Ivy Bleeding Time Research Articles

Pre-injury chronic alcohol abuse predicts intracranial hemorrhagic progression, unfavorable clinical outcome, and mortality in severe traumatic brain injury

ABSTRACT Objective We aimed to determine the incidence of pre-injury alcohol abuse in TBI at our neurointensive care unit (NICU), the relation to intracranial hemorrhage evolution, and clinical outcome. Methods Patients with TBI treated at our NICU at Uppsala university hospital, Sweden, 2008–2018, were included. Clinical, radiological, and outcome variables were evaluated. Results Of 844 patients with TBI, 147 (17%) had a history of pre-injury alcohol abuse and these patients were slightly older, but had a similar Charlson co-morbidity index as the other patients. They were more often injured by falls and more frequently developed acute subdural hematomas and cerebral contusions. Their platelets were lower and their IVY bleeding time slightly longer. Patients with pre-injury alcohol abuse more often exhibited an intracranial hemorrhage progression on the second computed tomography. Pre-injury alcohol abuse was an independent predictor of increased mortality (odds ratio = 2.96, p-value = 0.001) and decreased favorable outcome (odds ratio = 0.46, p-value = 0.001) in multiple regression analyses. Conclusions Pre-injury alcohol abuse was common in severe TBI, associated with coagulopathy, worse intracranial hemorrhage/injury evolution, and independently predicted poor clinical outcome. These patients deserve more attention in care and research to address specific challenges including disturbed hemostasis.

Assessment of platelet function and resistance to aspirin and clopidogrel in patients with peripheral arterial disease undergoing percutaneous transluminal angioplasty

Introduction: Analysis of platelet function, acetylsalicylic acid (ASA) and clopidogrel resistance in patients with peripheral arterial disease (PAD) undergoing percutaneous transluminal angioplasty (PTA), the impact of procedure on this phenomenon, connection with diabetes, hypertension, smoking. Material and methods: The study included 72 patients, with a group of patients taking ASA on a permanent basis and a group of patients in whom treatment was implemented after the procedure. Patients were also divided according to the antiplatelet therapy applied, either double-therapy, or ASA monotherapy. Daily doses were 75 mg. Three methods were used for the evaluation of the platelet function: IVY bleeding time, cytometric evaluation of platelet surface antigen (CD62p and CD63) expression and hemostasis measurement by PFA-200®. Results: In the PFA-200 analysis, ASA resistance was found in 37.8% (64.7% were tobacco smokers) before surgery. Patients not taking ASA before, after PTA and first dose of ASA presented resistance in 63%. The first dose of clopidogrel after surgery was associated with resistance in 73.7%. Significant differences in the expression of CD62p and CD63 markers before and after PTA were observed. According to IVY method, aspirin resistance was found in 40% of patients permanently receiving ASA. Conclusions: Patients with PAD who undergo PTA are resistant to ASA in 40%, smoking is associated with this phenomenon. PTA increases the expression of CD62P and CD63, and thus the platelet activation, which is not adequately prevented by antiplatelet drugs at a dose of 75 mg. Dual antiplatelet therapy reduces the activation of thrombocytes more than the monotherapy of ASA.

Association of the bleeding time test with aspects of traumatic brain injury in patients with alcohol use disorder

