β-Thromboglobulin, Platelet Production Time and Platelet Function in Vascular Disease

Plasma beta-thromboglobulin (beta TG) levels were measured in 103 healthy controls and 112 patients suffering from either peripheral vascular disease (PVD), or cerebrovascular disease (CVD) or deep vein thrombosis (DVT). Plasma beta TG was significantly elevated in 46 PVD patients and 24 recent DVT patients compared to controls, but did not differ significantly in 18 chronic DVT and 24 old CVD patients. In addition, heparin neutralizing activity (HNA) and platelet aggregation induced by adenosine diphosphate, 1-epinephrine and thrombin were compared in 33 out of the 46 PVD patients to 33 controls. The mean HNA was significantly shorter in the PVD patients than in controls. The rate and extent of platelet aggregation were increased in PVD patients compared to controls, but the difference was not statistically significant. Platelet production time (PPT) was measured in 20 controls, 35 PVD patients, nine chronic DVT and 12 chronic CVD patients; significantly shorter PPT was only observed in 14 patients with advanced PVD compared to controls, suggesting increased platelet consumption in these patients. All four assays (plasma beta TG, HNA, platelet aggregation and PPT) were performed in 25 patients; no correlation between the four tests was found in these patients suggesting that the tests were measuring various aspects of platelet function. These results suggest that in vivo platelet consumption as well as platelet aggregation and 'release reaction' are presumably enhanced in PVD and recent DVT patients and that plasma beta TG and PPT assays may be better and more specific indicators of in vivo platelet activation than in vitro platelet aggregation test.     

Platelet proteins (beta-TG and PF4) in atherosclerosis and related diseases

The mean plasma concentrations of beta-TG and PF4 were significantly elevated in patients with diabetes mellitus, peripheral vascular disease and coronary artery disease reflecting enhanced in vivo platelet activity in some of these patients. No correlations could be observed between state of metabolic control and concentrations of platelet specific proteins in diabetic subjects. High mean beta-TG levels were noticed in diabetic patients with increasing severity of retinopathy. Raised beta-TG values decreased significantly after two weeks of treatment with dipyridamole in 10 type-I diabetics. In patients with peripheral vascular disease the WU-test, but not the ADP- or collagen induced platelet aggregation was significantly different between patients and controls, but there were no correlations between the mentioned platelet function tests.     

Platelet aggregation in portal cirrhosis.

Primary and secondary platelet aggregation in response to adenosine diphosphate was studied in 24 patients with portal (La?nnec) cirrhosis and compared with platelet aggregation in 14 normal subjects. In 12 patients with cirrhosis, platelet aggregation was diminished when compared to controls. Of the 12 patients with impaired aggregation, 6 had elevated levels of fibrinogen-fibrin degradation products (FDPs), 11 had thrombocytopenia, 10 had shortened euglobulin lysis times, 11 had prolonged bleeding times, 4 had hypofibrinogenemia, and all had prolonged thrombin clotting times. The data suggest that elevated levels of serum FDPs do not explain fully the impairment of platelet aggregation or the prolongation of the thrombin clotting time that was noted in patients with advanced liver disease. A possible explanation for the prolongation of the thrombin clotting time is the presence of "altered" plasma fibrinogen.     

