Increased blood coagulation is associated with poor neurological outcome in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have demonstrated increased blood coagulation which is thought to contribute to delayed cerebral ischemia (DCI) and to a worse outcome. Therefore, we sought to determine whether this increased blood coagulation, detectable with rotational thromboelastometry (ROTEM), was associated with DCI and neurological outcome. METHODS: We conducted a prospective observational study of 60 consecutive adult aSAH patients. ROTEM's EXTEM and FIBTEM assays and D-dimer were analyzed at admission and post-bleed days (PBDs) 2-3, 4-5, 7-8, and 11-12. ROTEM's clot formation time (CFT) represents the stabilization of the clot, and the maximum clot firmness (MCF) the maximum clot strength. Glasgow Outcome Scale extended (GOSe) at three months determined the neurological outcome. RESULTS: DCI incidence was 41.7%. EXTEM-CFT was significantly shorter in patients with unfavorable neurological outcome (GOSe 1-4) on PBDs 4-5 and 7-8, p < 0.05, respectively. FIBTEM-MCF was significantly higher in patients with unfavorable neurological outcomes on PBD 4-5 (p < 0.05), PBD 7-8 (p < 0.05), and PBD 11-12 (p < 0.05). EXTEM-CFT decreased, and FIBTEM-MCF rose during the study period in all patients. Patients with unfavorable neurological outcome had a higher D-dimer at all studied time points, p < 0.05. No difference was found in the ROTEM parameters or D-dimer when assessing patients with and without DCI. CONCLUSIONS: Patients were in a state of increased blood coagulation after aSAH, with those with unfavorable neurological outcome being more coagulable than those with favorable outcome. However, increased blood coagulation was not associated with DCI. CLINICALTRIALS: gov, NCT03985176.

Anti-factor X activity levels with continuous intravenous infusion and subcutaneous administration of enoxaparin after coronary artery bypass grafting: A randomized clinical trial.

BACKGROUND: Low-molecular-weight heparin enoxaparin is widely used in pharmacological thromboprophylaxis after coronary artery bypass grafting (CABG). The aim of this study was to compare anti-factor X activity (anti-Xa) levels when the thromboprophylactic dose of enoxaparin was provided after CABG, with two different administration routes: continuous intravenous infusion (CIV) and subcutaneous bolus (SCB) injection. We hypothesized that the current standard method of SCB administration might lead to lower anti-Xa levels than recommended in other patient groups, due to reduced bioavailability. METHODS: In this prospective, randomized, controlled clinical trial, 40 patients scheduled for elective CABG were randomized to receive 40 mg of enoxaparin per day either as CIV or SCB for 72 h. Enoxaparin was initiated 6-10 h after CABG. Anti-Xa levels were measured 12-14 times during the study period. The primary outcome, that is, the maximum anti-Xa concentration over 0-24 h (Cmax0-24h ), was calculated from these measured values. Secondary outcomes were Cmax25-72h and the trough concentration of anti-Xa after 72 h of enoxaparin initiation (C72h ). RESULTS: Twenty patients were randomized to the CIV-group and 19 to the SCB-group. The median anti-Xa Cmax0-24h was significantly lower in the CIV-group than in the SCB-group: 0.15 [interquartile range (IQR) 0.13-0.19] IU/ml versus 0.25 (IQR 0.18-0.32) IU/ml, p < .005. The median anti-Xa Cmax25-72h was 0.12 (IQR, 0.1-0.17) IU/ml versus 0.23 (IQR 0.19-0.31) IU/ml, respectively, p < .005. At 72 h, there was no difference between the groups in their anti-Xa levels. CONCLUSIONS: In this low-risk CABG patient population, SCB administration of a thromboprophylactic dose of enoxaparin provided anti-Xa levels that are considered sufficient for thromboprophylaxis in other patient groups. CIV administration resulted in lower anti-Xa levels compared to the SCB route.

Platelet count is not associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as defined by the 2010 consensus definition.