Background—aimTraumatic brain injury (TBI) and alcohol use disorder (AUD) can occur concomitantly and be associated with coagulopathy that influences TBI outcome. The use of bleeding time tests in TBI management is controversial. We hypothesized that in TBI patients with AUD, a prolonged bleeding time is associated with more severe injury and poor outcome.Material and methodsModerate and severe TBI patients with evidence of AUD were examined with bleeding time according to IVY bleeding time on admission during neurointensive care. Baseline clinical and radiological characteristics were recorded. A standardized IVY bleeding time test was determined by staff trained in the procedure. Bleeding time test results were divided into normal (≤ 600 s), prolonged (> 600 s), and markedly prolonged (≥ 900 s). Normal platelet count (PLT) was defined as > 150,000/μL. This cohort was compared with another group of TBI patients without evidence of AUD.ResultsFifty-two patients with TBI and AUD were identified, and 121 TBI patients without any history of AUD were used as controls. PLT was low in 44.2% and bleeding time was prolonged in 69.2% of patients. Bleeding time values negatively correlated with PLT (p < 0.05). TBI patients with markedly prolonged values (≥ 900 s) had significantly increased hematoma size, and more frequently required intracranial pressure measurement and mechanical ventilation compared with those with bleeding times < 900 s (p < 0.05). Most patients (88%) with low platelet count had prolonged bleeding time. No difference in 6-month outcome between the bleeding time groups was observed (p > 0.05). Subjects with TBI and no evidence for AUD had lower bleeding time values and higher platelet count compared with those with TBI and history of AUD (p < 0.05).ConclusionsAlthough differences in the bleeding time values between TBI cohorts exist and prolonged values may be seen even in patients with normal platelet count, the bleeding test is a marker of primary hemostasis and platelet function with low specificity. However, it may provide an additional assessment in the interpretation of the overall status of TBI patients with AUD. Therefore, the bleeding time test should only be used in combination with the patient’s bleeding history and careful assessment of other hematologic parameters.

Acquired Von Willebrand Syndrome (AVWS) Type 2A as the Presenting Feature of JAK2 Wild type Thrombocythemia in a Child: Effectiveness of Platelet Reduction by Anagrelide

A 9-year-old Caucasian boy presented in 1994 with severe headache, attacks of migraine, aggressive behavior and minor bleeding symptoms. Initial abnormal laboratory data were a platelet count of 1596 × 109/L and slight splenomegaly on echogram. Low-dose aspirin 100 mg/day relieved the cerebral symptoms, but a pronounced spontaneous bleeding tendency became evident. Severe epistaxis, bruises, hematomas and gum bleedings resulted in an iron deficiency state (hemoglobin 5.7 mmol/L,hematocrit 0.30, MCV 77 fl, ferritine 6 ug/l) in November 1995. The combination of mucocutaneous bleeding, high platelet counts (1946 × 109/L), and increase of enlarged megakaryocytes in a bone marrow smear was consistent with the diagnosis of hemorrhagic thrombocythemia. Coagulation studies revealed the presence of an acquired von Willebrand syndrome type 2A featured by a prolonged Ivy bleeding time, near normal factor VIII coagulant activity (0.53 u/ml) and von Willebrand factor (VWF) antigen (0.55 u/ml), low VWF ristocetine cofactor activity (0.29), very low VWF collagen binding activity (0.16 u/ml) and absence of large VWF multimers. A severe epistaxis lasting for several hours stopped immediately after correction of the VWF parameters by substitution of 3000 units Bone marrow histopathology showed a pronounced increase of large immature megakaryocytes with hyperlobulated nuclei and maturation defects of nuclei and cytoplasm, and absence of reticuline fibrosis consistent with the diagnosis of JAK2 wild type thrombocythemia in primary megakaryocytic granulocytic myeloproliferation (PMGM). Initial treatment with hydroxyurea (500 mg daily) followed by anagrelide resulted in correction of platelet count from 2000 × 109/L to near normal (400-600 × 109/L) by), which was associated with relief of bleeding symptoms, and correction of plasma VWF values and VWF multimeric pattern to normal. The subsequent natural history was featured by spontaneous reduction of platelet count to near normal and no progression of JAK2 wild type myeloproliferative neoplasms for more than 13 years follow-up.

Which Laboratory Investigation Should be Ordered to Assess Haemostasis in Patients on Platelet Function Altering Medications?

