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ORIGINAL ARTICLES |
From the Department of Psychiatry, University of California, San Diego, La Jolla, CA.
Address reprint requests to: Joel E. Dimsdale, MD, Department of Psychiatry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0804. jdimsdale{at}ucsd.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Key Words: platelets • psychopathology • stress • psychophysiology.
Abbreviations: ADP = adenosine diphosphate; AMP = adenosinemonophosphate; ATP = adenosine triphosphate; ß-TG =ß-thromboglobulin; CAD = coronary artery disease; GP =glycoprotein; IL = interleukin; MAO = monoamine oxidase; PBR = platelet benzodiazepine receptor; PDGF =platelet-derived growth factor; PF-4 = platelet factor 4; PTSD = posttraumatic stress disorder; SSRI = selectiveserotonin reuptake inhibitor; TGF-ß = transforming growth factorß; 5-HT = 5-hydroxytryptamine (serotonin).
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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In the following section, we review the basic concepts of platelet embryology, anatomy, and physiology. This part of the article provides a general introduction to some provocative early psychodynamic studies. After reviewing older reports on psychoanalysis and hemostasis, we describe how platelets have been used as valuable tools in more contemporary cardiovascular, psychosomatic, and psychopharmacological research.
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OVERVIEW OF PLATELET ANATOMY AND PHYSIOLOGY |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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There are several important organelles in the platelet cytoplasm. The dense bodies contain high concentrations of 5-HT, ADP, ATP, and calcium. The alpha granules are the most abundant organelles, containing the largest amounts of proteins and products normally secreted by platelets during their activation. These include proteins, such as PF-4 and ß-TG; adhesive GPs, such as von Willebrand factor and fibronectin; coagulation factors, such as factor V, factor XI, protein S, and factor XIII; and mitogenic factors, such as PDGF and TGF-ß. The alpha granules also contain fibrinolytic inhibitors, such as 
-2 plasmin inhibitor, plasminogen activator inhibitor 1, and P selectin (1, 5, 6). Platelets take up most of these proteins from the plasma, but PDGF, PF-4, ß-TG, and thrombospondin are exclusively synthesized by platelets. In addition, platelets also express different kinds of receptors, including adrenoceptors (-2 and ß-2), benzodiazepine, and 5-HT receptors (1, 2, 5, 6).
Different platelet proteins, such as PF-4, bind to heparin with very high affinity, thereby neutralizing the anticoagulant activity of heparin. Other activities ascribed to PF-4 are histamine release from basophils, neutrophil and monocyte chemotaxis, inhibition of tumor growth angiogenesis, reversal of immunosuppression, and potentiation of platelet aggregation (1, 5, 6).
Platelets are the first line of defense in hemostasis. Conditions that create platelet response are the age of the individual, blood vessel and oral mucosa capillary injury, the hematocrit, forces tending to pull platelets from the vessel wall (shear rate), and the size of the blood vessel. When platelets are faced with a blood vessel injury, the following events may occur (1–3): adhesion, activation, and aggregation.
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ADHESION |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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ACTIVATION |
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AGGREGATION |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Finally, there are several inhibitory factors that prevent excessive platelet deposit. Endothelial cells synthesize two potent factors, prostacyclin and nitric oxide. Other inhibitory factors are platelet leukocyte interactions and the speed of blood flow (1, 3, 5). Figure 1 summarizes these diverse interactions (7).
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HISTORICAL BACKGROUND OF HEMOSTASIS, PSYCHOANALYSIS, AND STRESS |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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In 1955, Gardner and Diamond (8) described a chronic purpuric state seen primarily in women. This disorder was manifested by numerous ecchymoses that appeared after injury or a surgical procedure; the authors observed that trivial daily injuries could reproduce them. They suspected that the patients were becoming sensitive to their own blood products and called this syndrome "autoerythrocyte sensitization." They could reproduce the ecchymoses by intracutaneous injection of the patients’ own blood. In addition to the ecchymoses, the patients also presented with gastrointestinal bleeding, hematuria, abdominal pain, and neurological abnormalities. However, none of these patients had a coagulation disorder.