BACKGROUND: Although delayed cerebral ischemia (DCI) commonly complicates recovery in survivors of aneurysmal subarachnoid hemorrhage (aSAH), its pathophysiology is incompletely understood. Previous studies examining the association of DCI and platelet count have demonstrated contradictory results. This study aimed to investigate this association in a cohort of aSAH patients using the 2010 consensus definition of DCI. METHODS: We conducted a retrospective single-center observational study of consecutive adult aSAH patients admitted to the intensive care unit from January 2010 to December 2014. Platelet count and DCI evaluations were performed daily in the first 14 days after admission. DCI was defined according to the 2010 consensus criteria. RESULTS: A total of 340 patients were included for analysis. DCI incidence was 37.1%. Platelet count was not significantly associated with occurrence of DCI on any day. Mean platelet count was lowest on day 3 after aSAH and then increased to exceed the count at admission on day 6. Treatment modality and use of dual antiplatelet therapy were not associated with DCI. CONCLUSIONS: Platelet count was not associated with DCI as defined by the 2010 consensus criteria. Future studies adhering to the 2010 consensus definition of DCI are needed to clarify the role of platelets and platelet function in DCI pathophysiology.

Continuous intravenous infusion of enoxaparin controls thrombin formation more than standard subcutaneous administration in critically ill patients. A sub-study of the ENOKSI thromboprophylaxis RCT.

INTRODUCTION: Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis. MATERIALS AND METHODS: Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h. RESULTS: At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05). CONCLUSIONS: Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.

Prognostic value of the 2010 consensus definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) complicates the recovery of approximately 30% of patients with aneurysmal subarachnoid hemorrhage (aSAH). The definition of DCI widely varies, even though a consensus definition has been recommended since 2010. This study aimed to evaluate the prognostic value of the 2010 consensus definition of DCI in a cohort of patients with aSAH. METHODS: We conducted a single-center, retrospective, observational study that included consecutive adult patients with aSAH who were admitted to the intensive care unit from January 2010 to December 2014. DCI was evaluated 48 h to 14 days after onset of aSAH symptoms using the 2010 consensus criteria and outcome was assessed by the Glasgow Outcome Scale (GOS) at discharge from hospital. RESULTS: A total of 340 patients were analyzed and the incidence of DCI was 37.1%. The median time from primary hemorrhage to the occurrence of DCI was 97 h. Neurological deterioration was observed in most (89.7%) of the patients who fulfilled the DCI criteria. The occurrence of DCI was strongly associated with an unfavorable outcome (GOS 1-3) at hospital discharge (OR 2.65, 95% CI 1.69-4.22, p < 0.001). CONCLUSIONS: The incidence of DCI after aSAH is high and its occurrence is strongly associated with an unfavorable neurological outcome. This finding adds to the previous literature, which has shown that DCI appears to be a major contributor affecting the functional ability of survivors of aSAH. To further advance reliable knowledge of DCI, future studies should adhere to the consensus definition of DCI.

Activation of Blood Coagulation After Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Trial of Rotational Thromboelastometry.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) has been reported to actuate blood coagulation. Rotational thromboelastometry (ROTEM) is a dynamic hemostatic test that can differentiate various coagulation abnormalities. For example, increased coagulation activity can be detected as a wider amplitude of tracing (maximal clot firmness [MCF]). ROTEM had not been used to evaluate coagulation changes after aSAH. We evaluated the on-going coagulation process in patients with aSAH in a prospective, observational study to compare their ROTEM assay results with the control values obtained from patients undergoing clipping of nonruptured aneurysms. METHODS: ROTEM analyses were performed at 12, 24, 48, and 72 hours after the onset of aSAH and compared with the preoperative analyses from the control group. A total of 17 patients with aSAH treated in the intensive care unit and 16 control patients were enrolled. RESULTS: At 72 hours, EXTEM-MCF was significantly greater in patients with aSAH compared with the baseline values of the control group (68.0 mm [interquartile range (IQR), 66.0-71.0] versus 64.5 mm [IQR, 59.5-66.8]; P = 0.024). This was mainly due to increased fibrin formation and fibrin polymerization. The same comparison in the FIBTEM-MCF analysis yielded similar results (aSAH group, 23.0 mm [IQR, 19.0-25.0] vs. control group, 15.4 mm [IQR, 12.5-17.8], respectively; P = 0.001). CONCLUSIONS: Blood coagulation is activated at 72 hours after aSAH onset, which can be detected by ROTEM EXTEM-MCF analysis. Also, the FIBTEM-MCF was elevated, implying that the relative contribution of fibrin formation and fibrin polymerization is essential.