Evaluation of platelet function in aspirin treated patients with CAD

Background: Studies of platelet function in the acute coronary syndrome (ACS) have revealed both increased and unchanged platelet activation. To obtain a better understanding of platelet function in coronary artery disease in the setting of aspirin therapy, we performed platelet functional testing in patients with ACS and compared results to patients without CAD. Methods: We measured platelet aggregation and activation in response to ADP and epinephrine in 80 age and gender matched hospitalized patients (40 with ACS, 40 with non-cardiac chest pain (NCCP)). All subjects received ASA (81–325 mg). Platelet aggregation was performed using standard light transmission in platelet-rich plasma and activation was measured via flow cytometric analyses. We also studied platelet function under high shear rates measured by the platelet function analyzer (PFA-100). Results: ASA effect was found to be present in all subjects by blunted platelet aggregation in response to arachidonic acid. Patients with ACS showed significantly higher levels of platelet aggregation to epinephrine compared to patients with NCCP (p = 0.001). Other measures of platelet function including ADP aggregation, Pselectin, activated glycoprotein IIb/IIIa expression, and PFA-100 were unchanged between the two groups. Conclusions: We have found conflicting results of platelet functional testing in ACS. Specifically aspirin therapy in patients with ACS is effective in suppressing the platelet release response and is effective in the partial suppression of platelet aggregation; however, it appears that ACS patients have increased platelet aggregation to adrenergic stimuli when compared to age and gender matched controls without CAD despite the use of aspirin. In some studies, because ACS patients have an accentuated response to adrenergic stimuli this might be interpreted as aspirin resistance. Our study suggests that depending on the assay used to determine aspirin resistance, not all patients with this label are resistant to the biological effects of aspirin but they may have higher than normal baseline platelet sensitivity to adrenergic stimuli. This research was supported by grant K23HL67066 from the National Institute of Health.     

Platelet aggregation and blood rheology in severe sepsis/septic shock: relation to the Sepsis-related Organ Failure Assessment (SOFA) score

Abnormalities in blood rheology and platelet dysfunction might play a role in the pathogenesis of multiple organ failure in septic patients by reducing microvascular blood flow. To determine whether alterations in blood rheology and in platelet function are related to the severity of organ dysfunction, we prospectively studied plasma fibrinogen, red cell aggregation, plasma viscosity, hematocrit, whole blood viscosity and platelet aggregation in relation to the Sepsis-related Organ Failure Assessment (SOFA) score in 34 consecutive patients with severe sepsis/septic shock. We found that patients had higher plasma fibrinogen, red cell aggregation and plasma viscosity (p < 0.01), but lower hematocrit, whole blood viscosity and ADP-induced platelet aggregation than controls (p < 0.01). Platelet aggregation (p < 0.01), but not other rheological variables, were inversely related to the SOFA score. Only platelet count was linked to poor clinical outcome (p < 0.05). We conclude that blood rheology and platelet function are severely altered in patients with severe sepsis/septic shock. Our findings suggest progressive platelet dysfunction with advancing severity of the disease. Platelet dysfunction might play a more important role in the pathogenesis of the multi organ dysfunction syndrome than abnormalities in blood rheology.     

Sulfonylureas and platelet function

The platelets of many patients with diabetes mellitus are abnormally sensitive to the effects of aggregatory agents in vitro. It has been proposed that this abnormal platelet function may play a role in the pathogenesis of vascular disease in diabetic subjects. We have investigated the effects of six weeks of treatment with the sulfonylurea agents gliclazide and glyburide on platelet aggregation in 10 noninsulin-dependent diabetic subjects. During treatment with diet alone, the platelets of these patients were abnormally sensitive to aggregation in response to 1 microM of adenosine diphosphate, as compared with those in normal controls. Treatment with both drugs normalized ADP-induced aggregation in these patients. Treatment with glyburide significantly reduced aggregation in response to 10 microM of epinephrine and collagen at 750 microgram/ml. The alteration in platelet function did not correlate with the improvement in plasma glucose concentration, thus suggesting that this may be an effect of the drug. Although one must be cautious in extrapolating these in vitro findings to the clinical situation, this alteration in platelet aggregatory function may be of importance in the prevention of vascular disease in diabetic subjects.     

A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy.

