Alternative Anticoagulants Research Articles

A Difficult Task: Determining Oral Anticoagulation Efficacy (OAC) in Patients with HIT Type II

Since 1937, heparin has remained the anticoagulant of choice for a wide variety of clinical scenarios. There remains a relatively high prevalence of heparin-induced thrombocytopenia (HIT), an immune-mediated syndrome in which antibodies (most frequently IgG) bind to a complex of heparin and platelet factor IV, resulting in platelet destruction and the release of prothrombotic platelet derived microparticles. Serious complications include thrombocytopenia (usually occurring between 6-12 days after initiating therapy) and thrombosis. The risk of thrombosis in patients with HIT is estimated at 30% and mortality rates have been reported as high as 20-30%. In cases of HIT type II when patients require continuous anticoagulation, such as following implantation of mechanical heart valves, alternative anticoagulants such as direct thrombin inhibitors can be used. The difficulty of using drugs such as argatroban for bridging therapy to warfarin is that they have been found to elevate both the aPTT as well as INR. Therefore, is it difficult to assess whether patients will maintain therapeutic INRs when argatroban is held and they are continued on warfarin monotherapy. The standard treatment regimen calls for argatroban to be started until INR reaches some therapeutic level at which time argatroban is held and INR is rechecked 4-6 hours later. The risk of major bleeding associated with supra-therapeutic INR's is substantial, and as such patients should be continued on bridging therapy to the lowest INR level that is still found to be therapeutic once argatroban is held. Previous research has examined the efficacy of transitioning from argatroban to warfarin in patients with HIT type II. This case report reviews the care of a patient following a diagnosis of HIT, the methods used to measure the efficacy of oral anticoagulation (OAC), and the complications that arose with management. The patient is a 51-year-old woman who received a mechanical mitral valve replacement for mitral valve regurgitation. Two weeks later, she returned to the hospital with lower extremity swelling. On admit, the patient's INR was sub-therapeutic at 1.2. Enoxaparin was initiated with plans to bridge to warfarin until the INR reached 2.5-3.5. Within four days of enoxaparin initiation, platelets decreased from 238,000/uL to 114,000/uL. On day four, a new non-occlusive right internal jugular thrombus was found. A serotonin release assay (SRA) and HIT antibody with reflex were ordered. While labs were in process, enoxaparin was held and argatroban initiated. The PTT was checked and found to be 62.6 seconds, and it was determined that the patient was adequately anticoagulated. A 4-T score of 6 indicated a ~64% probability of HIT with the patient requiring indefinite anticoagulation due to the mechanical mitral valve. When the patient's INR reached 2.5 argatroban was held, however the following INR was found to be subtherapeutic at 1.3. Argatroban was restarted with plans to continue argatroban therapy until INR>4, at which time argatroban was to be held and INR rechecked in 4-6 hrs. If the INR remained therapeutic off argatroban then it was determined that the patient was appropriately anticoagulated. When the INR reached 4.9 and argatroban was held, the recheck 5 hours later was 3.1. Using this algorithm, the patient ultimately achieved a therapeutic INR with platelet counts of >300,000/uL at time of discharge without any major bleeding events or other serious complications. For patients in whom HIT is diagnosed, immediate discontinuation of heparin infusions and elimination of heparin from all flushes and ports is a necessity as the first step of treatment. Argatroban may be used as a bridging agent, but OAC efficacy cannot be monitored solely using the parameter of INR due to argatroban's INR-elevating effect. By trending the aPTT to monitor anticoagulation status and only utilizing the INR once argatroban therapy was removed, we ensured that the patient had achieved OAC efficacy prior to discharge. In our patient an INR of 5 did not result in any major bleeding incident; however, by initially discontinuing prematurely at an INR of 2.5, the patient's hospital stay was extended. The chromogenic factor X assay has shown some accuracy in predicting INR free of argatroban influence by measuring the amount of vitamin x, but further studies are warranted to establish an optimal method by which to convert patients from argatroban to warfarin. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric Spontaneous Heparin-Induced Thrombocytopenia and Thrombosis Resulting in Thrombotic Storm

