Transfusion for hemolysis, elevated liver function tests, and low platelet count in pregnancy.
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Adrenal Cortex Hormones↗
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Platelet aggregation in myotonia.
Platelet function tests were carried out on 21 patients with myotonic dystrophy (MyD) and 7 patients with myotonia congenita (MC) together with 22 healthy subjects. Compared to the controls, the MyD and MC patients showed significantly greater sensitivity to the calcium ionophore A23187 but not to adenosine diphosphate, collagen, ristocetin or adrenaline. In addition, with the MyD patients, a significantly higher concentration of chlorpromazine and lignocaine was required to inhibit aggregation induced by a standard dose of adrenaline. A similar trend was noted with the MC patients but because of the small numbers tested, statistical analysis was not possible. Plasma levels of betathromboglobulin were also significantly higher in MyD patients than in controls. Platelet adenine nucleotide levels were within the normal range in both groups of patients and were not significantly different from those in controls. These preliminary results support the view that there is a defect in calcium metabolism in myotonic dystrophy and suggest that it may be possible to use the blood platelet as a model with which to carry out further studies in this disorder.
Adenosine Diphosphate↗
Antiplatelet therapy in neuroendovascular therapeutics.
Our understanding of the pharmacology of antiplatelet therapy continues to evolve rapidly. Although the existing data are primarily generated in the setting of interventional and preventative cardiology studies, these data may be extrapolated to guide the rational application of these agents in neuroendovascular procedures. Platelet function testing represents an increasingly available and practical method by which to verify the adequacy of therapy and guide clinical decision making. The optimal application of these agents will undoubtedly improve the risk profile of neuroendovascular procedures, increase the success rate of acute stroke intervention, and facilitate more effective secondary stroke prevention.
Adult↗
The pony as an animal model for vascular implants.
This study evaluated the pony as a potentially suitable model for vascular implant research. Healthy, conditioned ponies were randomly assigned to one of three groups: group I, carotid artery autografts (n = 6); group II, e-PTFE carotid interpositional grafts (n = 5); and group III, e-PTFE carotid interpositional grafts plus aspirin (10 mg/kg) and dipyridamole (3.5 mg/kg) drug administration. It was found that autografts remained patent longest (mean = 396.2 days; grafts were still patent at time of writing) followed by group III grafts (157.5 days), with group II grafts remaining patent for the shortest duration (61.1 days), (p less than 0.01). Patency was determined using two-dimensional real-time ultrasonography with Doppler velocimetry and/or arteriography. It was demonstrated that the pony's response to antithrombotic drugs was consistent and comparable to that in other animal models, both with respect to platelet function and affect on patency rate. The combination of the ease of surgical manipulation, drug administration, and platelet function testing, the comparable size of the pony and its heart and blood vessels to that of an adult human, the long life span of ponies, and the patency results of this study have demonstrated that the pony is a valuable animal model for vascular research.
Animals↗
Beraprost sodium-fluindione combination in healthy subjects: pharmacokinetic and pharmacodynamic aspects.
Beraprost sodium (BPS), an orally active PGI2 (prostaglandine 12) analogue possesses vasodilatating and platelet aggregation inhibiting properties. It is being developed in peripheral arterial occlusive disease. As in future clinical practice BPS might be co-prescribed with oral anticoagulants, we investigated its interaction with fluindione, a vitamin K antagonist in healthy subjects in a randomised, double-blind, placebo-controlled, crossover study. Twelve healthy Caucasian male subjects randomly received BPS 40 microg t.i.d. or placebo for 3 days. There was a 7 day wash out between the two treatment periods. On day 3 of each treatment, the subjects ingested concomitantly a single oral dose of 20 mg of fluindione. The main assessment criterion was fluindione's pharmacokinetics. Secondarily, pharmacodynamic measurements of coagulation (prothrombin time, and International Normalised Ratio, INR) and platelet function (in vitro closure time assessed by PFA-100) were performed. Fluindione was assayed by HPLC with UV detection up to 96 h post-drug. No statistical difference could be evidenced on any fluindione pharmacokinetic parameters between BPS and placebo phases: t 1/2 (h): 35.9 (8.2) vs. 34.0 (4.2) [90% CI 105.8 (95.5-116.2)]; T(max) (h): 2.0 (0.5-6.0) vs. 4.0 (0.5-6.0) [90% CI 136.4 (70.7-208.9)]; Cmax (mg/L): 3.1 (0.6) vs. 2.9 (0.5) [90% CI 94.1 (85.8-103.2)]; AUC 0-inf (mg/h/L): 117.0 (31.5) vs. 113.9 (33.8) [90% CI 97.6 (87.5-108.8)]. The studied doses of BPS did not affect platelet function, at least as assessed by the in vitro platelet function testing. Twenty milligrams of fluindione marginally modified the PT ratio and INR, however, no statistically significant difference was found between BPS and placebo phases. In conclusion, a 3 day regimen of BPS 40 microg t.i.d. by oral route does not seem to affect pharmacokinetic parameters of a fluindione 20 mg single dose.
