Thomas Kander

The Effect and Duration of Prophylactic Platelet Transfusions Before Insertion of a Central Venous Catheter in Patients with Bone Marrow Failure Evaluated with Point-of-Care Methods and Flow Cytometry

BACKGROUND:Patients with bone marrow failure and severe thrombocytopenia are frequently given prophylactic platelet transfusion before interventions. The clinical effects of such transfusions, however, are poorly defined. We performed a prospective observational study on patients with bone marrow failure scheduled for prophylactic platelet transfusion before the insertion of a central venous catheter. The objectives were to evaluate the effect and duration of prophylactic platelet transfusions on central venous catheter insertion in thrombocytopenic patients with bone marrow failure. METHODS:Thirty-nine adult patients with bone marrow failure and platelet counts below 50 × 109/L were consecutively enrolled before prophylactic platelet transfusion for subclavian central venous catheter insertion. Blood samples were drawn from the patients before platelet transfusion, 1 hour, and 4 hours after completion of the transfusion. The coagulation profile was assessed by conventional hematological tests, thromboelastometry (ROTEM®) assays (EXTEM® and FIBTEM®), multiple electrode aggregometry (Multiplate®) assays including adenosine diphosphate, collagen, and thrombin receptor agonist peptide, and by flow cytometry for the platelet expression of P-selectin (CD62P) and activated glycoprotein IIb–IIIa (PAC-1). Bleeding complications were classified with a 5-grade scale, according to the Common Terminology Criteria for Adverse Events. RESULTS:Seventeen women and 22 men were included in the study. Platelet count was increased from 24 × 109/L (18–32) before to 42 × 109/L (31–50) 1 hour after transfusion (P < 0.0001) and was not significantly different 4 hours after transfusion (40 × 109/L (29–50), P = 0.047). Maximal clot firmness EXTEM was increased from 38 mm (32–45) before to 46 mm (41–52) 1 hour after transfusion (P < 0.0001) and did not change 4 hours after transfusion. Clotting time EXTEM was decreased from 58.5 seconds (50–78) beforehand to 53 seconds (45–61) 1 hour after transfusion (P = 0.0006) and was not significantly different 4 hours after transfusion (57 seconds (52–70, P = 0.025). FIBTEM results were all unchanged after transfusion. All Multiplate analyses were significantly increased after 1 hour and were not diminished 4 hours after transfusion. Four grade 1 bleeding episodes occurred, but no grade 2 to 5 bleeding could be detected. Flow cytometry analyses showed mixed results with no overall trend. CONCLUSIONS:Prophylactic platelet transfusions in thrombocytopenic patients with bone marrow failure improve hemostatic parameters on ROTEM and Multiplate by increasing the number of platelets, and not through enhancement of platelet function. Improved clotting parameters on ROTEM and platelet aggregation on Multiplate appear to persist between 1 and 4 hours after transfusion.

Bleeding complications after central line insertions: relevance of pre‐procedure coagulation tests and institutional transfusion policy

The aim of this study was to map pre‐procedural variables for insertion of a central venous catheter, prophylactic blood component use and to investigate whether any independent variable could be identified as an independent risk factor for associated bleeding complications in patients outside the intensive care unit.

Temperature effects on haemostasis in whole blood from ticagrelor- and aspirin-treated patients with acute coronary syndrome.

Abstract Background. Comatose survivors after cardiac arrest are treated with mild induced hypothermia and potent platelet- inhibiting drugs after coronary stenting. Previous studies have shown an increased incidence of stent thrombosis during clopidogrel and aspirin treatment in conjunction with induced hypothermia. The aim of this study was to investigate the in vitro effect of induced hypo- and hyperthermia on blood from patients undergoing ticagrelor- and aspirin-mediated platelet inhibition. Methods. Whole blood from 15 patients with acute coronary syndrome who were treated with ticagrelor and aspirin and from eight healthy volunteers was incubated for 1 hour at 28, 33, 37, and 39°C. Results. In blood from patients with acute coronary syndrome, the activated clotting time (Sonoclot) was prolonged in mild hypothermic (33°C) compared to normothermic (37°C) samples. Sonoclot, clotting rate and platelet function were decreased in hypothermic compared to normothermic samples. Platelet-induced activation and aggregation (Multiplate®) was unchanged in mild hypothermic compared to normothermic samples. In contrast, mild hypothermia supported increased platelet activation as measured with flow cytometry with up-regulation of PAC-1 and P-selectin on the platelet surface. Conclusion. In acute coronary syndrome patients treated with ticagrelor and aspirin, in vitro hypothermia to 33°C markedly increased platelet activity measured with flow cytometry, whereas viscoelastic coagulation test (Sonoclot) revealed a hypocoagulative response. Prospective clinical trials studying platelet inhibition at different temperatures and correlating changes in platelet function to bleeding or stent occlusion are needed.