BACKGROUND: Platelet function may be abnormal in patients with atrial fibrillation (AF) and could be related to abnormal thrombogenesis. The aim of this cross-sectional study was to investigate new aspects of platelet biology in AF, predominantly focusing on platelet activation and the effects of concomitant antiplatelet and anticoagulant therapy. PATIENTS AND METHODS: The study group of 238 patients were (i). 93 patients on no antithrombotic therapy, (ii). 60 patients taking 75-325 mg aspirin/day, and (iii). 85 patients on dose-adjusted warfarin (International Normalised Ratio [INR] range 2.0-3.0). Results were compared with those from 50 age- and sex-matched normal subjects. Platelet markers (plasma beta-thromboglobulin, soluble glycoprotein V [both ELISA]), coagulation markers (fibrin D-dimer [ELISA] and fibrinogen [Clauss]), and platelet aggregation in response to standard platelet agonists were studied. RESULTS: beta-thromboglobulin (P=0.01), soluble glycoprotein V (P<0.001) and fibrin D-dimer (P=0.002) were higher in untreated AF patients compared to healthy controls. AF patients on warfarin had lower fibrin D-dimer (P<0.001) when compared to AF patients on no therapy. Plasma fibrinogen and platelet aggregation was no different between patients with AF and healthy controls. Aspirin use was associated with reduced platelet aggregation response to epinephrine (P=0.01), whilst patients established on warfarin had significantly lower plasma fibrin D-dimer levels.CONCLUSION: AF patients exhibit changes in plasma markers of platelet function but no significant abnormalities of platelet aggregation. However, treatment with warfarin or aspirin failed to demonstrate any significant benefit on platelet activation, although warfarin use was associated with reduced thrombogenesis (fibrin D-dimer). We suggest that platelet activation may not play an important role in the pathogenesis of thromboembolism in AF.     

Mechanisms underlying increased platelet reactivity in patients with peripheral arterial disease. Preliminary results.

BACKGROUND: In peripheral arterial disease (PAD) atherosclerosis is disseminated and thrombosis risk is high. We have not only shown the platelets of PAD patients to by hyperreactive and aspirin resistant, but have recently verified them to be hypersensitive to heparin as well. In the present study we have begun to clarify the mechanisms underlying these regularly observed clinical findings. METHODS: Platelet function was tested with conventional, ADP-primed aggregation and with stagnation point flow adhesio-aggregometry (SPAA). SPAA permits real time, quantitative assessment of platelet adhesion and aggregation under biologically relevant flow conditions. The platelets from a female patient with congenital afibrinogenemia, were analyzed before and after intravenous fibrinogen substitution. In 14 PAD patients and 14 controls, platelet reactivity was assessed before and after incubation with the two platelet membrane glycoprotein (GP)-IIb/IIIa inhibitors Ro 43-8857 and 7E3. Lastly, experiments were performed before and after addition of plasma aliquots stemming from 4 PAD patients to platelet rich plasma and to solutions of gel-filtered platelets (GFP) stemming from 4 healthy volunteers. Before fibrinogen substitution, the platelets of the afibrinogenemic patient were unable to adhere in the SPAA-system and maximal ADP-primed aggregability was below 10%. After substitution, normal platelet adhesion was measured and primed aggregation increased three-fold. Mean baseline adhesion in the patient collective was twice that compared to controls (p<0.001). SPAA-measured, spontaneous aggregation was observed in ten patients and in none of the controls (p<0.001). RESULTS: Both SPAA-measured and primed aggregation were abolished at the lowest substrate concentrations (0.1 microM Ro 43-8857, 1 microg/ml 7E3). At these concentrations adhesion was reduced by 65% and 40% (respectively) in patients, and by 55% and 25% in controls. Total abolition of adhesion in both groups was seen with 0.5 microM Ro 43-8857 and 10 microg/ml 7E3. Platelet response to inhibitory agent was similar in patients and controls, as were the differences in dose-response between aggregation and adhesion. Upon addition of patient plasma to volunteer PRP, the platelets of all 4 healthy individuals aggregated spontaneously and the mean adhesivity in the group rose three-fold. The overall ability of the GFP to adhere when re-added to their own plasma was decreased, whereas, in the presence of patient plasma, adhesion increased significantly. CONCLUSIONS: On the basis of these findings we conclude that: 1) SPAA measures and quantifies platelet interactions with both fluid-phase (aggregation) and immobilized (adhesion) fibrinogen, 2) these reactions are mediated by the GP, IIb/IIIa receptor complex 3) the binding affinity, metabolic pathways and signal transduction underlying platelet adhesion differ from those involved in aggregation (possibly reflecting their varying roles in hemostasis), 4) the functionally normal platelets of patients with PAD are primed in vivo by a circulating plasma constituent, which leads to enhanced recruitment of activated GP, IIb/IIIa onto the platelet surface and, thereby, to an overall increase in reactivity.     

