Assessment of Jordanian physicians' knowledge about venous thromboembolism risk and management among COVID-19 patients

Objectives: The aim of this study was to assess Jordanian physicians' awareness about venous thromboembolism (VTE) risk among COVID-19 patients and its treatment protocol. Method(s): This was a cross-sectional-based survey that was conducted in Jordan in 2020. During the study period, a convenience sample of physicians working in various Jordanian hospitals were invited to participate in this study. Physicians' knowledge was evaluated and physicians gained one point for each correct answer. Then, a knowledge score out of 23 was calculated for each. Key Findings: In this study, 102 physicians were recruited. Results from this study showed that most of the physicians realize that all COVID-19 patients need VTE risk assessment (n = 69, 67.6%). Regarding VTE prophylaxis, the majority of physicians (n = 91, 89.2%) agreed that low molecular weight heparin (LMWH) is the best prophylactic option for mild-moderate COVID-19 patients with high VTE risk. Regarding severe/critically ill COVID-19 patients, 75.5% of physicians (n = 77) recognized that LMWH is the correct prophylactic option in this case, while 80.4% of them (n = 82) knew that mechanical prevention is the preferred prophylactic option for severe/critically ill COVID-19 patients with high bleeding risk. Moreover, 77.5% of physicians (n = 79) knew that LMWH is the treatment of choice for COVID-19 patients diagnosed with VTE. Finally, linear regression analysis showed that consultants had an overall higher knowledge score about VTE prevention and treatment in COVID-19 patients compared with residents (P = 0.009). Conclusion(s): All physicians knew about VTE risk factors for COVID-19 patients. However, consultants showed better awareness of VTE prophylaxis and treatment compared with residents. We recommend educational workshops be conducted to enhance physicians' knowledge and awareness about VTE thromboprophylaxis and management in COVID-19 patients.Copyright © 2022 The Author(s). Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved.

Novel Monitoring and Dose Adjustment of Argatroban, a Direct Thrombin Inhibitor, to Maintain Therapeutic Anticoagulation in a Patient With Antiphospholipid Antibody Syndrome, Heparin-Induced Thrombocytopenia, and COVID-19 Pneumonia.

In patients who require systemic anticoagulation, a reliable monitoring method is required to ensure anticoagulation is maintained within the correct therapeutic window and patients are treated appropriately. When titrating direct thrombin inhibitors (DTIs), dilute thrombin time (dTT) measurements have been demonstrated to be more reliable and accurate than activated partial thromboplastin time (aPTT) measurements and thus often the preferred DTI assessment. However, a clinical need arises when both dTT measurements are not readily available and aPTT measurements are unreliable. CASE SUMMARY: A 57-year-old woman with a history of antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, and multiple prior deep venous thromboses and pulmonary emboli was admitted with COVID-19 pneumonia and intubated due to hypoxic respiratory failure. Argatroban was initiated in place of her home medication warfarin. However, the patient had a prolonged aPTT value at baseline and overnight dTT assay measurements were limited at our institution. A multidisciplinary team of hematology and pharmacy clinicians created a modified patient-specific aPTT target range and argatroban dosing was titrated accordingly. Subsequent aPTT values in the modified target range corresponded to therapeutic dTT values, indicating therapeutic anticoagulation was successfully achieved and maintained. Patient blood samples were additionally evaluated retrospectively using an investigational novel point-of-care test that detected and quantified the argatroban anticoagulant effect. CONCLUSIONS: Therapeutic anticoagulation with a DTI in a patient with unreliable aPTT measurements can be achieved with use of a modified patient-specific aPTT target range. Early validation of an investigational rapid testing alternative for DTI monitoring is promising.