Platelet aggregation and clot formation in comatose survivors of cardiac arrest treated with induced hypothermia and dual platelet inhibition with aspirin and ticagrelor; a prospective observational study

IntroductionWe conducted a prospective observational study in cardiac arrest survivors treated with mild induced hypothermia, evaluating different platelet function tests at hypo- and normothermia. We also investigated the relation between gastric emptying and vasodilator stimulated phosphoprotein (VASP).MethodsComatose survivors of out of hospital cardiac arrest were included and divided into two groups, depending on whether dual platelet inhibition with peroral ticagrelor and aspirin was given or not. The first blood samples (T1) were collected 12–24 hours after reaching target temperature (33°C) and were compared to blood samples collected 12–28 hours after reaching normothermia (37°C) (T2) within each group. All samples were analysed by Sonoclot viscoelasticity, flow cytometry based VASP and with multiple electrode aggregometry, Multiplate®; adenosine diphosphate (ADP), collagen (COL), thrombin receptor agonist peptide (TRAP) and arachidonic acid (ASPI). Sonoclot and Multiplate® instruments were set on in vivo temperatures. Gastric secretion from the nasogastric tube was measured to assess absorption of per orally administered antiplatelet drugs. Differences between T1 and T2 within each group were calculated using Wilcoxon matched pairs signed test. Significance levels were set at P <0.01.ResultsIn total, 23 patients were included. In patients with dual platelet inhibition (n =14) Multiplate®-analyses showed no changes in ADP stimulated platelets. COL, TRAP and ASPI aggregations were higher at T2 compared to T1. Sonoclot-analyses showed that activated clotting time (ACT) was unchanged but both clot rate (CR) and platelet function (PF) were higher at T2 compared to T1. VASP decreased from 53 ± 28(T1) to 24 ± 22(T2), (P <0.001). The average volume of gastric secretion aspirated before T1 correlated well with VASP (T1), r =0.81 (P <0.001). In patients with no platelet inhibition, (n =9) similar changes between T1 and T2 were seen as in patients with dual platelet inhibition while VASP was unchanged.ConclusionsWe have demonstrated increased platelet aggregation and strengthened clot formation over time in out of hospital cardiac arrest patients treated with hypothermia. In patients on oral dual platelet inhibition, the effect of ticagrelor was delayed, probably due to slow gastric emptying.

Wide Temperature Range Testing with ROTEM Coagulation Analyses.

Mild induced hypothermia is used for neuroprotection in patients successfully resuscitated after cardiac arrest. Temperature-dependent effects on rotational thromboelastometry (ROTEM(®)) assays with EXTEM(®), FIBTEM(®), or APTEM(®) in cardiac arrest patients have not previously been studied. Ten patients with out-of-hospital cardiac arrest who underwent induced hypothermia were studied during stable hypothermia at 33°C. ROTEM temperature effects on EXTEM, FIBTEM, and APTEM assays were studied at temperatures set between 30°C and 42°C. Citrated whole blood test tubes were incubated in temperature-adjusted heating blocks and then investigated at respective temperature in the temperature-adjusted ROTEM. The following variables were determined: clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF). The results from hypo- and hyperthermia samples were compared with the samples incubated at 37°C using the Wilcoxon matched-pairs signed-rank test. A p-value of <0.05 was considered significant. CT-EXTEM(®) and CT-APTEM(®) were prolonged by hypothermia at 30°C (p<0.01 for both) and 33°C (p<0.05 for both). Hyperthermia at 42°C shortened CT-EXTEM (p<0.05) and CT-APTEM (p<0.01). CFT-EXTEM(®) and CFT-APTEM(®) were markedly prolonged by hypothermia at 30°C, 33°C, and 35°C (p<0.01 for all except CFT-EXTEM, 35°C [p<0.05]). The α-angle-EXTEM was markedly decreased at 30°C, 33°C, and 35°C (p<0.01) but increased at 40°C (p<0.05) and 42°C (p<0.01); α-angle-APTEM showed similar results. MCF was unchanged at different temperatures for all tests. ROTEM (EXTEM, FIBTEM, and APTEM assays) revealed a hypocoagulative response to in vitro-applied hypothermia in the blood of cardiac arrest patients reflected in the prolonged clot initiation and decreased clot propagation. Hyperthermia showed the opposite effects. Clot firmness was not affected by temperature.