Administration, Oral↗
Platelet cold agglutinins: a flow cytometric analysis.
Spontaneous EDTA-independent cold platelet agglutination is a rare phenomenon that produces pseudothrombocytopenia when blood samples are analyzed in automated cell counters. We report a case of platelet cold agglutinins and an analysis by flow cytometry. A 49 year old woman presented with abnormal vaginal bleed secondary to uterine fibroids. Platelet clumping was observed in blood samples taken in EDTA-, heparin- and citrate-containing tubes. In flow cytometric tests, patient serum agglutinated 16% of normal platelets at 22 degrees C, and 7% of platelets after incubation at 37 degrees C; in contrast, 3% and < 1% of platelets were agglutinated at 22 and 37 degrees C, respectively, after incubation with normal serum. Minimal agglutination (< 10%) was observed with patient serum at a titre of 1:5 or at temperatures > 30 degrees C. After incubation at 4 degrees C, IgM antibody and C3 were increased on the patient's platelets; no significant amount of IgM or C3 was detected on normal platelets. The specificity of the platelet cold agglutinin was determined by competitive inhibition by monoclonal anti-CD41(GPIIbIIIa). Before the addition of monoclonal antibody, patient's serum agglutinated 16% of normal platelets at 22 degrees C; after addition of anti-CD41 only 2% of the platelets were agglutinated. This blocking effect was not observed with anti-CD42. The patient's platelets functioned normally as determined by CD62 and CD63 expression in response to thrombin, normal platelet aggregation in response to collagen, ADP, and ristocetin, and a normal template bleeding time. In summary, platelet agglutination by a platelet cold agglutinin was quantitated by flow cytometry, the responsible antibody was characterized as a low titre IgM with minimal activity > 30 degrees C, and competitive binding studies supported the GPIIbIIIa complex as the binding site for the antibody. Since the antibody did not affect platelet function, we believe that these patients will not suffer complications from their platelet cold agglutinin, but it could pose a problem under circumstances such as cardiac surgery with hypothermia.
Adenosine Diphosphate↗
First chronic platelet glycoprotein IIb/IIIa integrin blockade. A randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions.
BACKGROUND: Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy. METHODS AND RESULTS: Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding. CONCLUSIONS: Xemilofiban, an orally active glycoprotein IIb/ IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.
Adult↗
Antithrombin III activity, von Willebrand factor antigen and platelet function in young diabetic patients treated with multiple insulin injections versus insulin pump treatment.
In a prospective study with cross-over design 20 patients with insulin-dependent diabetes mellitus of more than 2 years duration were treated for 6 months with continuous subcutaneous insulin infusion (CSII) and multiple insulin injections (MII). Metabolic control, platelet aggregability, thromboxane B2 levels in serum and plasma as well as antithrombin III (ATIII) activity and von Willebrand factor antigen were evaluated. A good metabolic control was obtained by both intensified regimens. No difference could be demonstrated between either platelet function tests or serum level of von Willebrand factor antigen during treatment with CSII and MII. However, the plasma level of ATIII activity was significantly higher (P less than 0.01) during MII treatment as compared to CSII treatment. There was no correlation between ATIII activity and daily insulin requirement or serum fructosamine. In conclusion, long-term metabolic control with MII has a favourable effect on ATIII activity in plasma. This may be important for a delay in onset and progression of diabetic vascular complications.
Adult↗
Perioperative platelet transfusion: recommendations of the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSaPS) 2003.