Background: The annual incidence of venous thromboembolism in pediatric patients is approximately 6 out of 1000 in the United States. In rare cases, rapid progression of multifocal thrombosis occurs despite therapeutic anticoagulation with heparin or low molecular weight heparin. Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic disorder caused by an IgG-mediated immune response against platelet factor 4 resulting in platelet activation and risk of thrombosis, classically associated with prior exposure to heparin. The literature reports rare cases of adult patients developing HIT and thrombosis (HITT) without prior exposure. Objective: Aim to describe a case of spontaneous HITT in a pediatric patient which has never previously been published in the literature. Design/Method: Single subject case report developed with literature review. Results: 2-year-old male with no past medical history who presented with 5 days of frontal headaches and irritability. Neuroimaging, including CT, MRI, and MRV demonstrated extensive sinus venous thrombosis requiring initial anticoagulation with heparin. However, within 48 hours of initiation, the patient developed significant thrombocytopenia concerning for HIT. Lab testing was positive for both heparin-induced antibody and serotonin release assay, despite no prior heparin exposure. The remainder of the hypercoagulability workup was negative. Heparin was discontinued and the patient subsequently showed inadequate response to initial treatment with first-generation1 direct thrombin inhibitor (DTI) (Argatroban). Due to ongoing severe progressive symptomatic thrombocytopenia and thrombosis concerning for HIIT with thrombotic storm, the patient was treated with DTI (Bivalirubin), high dose methylprednisolone, and anti-CD20 therapy (Rituximab). This resulted in an improved clinical, laboratory, and neuroimaging response, and the patient was able to be gradually weaned off steroid therapy, and transitioned to anticoagulation with warfarin, with plans to remain on long-term anticoagulation. Conclusion: This is the first reported case in the literature of spontaneous HIIT in a pediatric patient. Spontaneous HITT is the primary explanation due to fulminant thrombosis and positive heparin-induced antibody and serotonin release assay with no prior heparin exposure, thrombocytopenia without immediate improvement upon heparin discontinuation, and blood smear showing normal red blood cell and platelet morphology. Spontaneous HIIT is a rare but important differential to consider in patients presenting with thrombosis and thrombocytopenia as the treatment differs from that of classic HIT, requiring heparin discontinuation, alternative anticoagulation, and immunomodulation.

DP-Filter, a Rapid and Ergonomic Device to Remove Direct Thrombin Inhibitor Argatroban from Plasma for Routine Hemostasis Tests

Argatroban is a direct thrombin inhibitor (DTI) used as an effective alternative anticoagulation therapy in patients suffering from heparin-induced thrombocytopenia (HIT), a serious and potentially life-threatening condition. One of its limitations is its need to be administered intravenously in a continuous manner because of its short half-life in patients without hepatic dysfunction. Thus, a transition towards another long-term anticoagulation therapy, for instance with anti-vitamin K drugs, is usually recommended once HIT is no longer acute and platelet count is stabilized. However, during the transition, remaining plasma levels of argatroban may interfere with hemostasis testing used to monitor the patient response to new anticoagulation drug dosage. The DP-Filter is a functional and user-friendly device used for plasma preparation. This device was already proven effective to substitute the second centrifugation step for platelet poor plasma preparation and to remove direct oral anticoagulants from citrated plasma. We aimed to assess the efficacy of the DP-Filter to remove argatroban from human plasma samples in a fast, practical, and ergonomic way. Argatroban was spiked in human normal pooled plasma (NPP) samples at six concentrations (0.0 [Hepes buffer], 0.1, 0.25, 0.5, 1.0 and 2.0 µg/mL). NPP samples were provided by NAB-X biobank from the University of Namur (Belgium) and were collected on March 23rd, 2022. NPP samples were collected from 8 men and 24 women, with mean age of 22 years old (min = 19 ; max = 48) and mean BMI of 23 (min = 19 ; max = 29). Blood samples were collected in accordance with the Declaration of Helsinki following approval by the Ethical Committee of the CHU UCL Namur (Yvoir, Belgium) under the approval number B03920096633. Argatroban levels were assessed in duplicates in spiked NPP samples before and after filtration with DP-Filter using argatroban-calibrated STA-ECAII testing (Argatroban Plasma Calibrator from Hyphen BioMed). Increasing concentrations of argatroban were measured in non-filtered spiked NPP samples while filtration through DP-Filter reduced argatroban levels close to 0.0 µg/mL, even when spiked concentration was as high as 2.0 µg/mL (Figure 1). Among routine coagulation tests, the activated partial thromboplastin time (aPTT) can be used to assess the anticoagulant effect of DTI. Thus, aPTT was used as a sensitive clotting test to assess the performance of the DP-filter to restore the baseline (i.e. in absence of argatroban) clotting capacity of the plasma. This was determined in duplicates using STA-PTT A5 testing with silica as activator. Filtration through DP-Filter was able to restore normal aPTT values, even at the highest tested argatroban concentration (i.e. 2.0 µg/mL). Similar results were obtained on filtered and non-filtered NPP samples spiked with 0.0 µg/mL of argatroban, confirming the absence of impact of DP-Filter on aPTT testing itself (Figure 2). Altogether, our results show that DP-Filter is an effective, rapid and ergonomic tool to remove argatroban from plasma. It can be used in clinical routine to remove the interference of argatroban with hemostasis tests and therefore avoid false positive or false negative results and unnecessary testing. It also emerges as a solution to ease the monitoring of the transition from patient anticoagulation with argatroban to another anticoagulation therapy such as anti-vitamin K drugs. This might be of particular importance in patients suffering from HIT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Potential of Garlic Filtrate as An Alternative Anticoagulant for Whole Blood Samples

