactivity (P < 0.001), delayed P-selectin recovery (P = 0.039) in CG with DEP vs non-CG
		Coronary artery disease			imm post-stress	% FbR exp
	Cross-sectional design	Diabetes		Role overload scale	14 min post-stress	% P-sel exp
	39 care-givers vs 31 non care-givers	Hypercholesterolemia			FACS
		Hypertension
		CVD condition
Aschbacher et al[90] 2007	Acute mental stress on CG women +/- HRT	Coronary artery disease	Aspirin, NSAIDs, antidepressants, anti-platelet drugs, antihypertensives, statins	3 min impromptu speech	Baseline	% plt agg	HRT x CG effect on recovery of AGG (P = 0.025), P-sel (P = 0.013), FbR (P = 0.012); CG +HRT delayed post stress recovery of AGG (P = 0.038) and P-sel (P = 0.004) vs NCG + HRT, no CG effect among non-HRT
		Cerebrovascular disease			imm post-stress (reactivity)	% FbR exp
	Cross-sectional design	Diabetes			14 min post-stress (recovery)	% P-sel exp
	51 CG women (24 HRT) vs 27 non-CG (15 HRT)	Hypercholesterolemia			FACS
		Hypertension

%: The percentage of; PF-4: Platelet factor 4; β-TG: β-thromboglobulin; PLA: Platelet-leukocyte aggregates; PMA: Platelet-monocyte aggregates; Plt-mo: Platelet-monocyte aggregates; Plt-ly: Platelet-lymphocyte aggregates; Plt-ne: Platelet-neutrophil aggregates; P-sel: P-selectin; CG: Care-giver; non-CG: Non care-giver; HRT: Hormone replacement therapy; CG X HRT: Interaction between care-giving stress and hormone replacement therapy; AGG: Aggregates; FbR: Fibrinogen binding receptor; DEP: Depressive symptoms; Plt: Platelet; Mo: Monocyte, Ly: Lymphocyte; Ne: Neutrophils; Exp: Expression; NSAIDs: Non steroidal anti-inflammatory drug; FACS: Fluorescence-activated cell sorting; imm: Immediately.

Table 2 Effects of mental and physical stress on platelet reactivity of patients with cardiovascular disease