Platelet thrombospondin and glycoprotein IV abnormalities in patients with essential thrombocythemia: effect of alpha-interferon treatment.

Platelet aggregability and some biochemical parameters were evaluated in seven patients with essential thrombocythemia (ET) compared with seven patients with secondary thrombocytosis (ST). Defective platelet aggregation with one or more agonists was seen in five patients with ET whereas aggregation was increased in two other patients. In addition, three patients with ET demonstrated spontaneous platelet aggregation in citrated plasma. This was associated with increased level of thrombospondin (TSP) in the plasma membrane. Interestingly, the presence of a proteolyzed 160 kDa form of TSP was detected in all patients with ET, whereas it was never found in patients with ST. Furthermore, three patients with ET demonstrated increased levels of platelet surface glycoprotein IV (GP IV), the putative receptor for TSP in the plasma membrane. In two of these patients, this correlated with increased surface expression of TSP and spontaneous platelet aggregation. The results suggest a possible link between the increased number of plasma membrane GP IV molecules, the spontaneous expression of TSP on the platelet surface and platelet hyperaggregability in some ET patients. The levels of plasma membrane GP IV and platelet surface-associated TSP tended to be normalized during alpha-interferon treatment, whereas the presence of an altered form of TSP persisted. This last parameter might be of practical usefulness in the characterization of the disease, permitting a clear distinction from ST.     

Attenuated platelet sensitivity to collagen in patients with neurofibromatosis type 1

Haemostatis has not previously been studied in patients with neurofibromatosis 1 (NF-1), despite case reports of an association with von Willebrand disease and reported excessive bleeding in those undergoing surgery for neurofibromas. Platelets from NF-1 patients ( n = 28) were tested for aggregation and ATP release with agonists including ADP, arachidonic acid, thrombin and collagen. Mepacrine staining of platelets and three different assays for von Willebrand factor (VWF) were also performed.
In response to collagen as the platelet agonist, tested at both 2 and 1 μg/ml, NF-1 patients had an attenuated rate of aggregation ( P < 0.007), aggregation lag phase ( P < 0.005) and ATP release ( P < 0.045), as well as requiring higher collagen concentrations to attain threshold aggregation response ( P = 0.041). Normal platelets resuspended in selected NF-1 plasma exhibited significantly reduced platelet aggregation and release compared to controls, which was not corrected by mixing 1:1 with normal plasma. Collagen binding activity was reduced in NF-1 patients compared with controls (127% v 161%, P = 0.05).
As a group, patients with NF-1 display defective platelet function characterized by in vitro evidence of impaired responsiveness to collagen. It is suggested that a plasma factor, present in a significant proportion of NF-1 patients, may interfere with the ability of collagen to interact with other proteins such as von Willebrand factor and the platelet collagen receptor.     