Synthetic anticoagulants such as heparin, citric, and ethylenediaminetetraacetic acid (EDTA) are commonly used to prevent blood clots. In contrast, its widespread use in clinical laboratories is still constrained by price, its toxic nature, and its short shelf life. Therefore, an alternative material that is relatively cheap, non-toxic, and easy to obtain and process in a ready-to-use form is needed. Garlic contains allicin and ajoene, which are anti-platelet and anti-thrombogenic. This study’s aim is to explore the potential of garlic filtrate as an alternative anticoagulant. Blood from 16 individuals was used and separated into four groups: non-anticoagulant, 50 μL/mL garlic filtrate, 100 μL/mL garlic filtrate, and 150 μL/mL heparin, for a total of 64 treatments. The Lee and White method showed that non-anticoagulated blood had normal clotting times (mean 8 minutes and 56 seconds), whereas heparin plasma and garlic filtrate plasma had longer clotting times (more than 20 minutes); and this is statistically different based on the ANOVA test with a significance value (p) of 0.000 < 0.05. On spectrophotometric measurements, the levels of calcium ions in heparinized plasma and serum were 8.66 mg/dL and 8.52 mg/dL, respectively, while in garlic plasma filtrate of 50 μL/mL and 100 μL/mL were 4.13 mg/dL and 3.58 mg/dL, respectively; this is also statistically different based on the ANOVA test with a significance value of 0.000 < 0.05. The differences indicate that garlic filtrate can extend clotting time and reduce calcium ions therefore it is worth reviewing as an alternative anticoagulant.