Author	Study design	Comorbidities	Medication allowed and health behavior	Stress task and assessment inventory	Sampling	Platelet outcome parameters	Results
Markovitz et al[95] 1996	Hostility and stress task in post MI-patients	Not specified	Sublingual nitro, no calcium-channel blockers or platelet inhibitors for 10 d, NSAIDs for 10 d, no β-blockers for 48 h	Structured Interview Type A behavior and “Potential for Hostility”	Baseline	β-TG	↑β-TG (P = 0.006) in healthy controls vs post-MI, correlation of ↑levels of Type A and ↑β-TG reactivity (P = 0.02)
					Post-stress task
	Cross-sectional design
	14 stable post-MI vs 15 age matched healthy men			Speech Task
				“Cook-Medley Hostility” Scale
				BDI
				Paffenberger Questionnaire
				Spielberger State Anxiety Inventory
Markovitz et al[96] 1998	Hostility in patients with CHD	Not specified	Sublingual nitro statins, no aspirin/anti-platelet medication for 14 d, no oral or topic nitrates for 48 h, no calcium channel blockers for 48 h, no SSRIs	Type A Structured Interview	Wound incision	Wound induced fibrinogen receptor activation indicators	Relationship between hostility and FbR activation at 2 min and FbR binding at 1 min (P = 0.02) in CHD patients vs healthy controls
	Cross sectional design			BDI	1 min after incision
	32 non-smoking patients vs 23 non-smoking healthy controls aged 45 to 73 yr				2 min after incision
						FbR activation
						FbR binding
						FACS
Reid et al[99] 2009	Acute mental stress in CAD patients requiring coronary angioplasty	Diabetes	Diabetes hypertension, aspirin, ACE inhibitors, β-blockers, topical or oral nitrate statins, clopidogrel	Mental arithmetics	Baseline	GPIIa/IIIb expression	↑GPIIb/IIIa (P = 0.002), ↑% of MNC bound plt (P = 0.01) and ↑P-sel (P = 0.005) in stress vs baseline, ↑% of plt P-sel (P < 0.01) in stress vs baseline
		Hypertension		Anger recall	imm post stress	% of MNC bound plt
		Previous MI		BDI		P-sel expression
	Cross sectional design	Previous PCI		Maastricht Questionnaire		% of P-sel expression
	249 patients (15, 3% women)			STAEI		β-TG
				Cook-Medley Hostility short-form		FACS
				PSS		ELISA
Bacon et al[97] 2006	Acute mental and acute physical stress in CAD patients with elective cardiological intervention	Hypertension	Aspirin/copidrogrel, ACE-inhibitors, β-blockers, calcium-channel blockers, diuretics, nitrates, statins, antidiabetic medication	Rest 1 8 min Paced Auditory Serial Addition	Rest 1 post task	PF-4	Mental stress: PF-4 ns changes vs baseline, physical stress: PF-4 ns changes vs baseline
		Hyperlipidemia			Rest 2 post task	ELISA
		Diabetes		Rest 2 8 min submaximal exercise test
	Cross-sectional design	Smokers
	72 patients (57 men, 15 women)
Strike et al[101] 2006	Acute stress in male patients with survived ACS		18 patients withdrawn medication vs 16 patients taking β-blockers, aspirin, statins, ACE inhibitors, no antidepressants	Stroop Colour Word Interference Test	Baseline	PLA	Emotion-trigger group: sig ↑all platelet outcome parameters (P < 0.001) in stress vs baseline vs non-emotion trigger group (P < 0.05), ↑Plt-mo agg at 30 min post stress (P < 0.05) in the emotion trigger group vs baseline vs non emotion trigger group
					imm post-stress task	% Plt-mo agg
	Cross sectional design			Speech task	30 min post stress	% Plt-ne agg
	14 Emotion trigger group vs 20 non-trigger group			HADS	75 min post stress	FACS
				Scale for MI-patients	120 min post-stress
Strike et al[98] 2004	Acute stress in male CAD patients, stable disease and PCTA or coronary intervention		Aspirin	Stroop Colour Word interference task	Baseline	% of PLA	↑PLA (P < 0.05) in CAD at 75 min post stress vs healthy controls, group by trial interaction on PLA (P < 0.01)
			No statins 72 h		Stress	FACS
			No β-blockers 72 h	Mirror tracing task	30 min post-stress
	Cross-sectional design			HADS	75 min post-stress
	17 patients vs 22 healthy			Sleep quality assessed by Scale of Jenkins et al
Wallén et al[100] 1997	Acute mental and acute physical stress in patients with stable angina pectoris vs healthy controls		Aspirin, ACE inhibitors, digoxin, diuretics, β-blockers, calcium–channel blockers switched to study medication metoprolol and verapamil	Stroop Colour Word Conflict Test	Baseline	PF-4	Physical exercise: patients ↑PF-4 (P < 0.05) and ↑β-TG (P < 0.01) vs baseline, healthy controls ↑β-TG (P < 0.01) and ↑PF-4 (P < 0.01) vs baseline; mental stress: ↑PF-4 (P = 0.06)NS and ↑β-TG (P < 0.05) in patients vs healthy controls
	Cross sectional design			Ergometer examination	Stress-task	β-TG
	113 patients (21 on aspirin) vs 50 matched controls					ELISA
Tomoda et al[103] 1999	Acute mental stress in patients with essential hypertension	WHO stage II patients with proteinuria, elevated serum creatinin, left ventricular hypertrophy, hypertensive retinopathy	Not specified	10 min arithmetic test	Baseline	β-TG	Stress induced increase β-TG (P < 0.05) in WHO stage I and II patients vs rest, baseline β-TG levels (P < 0.05) in WHO stage II vs WHO stage I vs controls
					Immediately post stress task	RIA
	Cross-sectional design
	24 hypertensive (11 WHO stage I, 13 WHO stage II) patients vs 14 normotensive controls

Plt: Platelet; %: Percentage of; P-sel: P-selectin; PF-4: Platelet factor 4; β-TG: β-thromboglobulin; FbR: Firbrinogen receptor binding; MNC: Mononuclear cell; CAD: Coronary artery disease; CHD: Coronary heart disease; MI: Myocardial infarction; PCI: Percutanuos coronary intervention; PCTA: Percutaneous coronary angiography; BDI: Beck Depression Inventory; STAEI: State-Trait Anger Expression Inventory; PSS: Perceived Stress Scale; HADS: Hospital Anxiety and Depression Scale; ACE: Antgiotensin converting enzyme; MI: Myocardial infarction; PLA: Platelet-leukocyte aggregates; Plt-mo agg: Platelet-monocyte aggregates; Plt-ne agg: Platelet-neutrophil aggregates; imm: Immediately; SSRI: Selective serotonin reuptake inhibitor; ELISA: Enzyme linkes immunosorbent assay; FACS: Fluorescence-activated cell sorting; NS: Not significant.

Table 3 Platelet serotonin content and MAO activity and platelet activation markers in PTSD in cross sectional investigations