In 1962, Agle and Ratnoff (9) reported on the psychological components of autoerythrocyte sensitization. Nine women with ecchymotic lesions that appeared a few months after trauma or surgery were studied. The patients described the new lesions beginning as a sharp, burning, stabbing, stinging sudden pain. In all cases, there was no evidence of hematological or hemostatic defects. The diagnosis was made with Gardner and Diamond’s test, intracutaneous injection of the patients’ own blood. Interestingly, Agle and Ratnoff reported that ecchymoses developed in three patients after intracutaneous injection of saline solution. All nine patients in the Agle and Ratnoff study had apparent conversion reactions associated with psychological stress, and three of them were receiving psychiatric treatment before the onset of the purpura. The authors concluded that autoerythrocyte sensitization might be a psychophysiological entity in which the reaction to emotional stress involved the autonomic nervous system and a way of relieving anxiety.
Agle and Ratnoff cited Schindler (10), a German psychiatrist who in 1927 described 16 cases of patients with the same cutaneous bleeding reaction. The bleeding phenomena were described incidentally and were not incapacitating. In three of Schindler’s patients, the bleeding episodes were severe, and he believed he could induce hemorrhages or remission by hypnotic suggestion. He also believed that his work confirmed what Weir Mitchell wrote in 1869, "We have the right to ask if certain nervous disorders are not able to weaken the vascular walls so they become permeable to red corpuscles."
Agle and Ratnoff also cited Jacobi (11), who described in 1929 two similar cases of bleeding on an apparently hysterical basis. Jacobi could not replicate Schindler’s work on the effects of hypnosis. He questioned why certain people react with vascular symptoms instead of more common conversion symptoms under certain stress situations. Jacobi postulated that stressful situations associated with hysterical traits could explain the bleeding phenomena. In addition, he stated that specific psychological mechanisms can influence the central nervous system, and this mechanism can be expressed as bleeding episodes or stigmata.
Lifschutz (12) reviewed the history of stigmatization. In his work, he cited Ferenczi, who stated that the "stigma is historically of clerical origin and indicates the amazing fact that the wound marks of Christ were transferred to believers by fervent prayer." Lifschutz stated that the most famous case of stigmatization was St. Francis of Assisi, who displayed the stigmata of crucifixion. Lifschutz suggested that nonreligious stigmatization involved hysterical episodes in which unresolved oedipal conflicts were expressed. Again, these lesions clinically resemble ecchymoses and could possibly be attributed to platelet dysfunction, but that has never been proven.
Agle and Ratnoff continued their studies on autoerythrocyte sensitization. In 1967, Agle et al. (13) reported on four more female patients, ranging in age from 15 to 66 years. The investigation included daily psychiatric interviews and psychological tests (ie, the Minnesota Multiphasic Personality Inventory, the Draw-a-Person Test, and Rorschach Projective Tests). Test results suggested a masochistic orientation, emotional lability, sexual maladjustment, and many references to damaged or incomplete body sensations. The authors concluded that these patients had hysterical and masochistic traits with a strong tendency to have somatic responses to emotional stimuli. The authors also reported that none of the factors explained why patients with autoerythrocyte sensitization responded to stressful situations with bleeding when other patients developed different psychiatric or psychophysiological disorders. On the basis of these findings, they suggested changing the term autoerythrocyte sensitization to "psychogenic purpura."
Agle and Ratnoff added more patients to their series; their 1968 report (14) was based on findings in 27 women in whom the diagnosis of psychogenic purpura had been made. All patients had normal results on hematological tests (eg, clotting time of whole blood, prothrombin and partial thromboplastin times, platelet count, bleeding time, and clot retraction). No antibodies against platelets were found in the patients’ sera. The authors stated that these patients always presented with hysterical and masochistic traits, depression, anxiety, and the inability to deal appropriately with their own hostile feelings. The husbands of most of the patients were sexually or physically abusive. One patient’s husband described the spontaneous bleeding episodes as follows: "I don’t understand my wife, her first husband was an alcoholic and beat her until she had to go to the hospital black and blue. I am not an alcoholic, I don’t beat her, but still she has to go to the hospital black and blue." The investigators hypothesized that psychogenic purpura appeared in the context of emotional stress; interestingly, they never found any platelet dysfunction. Finally, they suggested that autoerythrocyte sensitization or psychogenic purpura is an interesting manifestation of a conversion reaction (14, 15).