Presence of a platelet aggregating factor in the plasma of patients with thrombotic thrombocytopenic purpura (TTP) and its inhibition by normal plasma

Three patients with thrombotic thrombocytopenic purpura (TTP) were treated by infusion of normal plasma with dramatic responses. The plasmas collected from these patients during relapse induced in vitro aggregation of washed platelets from both normal donors and the patients during remission. The platelet aggregating factor was not dialyzable or adsorbable by Al(OH)3 and was not inactivated by diisopropylfluorophosphate, hirudin, or heparin in the presence of normal amounts of antithrombin. In contrast to the platelet aggregation induced by platelet isoantibody, the platelet aggregating activity of TTP plasma diminished as a function of time when it was incubated with normal plasma at 37 degrees C. These observations suggest that at least some instances of TTP appear to be due to deficiency of a plasma inhibitor to counteract a platelet aggregating factor demonstrated to be present in the plasma of these patients.     

Altered platelet function in cirrhosis of the liver: impairment of inositol lipid and arachidonic acid metabolism in response to agonists

Hemorrhagic disorders are common in patients with liver cirrhosis and result from several factors including impaired platelet function. We evaluated platelet aggregation and arachidonic acid metabolism in response to standard agonists in platelet-rich plasma from 12 cirrhotic patients with mild impairment of liver function (Child A), 12 patients with severe liver dysfunction (Child B and C) and 12 healthy subjects. Platelet aggregation and thromboxane A2 production were consistently reduced in patients with severe liver impairment. To determine whether the platelet dysfunction is due to an intrinsic platelet defect or a circulating inhibitor, we measured platelet aggregation and thromboxane A2 synthesis on washed platelets in healthy subjects and in Child B and C patients. The aggregating response of washed platelets in response to thrombin, collagen and arachidonic acid was markedly reduced, suggesting an intrinsic platelet defect. The biochemical events underlying platelet aggregation were investigated by prelabeling platelets with [1-14C]arachidonic acid. Thrombin-induced activation of phospholipase C (measured as the release of [1-14C]phosphatidic acid) and phospholipase A2 (measured as the release of [1-14C]arachidonic acid and its metabolites) was greatly impaired in platelets from patients with severe liver impairment. We conclude that in advanced cirrhosis there is a severe reduction in platelet aggregatory response to physiologic agonists due to an intrinsic platelet defect which is related to an impairment of the platelet transmembrane signaling mechanism induced by receptor stimulation.     

Platelet function abnormalities in Gaucher disease patients.

Bleeding manifestations are common in Gaucher disease patients. Although usually attributed to thrombocytopenia, some patients with relatively high platelet counts and normal coagulation tests have hemorrhagic phenomena. To investigate whether perturbed platelet function could explain these bleeding manifestations we performed platelet aggregation tests on 32 type I adult Gaucher patients who were not severely thrombocytopenic (platelet counts >50 x 10(9)/L). Seven patients (22%) had abnormal platelet aggregation. In five, platelet aggregation was markedly reduced in response to collagen and ADP and virtually absent in response to epinephrine, whereas two patients had isolated severely impaired epinephrine-induced aggregation. In one patient platelet aggregation markedly improved following one year of enzyme replacement therapy. Incubating normal platelets with high concentrations of glucocerebroside did not impair their ability to aggregate, suggesting that plasma glucocerebroside does not directly interfere with platelet function. Platelet dysfunction is a hitherto unrecognised, relatively common cause of excessive bleeding in Gaucher patients.     

Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity

Cirrhosis of the liver is frequently accompanied by complex alterations in the hemostatic system, resulting in a bleeding tendency. Although many hemostatic changes in liver disease promote bleeding, compensatory mechanisms also are found, including high levels of the platelet adhesive protein von Willebrand Factor (VWF). However, conflicting reports on the functional properties of VWF in cirrhosis have appeared in literature. We have measured a panel of VWF parameters in plasma from patients with cirrhosis of varying severity and causes. Furthermore, we assessed the contribution of VWF to platelet adhesion, by measuring the ability of plasma from patients with cirrhosis to support adhesion of normal or patient platelets under flow conditions. VWF antigen levels were strongly increased in patients with cirrhosis. In contrast, the relative collagen binding activity, as well as the relative ristocetin cofactor activity, was significantly lower in patients as compared with controls, indicating loss of function. Accordingly, patients had a reduced fraction of high-molecular-weight VWF multimers. Both strongly elevated and reduced activity and antigen levels of the VWF cleaving protease ADAMTS13 were found in individual patients. Adhesion of either normal or patient platelets to a collagen surface was substantially increased when these platelets were resuspended in plasma of patients with cirrhosis, as compared with control plasma. In conclusion, highly elevated levels of VWF in patients with cirrhosis contribute to the induction of primary hemostasis despite reduced functional properties of the molecule. This phenomenon might compensate for defects in platelet number and function in patients with cirrhosis.     