Acute limb ischemia secondary to vaccine-induced inmune thrombotic thrombocytopenia (VITT) after ChAdOx1 nCoV-19

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a syndrome that resembles to heparin-induced thrombocytopenia (HIT). Platelet factor 4 (PF-4) reacts to a vaccine component resulting formation of immune complex that stimulates an autoimmune reaction triggering platelet consumption causing thrombus formation and producing thrombotic events. When suspected is important to confirm for make a correct anticoagulation management to avoid complications related to unfractioned and low weight heparins use. In this report we describe a case of acute limb ischemia secondary to ChAdOx1 nCoV-19 vaccine (Astrazeneca, Cambridge, UK)Copyright © 2022

Monitoring of argatroban in COVID-19 ICU patients: A prospective study comparing aPTT, point-of-care viscoelastic testing with ECA-test and dTT to LC/MS/MS

Introduction Argatroban is indicated for treatment of heparin-induced thrombocytopenia, but is also used in critical ill COVID-19 patients presenting with extensive thrombin overload. Direct drug monitoring is not available and argatroban dosing is mainly based on activated partial plasmin time (aPTT), which has limitations in hypercoagulable patients with increased FVIII [1, 2]. The aim of this study was to compare correlation of routine clotting tests (aPTT, ecarin clotting time [ECA-CT] and diluted thrombin time [dTT]) [3] to argatroban plasma levels measured by gold standard mass spectrometry (LC/MS/MS). Method From 06/2021 to 03/2022, 205 samples from 22 COVID-19 ICU patients were analyzed: aPTT and dTT on STA R Max3-Analyzer (Stago Deutschland GmbH, Germany) using the BIOPHEN DTI Kit with Argatroban-calibration (CoaChrom Diagnostica GmbH, Austria);ECA-CT was measured using ClotPro ecarin assay. LC/MS/MS was performed using an RP column, a solvent gradient and an API4000 mass spectrometer with electrospray. Correlation was analyzed using Pearson correlation coefficient r in R version 3.2.4. This study was approved by the Ethics Committee of the Technical University of Dresden, Germany (BO-EK-64022022) and registered with German Clinical Trials Register DRKS00028689. Results From 205 samples with LC/MS/MS analysis, 195 were compared to aPTT, 153 to ECA-CT and 105 to dTT. In 40 samples, dTT was not measureable due high bilirubin values. Compared to LC/MS/MS, correlation of dTT was highest (r = 0.924), followed by ECA-CT (r 0.609) and aPTT (r 0.367;p < 0.001;Fig. 1). When recommended cut-offs for argatroban plasma levels (500-1000 ng/ml according to SmPC) were applied, dTT (when measurable) and ECA-CT better identified critical values of argatroban plasma values > 1000ng/ml than aPTT (Fig. 2). Conclusion Argatroban in critical ill COVID-19 patients should be monitored using dTT. If dTT is not possible or measurements are highly time-sensitive, point-of-care ClotPro ECA-test should be preferably used instead of aPTT. (Table Presented).

Membrane oxygenator longevity was higher in argatroban-treated patients undergoing vvECMO.

BACKGROUND: In severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (vvECMO) can be a lifesaver. However, anticoagulation therapy is mandatory because the nonendothelial extracorporeal surface increases the risk of thromboembolic problems. Heparin is still the most common anticoagulant, but argatroban could be an alternative. This work investigates whether argatroban offers a therapeutic advantage over heparin during vvECMO. METHODS: We performed a retrospective cohort study of patients who underwent vvECMO for severe ARDS and received heparin or argatroban as anticoagulation therapy. Demographic variables, intensive care unit (ICU) treatment and outcome parameters were evaluated. The primary outcome parameter was the operating time of the membrane oxygenator normalized to the duration of vvECMO treatment. Secondary outcome parameters were transfusion requirements normalized to the duration of vvECMO therapy. RESULTS: Fifty seven patients from January 2019 to February 2021 underwent vvECMO and were included in this study. Thirty three patients received heparin and 24 patients argatroban as anticoagulatory therapy. The groups did not differ in demographics, ICU scoring systems, or comorbidities. Platelet counts and partial prothrombin time did not differ between the two groups during the first 6 days of vvECMO. The argatroban group had lower requirements for red blood cells, platelets and fresh frozen plasma. The mean runtime of the individual membrane oxygenator increased from 12.3 days (heparin group) to 16.6 days in the argatroban group. CONCLUSIONS: Our findings suggest that argatroban can be considered as anticoagulant during vvECMO.