It is not uncommon to come across patients on platelet altering medications requiring a minor oral surgical procedure in clinical practice. Although, now it remains an evidence based common consensus among practicing maxillofacial and oral surgeons to not to stop platelet altering medication before a minor oral surgical procedure, many clinicians prefer to assess bleeding parameters before a surgical intervention. It is usually noticed that the laboratory investigation(s) ordered to assess haemostasis in patients on platelet altering medications are irrelevant or unnecessary. In cases where the treating clinician/dentist prefers to order a laboratory investigation, it should be targeted to serve the intended purpose. Stopping the low-dose aspirin 7–10 days before oral surgery procedures is still being practiced by some clinicians due to the mere fear of a bleed intra or post operatively, which renders the patient to an increased risk of a thromboembolic event. Similarly some clinicians prefer stopping other platelet altering medications too. Currently there is sufficient clinical evidence available to support non-stoppage of platelet altering medications for a minor oral surgical procedure in patients taking these drugs for various medical problems. The benefit of prevention of a thromboembolic episode in a patient outweighs the risk of minor bleeding, that if happens can be easily controlled by local measures. Ordering haematological investigation to assess haemostasis purely remains a treating clinician’s personal preference and may be wise at some centers for legal purposes and prevention of litigations. The commonly prescribed platelet altering medications in clinical use are aspirin, clopidogrel and dipyridamole. Each of these medications has a well defined and specific mechanism of action to produce the desired pharmacological effect. (Table 1) [1] The best screening test recommended to assess the effect of platelet altering medications on cessation of bleeding may be evaluated with the platelet function analyser, which may not be available at all haematological laboratories. The Ivy bleeding time is the alternate test to assess and screen patients on platelet function altering medication. [2] It needs emphasis that investigations that assess coagulation cascade like prothrombin time (PT), partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) and international normalized ratio (INR), have ‘no’ role in screening patients on medication that alter platelet function. Some authors do not recommend any laboratory monitoring for patients on aspirin therapy as bleeding time test is not a very reliable indicator of anticipating post-surgical haemorrhage in these patients [3]. Table 1 Mechanism of action (MOA) of commonly prescribed antiplatelet drugs

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.

A Myelodysplastic Syndrome Associated with a Clonal GATA1 Mutation.

Germline exon 4 mutations in the N-terminal zinc finger (N-finger) of transcription factor GATA1 cause a variable degree of X-linked dyserythropoiesis with macrothrombocytopenia. Congenital neutropenia and anemia are described in patients with an exon 2 germline splicing mutation resulting in exclusive expression of the short isoform of GATA1 (GATA1s). Similar but acquired somatic GATA1 exon 2 splicing mutations occur in children with Down Syndrome (DS) and congenital transient myeloproliferative syndrome (TMD) or acute megakaryoblastic leukemia (AMKL). The present study describes a somatic exon 4 GATA1 mutation in a 19-year-old boy with myelodysplastic syndrome (MDS) who has a lifelong history of anemia, neutropenia, severe bone pains and hepatosplenomegaly. Bone marrow biopsy demonstrates bilineage dysplasia with deficient granulopoiesis and dysmegakaryopoiesis. The patient has a normal platelet count but an increased Ivy bleeding time and a prolongation of the PFA100 occlusion time. Platelet ATP secretion and platelet aggregation are decreased. The a to g substitution is present in GATA1 mRNA from platelets and bone marrow mononuclear cells. The mutation is also detected in genomic DNA from purified common myeloid progenitors, but not in common lymphoid progenitors, peripheral blood lymphocytes and skin fibroblasts. This GATA1- E200G mutation is located in a highly conserved residue at the beginning of the N-finger, but does not perturb DNA binding to GATA sites nor reduces its interaction with FOG1. In contrast, the mutation is located at the exonic splice site and is associated with alternative splicing and reduced GATA1 protein levels. In conclusion, this study expands the GATA1 phenotype-genotype spectrum with the development of MDS and platelet dysfunction due to a somatic GATA1 splice mutation.