Effect of propranolol on platelet function.

Excessive reactivity of blood platelets may contribute to atherosclerotic vascular disease. Hence drugs which alter platelet function may be protective. Prompted by findings that propranolol therapy normalized hyperactive platelet aggregation in patients with coronary artery disease, we studied propranolol in vitro to assess its action on platelets. At concentrations similar to those achieved in vivo (0.1-1 muM), propranolol raised the thresholds for aggregation of some normal paltelets by adenosine diphosphate (ADP). At higher concentrations (10-50 muM), propranolol abolished the second wave of platelet aggregation induced by ADP and epinephrine, and inhibited aggregation induced by collagen, thrombin, and the ionophore A23187. Propanolol blocked the release of 14C-serotonin from platelets, inhibited platelet adhesion to collagen, and interfered with clot retraction. Propranolol blocked ionophore-induced uptake of 45Ca by platelets. Inhibition appeared unrelated to beta-adrenergic blockage, as d(+) propranolol (which lacks beta-blocking activity) was equipotent with 1(-) propranolol. Moreover, practolol, a beta-blockading drug which is nonlipophilic, did not inhibit platelet function. These studies suggested that propranolol, like local anesthetics, decreased platelet responsiveness by a direct action on the platelet membrane, possibly by interfering with calcium availability. Modulation of platelet function by propranolol may occur at concentrations achieved at usual clinical doses of the drug.     

Platelet function and coagulation in patients with Wilson disease.

Sixteen patients with Wilson disease (hepatolenticular degeneration) were studied from the hemostatic point of view, particularly with regard to platelet function. Five of the patients had a mild bleeding tendency that was characterized by easy bruising. Moderate thrombocytopenia was observed in three of the five bleeders and in two of the others. One bleeder was thrombocytotic and hyperfibrinogenemic. Bleeding times, platelet retention and prothrombin consumption were abnormal rarely. However, 15 of the 16 patients had some abnormality of platelet aggregation: one when adenosine diphosphate was added to platelet rich plasma, three when epinephrine was added, and the remainder when collagen was added. The collagen abnormalities were delayed or absent aggregation (five patients, four of whom were bleeders) and absence of a change of shape (12 of the 16 patients). Platelet aggregation was completely normal in only one patient.     

Differentiation of patients with subtype IIb-like von Willebrand''s disease by means of perfusion experiments with reconstituted blood

Four unrelated patients with a bleeding diathesis (bleeding time longer than 30 min), some spontaneous platelet aggregation, thrombocytopenia and large platelets, had decreased levels of factor VIII-von Willebrand factor (FVIII-VWF) related properties and impaired platelet adherence to human artery subendothelium. The largest multimers of plasma FVIII-VWF were absent and enhanced ristocetin induced platelet aggregation in platelet-rich plasma was observed. 'Pseudo-von Willebrand's disease' was excluded, because FVIII-VWF from normal subjects did not initiate platelet aggregation. Perfusion studies with reconstituted blood, consisting of respectively patient platelets in normal plasma or normal platelets in patient plasma, yielded evidence for an intrinsic platelet abnormality in two out of the four patients and a plasma defect in the other two patients. Similar experiments with platelets and plasma from four patients with von Willebrand's disease (VWD) subtype I and four patients with VWD subtype IIa showed that the impaired platelet adherence in blood from these patients was caused by a plasma defect. These experiments indicate that patients with laboratory findings in many respects similar to those originally reported for patients with VWD subtype IIb may represent a heterogeneous group of individuals. The data derived from our study imply that perfusion experiments with reconstituted blood offer a new approach in characterization of these patients, which may be more relevant for the treatment of the patients than characterization by ristocetin induced adsorption of FVIII-VWF to platelets.     