Considering the studies reported by these authors, it is fascinating to ask how different psychological conditions could be associated with hemostatic disorders. The phenomenon is not an ancient clinical finding. In a recent report by Moll (16), a woman being treated for depression presented with multiple spontaneous skin bruises and reported severe emotional stresses (breast cancer and a pending lawsuit for divorce). Results of an extensive workup for bleeding disorder were negative. The patient was thought to have psychogenic purpura.
From these descriptions, it is natural to wonder about the biochemical links between the various receptors of platelets, depression, psychological stress, and a hematological diathesis. Future research might well focus on personality traits, ways of coping with stress, and neurohormonal influences on platelet function. Such work should include contemporary studies of platelet function.
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METHODS TO ASSESS PLATELET FUNCTION |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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-2, whereas MAO activity is measured by radioenzymatic assay. Platelet aggregation and secretion in whole blood are measured with use of a whole-blood Lumi-Aggregometer. For wound-induced platelet activation, and platelet membrane harvesting to analyze platelet membrane adenylate cyclase activity, other methods are used. Adenylate cyclase synthesizes the second messenger cyclic AMP, which is involved in the expression of platelet membrane receptors and the production of phosphatidylinositol triphosphate, resulting in intracellular mobilization of calcium, a potent platelet activator (1, 3, 17–22). Current techniques include analysis of specific membrane receptors with monoclonal antibodies, using flow cytometry, to determine specific platelet membrane receptor activity and the binding affinity for specific antibodies. The GPIIb-IIIa receptor is commonly studied. Flow cytometry is the most sensitive method to determine platelet function and platelet activation when exposed to different stressor situations (21, 23).
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STRESSORS AND PLATELET FUNCTION |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Certain personality traits have also been associated with platelet function and stress. Schonwetter et al. (24) described the interactions between Type A behavior, hostility, and bleeding time. They studied 66 male university students and classified them as Type A or Type B. The subjects were also classified as hostile or nonhostile using the Cook-Medley Hostility Scale. The investigators found that subjects with high hostility and Type A behavior had shorter bleeding times than subjects with type B behavior. The authors concluded that hostility is positively correlated with Type A behavior and decreased bleeding time. In addition, they proposed future studies to characterize more precisely the association between behavior and platelet function.
Markovitz et al. also reported (25) certain personality traits (specifically hostility and Type A behavior) associated with stress, CAD, and platelet reactivity. They studied 14 male postmyocardial infarction patients and 15 healthy men and evaluated their stress response and personality traits with a Type A structured interview. The investigators also measured ß-TG before and after the stressor. The two groups had similar ratings in the Type A structured interview task. The investigators found a significant correlation between Type A attributes and levels of ß-TG (p = .02), confirming the relationship between certain personality traits and increased platelet activity. Interestingly, healthy men had a greater change in ß-TG with stress than men in the postmyocardial infarction group. Future research may look at this association as a possible predictor for CAD in individuals under great amount of stress.
In a more recent study, Markovitz (21) compared hostility traits in a group of patients with CAD with those of a healthy control group. They used wound-induced platelet activation and flow cytometry to assess platelet function. They did not find any correlation between hostility ratings and platelet activation among the two groups. However, in the CAD group, they found a significant correlation (p < .05) between hostility ratings and increased GPIIb-IIIa receptor activity.
Some studies have described the fact that psychological stress can decrease the antiaggregatory effects of dietary fish oil in patients with a history of CAD. Mills and Prkachin (26) compared individuals receiving olive oil and individuals receiving fish oil. The subjects were exposed to different stressors (mental arithmetic and the Stroop color-word conflict test) for 2 minutes. They found that olive oil did not affect platelet aggregation responses to epinephrine, ADP, or collagen before stressors. In contrast, fish oil reduced the platelet aggregation response to high and low doses of epinephrine before stressors.