Platelet Dysfunction in Patients with Severe Traumatic Brain Injury

Coagulopathy is a common phenomenon in traumatic brain injury (TBI) and a major contributor to a poor outcome. Thrombocytopenia is a strong negative prognostic factor in TBI, but bleeding tendency can be present even with a normal platelet count. We investigated platelet function in patients with TBI by means of modified thromboelastography (i.e., platelet mapping [TEG-PM]). Four groups were studied: (1) patients with severe isolated TBI (n = 20), (2) patients with general trauma without TBI (the ICU group, n = 10), (3) patients with chronic alcohol abuse (n = 7; as alcohol abuse is common in patients with TBI), and (4) healthy volunteers (n = 10). We measured platelet counts in venous blood (Plt), Ivy bleeding time, standard TEG parameters, and platelet responses to arachidonic acid (AA) and adenosindiphosphate (ADP), using TEG-PM. TBI patients had a lower Plt (180 +/- 68 x 10(9) ; mean +/- SD) and a longer bleeding time (674 +/- 230 sec) than healthy controls, (256 +/- 43 x 10(9), p < 0.01) and (320 +/- 95 sec, p < 0.005), respectively. TBI patients had dramatically lower platelet responses to AA (0-86%, mean 22%) compared to healthy controls (57-89%, mean 73%), the ICU group (4-75%, mean 49%), and the alcohol abusers (17-88%, mean 64%; p < 0.001). Responses to ADP did not differ significantly between the groups. Patients with low responsiveness to AA at admittance to the hospital were likely to develop bleeding complications later. Patients with TBI develop platelet dysfunction, which most likely contributes to bleeding complications. The observed platelet dysfunction appears to involve the cyclooxygenase pathway. TEG-PM analysis can be used to identify patients with a high risk of bleeding complications.

Estudo Comparativo do Tempo de Sangramento Avaliado pelo Método Convencional de Ivy e do Tempo de Sangramento da Mucosa Bucal

Surgical procedures must be preceded by an accurate evaluation of the local and systemic health status and complementary exams can confirm or not clinical suspect and diagnosis hypothesis in order to adequate the patient to the proposed surgical treatment.The literature is generous with respect of hemostasia tests employing several methodologies although there are not studies that compare the Bleeding Time Test by Ivy's method with bleeding time accessed at the oral mucosa. We propose at this study the evaluation of a bleeding time method in the oral mucosa comparing the results with the conventional Ivy's test in patients with bleeding disorders history in past surgical procedures.The patients were those attending the Oral Surgery Clinic of the Dental School of University of São Paulo which underwent oral minor surgery. The Ivy's Bleeding time test was previously obtained before the evaluation of the bleeding time of the mucosa in 30 patients. It was concluded that the bleeding time of the mucosa did not present statistical difference when compared to the Ivy's test (p=0,755). The results evaluated by KOLMOGOROV-SMIRNOV's method followed a normal distribution in both samples (p>0,15) and the mean bleeding time at the skin and at the oral mucosa was 295 seconds and 291 seconds respectively showing similarity between the groups.

Myelodysplastic Syndrome Due to Somatic GATA1 Mutation.

Inappropriate hematopoietic differentiation resulting in trilineage dysplasia is a diagnostic hallmark of myelodysplastic syndrome (MDS). Understanding the molecular basis of MDS will not only shed insight into this common hematological disease, but also Acute Myeloid Leukemia (as MDS often progresses to AML) and normal hematopoiesis. The genetic basis of MDS is unclear and in particular the role of deregulated transcription factor activity, which is often seen in AML, has not been clearly defined. For the first time we describe a novel somatic GATA1 mutation in a 13-year-old boy with MDS who has 10-year history of anemia, neutropenia, moderate thrombocytopenia, bone pain and hepatomegaly. Bone marrow biopsy demonstrated trilineage dysplasia with a normal karyotype of bone marrow mononuclear cells. Sequence analysis showed an A to G mutation in the X-linked GATA1 gene at residue 598 in exon 4 in platelets and bone marrow mononuclear cell cDNA. The mutation was also detected in genomic DNA from purified myeloid progenitors but not peripheral blood leucocytes. This discrepancy may be due to selection of peripheral blood leucocytes that do not carry the GATA1 mutation. The mutation was also not seen in skin fibroblasts. The predicted amino acid substitution E200G is located in a highly conserved residue at the beginning of the N-terminal zinc finger (Nf). This did not perturb DNA binding to GATA sites by EMSA analysis nor reduce interaction with FOG1. Importantly, immunoblot analysis of the patient's platelets showed strongly reduced protein levels of GATA1, normal FOG1 and increased RUNX1. The index case had an increased Ivy bleeding time (>15 min) and a significant prolongation of the PFA-100 occlusion time (collagen/ADP and collagen/epinephrine). Platelet ATP secretion and platelet aggregation (epinephrine, ADP and U46) were decreased compared to control platelets. In contrast to patients with an inherited GATA1 mutation, the platelet phenotype in the MDS patient is completely different. Platelets from the patient are smaller in size (MPV 8.6fL) and electron microscopy revealed a markedly reduced number of dense granules. His platelets have a normal GPIbα expression and normal ristocetin-induced platelet agglutination. The previously described patients with inherited Nf GATA1 mutations (D218G GATA1 Blood,2001,98,85) have giant platelets with characteristic membrane complexes and reduced GPIbα expression with abnormal ristocetin-induced platelet agglutination. Further study of the index patient will provide important detailed insight into GATA1 function and help unravel how perturbed activity of key myeloid transcription factors results in MDS.