Acute pulmonary thromboembolism after messenger RNA vaccination against coronavirus disease 2019: A case report.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is defined as thrombosis after inoculation of adenovirus vector vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VITT rarely occurs with messenger RNA vaccines, and the use of heparin for VITT is also controversial. A 74-year-old female patient with no risk factors for thrombosis was brought to our hospital after loss of consciousness. Nine days before admission, she had received the third vaccine against SARS-CoV-2 (mRNA1273, Moderna). Immediately after transport, cardiopulmonary arrest occurred, prompting extracorporeal membrane oxygenation (ECMO). Pulmonary angiography showed translucent images of both pulmonary arteries, resulting in the diagnosis of acute pulmonary thromboembolism. Unfractionated heparin was administered, but D-dimer subsequently became negative. Pulmonary thrombosis remained in large volume, indicating that heparin was ineffective. Treatment was shifted to anticoagulant therapy using argatroban, which increased D-dimer level and improved respiratory status. The patient was successfully weaned from ECMO and ventilator. Anti-platelet factor 4 antibody examined after treatment initiation showed negative results; however, VITT was considered as an underlying condition because of the time of onset after vaccination, the ineffectiveness of heparin, and the absence of other causes of thrombosis. In case heparin is not effective, argatroban can be an alternative therapy against thrombosis. Learning objective: During the coronavirus disease 2019 pandemic, treatment with vaccine against severe acute respiratory syndrome coronavirus 2 has been widely performed. Vaccine-induced immune thrombotic thrombocytopenia is the most common thrombosis after adenovirus vector vaccines. However, thrombosis can also occur after messenger RNA vaccination. Though commonly used for thrombosis, heparin may be ineffective. Non-heparin anticoagulants should be considered.

Pre-analytical screening and removal of Argatroban interference for haemostasis assays

Background: Argatroban is a direct thrombin inhibitor licenced in the UK and USA for treatment of Heparin Induced Thrombocytopenia and has been utilised as alternative anticoagulation for critically ill COVID-19 patients. Interferences in specialised haemostasis assays may be clinically important when bridging anticoagulant regimens or investigating thrombotic and bleeding complications common in critically ill patients. Aim(s): * Assess effect of Argatroban on specialised haemostasis assays * Assess effectiveness of DOAC-Remove (DR) in removing Argatroban interference Methods: Argatroban calibration plasma, spanning concentrations of 0 mug/ml-2.08 mug/ml, was tested for Antithrombin (IIa activator), Factors IX, and XI, and dilute Russel's viper venom time (dRVVT) to assess Argatroban interference. Samples were treated with DOAC-Remove and re-run for these assays. A p value of <0.05 was used to assess significance using paired t-tests Results: * Antithrombin results were significantly and linearly increased by increasing Argatroban concentrations (R -0.99). * Factor IX and XI concentrations were significantly decreased by increasing Argatroban concentrations from 83.4 IU/dl at 0 mug/ml to 3.79 IU/ dL at 2.07 mug/ml Argatroban * dRVVT screen results were significantly increased by increasing Argatroban concentrations (DRVVT ratio 1.07 (no Argatroban) to 3.79 at 2.07 ng/ml Argatroban) * Pre-treatment of samples with DOAC-Remove completely removes Argatroban interference to baseline. Conclusion(s): Argatroban has significant effects on specialist haemostasis assays. Antithrombin overestimation was observed when IIa activator is used, a Xa activator should be considered in such patients. dRVVT screen ratios were significantly increased, which could lead to false positive Lupus anticoagulant results. Factors IX and XI results were significantly decreased. Similar results have been published for direct oral anticoagulants with the need for pre-analytical screening, where anticoagulant status is unknown, becoming more important. For Argatroban, dilute thrombin time can be used as a pre-analytical screening tool. (Table Presented).