Study	Participants	Assessment inventory	Comorbidities	Medication allowed	Platelet outcome parameters	Results
Vidović et al[116] 2011	Platelet reactivity in PTSD	Mini International Neuropsychiatric Interview		Benzodiazepins	Platelet reactivity to agonists (EPI, ADP, combination)	PTSD patients ↑P-sel exp (P = 0.003), ↑% P-sel exp (P = 0.006), ↑% Plt-ne agg (P < 0.001) vs healthy controls
	15 PTSD veterans vs 12 healthy controls			Atypical antipsychotics
		CAPS		No antidepressants	P-sel exp
		HAMD		No NSAIDs	% of P-sel
		HAMA		No anti-hypertensives	% of PLA
				No statins	% of P-mo agg
					% of P-ne agg
					% of P-ly agg
					FACS
Kovacic et al[112] 2008	Platelets as a marker of suicidality in PTSD patients	SCID	Non-PTSD group: depression, psychosis, acute stress disorder, personality Disorder	Drug free veterans	5-HT content	↓5-HT (P < 0.029) suicidal PTSD vs non-suicidal PTSD, ↓5-HT (P < 0.01) suicidal PTSD vs healthy
		CAPS		Drug free non-PTSD patient group (drug-naïve or wash-out period of 2 wk or no SSRI for 6 wk)	Spectrofluorometric assessment
	73 suicidal and 47 non-suicidal PTSD patients vs 45 suicidal and 30 non suicidal non-PTSD patients. 147 healthy men	HDRS
		HAMA
		PANSS
Pivac et al[108] 2007	MAO-B activity and MAO intron 13 polymorphism in PTSD	SCID	PTSD patients wit h comorbid depression	Drug-free	MAO-B activity	Non-Smokers: psychotic PTSD vs veterans (P = 0.001), vs healthy (P = 0.006) ↑MAO-B activity; non-psychotic PTSD vs veterans (P = 0.046) ↑MAO-B activity
		CAPS			Spectrofluorimetric assay
	28 PTSD patients with psychotic features vs 78 PTSD without psychotic features vs 41 veterans without PTSD vs 242 male healthy control	PANSS	Alcoholism		Intron 13 polymorphism
		HAMD	Anxiety disorders		Taqman PCR
			Panick disorder			Smokers: psychotic PTSD vs veterans (P = 0.002), vs healthy (P = 0.001) ↑MAO-B activity
Vidović et al[117] 2007	Platelet activation markers in PTSD	CAPS	Hypertension	No psychopharmacotherapy	% PLA	Platelet outcome parameters: ns changes
	20 PTSD war veterans vs 20 age comparable healthy civilians	Clinical Global Impressions Scale	Hyperlipidaemia		% Plt-mo agg
			Diabetes		% Plt-ne agg
					% Plt-ly agg
					FACS
					sP-sel
					ELISA
Pivac et al[113] 2006	Platelet serotonin in PTSD patients with psychotic features	CAPS		Drug-free	5-HT contents	↑5-HT psychotic PTSD vs PTSD (P = 0.019), vs veterans (P = 0.040), vs controls (P = 0.029)
		PANSS			Spectrofluorimetric assay
	67 veterans with PTSD vs 36 veterans without PTSD vs 35 veterans with psychotic PTSD	HAMD
Mück-Seler et al[114] 2003	Platelet serotonin in PTSD with comorbid depression	CAPS	Headaches	Drug-free for 2 wk	5-HT content	5-HT contents PTSD vs non PTSD vs healthy controls (P = 0.11)NS changes; ↑5-HT depressed veterans with severe appetite loss (P < 0.05) vs depressed PTSD without appetite loss vs controls
		HAS	Back-pain		Spectrofluorimetric assay
	48 PTSD veterans (31 depressed vs 16 non-depressed) vs 17 non PTSD war veterans (4 depressed vs 13 non-depressed)	DTS	Gastro-intestinal symptoms
		MADRS
Pivac et al[115] 2002	Platelet 5-HT and MAO activity in PTSD	MADRS	No alcohol or drug abuse 1 mo prior	Drug-free	5-HT content	5-HT (P = 0.31)NS; MAO activity (P = 0.12)NS; No correlation to rating scales
	31 war veterans with PTSD vs 22 war veterans without PTSD vs 22 prisoners of war with PTSD	CAPS			MAO-activity
					Spectrofluorimetric method
Cicin-Sain et al[118] 2000	5-HT level, kinetics of serotonin transporter, MAO activity	Watsons PTSD questionnaire	PTSD patients comorbid depression, alcohol dependence, personality disorder, psychosis	Benzodiazepines, neuroleptics, TCAs, SSRIs, atypical anti-depressants	5-HT content	5-HTNS; Serotonin transporter kineticsNS, ↓MAO-B velocity (P < 0.05) in patients vs healthy controls
					5-HT uptake
	63 PTSD patients vs 43 healthy controls				MAO-B activity
					Spectrofluorimetric
					Radioisotypic method

PTSD: Posttraumatic stress disorder; 5-HT: Serotonin; MAO: Monoamine oxidase; EPI: Epinephrine; ADP: Adenosine-di-phosphat; SCID: Structured clinical interview; CAPS: Clinician Administred PTSD Scale; HDRS: Hamiton Depression Rating Scale; HAMA: Hamilton anxiety rating scale; PANSS: Positive and negative syndrom scale; MADRS: Montgomery asperg depression scale; HAMD: Hamilton rating scale for depression; HAS: Hamilton anxiety scale; DTS: Davidson trauma scale; %: Percentage of; PLA: Platelet-leukocyte aggregates; Plt-mo agg: Platelet-Monocyte aggregates; Plt-ne agg: Platelet-neutrophil aggregates; P-ly agg: Platelet-lymphocyte aggregates; P-sel: P-selectin; sPsel: Soluble P-selectin; exp: Expression; TCA: Tricyclic antidepressants; SSRI: Selective serotonin reuptake inhibitor; NSAID: Non steroidal anti inflammatory durg; FACS: Fluorescence-activated cell sorting; NS: Not significant.