The Acute Effect of Chamomile Intake on Blood Coagulation Tests in Healthy Volunteers: A Randomized Trial.

BACKGROUND: Chamomile administration may have desirable effects in the perioperative setting. Current practice, however, discourages perioperative chamomile use due to a theoretical increase in bleeding. Therefore, we evaluated if chamomile acutely (within 4 h of ingestion) prolongs coagulation assays. METHODS: Eight healthy volunteers were randomized to receive 2 interventions in a crossover design: (a) single dose of chamomile extract capsule (500 mg) and (b) single dose of chamomile tea (3 g in 150 mL water). Interventions were separated at least 3 days apart from each other. Blood was sampled pre-ingestion, 2 h post-ingestion, and 4 h post-ingestion for each intervention. The primary outcome was the maximal change in prothrombin time (PT) before vs after each intervention. Secondary outcomes included changes in international normalized ratio, activated partial thromboplastin time, thrombin time, reptilase time, and fibrinogen levels. RESULTS: All 8 subjects completed the study. The average pre-ingestion PT values for tea and capsules were 11.9 (1.1) s and 12.0 (0.9) s, respectively. Tea significantly increased the average maximum PT by 0.7 (0.2) s (P = 0.0078). Extract capsules increased the maximum PT by 0.3 (0.2) s (P = 0.06). Neither PT prolongation met the predefined 10% threshold for clinical significance. No significant changes in secondary outcomes were observed. CONCLUSIONS: Chamomile tea ingestion prolongs PT. However, the clinical significance of this is unclear at this time and warrants further investigation. ClinicalTrials.gov Registration Number: NCT05272475.

Introduction of a high sensitivity troponin reduces ED length of stay.

BACKGROUND: High sensitivity cardiac troponins (hs-cTn) allow earlier identification and exclusion of acute myocardial infarction. We determined if transitioning from contemporary to high sensitivity troponin T (hs-cTnT) would reduce ED length of stay in chest pain (CP) patients. METHODS: We conducted a pragmatic, prospective, before and after study of implementing a hs-cTnT by reviewing the electronic health records in all adult ED patients presenting to a large, suburban academic medical center during the 3 months before and after transitioning from a 4th generation troponin to a 5th generation hs-cTnT (Elecsys® Troponin T-high sensitive, Roche Diagnostics, Indianapolis, IN). RESULTS: There were 1431 and 1437 CP patients before and after the intervention. Mean (SD) age was 51.5 (18) yrs. and 54.3% were female. The median (IQR) ED LOS for chest pain patients directly discharged to home was 6.2 (4.7-8.4) and 5.3 (4.0-7.2) hours before and after introducing hs-cTn respectively; difference 47 min (95%CI, 35-59); P < 0.001. The median (IQR) ED LOS for chest pain patients admitted to the hospital was 9.5 (6.6-13.8) and 8.1 (5.7-11.2) hours before and after introducing hs-cTn respectively; difference 77 min (95%CI, 35-121); P < 0.001. Overall admission rates (22 vs 21% both before and after) did not change during the study. The rates of computed tomography coronary angiography before and after the intervention were 21 and 20.4% respectively. The rates of invasive coronary angiography before and after the intervention were 5.8 and 5.6% respectively. CONCLUSIONS: Transitioning to a hs-cTnT is associated with a clinically relevant and statistically significant reduction in ED LOS for both discharged and admitted patients with and without CP with no increase in admission or coronary angiography rates.

Effect of chamomile intake on blood coagulation tests in healthy volunteers: a randomized, placebo-controlled, crossover trial.