VACCINE-INDUCED THROMBOCYTOPENIA AND THROMBOSIS: SAILING CLOSE TO THE WIND IN A PANDEMIC

SESSION TITLE: Issues After COVID-19 Vaccination Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Ever since the global introduction of adenovirus-vector COVID-19 vaccines, cases of cerebral venous sinus thrombosis and thrombocytopenia after immunization has been reported, posing a challenge to global effects on vaccine implementation. CASE PRESENTATION: A previously healthy 33 year old male presented to emergency room with altered mental status after a left sided seizure episode at home. Patient had a 1week history of occipital headache after receiving Ad26.COV2·S Johnson and Johnson vaccine 2 weeks prior. MRI showed superior sagittal sinus thrombosis and right high frontal hemorrhage 8.6x4.7x4.9 cm. CT angiography confirmed nearly occlusive thrombosis of superior sagittal sinus with extension to right transverse sinus. Noted to have a hemoglobin of 15, platelet count of 74000, PT/INR 16/1.2 and PTT of 28. Started on intravenous heparin and intubated for GCS of 4. Heparin was stopped due to supra therapeutic PTT of 200 overnight, drop in platelet count to 55 and hemoglobin to 13. Repeat ct head done for change in neurological exam of dilated right pupil, showed frontoparietal hemorrhage 9.3 cmx4.1 cm and 7 mm midline shift. Heparin was reversed with protamine and transfused 1 unit platelets prior to emergent decompressive craniectomy and thrombectomy. Heparin induced platelet antibody and SRA came back positive confirming vaccine induced thrombocytopenia and thrombosis. Treatment was initiated with argatroban and IVIG. Platelet count improved with no further propagation of thrombus. Patient underwent feeding tube and tracheostomy placement after 10 days due to prolonged ventilator weaning period and poor mental status. Patient's neurological status continued to improve significantly over subsequent months in acute rehabilitation facility with only residual left sided hemiparesis. Patient was successfully decannulated and anticoagulation switched to apixaban DISCUSSION: Possible pathophysiology is thought to be due to a trigger in spike protein production after biodistribution of adenovirus vaccine and a subsequent autoimmune response resulting in thrombosis. Similar to HIT, platelet consumption leads to thrombocytopenia and the continued platelet and monocyte activation increases thrombin generation, resulting in thrombosis. CDC advices to maintain a high suspicion of cases with symptoms that may indicate an underlying thrombotic event along with simultaneous thrombocytopenia. Heparin use is discouraged, unless HIT testing is negative. The International Society on Thrombosis and Hemostasis (ISTH), recommend considering non-heparin anticoagulants and high-dose intravenous immunoglobulin (IVIG). While platelet transfusions are avoided, rapid progression with rising ICP may necessitate transfusion to enable neurosurgical intervention CONCLUSIONS: Management of complications including seizures and elevated intracranial pressure (ICP) is essential to reduce morbidity and mortality risk. Reference #1: Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021;384:2092–101. Reference #2: Muir KL, Kallam A, Koepsell SA, Gundabolu K. Thrombotic thrombocytopenia after Ad26.COV2.S vaccination. N Engl J Med 2021;384:1964–5 Reference #3: Pavord S, Scully M, Hunt BJ, et al. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis. N Engl J Med 2021;385:1680–9 DISCLOSURES: No relevant relationships by Axel Duval No relevant relationships by Nadish Garg No relevant relationships by ARCHANA SREEKANTAN NAIR