Aggregation of Human Platelets by Bovine Platelet Fibrinogen

Aggregation of human platelets by addition of purified bovine platelet fibrinogen is described. Bovine plasma fibrinogen showed the same but much weaker effect. Human fibrinogen produced no aggregation. No absolute requirement for divalent cations or plasma proteins could be demonstrated. The aggregation of washed platelets appeared monophasic whereas in platelet-rich plasma it was usually biphasic. The use of inhibitors of ADP-induced platelet aggregation, inhibition of intracellular ATP-production, enzyme-catalyzed removal of ADP, and direct determinations of ADP in the medium showed the second phase to be mediated by ADP released from the platelets whereas the first phase was nearly independant of ADP. While the ability of platelet fibrinogen to aggregate platelets and to clot with thrombin were otherwise intimately interconnected, some aggregation activity remained after heat-denaturation of the platelet fibrinogen.     

Investigations on platelet function in diabetes mellitus

Investigations on the platelet function in diabetes mellitus were performed on 28 patients with insulin-dependent diabetes and in 33 healthy controls of similar age. In the diabetic patients it was possible to induce 50% of maximal aggregation by lower concentrations of adenosine diphosphate or arachidonic acid than in the controls. In the presence of N-ethyl maleimide, platelets from diabetic patients produced significantly more malondialdehyde than those from normal controls. After addition of arachidonic acid the platelets from the diabetic patients also synthesized more thromboxane B2. This synthesis of thromboxane was inversely correlated to the minimal concentration of arachidonic acid necessary to induce 50% platelet aggregation. Circulating platelet aggregates were more common in the diabetic patients than in the controls. Plasma levels of beta-thromboglobulin and platelet factor 4 were raised in parallel in the diabetic patients and correlated with the increased production of thromboxane B2 by the platelets from the same patients. Platelets from patients with diabetes thus demonstrated signs of hyperreactivity both in vivo and in vitro. This may be of clinical importance for the development of vascular complications in this disease.     

Is chronic fatigue syndrome associated with platelet activation?

Chronic fatigue syndrome (CFS) is a debilitating condition that has no known aetiology or pathophysiology. Recent investigations by other workers have suggested that individuals with CFS may have a hypercoagulable state. This study investigated various aspects of platelet activation and function in 17 patients with CFS and in 16 age-matched and sex-matched healthy controls. Platelet aggregation, platelet volume and coagulation tests were performed. Platelet aggregation was investigated by means of the photometric changes using citrated platelet-rich plasma, whole blood aggregation was calculated as the percentage fall in single platelet counts and the coagulation tests were performed on an automatic microcentrifugal analyser.A trend was observed for the patients to have lower aggregation results and a reduced mean platelet volume. However, this only reached statistical significance for one result; the rate of the aggregation slope by 1.0 microg/ml collagen [CFS patients, 18 (9-28) versus controls, 32.5 (19-36); Mann-Whitney U test, P = 0.029]. No significant differences were found for any of the measurements of coagulation.These results are in contrast to previously reported findings. However, due to the heterogeneous nature of the disease, and the resulting lifestyles of the patients, caution should be taken when comparing one group of patients with another. Nevertheless, we certainly found no evidence of increased platelet activation or of a hypercoagulable state in patients with CFS and, on the basis of these results, anti-platelet or anti-coagulant therapy is not warranted.