Novel Coagulation Test Detects Anticoagulation Resistance and Is Associated With Thrombotic Events in Pediatric Patients Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES:Bivalirudin, an IV direct thrombin inhibitor, and unfractionated heparin (UFH) are frequently used anticoagulants in the pediatric critical care setting. An accurate, specific, point-of-care test to quantify and detect anticoagulation resistance is not currently available. This study evaluates the ability of a rapid (< 10 min), micro-volume (< 50 uL) coagulation test to detect and quantify the anticoagulation effect of bivalirudin and UFH using a functional, clot time endpoint in pediatric critical care patients.DESIGN:Single-site retrospective laboratory sample analysis and chart review.SETTING:A 105-bed pediatric and cardiac ICUs delivering extracorporeal membrane oxygenation.SUBJECTS:Forty-one citrated, frozen, biobanked plasma specimens comprising 21 with bivalirudin and 20 with UFH from 15 anticoagulated pediatric patients were analyzed. Thirteen patients were on extracorporeal membrane oxygenation, one had a submassive pulmonary embolism, and one was on a left ventricular assist device.INTERVENTIONS:None.MEASUREMENT AND MAIN RESULTS:A Clotting Time Score (CTS) was derived on each sample. The CTS detected patients that had developed a pathologic clotting event with 100% sensitivity and 82% specificity compared with prothrombin time with 25% sensitivity/76% specificity and activated partial thromboplastin time with 0% sensitivity/0% specificity. Additionally, the CTS detected subtherapeutic anticoagulation in response to UFH in patients that were clinically determined to be UFH resistant requiring alternative anticoagulation with bivalirudin.CONCLUSIONS:The CTS appears to be a clinically valuable indicator of coagulation status in patients treated with either UFH or bivalirudin. Results outside of the therapeutic range due to inadequate dosing or anticoagulation resistance appeared to be associated with clot formation. CTS testing may reduce the risk of anticoagulation-related complications via the rapid identification of patients at high risk for pathologic thrombotic events.

Marine Biological Macromolecules and Chemically Modified Macromolecules; Potential Anticoagulants.

Coagulation is a potential defense mechanism that involves activating a series of zymogens to convert soluble fibrinogen to insoluble fibrin clots to prevent bleeding and hemorrhagic complications. To prevent the extra formation and diffusion of clots, the counterbalance inhibitory mechanism is activated at levels of the coagulation pathway. Contrariwise, this system can evade normal control due to either inherited or acquired defects or aging which leads to unusual clots formation. The abnormal formations and deposition of excess fibrin trigger serious arterial and cardiovascular diseases. Although heparin and heparin-based anticoagulants are a widely prescribed class of anticoagulants, the clinical use of heparin has limitations due to the unpredictable anticoagulation, risk of bleeding, and other complications. Hence, significant interest has been established over the years to investigate alternative therapeutic anticoagulants from natural sources, especially from marine sources with good safety and potency due to their unique chemical structure and biological activity. This review summarizes the coagulation cascade and potential macromolecular anticoagulants derived from marine flora and fauna.

Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort.

BackgroundCOVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain.ObjectiveWe aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma.Patients/MethodsWe included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH.ResultsAnti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG.ConclusionIn a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19.

Effects of systemic anticoagulation in a murine model of compensatory lung growth.

Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.

Anticoagulation Prescribing Patterns in Intensive Care Unit Patients Admitted with Prehospital Direct Oral Anticoagulant Therapy: A Single Academic Center Experience.

To describe the current prescribing practices of direct oral anticoagulants (DOACs) in intensive care unit (ICU) patients and the associated clinical outcomes, including the incidence of major bleeding episodes and the need for intervention (endoscopic, surgical, or interventional radiology guided). Observational, retrospective chart review. Single large academic center study. Participants included patients with critical illness who were admitted to the intensive care units (ICU) at Mayo Clinic from January 1st, 2012, until May 4th, 2018. Adult ICU patients with a DOAC (apixaban, rivaroxaban, dabigatran, or edoxaban) listed as one of the active medications at the time of hospital admission were included. 37 249 patients in medical and surgical intensive care units were screened for the study period. After excluding patients who did not qualify, 558 unique encounters were included. The median age was 69 (IQR 59-78) years; most patients were male, white Caucasians, and had a median SOFA score of 4. After excluding the patients who had major bleeding episodes in the first 24 hours, 188 (39%) were continued on the same DOAC therapy, 204 (42%) were discontinued without transitioning to another agent, and 95 (20%) were transitioned to another agent. Finally, 410 (84%) were dismissed on DOAC therapy at the end of hospitalization. The difference in the continuation rate of the same DOAC agent beyond 24 hours, discontinuation without transition to an alternate agent, or discontinuation of DOAC with a transition to an alternate anticoagulation agent was not statistically significant (P = .60). A total of 52 major bleeding events were identified. Gastrointestinal bleeding was the most common bleeding complication [n (%): 34 (65)], followed by intra-abdominal and peri-procedural bleeding [7 (13.5) and 7 (13.5)]. Thirty-three (65%) patients had a major bleeding complication requiring intervention. Our single-center retrospective study describes the current prescribing practices and preliminary outcomes in ICU patients with prehospital use of DOACs. Up to 20% of the patients were transitioned to a different agent within 24 hours of ICU admission, whereas a significant proportion of patients (42%) had anticoagulation discontinued altogether. Most patients who suffered a major bleeding episode required either endoscopic or surgical intervention to control bleeding.