The association between psychological stress and platelet activation has been widely studied. In 1985, Levine et al. (27) measured PF-4 and ß-TG levels in medical residents who were to give a public speech at the beginning of the academic year. In this study, baseline blood samples were taken before subjects started the speech, and samples were again taken after they finished the speech. Levine et al. found increased levels of PF-4 and ß-TG after the speech was given. Malkoff et al. (17) tested 40 young, healthy men to evaluate the effects of mental stress on blood platelet activity, secretion, and aggregation. In this study, a 21-minute computerized version of the Stroop color-word conflict test was used as a mental stressor. The authors found acute changes in platelet function, that is, increased release of platelet ADP after the stressors. Although the mechanisms linking mental stress and platelet secretion remain unclear, the authors hypothesized that such changes may be mediated by neuroendocrine factors. These neuroendocrine mechanisms might be associated with the activating properties of epinephrine and norepinephrine on the platelet.
Patterson et al. (28) examined the effects of diverse physiologically stressful events on platelet function. They studied 55 healthy males, measuring heart rate, blood pressure, catecholamine levels, and PF-4. There were significant increases in catecholamine levels, PF-4, heart rate, and blood pressure associated with both active (performing a Stroop color test) and passive (watching a surgery film) stressors. The authors also proposed that future research should further assess relationships between catecholamine levels and stress-mediated platelet reactivity by measuring other platelet components, such as thrombin and plasminogen.
The relationship between platelet function and physical stress has also been studied. The most common physical stressors are cold and heat exposure. Physical stimuli, such as exposure to cold, increase platelet reactivity. In another study, Patterson et al. (29) compared the effects of physical and psychological stress on platelet function. The investigators tested 22 healthy men and found significant increases in PF-4 and ß-TG associated with exposure to cold and mental arithmetic tests. They concluded that both mental and cold pressor stressors increase platelet activation, as indexed by secretion of PF-4 and ß-TG. In addition, the authors found that mental stress had a slightly more potent effect than cold stress on platelet activation. The investigators emphasized that to avoid variability in the results of platelet secretion, standardized methods of platelet collection and handling must be used.
Another technique used to study physical stress involves studying PBRs. PBRs are expressed in various stressful situations. Dar et al. (30) studied PBRs in soldiers at the beginning of a parachute training course. They determined the density of platelets’ radiolabeled benzodiazepine receptors. The investigators found a reduction in the number PBRs at the end of the exercise period, before the first jump. Also, they observed reduced density of this receptor after repeated jumps. The authors concluded that PBR seems to be a sensitive indicator of stress. In addition, they proposed future investigations based on the physiological and pharmacological implications of PBRs and stress.
Weizman et al. (31) also studied PBR density in 11 civilians during the Persian Gulf War. The investigators determined the density of platelet mitochondrial PBRs. They found decreased density of PBRs during the war and 4 weeks later. After the end of the war, there was an increase in PBR density. The authors concluded that the low density of PBRs was correlated with a high level of anxiety and that exposure to war may lead to downregulation of the PBRs. Future studies may assess the level of anxiety in individuals exposed to stressful military conditions and correlate it with increased platelet activity.
Surprisingly few studies of platelet function and stress in animals have been conducted. Malyszko et al. (32) investigated the effects of different kinds of acute stress on collagen-induced whole-blood platelet aggregation. They subjected different groups of rats to a variety of physical stimuli, such as restraint, water immersion, and foot-shock stress. They found that platelet aggregation induced by collagen was markedly reduced after the foot-shock stress. On the other hand, they did not find any alteration in platelet activity in rats subjected to water immersion. Future animal research needs to scrutinize how different stressors influence platelet dysfunction (ie, thrombosis or bleeding diathesis).
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STUDIES ABOUT PLATELETS AND NEUROTRANSMITTERS IN PSYCHIATRY |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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-2 adrenoceptor, and MAO activity. The following studies illustrate some of the myriad possibilities for research that platelets offer, not only for stress studies but also for psychiatric and psychopharmacological investigations. This section is not an exhaustive review of neurotransmitters and psychiatry. Rather, all we are trying to communicate is the intellectual ferment concerning studies of platelet neurotransmitters and psychiatry.