BACKGROUND: Chamomile is consumed worldwide for enjoyment and its potentially desirable properties. Widespread patient resource websites, however, discourage preoperative chamomile intake, lest bleeding could worsen. This precaution, though, stems largely from indirect evidence in one case report. To evaluate if chamomile ingestion impacts coagulation assays via coumarin-like substances, we designed a randomized, placebo-controlled, crossover study. MATERIALS AND METHODS: Healthy volunteers were randomized to three interventions in a cross-over-design spanning 5 weeks per subject. Interventions included 7-day consumption of chamomile tea (3 tea bags × 3 times daily = 9 tea bags daily), a chamomile extract capsule (3 times daily), or a placebo capsule (3 times daily). A 7-day washout period elapsed between intervention periods. The primary outcome was the change in prothrombin time (PT) before vs. after each intervention. Secondary outcomes included changes in the international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), reptilase time (RT), and fibrinogen (FG) surrounding each intervention. RESULTS: All 12 enrolled subjects were randomized and completed the study. The primary outcome of PT change (mean ± SD) was similar across interventions (chamomile tea = - 0.2 ± 0.4 s, extract capsule = - 0.2 ± 0.4 s, and placebo capsule = 0.1 ± 0.5 s; p = 0.34). INR change was 0 s (p = 0.07) for each intervention. The aPTT, TT, RT, and FG, did not change significantly across interventions (p = 0.8, p = 0.08, p = 0.8, and p = 0.2 respectively). CONCLUSIONS: Chamomile intake by tea or capsule does not prolong PT. These findings challenge the notion to avoid perioperative chamomile intake in patients not taking warfarin. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05006378; Principal Investigator: Jonathon Schwartz, M.D.; Registered August 16, 2021.

Novel characteristics of soluble fibrin: hypercoagulability and acceleration of blood sedimentation rate mediated by its generation of erythrocyte-linked fibers.

Soluble fibrin (SF) in blood consists of monomers lacking both fibrinopeptides A with a minor population in multimeric clusters. It is a substantial component of isolated fibrinogen (fg), which spontaneously self-assembles into protofibrils progressing to fibers at sub-physiologic temperatures, a process enhanced by adsorption to hydrophobic and some metal surfaces. Comparisons of SF-rich (FR) and SF-depleted (FD) fg isolates disclosed distinct molecular imprints of each via an adsorption/desorption procedure using gold surfaced silica microplates. Accelerated plasminogen activator-induced lysis and decreased stiffness (G') of thrombin-induced FR fg clots were revealed by thomboelastography. Erythrocyte sedimentation (ESR) in afibrinogenemic plasma (Hematocrit 25-33%) was accelerated by FR fg nearly threefold that of FD fg. Stained smears disclosed frequent rouleaux formations and fibers linking stacked erythrocytes in contrast to no rouleaux by FD fg. Rouleaux formations were more pronounced at 4 °C than at ambient temperatures and at fiber-membrane contacts displayed irregular, knobby membrane contours. One of several FR fg isolates also displayed incomplete fiber networks in cell-free areas. What is more, pre-mixing FR fg with each of three monoclonal IgG anti-fg antibodies at 1.5 mol/mol fg, that inhibited fibrin polymerization, prevented rouleaux formation save occasional 2-4 erythrocyte aggregates. We conclude that spontaneously generated SF fibers bound to erythrocytes forming intercellular links culminating in rouleaux formation and ensuing ESR acceleration which in clinical settings reflects hypercoagulability. Also, the results can explain the reported fg binding to erythrocytes via ligands such as CD47, stable in vivo RBC aggregates in capillaries, and red areas of pathologic thrombi.

Thrombin Generation in Cardiac Versus Noncardiac Surgical Cohorts.

BACKGROUND: Bleeding can be a significant problem after cardiac surgery. As a result, venous thromboembolism (VTE) or anticoagulation or both following mechanical valve implantation are often delayed in these patients. The calibrated automated thrombin (CAT) generation assay has become the gold standard to evaluate thrombin generation, a critical step in clot formation independent of other hemostatic processes (eg, platelet activation, fibrin cross-linking, and fibrinolysis), and is increasingly used to examine thrombotic and hemorrhagic outcomes. No study has currently used this assay to compare the thrombin generation profiles of cardiac surgical patients to noncardiac surgical patients. We hypothesize that noncardiac patients may be less prone to postoperative changes in thrombin generation. METHODS: A prospective, observational, cohort study was undertaken using blood samples from 50 cardiac and 50 noncardiac surgical patients preoperatively, immediately postoperatively, and on postoperative days 1 to 4. Platelet-poor plasma samples were obtained from patients preoperatively, on arrival to the postanesthesia care unit (PACU) or intensive care unit (ICU), and daily on postoperative days 1 to 4 if patients remained inpatient. Samples were evaluated for CAT measurements. Patient and surgical procedure characteristics were obtained from the electronic medical record. RESULTS: The primary outcome variable, median endogenous thrombin potential (ETP), measured in nanomolar × minutes (nM × min), was decreased 100% in cardiac surgical versus 2% in noncardiac patients (P < .001). All parameters of thrombin generation were similarly depressed. Cardiac (versus noncardiac) surgical type was associated with -76.5% difference of percent change in ETP on multivariable regression analysis (95% confidence interval [CI], -87.4 to -65.5; P value <.001). CONCLUSIONS: Cardiac surgical patients exhibit a profound decrease in thrombin generation postoperatively compared with noncardiac surgical patients evaluated by this study. Hemodilution and coagulation factor depletion likely contribute to this decreased thrombin generation after cardiac surgery.