The effect of IM ketorolac tromethamine on bleeding time: a prospective, interventional, controlled study

Opiates, although effective analgesics, have significant adverse side effects. Ketorolac, the only parental nonsteroidal antiinflammatory drug available for use in the United States does not cause significant respiratory depression or hypotension, but it is a reversible inhibitor of platelet aggregation with a theoretical increased bleeding risk, which limits its use. The objective of this study was to determine the effect of a single intramuscular dose of 60 mg ketorolac on 4-hour bleeding times in healthy volunteers. This was a prospective, paired, unblinded, before-and-after interventional study performed in a suburban university-based EM residency training program. Subjects were 20 healthy volunteer EM residents. Standard Ivy bleeding times were measured before and 4 hours after intramuscular administration of 60 mg ketorolac. Before-and-after bleeding times were compared using a paired t-test. The study had 90% power to detect an effect size of 0.5. The subjects' mean age was 31.6 and 7 (35%) were females. Bleeding time was increased from a mean baseline time of 3 minutes 34 seconds (+/- 1 min 20 sec) to a mean 4-hour postinjection time of 5 minutes 20 seconds (+/- 3 min 8 sec). The mean prolongation of bleeding time was 1 minute 46 seconds (50% increase with 95% confidence interval, 25%-75%). There were no adverse events. A standard intramuscular dose of 60 mg ketorolac resulted in prolongation of the bleeding time in healthy volunteers. The clinical significance of this prolongation in patients is unclear.

Excessive prolongation of the Ivy bleeding time after aspirin in essential thrombocythemia is also demonstrable in vitro in the high shear stress system PFA-100

Excessive prolongation of the Ivy bleeding time after aspirin in essential thrombocythemia is also demonstrable in vitro in the high shear stress system PFA-100

On the mechanism of action of recombinant activated factor VII administered to patients with severe thrombocytopenia and life-threatening haemorrhage: focus on prothrombin activation.

We report the ex vivo effect of recombinant activated factor VII (rFVIIa) on prothrombin activation after whole blood clotting. Two patients with severe thrombocytopenia and life-threatening haemorrhage were successfully managed using a single dose of rFVIIa (90 microg/kg). Western blotting using antiprothrombin antibody showed that rFVIIa did not induce thrombin generation in citrated platelet-poor plasma. Patient sera showed significantly impaired prothrombin activation before and after rFVIIa administration. rFVIIa administration shortened the prothrombin time, activated partial thromboplastin time and Ivy bleeding time, and normalized the clot retraction. These data indicate that rFVIIa accelerated thrombin generation without significant increase of generated thrombin.