Platelets and 5-HT
During the past years, several important studies have discussed the association between platelet 5-HT, psychopathology, and psychopharmacology. 5-HT has been considered an important element in understanding mood disorders, autism, and attention deficit disorder (33–35). In addition, platelet 5-HT has served as a crucial research tool in psychopharmacology because of its variety of membrane receptors and different physiological interactions. Various 5-HT receptors are involved in vasodilation, vasoconstriction, and platelet aggregation (36, 37).
Investigators have used different labels and techniques to examine platelet 5-HT in psychiatry. Among the most common are measurement of platelet receptor density and measurement of platelet 5-HT uptake. Some studies have reported increased platelet 5-HT-2A receptor density (B-Max) in unipolar depression. Some have reported a positive correlation between a platelet’s 5-HT-2A receptor density and the Hamilton scale suicidality item (4, 38). Recent studies have correlated the increased density of platelet 5-HT-2A receptors with the loss of impulse control in suicide attempts (39). Although suicidal behavior is correlated with low levels of 5-HT metabolites in cerebrospinal fluid, future research should study the relationship between levels of 5-HT, transporter mechanism, and sensitivity of the platelet 5-HT receptor (40). Le Quan-Bui et al. (18) also examined platelet 5-HT and its association with depression. They studied 11 men and 19 women diagnosed with major depression. In contrast to other studies, both male and female patients had significantly lower levels of 5-HT than subjects in the control group. Another interesting finding was that platelet 5-HT levels were significantly higher in women than in men in the control group. The author postulated that this gender difference in the control group may have been related to a stimulatory effect of estradiol on 5-HT uptake in platelets.
Platelet 5-HT uptake has also been studied in other psychiatric disorders. Meltzer et al. (41) found decreased levels of serotonin uptake in some patients with bipolar depression. The authors suggested that platelet 5-HT uptake could shift in some bipolar patients as they move from one clinical state to the other. He suggested that a longitudinal study with rapid-cycling patients might help to clarify these findings. Modai and Zemishlany (33) found a decreased amount of active transported 5-HT in the platelets of patients with major depression, a high rate of 5-HT platelet uptake in patients with bipolar depression, and normal 5-HT uptake in bipolar manic and euthymic patients. Several studies have reported the relationship between increased platelet membrane enzymes and mood disorders (42–44). Future studies may look at the clinical correlation of these molecular abnormalities with the different types of affective disorders and how platelets might be useful in confirming these associations.
Platelet 5-HT has also been an important component in schizophrenia research. Giret et al. (45) reported that patients with paranoid schizophrenia had increased platelet 5-HT uptake. In another study, Freedman et al. (46) reported that platelet 5-HT concentrations varied among patients with different types of schizophrenia: Individuals with chronic undifferentiated schizophrenia had higher platelet 5-HT levels than individuals with chronic paranoid schizophrenia. Stahl et al. (47) also found elevated platelet 5-HT concentrations in patients with chronic paranoid schizophrenia. Future research might clarify the clinical significance of these findings.
Platelet 5-HT has been associated with certain anxiety disorders. Pecknold et al. (48) found increased platelet 5-HT uptake in patients with panic disorder and concurrent major depression. Platelet 5-HT has also been implicated as reflecting mood, arousal, sleep, and intrusive thoughts seen in PTSD and obsessions, but the findings are inconsistent (49).
Blood platelet uptake of 5-HT has also been studied in alcohol dependence. Kent et al. (50) found decreased 5-HT uptake in this group. They concluded that these findings reflected a dysfunction in the neuronal transport of 5-HT, because altered blood platelet 5-HT uptake may reflect neuronal 5-HT uptake. More recently, it has been postulated that low levels of platelet adenyl cyclase are correlated with certain diagnostic criteria for alcoholism (51). This could be a significant contribution for genetic studies, using platelet enzyme abnormalities as potential markers for predisposition to alcohol dependence, although these changes are not specific to any diagnostic category.