Clinical pathology resident education during the COVID-19 pandemic.

COVID-19 arrived at our medical centre in March 2020 with substantial force. Clinical pathology concepts began to have a new, direct relevance to our residents' lives. As we wondered 'Have I been exposed? Do I need to self-isolate? Are the tests reliable? Am I protecting myself adequately while handling specimens?', these questions drew new interest in laboratory methods, test interpretation and limitations, supply chain issues, safety and quality. By incorporating SARS-CoV-2 teaching points into laboratory medicine lectures, we enlivened concepts of sensitivity, specificity, predictive value and methodologic issues in serologic, molecular and antigen testing for pathology residents. We drew from the emerging literature on SARS-CoV-2 to create lectures and added details from our own institutional experience with COVID-19. When the pandemic fades from memory, clinical pathology education can still benefit from mnemonics, analogies, anecdotes and creative efforts that capture the attention of the audience.

Targeting Two Antigens Associated with B-ALL with CD19-CD123 Compound Car T Cell Therapy.

The recent FDA approval of the first CAR immunotherapy marks a watershed moment in the advancement toward a cure for cancer. CD19 CAR treatment for B cell acute lymphocytic leukemia has achieved unprecedented remission rates. However, despite success in treating previously relapsed and refractory patients, CD19 CAR faces similar challenges as traditional chemotherapy, in that malignancy can adapt and overcome treatment. The emergence of both antigen positive and negative blasts after CAR treatment represents a need to bolster current CAR approaches. Here, we report on the anti-tumor activity of a CAR T cell possessing 2 discrete scFv domains against the leukemic antigens CD19 and CD123. We determined that the resulting compound CAR (cCAR) T cell possesses consistent, potent, and directed cytotoxicity against each target antigen population both in vitro and in vivo. Our findings indicate that targeting CD19 and CD123 on B-ALL cells may be an effective strategy for augmenting the response against leukemic blasts and reducing rates of relapse.

Laboratory Monitoring of Platelet P2Y12 Receptor Inhibitors and Reversal of Antiplatelet Agents.

OBJECTIVES: To review the use of laboratory tests for antiplatelet agents to determine escalation of antiplatelet therapy and for emergent reversal of P2Y12 inhibitors. METHODS: A case scenario and review of cardiovascular and neurointerventional literature are described. RESULTS: In cardiovascular disease patients, large randomized trials failed to demonstrate superiority of tailored antiplatelet regimens using the VerifyNow P2Y12 assay, where earlier studies had shown promise. Platelet transfusions restored platelet function measured by vasodilator-stimulated phosphoprotein, light transmission aggregometry, or thromboelastography but not VerifyNow P2Y12, with the most restoration for clopidogrel and the least for ticagrelor. CONCLUSIONS: Current evidence does not support changing antiplatelet therapy based on the results of platelet function monitoring tests. For emergent reversal of P2Y12 inhibitors, test method can affect platelet dosing recommendations, as different methods may give different results.

Negative Heparin-Induced Thrombocytopenia Test Result After Massive Transfusion: Believe It or Not?