SUCCESSFUL USE OF BIVALIRUDIN DURING THE THIRD TRIMESTER OF PREGNANCY WHILE ON EXTRACORPOREAL MEMBRANE OXYGENATION

SESSION TITLE: Close Critical Care Calls SESSION TYPE: Case Reports PRESENTED ON: 10/18/2022 11:15 am - 12:15 pm INTRODUCTION: Heparin is the preferred anticoagulant for use in pregnancy while on extracorporeal membrane oxygenation (ECMO) (1). Alternatives to heparin in this patient population are not well studied as heparin-induced thrombocytopenia is rare in pregnancy. Parenteral non-heparin anticoagulants available in the United States include the direct thrombin inhibitors argatroban and bivalirudin, both of which are utilized in ECMO. Guidelines recommend avoidance of these agents in pregnancy if at all possible (2). Whereas case reports support the safe use of argatroban in pregnancy, to our knowledge, there are no known documented reports of bivalirudin use in this patient population (3). Here we describe the successful use of bivalirudin during pregnancy. CASE PRESENTATION: A 25 year old G2P1 was transferred to our institution at 28 weeks gestation for further management of acute hypoxic respiratory failure secondary to COVID-19. On hospital day 2 the patient was urgently placed on venovenous (VV) ECMO for refractory hypoxemia, high dead space with acidosis, and the inability to provide adequate gas exchange and lung protection with mechanical ventilation alone. Following ECMO cannulation with a 25f cannula in the right femoral vein and a 21f cannula in the right internal jugular vein, she was anticoagulated with heparin at a rate of 12 units/kg/hr. This was titrated to target a PTT goal of 60-80 seconds. On ECMO day 2, the TEG demonstrated a markedly hypocoagulable state, and the heparin nomogram called for increasing heparin dosing based on PTT. Given the already high dose of heparin that the patient was on (32.9 units/kg/hr), the decision was made to switch from heparin to bivalirudin to prevent over anticoagulation and reduce bleeding risk. Bivalirudin was titrated to a goal PTT of 50-60 seconds, with an initial rate of 0.15 mg/kg/hr (dose range 0.15-0.22 mg/kg/hr). Therapy was continued and on ECMO day 11, at 29w6d the patient delivered via cesarean section. Bivalirudin was discontinued 2.5 hours prior to the surgical procedure which resulted with no fetal bleeding complications. The patient was decannulated from ECMO on day 20 and was later discharged from the hospital. The newborn is developing well and meeting age adjusted milestones. DISCUSSION: Bivalirudin was selected based on institutional experience and the pharmacokinetic properties of the drug (half-life of 25 minutes) as we considered a situation where an emergent delivery may be indicated. Bivalirudin successfully prevented clotting of the circuit with no maternal or fetal bleeding complications during its use. CONCLUSIONS: Our case report describes a multidisciplinary approach to managing a pregnant patient on ECMO requiring anticoagulation using an alternative medication to heparin. This is the first documented use of bivalirudin in pregnancy. Reference #1: ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support Extracorporeal Life Support Organization, Version 1.4 August 2017. Ann Arbor, MI, USA www.elso.org. Reference #2: Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl): e691S–736S Reference #3: Young SK, Al-Mondhiry HA, Vaida SJ, et al. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy 2008;28: 1531–6. DISCLOSURES: No relevant relationships by Jacqueline Finger No relevant relationships by Caitlin Gluck No relevant relationships by Cameron Hypes No relevant relationships by John Rathbun

Successful Application of Argatroban During VV-ECMO in a Pregnant Patient Complicated With ARDS due to Severe Tuberculosis: A Case Report and Literature Review.

Severe tuberculosis during pregnancy may progress to acute respiratory distress syndrome (ARDS), and venovenous (VV) extracorporeal membrane oxygenation (ECMO) should be considered if conventional lung-protective mechanical ventilation fails. However, thrombocytopenia often occurs with ECMO, and there are limited reports of alternative anticoagulant therapies for pregnant patients with thrombocytopenia during ECMO. This report describes the first case of a pregnant patient who received argatroban during ECMO and recovered. Furthermore, we summarized the existing literature on VV-ECMO and argatroban in pregnant patients. A 31-year-old woman at 17 weeks of gestation was transferred to our hospital with ARDS secondary to severe tuberculosis. We initiated VV-ECMO after implementing a protective ventilation strategy and other conventional therapies. Initially, we selected unfractionated heparin anticoagulant therapy. However, on ECMO day 3, the patient's platelet count and antithrombin III (AT-III) level declined to 27 × 103 cells/µL and 26.9%, respectively. Thus, we started the patient on a 0.06 µg/kg/min argatroban infusion. The argatroban infusion maintenance dose ranged between 0.9 and 1.2 µg/kg/min. The actual activated partial thromboplastin clotting time and activated clotting time ranged from 43 to 58 s and 220-260 s, respectively, without clinically significant bleeding and thrombosis. On day 27, the patient was weaned off VV-ECMO and eventually discharged. VV-ECMO may benefit pregnant women with refractory ARDS, and argatroban may be an alternative anticoagulant for pregnant patients with thrombocytopenia and AT-III deficiency during ECMO.