A cohort study to assess risk of cutaneous small vessel vasculitis among users of different oral anticoagulants.

Cutaneous small vessel vasculitis (CSVV) was identified as a safety signal among patients treated with direct oral anticoagulants (DOAC). This study aimed to determine if CSVV risk differed among patients with atrial fibrillation (Afib) who newly initiated warfarin or a DOAC. We identified enrollees aged ≥21 years diagnosed with Afib who newly initiated rivaroxaban, dabigatran, apixaban, and warfarin in the Sentinel Distributed Database from October 19, 2010 to February 29, 2020. We selected and followed patients who did not have evidence of the following in the 183 days prior to initiating treatment: CSVV diagnosis, dispensing of other study drugs, select autoimmune diseases or autoimmune medications, cancer diagnoses or chemotherapeutic treatment, kidney dialysis or transplant, alternative anticoagulation indications, or an institutional (nursing home, hospice, hospital) stay on the treatment initiation date (index date) until CSVV outcome or pre-specified censoring. We conducted 1:1 propensity score matching in six comparisons. CSVV incidence rates for DOACs and warfarin ranged from 3.3 to 5.6 per 10 000-person years in our matched Afib population. The adjusted CSVV hazard ratio (HR) and 95% confidence interval (CI) was 0.94 (0.64, 1.39) for rivaroxaban versus warfarin; 1.17 (0.67, 2.06) for dabigatran vs. warfarin; 0.85 (0.62, 1.16) for apixaban vs. warfarin; 0.86 (0.49, 1.50) for rivaroxaban vs. dabigatran; 0.99 (0.68, 1.45) for rivaroxaban versus apixaban; and 1.70 (0.90, 3.21) for dabigatran versus apixaban. We did not find significant evidence of differential CSVV risk in pair-wise comparisons of DOACs and warfarin.

EP-351 Extended VTE prophylaxis in patients undergoing elective surgery for colorectal cancer in a district general hospital and its Compliance with NICE guidelines

Abstract Aim A This audit aims to assess the department's current compliance with guidance, understand reasons for non-adherence and implement a plan of action to improve future compliance and subsequent patient outcomes. Background NICE guidance recommends extended VTE prophylaxis for up to 28 days post colonic resection for cancer Methods A single centre, retrospective, observational study was performed between January 2018 –January 2019. We included all the Patients who underwent elective colorectal resections for cancer. Results A total of 123 patients had elective elective colorectal resections for cancer. 91 (73%) were laparoscopically, 8 (6.5%) laparoscopic converted to open and 24 (19.5%) were done as open operations from the start. The summary of the operations done were as follows; 62 RHC, 25 HAR and 36 LAR. LMWH for extended VTE prophylaxis for 28 days was prescribed for 91% (112/123) of the patients among the studied period. 5.7% (7/123) were already receiving alternative anticoagulation thus the NICE guidance was achieved for 96.7% (119/123). The patients who did not receive VTE prophylaxis were 3.3%, 4/123), there was no clinical reason documented or identified for this omission. A postoperative VTE was experienced in 4.8% (6/123), 3 of them required a hospital admission (50%). There was no VTE related mortality documented Conclusion This audit has demonstrated 96.7% of patients who underwent surgery for colorectal cancer received extended VTE prophylaxis as per NICE guidelines. This is a significant improvement from previous audit cycle, though the aim is for 100% compliance with guidelines. We implement plan of action to achieve that

Prevalence and outcomes of patients developing heparin-induced thrombocytopenia during extracorporeal membrane oxygenation.