PURPOSE: To present the recommendations of the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSaPS; French Safety Agency for Health Products). METHODS: A panel of experts reviewed and graded the literature on platelet transfusions; recommendations were formulated. MAIN FINDINGS: Threshold platelet counts (PC) for transfusions in the perioperative context have not been clearly defined and should be determined by the existence of hemorrhagic risk factors. In the case of commonly practiced invasive procedures, the recommendation is to transfuse in order to achieve PC > 50,000xmicroL(-1). In the absence of platelet dysfunction, regardless of the type of surgery, the standard hemorrhagic risk threshold for surgery is 50,000xmicroL(-1). It has not been proven that the risk threshold is different according to the type of surgery. For neurosurgery and ophthalmologic surgery involving the posterior segment of the eye, a PC of 100,000xmicroL(-1) is required. For axial regional anesthesia, a PC of 50,000xmicroL(-1) is sufficient for spinal anesthesia; a PC of 80,000xmicroL(-1) has been proposed for epidurals. During massive transfusion, prophylactic platelet infusion cannot be recommended beyond a loss of two blood volumes in less than 24 hr (Professional Consensus). As for the therapeutic transfusion of plasma and/or platelets, as much as possible, platelet deficit should be documented with test results (PC and fibrinogen) before transfusing. In the event of bleeding, platelet transfusion may precede plasma infusion. However, although this recommendation has been the subject of several professional consensus agreements, it is not based on any randomized studies. CONCLUSION: Threshold PC for perioperative transfusions have not been clearly defined and most recommendations are the result of a professional consensus.
Blood Coagulation Disorders↗
[Acquired platelet storage pool deficiency in rheumatoid arthritis].
A 64-year-old woman with a 15-years-history of rheumatoid arthritis developed generalized hemorrhagic diathesis. Routine coagulation tests revealed a slightly diminished platelet count only. Platelet aggregation in vitro induced by ADP, collagen, thrombin, arachidonic acid and ristocetin were reduced. The patient's plasma aggregating activity was significantly diminished which was due to a decrease of the intraplatelet nucleotide pool. The number of mepacrine labelled bodies as well as dense bodies in electron microscopy was below the normal values as well. Moreover, the intraplatelet concentration of cyclooxygenase--malonylodialdehyde (MDA) and lipoxygenase pathway products were lowered. Total platelet immunoglobulin G and M contents were significantly increased. The platelet survival time (in vitro aspirin method) was slightly shortened. Finally the diagnosis of delta-acquired platelet storage pool deficiency (delta-SPD) was established and possibilities of treatment were discussed.
Arthritis, Rheumatoid↗
Comparison of cilazapril and nifedipine retard on ambulatory blood pressure, metabolic, rheological and platelet function in hypertensive patients.
In a 12 week randomised, double-blind study, a total of 31 patients with a sitting DBP of between 95 and 115 mmHg were enrolled for comparison of the antihypertensive, metabolic and antiplatelet effects of the drugs cilazapril and nifedipine retard. A two week placebo treatment was given before either cilazapril (2.5 mg daily) or nifedipine retard (20 mg twice daily) was administered. After four weeks treatment, those patients with a sitting DBP > 90 mmHg were given a doubling of their initial doses for the next six weeks; the others were maintained at their initial doses. All patients received their drugs and reported any adverse effects every other week. Blood was taken for metabolic, rheological and platelet function tests. Ambulatory BP and heart rate were recorded at the start, fourth and tenth weeks of study. At the end of this trial, there was a significant decrease in both SBP and DBP in the cilazapril group (155 +/- 14 to 142 +/- 12 mmHg systolic, P < 0.01; 106 +/- 6 to 95 +/- 5 mmHg diastolic, P < 0.01). In the nifedipine group, there was also a significant decrease in SBP and DBP (161 +/- 18 to 139 +/- 5 mmHg, systolic, P < 0.01; 101 +/- 6 to 88 +/- 9 mmHg diastolic, P < 0.05) but with a significant increase in heart rate (79 +/- 14 to 91 +/- 10 beats/minute, P < 0.05). There were no significant changes in the biochemical or metabolic parameters in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Platelets↗
In vitro testing of fresh and lyophilized reconstituted human and baboon platelets.