Vaccine-Induced Immune Thrombocytopenia and Thrombosis Syndrome post second dose of ChAdOx1 nCov -19 vaccine: Case Presentation

We present the case of a 39-year-old female who presented to University Hospitals of Leicester 14 days after the second dose of ChAdOx1 nCov-19 vaccine. Her presenting symptoms included skin rash, nausea, intermittent abdominal pain and occasional episodes of dizziness. Her past medical history included Type 2 Diabetes Mellitus and hidradenitis suppurativa. The first dose of ChAdOx1 nCov-19 vaccine had been administered on 27th February 2021, following which the patient reported flu like symptoms that resolved after four days and did not require further medical input. Following this, a preplanned surgical procedure to incise and drain a vulval abscess was performed on 17th May 2021. Preoperative testing performed on 13th May 2021 showed a normal platelet count of 219 × 10 9 /l. The second dose of ChAdOx1 nCov-19 vaccine was subsequently administered on 23rd May 2021. On presentation, examination revealed mild epigastric tenderness and features of classical thrombocytopenic rash affecting all limbs with no other associated bleeding. Initial blood results confirmed thrombocytopenia of 11 × 10 9 /l, with D-Dimer 14.26 μg/ml and fibrinogen 2.1 g/l. Blood film microscopy revealed an occasional schistocyte and microangiopathic haemolysis was considered. Treatment with plasmapheresis of 1.5 x plasma volume using Octaplas was administered. Subsequent abdominal computed topography imaging identified extensive thrombotic events. This included bilateral pulmonary embolism, superior mesenteric vein non-occlusive thrombus and multiple soft atheromas lining the abdominal aorta causing moderate infrarenal stenosis. In view of the recent history, vaccine associated thrombosis and thrombocytopenia (VITT) was considered. Subsequent testing showed a normal ADAMTS13 level. Treatment for VITT with intravenous immunoglobulin along with oral steroids and anticoagulation using Argatroban was commenced in line with national guidance. Anti-PF4 antibody, tested using the Asserachrom HPIA ELISA assay, was positive at a level of 1.298 OD units confirming the diagnosis of VITT;the first case we are aware of in the UK following second dose administration. Given high-risk presentation, Rituximab therapy was given as an inpatient with good clinical response. Prior to discharge, anticoagulation was switched to oral apixaban with a platelet count on discharge of 170 × 10 9 /l. Subsequent follow-up has shown ongoing clinical remission with consistently negative Anti-PF4 antibody titres. This report outlines the first known definite case of VITT identified following administration of the second dose of ChAdOx1 nCov-19 vaccine in the United Kingdom. The subsequent clinical course was similar to those of patients presenting after their first dose but the atypical presentation mimicking that of Thrombotic Thrombocytopenia is noted..

Successful surgical-multimodal treatment for vaccine-induced complete splanchnic vein thrombosis after ChAdOx1 nCoV-19 vaccination

Objective Thrombotic-thrombocytopenic events are rare, but life-threatening, complications after ChAdOx1 nCoV-19 vaccination and sometimes present as symptomatic splanchnic vein thrombosis with critical illness. Life-saving aggressive and multimodal treatment is essential in these cases. Design We report on a critically ill 40-year-old male patient with complete splanchnic (portal/mesenteric/splenic) vein thrombosis, becoming symptomatic 7 days after ChAdOx1 nCoV-19 vaccination and diagnosed on day 12. Laparotomy for abdominal compartment syndrome and repeated transjugular/ transhepatic interventional and open surgical thrombectomy procedures were performed. Additional therapy consisted of thrombolysis with recombinant tissue-type plasminogen activator over 5 days, anticoagulation (argatroban), platelet inhibition (Acetylsalicylic acid /clopidogrel), immunoglobulins and steroids. Results This aggressive treatment included 5 laparotomies and 4 angiographic interventions, open abdomen for 8 days, transfusion of 27 units of packed red cells, 9 abdominal and 4 cerebral CT scans, thrombolysis therapy for 5 days, mechanical ventilation for 15 days, and an ICU stay of 25 days. Full patient recovery and near complete recanalization of splanchnic veins was achieved. Conclusion Without treatment, ChAdOx1 nCoV-19 vaccination-induced total splanchnic vein thrombosis has serious consequences with a high risk for death. The case described here shows that an aggressive multimodal surgical-medical treatment strategy in a specialized center can save these patients and achieve a good outcome.