A double-blind study of the effect on hemostasis of nabumetone (Relafen ®) compared to placebo

A double-blind, placebo-controlled clinical trial comparing the effect on hemostasis of nabumetone (Relafen) to placebo in patients who were about to undergo forefoot surgery was performed. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit platelet cyclooxygenase activity, resulting in altered platelet function and thus potentially enhanced bleeding. Nabumetone has been reported to have no effect on platelet aggregation and bleeding time in normal volunteers and in patients who have undergone knee arthroscopy. After fulfilling the inclusion criteria and after a 1-week washout period (acetaminophen controlled), 15 patients were enrolled in the nabumetone group and 15 patients were randomized in the placebo group. Hemostatic parameters [prothrombin time (PT), partial thromboplastin time (PTT), and Ivy bleeding time (IBT)] were assessed at baseline, visit 2, visit 3, and final visit. No meaningful differences were observed between treatment groups in any of the measured hemostatic parameters. No significant adverse events were reported. There was no significant change from baseline for PT, PTT, and IBT in the nabumetone group (PT, p < .06; PTT, p < .64; IBT, p < .17) versus the placebo group (PT, p < .61; PTT, p < .63; IBT, p < .25). The lack of bleeding diathesis and significant prolongation of PT, PTT, or IBT in this study suggests that nabumetone in dosages up to 1000 mg/day can be administered safely in the immediate preoperative period to patients undergoing forefoot surgery.

Effect of aspirin in pregnant women is dependent on increase in bleeding time

Objectives: Randomized trials with low-dose aspirin to prevent preeclampsia and intrauterine growth restriction have yielded conflicting results. In particular, 3 recent large trials were not conclusive. Study designs, however, varied greatly regarding selection of patients, dose of aspirin, and timing of treatment, all of which can be determinants of the results. Retrospectively analyzing the conditions associated with failure or success of aspirin may therefore help to draw up new hypotheses and prepare for more specific randomized trials. Study Design: We studied a historical cohort of 187 pregnant women who were considered at high risk for preeclampsia, intrauterine growth restriction, or both and were therefore treated with low-dose aspirin between 1989 and 1994. Various epidemiologic, clinical, and laboratory data were extracted from the files. Univariate and multivariate analyses were performed to search for independent parameters associated with the outcome of pregnancy. Results: Age, parity, weight, height, and race had no influence on the outcome. The success rate was higher when treatment was given because of previous poor pregnancy outcomes than when it was given for other indications, and the patients with successful therapy had started aspirin earlier than had those with therapy failure (17.7 vs 20.0 weeks' gestation, P = .04). After multivariate analysis an increase in Ivy bleeding time after 10 days of treatment by >2 minutes was an independent predictor of a better outcome (odds ratio 0.22, 95% confidence interval 0.09-0.51). Borderline statistical significance was observed for aspirin initiation before 17 weeks' gestation (odds ratio 0.44, 95% confidence interval 0.18-1.08). Abnormal uterine artery Doppler velocimetric scan at 20-24 weeks' gestation (odds ratio 3.31, 95% confidence interval 1.41-7.7), abnormal umbilical artery Doppler velocimetric scan after 26 weeks' gestation (odds ratio 37.6, 95% confidence interval 3.96-357), and use of antihypertensive therapy (odds ratio 6.06, 95% confidence interval 2.45-15) were independent predictors of poor outcome. Conclusions: Efficacy of aspirin seems optimal when bleeding time increases ≥2 minutes with treatment, indicating a more powerful antiplatelet effect. This suggests that the dose of aspirin should be adjusted according to a biologic marker of the antiplatelet effect. A prospective trial is warranted to test this hypothesis. (Am J Obstet Gynecol 1999;180:135-40.)