BACKGROUND: Studies have been performed on human fresh, liquid-preserved, and cryopreserved platelets (PLTs) to assess PLT-adhesive surface receptors, PLT membrane procoagulant activity, PLT aggregation, and thromboxane production. Lyophilization has been developed as a method to preserve PLTs. This study was performed to evaluate these measurements on human and baboon fresh and lyophilized reconstituted PLTs. STUDY DESIGN AND METHODS: In both human and baboon fresh and lyophilized PLTs, aggregation response and PLT production of thromboxane A2 were measured after stimulation, and PLT surface markers P-selectin, glycoprotein (GP) Ib, GPIIb-IIIa, and factor (F) V were measured before and after stimulation. RESULTS: Fresh PLTs responded to the dual agonists arachidonic acid and adenosine diphosphate (ADP) to aggregate and produce thromboxane A2, and in both the PLT surface markers P-selectin and GPIIb-IIIa increased and GPIb decreased after stimulation. Neither human nor baboon lyophilized reconstituted PLTs aggregated to dual agonists, and neither produced thromboxane A2, increased PLT surface markers P-selectin or GPIIb-IIIa, or decreased PLT GPIb after stimulation. Nevertheless, after recalcification the lyophilized reconstituted PLTs accumulated FV to a significantly greater degree than fresh PLTs. CONCLUSIONS: Lyophilized reconstituted PLTs exhibited modification of the PLT membrane that interfered with aggregation and thromboxane production, prevented increases in PLT P-selectin and GPIIb-IIIa and decreases in GPIb after stimulation, and increased FV accumulation after recalcification. The in vitro data suggest that lyophilized PLTs may have reduced in vivo survival. In vivo studies are needed to determine the survival and function of lyophilized PLTs.
Animals↗
Acquired delta-storage pool deficiency associated with idiopathic myelofibrosis.
A 73-year-old woman complained of easy bruising, as a consequence of prolonged bleeding time despite normal platelet counts. Platelet aggregation profile, mepacrine fluorescence test, flow cytometry and transmission electron microscopy studies led to the diagnosis of delta-storage pool deficiency (SPD) A few months later, she developed hyperleucocytosis with immature granulocytes and erythroblasts. The presence of bone marrow fibrosis and clonal cytogenetic abnormalities led to the diagnosis of idiopathic myelofibrosis (IM). Association between SPD and IM has never been reported. The pathogenesis of this unusual association remains unclear and may involve proliferation of abnormal monoclonal stem cells with differentiation into activated megakaryocytes associated with impaired dense granule development and increased cytokines release which may be. involved in myelofibrosis.
Aged↗
Recombinant albumins containing additional peptide sequences smaller than barbourin retain the ability of barbourin-albumin to inhibit platelet aggregation.
The previously described fusion protein BLAH(6) (Marques JA et al.,Thromb Haemost 2001; 86: 902-8) is a recombinant protein that combines the small disintegrin barbourin with hexahistidine-tagged rabbit serumalbumin (RSA) produced in Pichia pastoris yeast. We sought to determine: (1) if BLAH(6) was immunogenic; and (2) if its barbourin domain could be productively replaced with smaller peptides. Purified BLAH(6) was injected into rabbits, and anti-barbourin antibodies were universally detected in plasma 28 days later; BLAH(6) was, however, equally effective in reducing platelet aggregation in both naive and pre-treated rabbits. Thrombocytopenia was not observed, and complexing BLAH(6) to alpha(IIb)beta(3) had no effect on antibody detection. The barbourin moiety of BLAH(6) was replaced with each of four sequences: Pep I (VCKGDWPC); PepII (VCRGDWPC); PepIII (bar-bourin 41-54); and PepIV (LPSPGDWR). The corresponding fusion proteins were tested for their ability to inhibit ADP-induced platelet aggregation. PepIII-LAH(6) inhibited neither rabbit nor human platelets. PepI-LAH(6) and PepIV-LAH(6) inhibited rabbit platelet aggregation as effectively as BLAH(6), but PepIV-LAH(6) did not inhibit human platelet aggregation. PepI-LAH(6) and PepIILAH(6) inhibited human platelet aggregation with IC(50)s 10- and 20-fold higher than BLAH(6). Cross-immunoprecipitation assays with human platelet lysates confirmed that all proteins and peptides interacted with the platelet integrin alpha(IIb)beta(3), but with greatly varying affinities. Our results suggest that the antiplatelet activity of BLAH(6) can be retained in albumin fusion proteins in which smaller peptides replace the barbourin domain; these proteins may be less immunogenic than BLAH(6).
Adenosine Diphosphate↗
Management of bleeding in a multi-transfused patient with positive HLA class I alloantibodies and thrombocytopenia associated with platelet dysfunction refractory to transfusion of cross-matched platelets.