Novel monitoring and dose adjustment of argatroban to maintain therapeutic anticoagulation

INTRODUCTION: In patients with unreliable activated partial thromboplastin time (aPTT) measurements who require anticoagulation with a direct thrombin inhibitor (DTI), the only reliable alternative measurement at present is a dilute thrombin time (dTT). However, this assay is not always readily available, which limits accurate real-time dose adjustments necessary to maintain therapeutic anticoagulation. DESCRIPTION: A 57 year-old woman with a history of antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, and multiple prior deep venous thromboses and pulmonary emboli was admitted with COVID-19 pneumonia and intubated due to hypoxic respiratory failure. Argatroban was initiated in place of her home medication warfarin. This patient had a prolonged aPTT value at baseline and overnight dTT assay measurements were limited at our institution. To overcome this challenge, a multidisciplinary team of hematology and pharmacy clinicians created a modified aPTT algorithm. By measuring aPTT and dTT simultaneously from patient plasma samples, a patientspecific aPTT target range was derived and argatroban dosing was titrated accordingly. Subsequent aPTT values in the modified target range corresponded to therapeutic dTT values, indicating therapeutic anticoagulation was successfully achieved and maintained. Patient plasma samples were also evaluated retrospectively using a novel point-of-care (POC) coagulation test to detect and quantify the effect of argatroban. A Clotting Time Score (CTS) was derived for each sample tested. Comparison of CTS and dTT values demonstrated moderate positive correlation between test results. All CTS results accurately reflected if argatroban dosing achieved an appropriate level of anticoagulation. DISCUSSION: Therapeutic anticoagulation with a DTI in a patient with unreliable aPTT measurements is challenging but can be achieved with use of a modified aPTT scale, which in our case study was retrospectively confirmed by corresponding dTT measurements. Early validation of a novel test that could offer a rapid, POC alternative to dTT when dTT measurements are necessary but not readily available is promising. Such a technology could dramatically improve rapid accurate titration of DTIs to maintain therapeutic anticoagulation.

Novel, low-volume, point-of-care coagulation test successfully detects anticoagulation resistance in hospitalized patients with COVID-19

Introduction: Severe COVID-19 has been associated with aberrant coagulation factor activities, particularly in patients with a thrombotic event (TE). Management of anticoagulant is critical in the care of hospitalized patients with COVID-19.Hypothesis: Evaluation of a point-of-care (POC), functional, clot-time-based coagulation test to detect the anticoagulant effect of therapeutic unfractionated heparin (UFH) in hospitalized SARS-CoV-2-positive patients who developed a TE. Methods: An IRB-approved analysis of 36 citrated plasma specimens from 26 SARS-CoV-2-positive patients and 10 matched negative controls was performed. A Clotting Time Score (CTS), a measure of factor-specific inhibition (i.e. anticoagulant activity), was derived for each patient. CTS results were compared with traditional coagulation tests. Five UFH COVID-19 samples with low CTS scores (<10) were spiked with uniform dosing of UFH, low molecular weight heparin (LMWH), apixaban, or argatroban and retested to assess anticoagulation response. Results: The CTS detected subtherapeutic UFH anticoagulation levels more frequently in COVID-19 cases compared with controls (76% vs. 17%). Prothrombin Times, activated Partial Thromboplastin Times, anti-Xa levels, and antithrombin activity did not correlate with each other or with the CTS in the COVID-19 samples. CTS correlated with both FV and Factor X activity (R =0.49, Spearman R=-0.68), which form the prothrombinase complex. The CTS was 94% sensitive and 67% specific for the occurrence of TEs in patients on UFH. CTS demonstrated a consistent anticoagulant response only to argatroban (100%) compared with other anticoagulants (60%). Conclusions: The CTS, generated using a novel, low-volume, rapid POC coagulation test is a strong indicator of the therapeutic effect of UFH anticoagulation in COVID-19 patients and may provide a predictive measure of TEs potentially occurring from anticoagulation resistance.