Unfractionated heparin (UFH) is the commonly used anticoagulant to prevent clotting of the ECMO circuit and thrombosis of the cannulated vessels. A side effect of UFH is heparin-induced thrombocytopenia (HIT). Little is known about HIT during ECMO and the impact of changing anticoagulation in ECMO patients with newly diagnosed HIT. The aim of the study was to determine the prevalence, complications, impact of switching anticoagulation to argatroban and outcomes of patients developing heparin-induced thrombocytopenia (HIT) during either veno-venous (VV) or veno-arterial (VA) ECMO. Retrospective observational single centre study of prospectively collected data of consecutive patients receiving VV ECMO therapy for severe respiratory failure and VA ECMO for circulatory failure from January 2006 to December 2016 of the Medical intensive care unit (ICU) of the University Hospital of Regensburg. Treatment of HIT on ECMO was done with argatroban. 507 patients requiring ECMO were included. Further HIT-diagnostic was conducted if HIT-4T-score was ≥4. The HIT-confirmed group had positive HIT-enzyme-linked-immunosorbent-assay (ELISA) and positive heparin-induced-platelet-activation (HIPA) test, the HIT-suspicion group a positive HIT-ELISA and missing HIPA but remained on alternative anticoagulation until discharge and the HIT-excluded group a negative or positive HIT-ELISA, however negative HIPA. These were compared to group ECMO-control without any HIT suspicion. The prevalence of HIT-confirmed was 3.2%, of HIT-suspicion 2.0% and HIT-excluded 10.8%. Confirmed HIT was trendwise more frequent in VV than in VA (3.9 vs. 1.7% p = 0.173). Compared to the ECMO control group, patients with confirmed HIT were longer on ECMO (median 13 vs. 8 days, p = 0.002). Different types of complications were higher in the HIT-confirmed than in the ECMO-control group, but in-hospital mortality was not different (31% vs. 41%, p = 0.804). HIT is rare on ECMO, should be suspected, if platelets are decreasing, but seems not to increase mortality if treated promptly.

Heparin-induced thrombocytopenia post-cardiovascular interventional therapy: a case report

BackgroundHeparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction characterized by thrombocytopenia and thromboembolism. Herein, we present a case of HIT with subcutaneous hemorrhage after cardiovascular interventional therapy.Case presentationA 74-year-old man was admitted to the hospital for elective atrial fibrillation (AF) catheter ablation and left atrial appendage closure because of intermittent dizziness and palpitations. At presentation, the routine laboratory test results showed no abnormalities. He received subcutaneous enoxaparin for stroke prevention and unfractionated heparin for intraprocedural anticoagulation during coronary angiography and the AF procedure. On the second day after the AF procedure, the patient developed profound thrombocytopenia, moderate anemia, and mild subcutaneous hematoma. Blood tests and imaging examinations excluded acute hemolysis and other active bleeding. A 4Ts score of 5 and markedly positive platelet factor 4 IgG antibody established the diagnosis of HIT. Due to progressive subcutaneous hemorrhage in the thighs that could not be suppressed by pressure dressing, the patient received platelet transfusion and rivaroxaban for anticoagulation. The following days, the patient remained clinically stable from the hemorrhage, and his platelet count recovered. No thrombotic events occurred during hospitalization or follow-up.ConclusionThis case emphasizes the significance of suspecting HIT in patients with unexplained rapid thrombocytopenia after frequent heparin exposure. Decision-making regarding alternative anticoagulation and platelet transfusion in HIT with hemorrhage must be based on unique patient characteristics.

Anticoagulation on Extracorporeal Support: An Alternative Strategy.