Autoimmune heparin-induced thrombocytopenia of delayed onset: a clinical challenge.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) usually appears at 5 to 10 days after initiation of heparin. Autoimmune HIT can arise after discontinuation of heparin treatment (delayed-onset HIT) or without any preceding heparin exposure (spontaneous HIT syndrome). CASE REPORT: This case presents a course of autoimmune HIT with delayed onset. The patient was hospitalized due to influenza pneumonia and received low-molecular-weight heparin thromboprophylaxis for 9 days. Seven days after discharge, she was readmitted because of a cerebral sinus vein thrombosis and severe thrombocytopenia. Intracranial bleeding and brain infarction caused her death. DISCUSSION: Autoimmune HIT was confirmed by functional heparin-induced platelet (PLT) activation test. Intracranial bleeding prevented continuous and effective anticoagulation. PLT transfusions were given, although they are generally advised against in HIT patients due to potential risk of thromboembolic events. CONCLUSION: This case presents that testing PLT-activating antibodies both in the presence and in the absence of current heparin treatment helps to diagnose patients with autoimmune HIT. There is conflicting evidence to refuse PLT transfusion when HIT is complicated with life-threatening bleeding.

Plasma anti-FXa concentration after continuous intravenous infusion and subcutaneous dosing of enoxaparin for thromboprophylaxis in critically ill patients. A randomized clinical trial.

INTRODUCTION: In intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti-FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. MATERIALS AND METHODS: This was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40mg as a SCB once daily or 40mg as a CII over 24h for three consecutive days. The primary outcome was maximum serum anti-FXa concentration (Cmax24h) within the first 24h; the secondary outcome was anti-FXa area under the curve (AUC)(0-24h). Trough level was measured at 72h. RESULTS: Thirty-nine patients were included in the intention to treat analysis. The median anti-FXa Cmax24h was 0.05 (interquartile range, IQR, 0.05-0.18) IU/ml in the CII group and 0.18 (IQR, 0.12-0.33) IU/ml in the SCB group (p=0.05). Median anti-FXa AUC(0-24h) was 1.20 (IQR, 0.98-2.88) in the CII and 1.54 (IQR, 1.22-4.12) in the SCB group (p=0.095). After 72h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of >0.1IU/ml, compared with 16.7% in the SCB group (p=0.019). CONCLUSIONS: Continuous infusion of enoxaparin led to lower anti-FXa Cmax24h than standard SCB administration. No difference in anti-FXa AUC0-24h was detected.

Plasma anti-FXa level as a surrogate marker of the adequacy of thromboprophylaxis in critically ill patients: A systematic review.

BACKGROUND: Critical care patients are prone to venous thromboembolism (VTE) and, thus, pharmacological thromboprophylaxis is generally advised. Low-molecular weight heparins (LMWHs) have become the drug of choice in ICU patients, since their predictable and reproducible dose response. Monitoring their pharmacological effect is not usually necessary except in special occasions (i.e. with obese or renal failure patients), where anti-FXa level measuring is recommended. However, there is neither recommendation of adequate anti-FXa levels in critically ill patients nor is it known whether peak or trough level should be measured. The aim of this systematic review was to evaluate the recommended LMWH doses, and the reasons to monitor anti-FXa levels. METHODS: We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.com to identify all potentially relevant studies. Prospective studies done in critically ill patients were included if at least one anti-FXa level (i.e. peak or trough) after any specified LMWH thromboprophylaxis dose was measured. RESULTS: Total 18 eligible studies including 1644 patients were included. There was a wide variation in the median peak anti-FXa levels (<0.1-0.35IU/ml). Trough levels were generally low. Of note, none of the studies detected any correlation with bleeding events and anti-FXa levels. Low trough level increased incidence of DVT in one study only. CONCLUSION: Based on the current literature, no definite conclusions can be drawn on targeted anti-FXa level in critically ill patients when using LMWH thromboprophylaxis.