Assessment of Haemostasis in Disseminated Intravascular Coagulation by Use of Point-of-Care Assays and Routine Coagulation Tests, in Critically Ill Patients; A Prospective Observational Study.

Background Disseminated intravascular coagulopathy (DIC) relates to the consumption of coagulation factors and platelets with bleeding and micro thrombosis events. Aim The aim of this study was to compare haemostasis parameters in critically ill patients with DIC versus patients without DIC, and in survivors versus non-survivors over time. Correlations between the DIC-score, the degree of organ failure and the haemostasis were assessed. Method Patients admitted to the intensive care unit with a condition known to be associated with DIC and with an expected length of stay of >3 days were included. Routine laboratory tests, prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration and D-dimer were measured. Coagulation and platelet function were assessed with two point-of-care devices; Multiplate and ROTEM. DIC scores were calculated according to the International Society on Thrombosis and Haemostasis and Japanese Association for Acute Medicine. Results Blood was sampled on days 0–1, 2–3 and 4–10 from 136 patients with mixed diagnoses during 290 sampling events. The point-of-care assays indicated a hypocoagulative response (decreased platelet aggregation and reduced clot strength) in patients with DIC and, over time, in non-survivors compared to survivors. Patients with DIC as well as non-survivors had decreased fibrinolysis as shown by ROTEM. DIC scores were higher in non-survivors than in survivors. Conclusions Patients with DIC displayed signs of a hypocoagulative response and impaired fibrinolysis, which was also evident over time in non-survivors. Patients with DIC had a higher mortality rate than non-DIC patients, and DIC scores were higher in non-survivors than in survivors.

Comparison of point-of-care hemostatic assays, routine coagulation tests, and outcome scores in critically ill patients

PURPOSE The purposes of the study are to compare point-of-care (POC) hemostatic devices in critically ill patients with routine laboratory tests and intensive care unit (ICU) outcome scoring assessments and to describe the time course of these variables in relation to mortality rate. MATERIALS AND METHODS Patients admitted to the ICU with a prognosis of more than 3 days of stay were included. The POC devices, Multiplate platelet aggregometry, rotational thromboelastometry, and ReoRox viscoelastic tests, were used. All variables were compared between survivors and nonsurvivors. Point-of-care results were compared to prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration, and Sequential Organ Failure Assessment score and Simplified Acute Physiology Score 3. RESULTS Blood was sampled on days 0 to 1, 2 to 3, and 4 to 10 from 114 patients with mixed diagnoses during 237 sampling events. Nonsurvivors showed POC and laboratory signs of hypocoagulation and decreased fibrinolysis over time compared to survivors. ReoRox detected differences between survivors and nonsurvivors better than ROTEM and Multiplate. CONCLUSIONS All POC and routine laboratory tests showed a hypocoagulative response in nonsurvivors compared to survivors. ReoRox was better than ROTEM and Multiplate at detecting differences between surviving and nonsurviving ICU patients. However, Simplified Acute Physiology Score 3 showed the best association to mortality outcome.