After reading the descriptions of all these studies, it is important to understand the clinical and practical relevance of the different associations between platelet 5-HT and the described psychopathology. Future psychopharmacological research will be enhanced by using platelet 5-HT receptors as probes.
Psychopharmacological research has focused extensively on platelet 5-HT receptors, specifically the 2A type. These receptors have been important in understanding the pharmacological properties of SSRIs in certain psychiatric manifestations. Current studies have described the molecular aspects of the different platelet 5-HT receptors and their association with psychopharmacological probes. Using reverse transcriptase polymerase chain reaction and the appropriate primers, some investigators have found identical splicing mRNA sequences between human platelet 5-HT-2A receptor and human brain 5-HT-2A receptor. The authors concluded that human platelet 5-HT-2A receptor is a valid peripheral model of the brain 5-HT-2A receptor (52). On the basis of these findings, it may be possible to correlate platelet 5-HT receptor abnormalities with central nervous system 5-HT receptor abnormalities in patients with depression or other mental disorders. New studies on personality disorders, such as the borderline type, used platelet 5-HT receptor probes to elucidate a better psychopharmacological treatment approach (53). The platelet 5-HT receptor was useful in demonstrating the positive response that patients with borderline personality disorder can show when treated with SSRIs.
Because SSRIs block 5-HT uptake, it might be expected that they prolong bleeding time. There have been some reports associating SSRIs with bleeding manifestations, such as ecchymoses, epistaxis, and bleeding internal hemorrhoids (54–56). On the other hand, other reports document cases of thrombosis in patients with previous vascular disease receiving SSRIs (37). Because few cases have been reported, future research should be focused on platelet aggregation properties associated with the use of SSRIs and the different implications of SSRI treatment in patients with known vascular disease.
Other neurotransmitters and medications have been associated with 5-HT and platelet activity in some mental disorders. Giret et al. (45) found decreased platelet 5-HT uptake and decreased platelet MAO activity in patients with major depression. In another study, patients receiving lithium therapy had increased platelet activity; lithium increases platelet 5-HT type 2 receptor sensitivity, helping to restore the abnormal 5-HT transport rate in patients with mood disorders (57).
Platelet Function and -2 Adrenoceptors
As described in the previous section, platelet function is affected by stress and catecholamines. Stimulation of platelets’ -2 receptors promotes aggregation. Epinephrine and norepinephrine are nonselective -2 agonists (2). Increased plasma epinephrine levels have been described and related to psychological stress (public speaking) (58–61). Freedman et al. (62) studied 30 first-year medical students during final examination week and 1 month earlier. Their findings were that platelet -2 receptor–binding affinity was significantly reduced during final examination week and that plasma catecholamine levels were increased.
Platelet -2 receptors have been major research allies in helping us understand various neuropsychiatric conditions. In mood disorders, Garcia-Sevilla et al. (19) found increased numbers of platelet -2 adrenergic receptors in a group of depressed patients. They concluded that patients with symptoms of depression have increased -2 adrenergic sensitivity. In a similar study, Carstens et al. (63) found increased platelet -2 receptor density in 26 patients with major depression. They postulated that platelet -2 receptors can reflect central nervous system noradrenergic activity. This alteration in the noradrenergic system associated with depressive symptoms would be reflected in decreased norepinephrine release and an increased number of high-affinity -2 receptors on noradrenergic nerve terminals.
PTSD has been correlated with certain biochemical dysfunctions associated with platelet -2 adrenoceptor. In 1990, Lerer et al. (64) studied 19 men with PTSD. The authors found lower platelet adenylate cyclase activity (which is related to the -2 receptor activity) in these patients. In another study, Lerer et al. (65) suggested that forskolin-stimulated adenylate cyclase could be a biological marker of PTSD. In addition, they hypothesized that PTSD could be associated with certain dysfunction in cyclic AMP signal transduction, found at the level of the adenylate cyclase–-2 receptor complex, although other studies have not shown any correlation at this level (66). These findings were also correlated with the time of exposure to the traumatic event. Future research might look at the association between platelet -2 receptor activity, biochemical changes, and time exposed to a traumatic event.