To the Editor, We read with extreme interest the updated Extracorporeal Life Support (ELSO) guidelines for anticoagulation during extracorporeal membrane anticoagulation (ECMO)1 and would like to integrate this valuable document with a potential alternative therapeutic anticoagulation strategy for patients requiring veno-venous ECMO. This approach is based on subcutaneous administration of low-molecular-weight heparin (LMWH) 3 times a day, paired with antifactor Xa (anti-Xa) assay monitoring, 3 times a day, each sample equidistant between two administrations of LMWH. Anticoagulation monitoring is integrated on a regular schedule with additional blood tests, including hemoglobin and hematocrit, platelets count, Fibrinogen, D-dimers, haptoglobin levels, and with full coagulation tests and point-of-care viscoelastic testing on an as needed basis. We designed and started implementing an algorithmic protocol (detailed in Figure, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A838) to standardize dosage adjustment based on anti-Xa value, potential evidence of clinically significant bleeding or prothrombotic states, and eventual need for surgical interventions or other invasive procedures. Despite paucity of literature related to anticoagulation management based on LMWH only during ECMO support,2–4 we decided to introduce this approach since the second wave of Coronavirus disease 2019 (COVID-19) pandemic, to simplify and standardize anticoagulation management, reducing the strain on the team members, particularly on most recently recruited, and less experienced ones, involved to expand ECMO capacity. The rationale for the off-label three-daily dosing (despite the commonly recommended once/twice daily dosing) is to achieve and constantly maintain a therapeutic level of anticoagulation, avoiding excessive peaks and minimizing peak-to-trough variability, with the aim of effective prevention of thrombosis without increasing bleeding risk.5 The rationale for anti-Xa assessment 4 hours after LMWH administration is to thoroughly evaluate its effect, including peak, occurring 3–5 hours after subcutaneous administration, being able to properly adapt subsequent dosing. During the run, the protocol anticipates some conditions which demand to modify LMWH administration (dose or timing): need for invasive elective or emergent procedures; we do not consider percutaneuos central venous catheter, pulmonary artery catheter and arterial line placement, nor percutaneous tracheostomy among procedures requiring dosing adjustment; evidence of clinically significant bleeding defined (as per ELSO Registry definition); evidence of thrombotic complications (both intracircuit or patient complications). Since the implementation of this protocol, we did not notice increased ratio of thrombotic events; no patient required the circuit to be replaced more than once during the run (mean duration 19 days [6–52]). No cannula thrombosis, nor thrombosis involving the cannula or cannulated vessels have been observed, despite the high risk profile of this patient population. No brain hemorrhages, nor GI or cannulation site bleedings requiring more than medical approach were observed; and increased incidence of pulmonary hemorrhages was noticed: clinical evidence suggested these as presumably disease, rather than anticoagulation, related. We recognize that such an algorithm significantly deviates from conventional clinical practice and from guidelines, but in our limited, single center experience, its application in a population of COVID-19 patients requiring V-V ECMO was feasible and safe (unpublished data, manuscript in preparation), and easy to be implemented at bedside, in selected settings.

Delayed-Type Heparin Allergy: Intravenous Tolerance Despite Inflammatory Skin Reaction After Subcutaneous Injection

Heparin allergy most frequently manifests as delayed-type hypersensitivity (DTH) causing an itchy inflammatory skin reaction at the site of subcutaneous injection. An important differential diagnosis is circumscribed skin necrosis due to heparin-induced thrombocytopenia. An inflammatory skin reaction to subcutaneously injected heparin generally entails the quest for alternative anticoagulation; concerns may particularly arise in an emergency situation requiring intravenous heparin administration. All heparin DTH cases seen in our department over the last 17 years underwent standardized allergy diagnostics including challenge testing, that is, subcutaneous injection of fondaparinux and intravenous administration of unfractionated heparin (UFH). Of a total of 50 patients with confirmed heparin allergy, DTH was found in 48 (96.0%), and immediate-type, presumably IgE-mediated hypersensitivity was diagnosed in only 2 (4.0%). In the 48 DTH cases, intradermal testing revealed broad cross-reactivity between UFH and low-molecular-weight heparins (LMWH) including nadroparin, dalteparin, and enoxaparin. Cross-reactivity with (or concomitant sensitization to) fondaparinux was seen in only 3 (6.3%) cases. Intravenous administration of UFH was tolerated by all 45 patients challenged, despite DTH to UFH and LMWH as demonstrated by intradermal testing. If an inflammatory skin reaction at the site of subcutaneously injected heparin is observed or reported without any evidence of skin necrosis or thrombocytopenia, intravenous administration of UFH seems to be sufficiently safe and may be considered without allergy testing if urgently indicated in an emergency situation. Fondaparinux is the most suitable alternative for subcutaneous application.