Thrombocytopenia is a common condition in the critical care setting. Repetitive platelet transfusion might lead to formation of alloantibodies. HLA class I and human platelet antigen antibodies can lead to transfusion-refractory thrombocytopenia. Transfusion of cross-matched platelets often is effective in these patients. We report on the successful use of recombinant activated factor VII in an acute bleeding situation in a multi-transfused patient presenting with positive HLA class I alloantibody status and thrombocytopenia associated with platelet dysfunction refractory to even transfusion of cross-matched platelets. The 41-year-old female patient developed HLA class I antibodies during former episodes of massive transfusion. Her former medical history was empty concerning hemorrhagic events. During this specific bleeding episode the patient suffered from intractable profuse bleeding from the nasopharynx and oral cavity. Global coagulation tests were within the normal range. Platelet dysfunction was confirmed by PFA100. Initially the patient responded well to Desmopressin infusion, but after 36 h she became thrombocytopenic and refractory to even transfusion of cross-matched platelets. Recombinant activated factor VII was chosen as the last resort. Two identical boli of 160 microg/kg NovoSeven each were injected via a central line within an interval of 3 h. After the first injection bleeding was significantly reduced and vasopressor support discontinued. After the second bolus bleeding completely ceased and did not reoccur. We did not observe any side effects. The pluripotent hemostatic agent recombinant activated factor VII might be a new option in the treatment of hemorrhagic episodes in patients presenting with this rare disorder, especially when the patient is refractory to cross-matched platelets or matched platelets are not available.
Adult↗
Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients.
One hundred six patients with storage pool deficiency (SPD) were studied with respect to platelet count, bleeding time, total platelet ATP and ADP, platelet serotonin, and in vitro aggregation. The diagnosis of SPD was made on basis of a prolonged bleeding time, a decreased total platelet ADP, and a diminished level of serotonin. Fifty-one patients from 34 unrelated families had congenital SPD, and 55 patients had acquired SPD. Congenital SPD was a common disorder in patients with a lifelong bleeding tendency and a prolonged bleeding time. The frequency in this group of patients was 18%, about one-half the frequency of von Willebrand's disease (vWd). Twenty-three percent of all patients had normal aggregation responses to ADP, epinephrine, and collagen; 33% had aggregation tracings typical for a secretion defect; and 44% had miscellaneous aggregation abnormalities. These findings indicate that SPD is common, heterogeneous, and not necessarily associated with in vitro aggregation abnormalities.
Bleeding Time↗
Ex vivo evaluation of anti-GPVI antibody in cynomolgus monkeys: dissociation between anti-platelet aggregatory effect and bleeding time.
Recent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (> 80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0.2 mg/kg with a slight prolongation of bleeding time (1.3 times baseline value). Furthermore, at 18.8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1.9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5.0 times at 0.35 mg/kg, the lowest effective dose on platelet aggregation. In a pharmacodynamic study, a bolus injection of OM2 at 0.4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exert a potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.
Animals↗
Interactions of platelets with Synthocytes, a novel platelet substitute.
A platelet substitute, Synthocytes, is being developed for the prevention and treatment of thrombocytopenia. Synthocytes are composed of fibrinogen adsorbed on heat stabilised albumin microcapsules of defined size. The purpose of this study was to perform experiments in vitro to investigate the capacity of Synthocytes to interact with platelets, one of the means through which Synthocytes may contribute to haemostatic plug formation in vivo. Synthocytes were found to interact with platelets as shown by platelet aggregation assays and measurements of [(14)C]5HT release from platelets in whole blood and platelet-rich plasma. Platelet-Synthocytes co-aggregate formation was demonstrated directly using flow cytometry and the presence of activated platelets in these co-aggregates was demonstrated using an antibody to P-selectin. Synthocytes enhanced platelet responsiveness to conventional aggregating agents such as ADP. Indeed, antagonists of the action of ADP on platelets inhibited the direct effects of Synthocytes on platelets in whole blood, as did a GPIIb/IIIa antagonist. Enhancement of annexin V binding was also observed, indicative of increased pro-coagulant activity. Experiments performed with control microcapsules (lacking fibrinogen) confirmed the importance of fibrinogen in the interactions that occurred. The results suggest that fibrinogen on the surface of Synthocytes can interact with GPIIb/IIIa on platelets to induce platelet activation, secretory activity and aggregation, and that ADP contributes to this process. This initial interaction renders platelets more susceptible to the stimulatory effects of other platelet-activating agents. It is considered likely that in the clinical setting of thrombocytopenia any interaction between Synthocytes and residual platelets that are present may contribute to primary haemostasis.
Adenosine Diphosphate↗