Comparison of citrated and fresh whole blood for viscoelastic coagulation testing during elective neurosurgery

BACKGROUND Previous viscoelastic haemostatic tests studies have often indicated a hypercoagulative test signal with citrated blood, which could influence clinical decision makings. PURPOSE The aim of this study was to compare fresh and citrated whole blood using two non-automated viscoelastic ROTEM and Sonoclot tests. Our hypothesis was that citrated blood would demonstrate a hypercoagulative response in this setting, not tested before. METHODS Perioperative viscoelastic coagulation changes were evaluated with a ROTEM and Sonoclot in 38 patients undergoing elective brain tumor surgery. The citrated samples were recalcified with CaCl2. Wilcoxon nonparametric-paired tests and Bland-Altman plots were performed to compare the fresh and citrated blood analyses. RESULTS The citrated blood showed a hypercoagulative response in ROTEM NATEM-clot formation time and α-angle, Sonoclot-clot rate and platelet function, as compared to fresh blood (p<0.0001). CONCLUSIONS Fresh whole blood may theoretically reflect in vivo haemostasis more closely than citrated analyses, which indicated a hypercoagulative response as compared to the fresh whole blood analyses Bland-Altman plots also indicated that ROTEM reference ranges in patients undergoing brain surgery should be redefined. Future studies must establish the correlation between viscoelastic test results using fresh or citrate anticoagulated blood and clinical outcomes, such as bleeding, transfusion or reoperation for postoperative haematoma.

Effects of Dextran-70 and Albumin on Coagulation in Experimental Hemorrhage in the Guinea Pig

Background: Dextran-70 is a more potent plasma volume expander than albumin but use has been hampered because of its antithrombotic properties. However, also albumin has antithrombotic properties and little is known about relative effects of these two colloids on coagulation in vivo when controlling for differences in efficacy as plasma volume expanders. Aim: Compare effects of dextran-70 and albumin on coagulation at a dose resulting in equal plasma volume expansion. Methods: Guinea pigs were subjected to a 25 mL/kg hemorrhage during 20 min and randomized to resuscitation with either 6% dextran-70 at a dose of 15 mL/kg or 5% albumin at a dose of 25 mL/kg (n = 14 in each group) during 30 min starting 1 h of shock. Blood samples were collected at the completion of resuscitation and at 4 h. Plasma volume was measured using 125I-albumin and the effect on coagulation was evaluated using whole blood thrombelastography (TEG), measurement of plasma fibrinogen and von Willebrand factor (vWF) concentrations and vWF glycoprotein 1b (GP1b) A activity. Results: Plasma volumes after resuscitation were similar in the groups at both time points. Dextran-70 resulted in a transient prolongation of TEG clot amplification time (K) at the completion of resuscitation compared with albumin. TEG clot initiation (R) and strength (MA) did not differ between the treatments at any of the time points. Albumin reduced vWF concentrations to a larger extent than dextran at both time points, whereas no difference in vWF GP1bA activity or in plasma fibrinogen and could be detected. Conclusion: In equipotent doses with regard to plasma volume expansion, dextran-70 transiently prolongs clot amplification time more than albumin whereas dextran-70 reduces plasma vWF concentrations less than albumin.

Detection of subclinical vitamin K deficiency in neurosurgery with PIVKA-II

Abstract Vitamin K is known for supporting the carboxylation of hepatic coagulation proteins. Levels of proteins induced by vitamin K absence for factor II (PIVKA-II) reflect hypocarboxylated prothrombin and can be used to detect subclinical vitamin K deficiency. The aim of this study was to determine the prevalence of perioperative subclinical vitamin K deficiency among neurosurgical patients using PIVKA-II and investigate the existence of any correlation to standard coagulation assays. Also, the antitumor effects of vitamin K were reviewed. Thirty-five patients undergoing brain tumor resection were included. Blood samples were drawn preoperatively, at the end of surgery and in the morning after surgery. In addition to PIVKA-II, factor II and the Owren and Quick prothrombin times were analyzed. Seventeen of 35 patients had elevated PIVKA-II levels before surgery, which continued to be above normal range postoperatively. Median PIVKA-II and Owren prothrombin time (PT-INR) were increased on the morning day 1 postoperatively compared to before surgery, whereas Quick end-stage prothrombin time (EPT) decreased and factor II was unaffected. Postoperative complications were connected to high PIVKA-II increases. Positive correlations between PIVKA-II and factor II and body mass index (BMI) were found. In conclusion, PIVKA-II was increased in many patients preoperatively and then increased by the morning following surgery. Standard coagulation assays were largely non-pathological. Correlations were demonstrated between PIVKA-II and factor II and BMI. The effect of perioperative treatment with different vitamin K supplements should be investigated in future studies, as well as clinical trials evaluating their antitumor effects.