Improving compliance with appropriateness of testing for heparin-induced thrombocytopaenia: a quality improvement report

Heparin-induced thrombocytopaenia (HIT) is a serious complication of heparin therapy. Evidence-based guidelines recommend the use of the 4Ts scoring system to calculate pretest probability of HIT. However, this scoring system...

Letter to Editor Response RE: Apixaban: Alternative Anticoagulation for HeartMate 3 Ventricular Assist Device.

Letter to Editor Response RE: Apixaban: Alternative Anticoagulation for HeartMate 3 Ventricular Assist Device.

Direct Thrombin Inhibition in Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a widely used technique to provide circulatory and/or respiratory support in critically ill patients. ECMO treatment usually necessitates systemic anticoagulation. Unfractionated Heparin (UFH) is a commonly used anticoagulant in patients on ECMO support. In situations where UFH is contraindicated, alternative anticoagulation strategies can be applied, such as the use of direct thrombin inhibitors (DTI). Bivalirudin and argatroban are the most widely used DTIs. In this report we give account of the current evidence regarding dosing, monitoring and complications associated with the use of these agents in ECMO dependent patients.

A HeartMate 3 Implantation without Anticoagulation

<h3>Introduction</h3> Left ventricular assist device (LVAD) implantation is an established treatment for advanced heart failure. LVADs are implanted using intra-operative anticoagulation with or without cardiopulmonary bypass. However, the anticoagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. We report the first anticoagulant free implantation of a HeartMate 3. We prospectively followed a patient with heart failure and HIT. <h3>Case Report</h3> A 65-year-old man with ischemic cardiomyopathy was admitted with cardiac decompensation, pulmonary edema and cardiogenic shock in a regional clinic where VA-ECMO-therapy was initiated. After transfer to our hospital, he had 2 episodes of oxygenator thrombosis and later he was diagnosed with HIT. He was anticoagulated with argatroban for his VA-ECMO. The preoperative course was further complicated due to recurrent bronchial bleeding. A decision was made to proceed with mechanical circulatory support using a HeartMate 3 ventricular assist device (Abbott, Chicago, IL). To avoid the risk of bronchial bleeding, we performed an anticoagulant-free HeartMate 3 implantation through a full sternotomy on perioperative VA-ECMO support. Argatroban infusion was stopped 2 days before surgery and started again 4 days postoperatively and later switched to phenoprocoumon. There were no episodes of bronchial bleeding. More importantly, there was no signs of thrombosis, organ damage or neurological dysfunction and pump parameters remained stable during follow-up. <h3>Summary</h3> Anticoagulant-free HeartMate 3 implantation appears to be a safe alternative to performing implantation using alternative anticoagulation in patients with HIT.

Prior-Preconditioned Conjugate Gradient Method for Accelerated Gibbs Sampling in “Large n, Large p” Bayesian Sparse Regression

In a modern observational study based on healthcare databases, the number of observations and of predictors typically range in the order of 105–106 and of 104–105. Despite the large sample size, data rarely provide sufficient information to reliably estimate such a large number of parameters. Sparse regression techniques provide potential solutions, one notable approach being the Bayesian method based on shrinkage priors. In the “large n and large p” setting, however, the required posterior computation encounters a bottleneck at repeated sampling from a high-dimensional Gaussian distribution, whose precision matrix Φ is expensive to compute and factorize. In this article, we present a novel algorithm to speed up this bottleneck based on the following observation: We can cheaply generate a random vector b such that the solution to the linear system Φ β = b has the desired Gaussian distribution. We can then solve the linear system by the conjugate gradient (CG) algorithm through matrix-vector multiplications by Φ ; this involves no explicit factorization or calculation of Φ itself. Rapid convergence of CG in this context is guaranteed by the theory of prior-preconditioning we develop. We apply our algorithm to a clinically relevant large-scale observational study with n = 72 , 489 patients and p = 22 , 175 clinical covariates, designed to assess the relative risk of adverse events from two alternative blood anti-coagulants. Our algorithm demonstrates an order of magnitude speed-up in posterior inference, in our case cutting the computation time from two weeks to less than a day. Supplementary materials for this article are available online.