Inhibition of Platelet Aggregation by Inhaled Nitric Oxide in Patients with Acute Respiratory Distress Syndrome

Comment The ability of nitric oxide to inhibit platelet aggregation is predictable from the effects of nitric oxide on intraplatelet guanylate cyclase. Because of increased cyclic guanosine monophosphate, a protein kinase is stimulated that results in a reduction in fibrinogen binding to glycoprotein receptors on the platelets. This should induce an inhibition of platelet aggregation, and that is exactly what the authors found. Thus, the authors tested a logical scientific hypothesis, and it proved correct. What is rather surprising, however, is that this inhibited platelet aggregation ex vivo did not prolong Ivy bleeding time in patients. Although the authors did not definitively explain these relatively contradictory effects, they suggested several possible mechanisms in their paper. The reader is urged to review this manuscript for interesting details, but the take-home message for the clinician is that if there is a preexisting clotting defect, nitric oxide may not be a benign drug. On the other hand, because surgery and the acute respiratory distress syndrome can induce a hypercoa-gulable state, perhaps nitric oxide will prevent some unwanted clotting in vital organs of patients without preexisting coagulation disorders.

Intravenous Ketorolac Tromethamine Worsens Platelet Function During Knee Arthroscopy Under Spinal Anesthesia

Ketorolac prolongs bleeding time and inhibits platelet aggregation and platelet thromboxane production in healthy, awake volunteers. However, platelet function was recently shown not to worsen after ketorolac was given during general anesthesia. The purpose of this study was to investigate platelet function changes during a standardized spinal anesthetic and surgery, as well as after a single intraoperative dose of intravenous (IV) ketorolac. The study comprised 30 ASA physical status I patients undergoing spinal anesthesia for knee arthroscopy. Subjects were randomized to receive either ketorolac 60 mg IV 15 min after skin incision or placebo IV. Platelet function testing consisted of an Ivy bleeding time, platelet aggregometry with adenosine diphosphate (ADP) and collagen, thromboelastography (TEG), and serum thromboxane B2 (TxB2) assays. Platelet function testing was performed: 1) 15 min prior to the performance of spinal anesthesia; 2) 10 min after surgical skin incision; and 3) 45 min after administration of study drug. The placebo group demonstrated no changes in any platelet function variable during spinal anesthesia and surgery relative to preoperative values. The ketorolac group, however, demonstrated a significant increase in bleeding time from postincision to poststudy drug data points (213 +/- 60s to 275 +/- 85s, mean +/- SD; P < 0.01). Further, platelet aggregometry to collagen was diminished in the ketorolac group from preoperative to poststudy drug data points (90.8% +/- 7.6% to 60.5% +/- 32.5%; P < 0.01). Platelet aggregometry with ADP, however, was unchanged in the ketorolac group. Platelet TxB2 production decreased dramatically in the ketorolac group from preoperative to poststudy drug data points (157.2 +/- 129.4 to 0.3 +/- 0.3 ng/mL; P < 0.01). Platelet function does not appear to be accentuated during spinal anesthesia as it is during general anesthesia. Unlike during general anesthesia, platelet function during spinal anesthesia is impaired, with respect to bleeding time and platelet aggregometry to collagen, by a single intraoperative dose of IV ketorolac.

Intravenous Ketorolac Tromethamine Worsens Platelet Function During Knee Arthroscopy Under Spinal Anesthesia

Ketorolac prolongs bleeding time and inhibits platelet aggregation and platelet thromboxane production in healthy, awake volunteers.However, platelet function was recently shown not to worsen after ketorolac was given during general anesthesia. The purpose of this study was to investigate platelet function changes during a standardized spinal anesthetic and surgery, as well as after a single intraoperative dose of intravenous (IV) ketorolac. The study comprised 30 ASA physical status I patients undergoing spinal anesthesia for knee arthroscopy. Subjects were randomized to receive either ketorolac 60 mg IV 15 min after skin incision or placebo IV. Platelet function testing consisted of an Ivy bleeding time, platelet aggregometry with adenosine diphosphate (ADP) and collagen, thromboelastography (TEG), and serum thromboxane B2 (TxB (2)) assays. Platelet function testing was performed: 1) 15 min prior to the performance of spinal anesthesia; 2) 10 min after surgical skin incision; and 3) 45 min after administration of study drug. The placebo group demonstrated no changes in any platelet function variable during spinal anesthesia and surgery relative to preoperative values. The ketorolac group, however, demonstrated a significant increase in bleeding time from postincision to poststudy drug data points (213 +/- 60 s to 275 +/- 85 s, mean +/- SD; P < 0.01). Further, platelet aggregometry to collagen was diminished in the ketorolac group from preoperative to poststudy drug data points (90.8% +/- 7.6% to 60.5% +/- 32.5%; P < 0.01). Platelet aggregometry with ADP, however, was unchanged in the ketorolac group. Platelet TxB2 production decreased dramatically in the ketorolac group from preoperative to poststudy drug data points (157.2 +/- 129.4 to 0.3 +/- 0.3 ng/mL; P < 0.01). Platelet function does not appear to be accentuated during spinal anesthesia as it is during general anesthesia. Unlike during general anesthesia, platelet function during spinal anesthesia is impaired, with respect to bleeding time and platelet aggregometry to collagen, by a single intraoperative dose of IV ketorolac. (Anesth Analg 1996;82:1176-81)