OBJECTIVES: Diagnosis of heparin-induced thrombocytopenia (HIT) is complicated by a high false-positive rate for the screening enzyme immunoassay (EIA) and limited availability of confirmatory platelet activation assays such as serotonin release assay (SRA). We evaluate the impact of a massive transfusion on EIA and SRA testing and emphasize that the timing of the confirmatory sample is important. METHODS: We present a case in which separate samples for HIT testing were collected before and after a major bleed requiring massive transfusion. We also discuss a recent study in which HIT serum samples were diluted in vitro and in vivo. RESULTS: The EIA was strongly positive, but SRA was negative, leading to suspicion of a false-positive EIA result. However, SRA performed on the initial EIA specimen was strongly positive. A second EIA, drawn after a massive transfusion, was negative. CONCLUSIONS: Replacement of several blood volumes diluted the HIT antibodies below the limit of detection. Confirmatory testing for HIT antibodies should be done on the specimen that initially tested positive.

Enhancing bone marrow regeneration by SALL4 protein.

Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient's morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.

Platelet activity measured by a rapid turnaround assay identifies coronary artery bypass grafting patients at increased risk for bleeding and transfusion complications after clopidogrel administration.

BACKGROUND: We sought to establish a metric for easily estimating bleeding and transfusion risks for cardiac surgery patients after antiplatelet agent use. METHODS: Deidentified records of patients who underwent coronary artery bypass grafting (CABG) at our institution (January 2010-June 2011) were searched for patients without identified risk factors for excessive bleeding who underwent documented P2Y12 testing after clopidogrel administration (n = 276). Clinical outcomes were analyzed according to whether preoperative platelet function was higher (platelet reactivity units [PRUs], ≥237) or lower (PRU, <237) and according to preoperative PRU cutoffs: high (>290, or no clopidogrel), intermediate (200-290), or low (<200). RESULTS: Eighty-five patients (57%) received allogeneic blood products at 24 hours or less postoperatively: 33 (22%) received fresh frozen plasma, and 57 (38%) received platelets. The median 12-hour chest tube output (CTO) was 350 mL (interquartile range, 260-490 mL); CTO was "high" (>437 mL) in 62 (42%) of the clopidogrel-treated patients. Lower-PRU patients were more likely to receive coagulation factors (odds ratio [OR], 2.82; P = .0004) and to have high CTO or coagulation factor transfusion (OR, 2.35; P = .02) than higher-PRU patients. Likewise, intermediate- and low-PRU patients had incrementally greater incidences of high CTO (OR, 1.72; P = .002) and coagulation factor transfusion (OR, 2.08; P < .0001) than high-PRU/no clopidogrel patients. High CTO or coagulation factor transfusion was more frequent in intermediate-PRU (OR, 2.67; P = .02) and low-PRU (OR, 5.08; P = .0002) patients than in high-PRU/no clopidogrel patients. CONCLUSIONS: Among clopidogrel-treated CABG patients, preoperative platelet function testing can identify those at increased risk for postoperative bleeding and transfusion.

Contamination of patient blood samples by avian RBCs from control material during automated hematology analysis.

OBJECTIVES: Atypical nucleated RBCs (NRBCs) found on several patient blood smears between 2010 and 2012 were noted to resemble avian RBCs. NRBCs are not normally found in the circulation beyond the neonatal period and may indicate hematologic disease, malignancy in the bone marrow, or other severe conditions. Our blood smears with unusual NRBCs did not contain other abnormalities that typically accompany NRBCs, such as immature cells or dysplastic granulocytes. To investigate this anomaly, we considered possibilities such as contaminated collection tubes and instrument problems. The Retic-C Cell Control used with the LH 750 Hematology Analyzer contains a mixture of human and avian RBCs. METHODS: CBC count with differential tests were performed on blanks and routine laboratory samples run immediately after the Retic-C Cell Control on the LH 750 and LH 780 analyzers to recreate the conditions that might cause spillage into the next tube. RESULTS: We experimentally reproduced the phenomenon of contamination of a subsequent tube with avian cells from a multiply punctured reticulocyte control tube. CONCLUSIONS: We concluded that the NRBCs likely represented avian RBCs from the Retic-C Cell Control that had been introduced into the patient tubes.