Platelet -2 receptors have been measured in psychopharmacological research on antidepressants. Depressed patients have an increased sensitivity of the platelet -2 receptor. Long-term treatment with tricyclic antidepressants can decrease the number of platelet -2 adrenoceptors (63). In fact, Garcia-Sevilla et al. (19) reported that tricyclic antidepressants downregulated the expression of platelet -2 adrenoceptors as a consequence of blocking norepinephrine uptake. Numerous studies have used radiolabeled imipramine-binding affinity in platelets to predict the response to tricyclic antidepressant in patients with depression, agoraphobia, and panic attacks (67–69).
What does this really mean in terms of treating mental disturbances? Basically, we have an important tool that can be use to determine diverse mechanisms of action of psychiatric medications. Understanding how different platelet receptors and enzymes work in the described psychopathologies might help to improve the advances in psychopharmacological research. This will be reflected in possibly fewer side effects and more precise interventions at the level of the biochemical disturbance of the mental disorder.
Platelets and MAO Activity
MAO is an important enzyme that regulates the degradation of catecholamines and 5-HT. Platelet MAO activity has been used to assess the activity of this enzyme (70). Furthermore, some neuropsychiatric disorders have been linked to MAO activity. Several studies have used platelet MAO activity to understand their biochemical correlates.
Some personality traits found in patients diagnosed with major depression have been found to be related to MAO activity. Perris et al. (71) studied 143 depressed patients using the Karolinska Scale of Personality and found high rates of verbal aggression, irritability, and monotony avoidance. They did not find any significant correlation between MAO activity and these personality traits in men, although they did find a significant negative correlation in women. They concluded that nonspecific vulnerability characterized by low MAO levels might be implicated in the shaping of certain personality conditions. In addition, the investigators remarked that this vulnerability has been described in patients with alcoholism, drug abuse, and suicidal behavior.
Schildkraut et al. (20) studied patients with different types of schizophrenia. The authors measured platelet MAO levels in patients with schizophrenia and schizoaffective disorder. They measured platelet MAO activity, quantifying the amount of deaminated radiolabeled tryptamine (C14-tryptamine) produced. In their study, increased platelet MAO activity was found in patients with schizoaffective disorder. They also detected reduced platelet MAO activity in patients with chronic schizophrenia in whom auditory hallucinations often occurred in conjunction with paranoid features.
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COMMENTS AND IMPLICATIONS FOR FUTURE RESEARCH |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Another interesting field for research could involve studying the correlation between platelet function and environmental and social stressors, gender, and ethnicity. These questions could be addressed not only in psychosomatic research but also in psychopharmacological or neuropsychiatric research. Apart from these human studies, it is crucial to expand animal experimental research to elucidate the association between different stressors and platelet function.
Because of the rich diversity of components available in the platelet membrane and cytoplasm, platelets offer a unique vantage point for studying virtually every psychiatric disorder. Once again, these findings need to be correlated with clinical observations to find an objective application for all of these research suggestions. Using these approaches, it would be easier to clarify the complex interactions between certain psychiatric medications, their mechanisms of action, and how the brain responds to those pharmacological stimuli.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Stress and platelet activation have direct implications for CAD, especially thrombosis. Psychological factors, including certain personality traits, seem to influence platelet function. It is important to emphasize the significance of multidisciplinary research to provide a better understanding of the different implications of stress and platelet physiology in the general population. Considering that platelets provide a window into the central nervous system, they can be our allies in future studies of the different physiological responses to stress and biochemical changes in patients with known psychiatric problems.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Received for publication October 9, 1998.
Revision received September 7, 1999.
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TOPABSTRACTINTRODUCTIONOVERVIEW OF PLATELET ANATOMY...ADHESIONACTIVATIONAGGREGATIONHISTORICAL BACKGROUND OF...METHODS TO ASSESS PLATELET...STRESSORS AND PLATELET FUNCTIONSTUDIES ABOUT PLATELETS AND...COMMENTS AND IMPLICATIONS FOR...CONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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