Von Willebrand Factor Antigen and Factor XI Activity Levels As Predictors of Bleeding Tendency in Israeli Patients with Von Willebrand's Disease

Previous preliminary data and case reports have suggested an association of von Willebrand's disease (vWD) with factor XI deficiency and platelet abnormalities. We have analyzed the prevalence of factor XI deficiency and thrombocytopathy in a cohort of Israeli patients with vWD. Decreased factor XI levels (&lt;67 U/dl) were documented in 35 of 63 (36%) vWD subjects; factor XI levels were &lt;30 U/dl in five of 60 (8%). A significant decline in ADP-induced platelet aggregation (&lt;30% of control) was found in 48% of vWD patients. Likewise, epinephrine-induced aggregation was reduced in 41%, and collagen-induced aggregation was decreased in 7% of vWD patients. Logistic regression analysis showed that while Ivy bleeding time, ristocetin cofactor, and ristocetin-induced platelet aggregation did not predict bleeding, both von Willebrand factor antigen and factor XI activity levels predict bleeding in patients with vWD. These findings suggest that mild factor XI deficiency and thrombocytopathy are common in Israeli subjects with vWD and that associated factor XI deficiency can result in clinical bleeding in these patients. Key Words: Von Willebrand' s disease—Factor XI deficiency—Thrombocytopathy.

Inhibition of Platelet Aggregation by Inhaled Nitric Oxide in Patients with Acute Respiratory Distress Syndrome

Nitric oxide inhibits platelet adhesion and aggregation in vitro. The aim of this prospective study was to assess the platelet antiaggregating activity of nitric oxide administered to patients with acute respiratory distress syndrome (ARDS) at increasing concentrations. In six critically ill patients (mean age 37 +/- 16 yr) with ARDS (lung injury severity score > or = 2.2), the lungs were mechanically ventilated with inhaled nitric oxide (1, 3, 10, 30, and 100 ppm) randomly administered. Patients with cardiac dysrhythmias, septic shock, an underlying hemostasis disorder (constitutive or acquired), a platelet count less than 100 Giga/l, or a decreased platelet aggregation and those treated with antiplatelet or anticoagulant agents were excluded. Platelet aggregation was measured without nitric oxide and at each nitric oxide concentration in platelet-rich plasma issued from radial artery. Ivy bleeding time using a horizontal incision was simultaneously performed. After nitric oxide, a non-dose-dependent but statistically significant decrease in ex vivo platelet aggregation induced by three aggregating agents was observed: adenosine diphosphate = -56 +/- 18%, collagen = -37 +/- 18%, and ristocetin = -45 +/- 18% (P < 0.05). In each individual, Ivy bleeding time remained within normal values measured in healthy volunteers, and variations after nitric oxide did not correlate with changes in platelet aggregation. Simultaneously, arterial oxygenation improved significantly and pulmonary artery pressure decreased significantly. In patients with ARDS and without preexisting coagulation disorders, the beneficial effects of inhaled nitric oxide on arterial oxygenation and pulmonary circulation are associated with a significant inhibition of platelet aggregation. This antithrombotic effect is not associated with a significant prolongation of the bleeding time.