Vaccine-induced thrombotic thrombocytopenia (VITT)

Introduction: An unexpected accumulation of thrombotic events with thrombocytopenia emerged in association with the AZD1222 vaccine against COVID-19. We report our initial experience with emphasis on presenting characteristics, treatment, and short-term outcome. Methods: This is a retrospective, consecutive cohort of all patients admitted to Hannover Medical School between 8th March and 4th April 2021 with known or suspected thromboembolic events and thrombocytopenia within 2 weeks after vaccination with AZD1222. Results: Five patients were admitted during the observation period. These were women between 41 and 67 years of age, who had received AZD1222 5 to 11 days before. Clinical manifestations ranged from cerebral sinus vein thrombosis, splanchnic vein thrombosis, arterial ischemic stroke, and thrombotic microangiopathy (TMA) to mild symptoms without abnormal imaging results. Thrombocytopenia ranged between 12 and 105 /nl. All patients had markedly elevated D-Dimer. Heparin-induced thrombocytopenia (HIT) workup revealed anti-platelet factor 4 autoantibodies in sera from all patients. Platelet aggregation by these antibodies was observed in the presence of buffer or AZD1222 but suppressed by heparin. Treatment consisted of anticoagulation (heparin or argatroban), dexamethasone and, in severe cases, intravenous immunoglobulin (IVIG) or eculizumab. Two patients treated with anticoagulation, dexamethasone and IVIG had subsequent major thromboembolic events. One patient presenting with a picture of TMA responded to anticoagulation and eculizumab. Another patient responded to thrombolysis and eculizumab after failure of anticoagulation and IVIG. Long-term sequelae are expected in two patients with severe cerebrovascular events while remaining three patients have fully recovered. Anti-PF4 antibodies declined in recovering patients over a period of 8 weeks. Conclusions: The triad of thromboembolic events, thrombocytopenia and anti-PF4 autoantibodies is characteristic of VITT. The spectrum of clinical manifestations ranged from mild to unusually severe. Anticoagulation alone is not always sufficient to prevent recurrent or progressive thromboembolic events. IVIG and eculizumab are potential treatment options but their effects are currently uncertain.

Evaluation of Heparin-Induced Thrombocytopenia in Severe COVID-19 (Case Series)

Introduction: Thrombocytopenia is associated with severe coronavirus disease-2019 (COVID-19) with the reported incidence rate to be between 5-41.7%. Heparin-induced thrombocytopenia (HIT) is typically considered a minor contributor with low incidence of 0.2-3%. However, one study noted an 8% incidence of HIT in patients with severe COVID-19. Due to the potential higher risk of HIT and the baseline higher risk of thrombosis in severe COVID-19 infection, it is important to evaluate HIT prevalence in severe COVID-19 patients. We reviewed seven potential HIT cases. Case: All seven patients with positive heparin-PF4 antibodies had severe acute respiratory distress syndrome. D-dimer was elevated in four. Median duration of heparin and/or low-molecular-weight heparin exposure was 16 days. In five cases, HIT diagnosis was made greater than 10 days post exposure. All patients had intermediate to high pretest probability for HIT. Three patients had confirmed thrombosis, and one experienced multiple clotted lines (despite negative imaging for thrombosis). Argatroban was initiated in all patients. Serotonin release assay (SRA) was obtained for two patients-one resulted positive. Only two patients survived to be discharged from the intensive care unit/hospital. Discussion: HIT may be a larger contributor to thrombocytopenia in severe COVID-19 patients. When reviewing data from pre-COVID-19 years, the incidence rate of those screened for HIT ranged between 0-4.8%. During our study period, the incidence rate of those screened for HIT was 12.9%. 78% of those with positive antibodies had COVID-19. This potential increased incidence may be attributed to patient/disease specific factors or to increased doses of heparin treatment of possible thrombosis. Until it is further characterized, it is important to screen thrombocytopenic patients with severe COVID-19 for HIT. Conclusion: True incidence of HIT in severe COVID-19 is unclear, but it may be an important contributor to thrombocytopenia that can affect patients' thrombosis risk and anticoagulation choice which merits further review.

Spontaneous Heparin-Induced Thrombocytopenia and COVID-19 Infection

Background and Objective: Heparin-induced thrombocytopenia (HIT) can develop if immune responses to infections become pathologic in the presence of heparins. Low molecular weight heparin or unfractionated heparin are recommended for prophylaxis and treatment of venous thromboembolic disease in hospitalized patients with Covid-19 infection but may trigger HIT. Our aim is to alert clinicians that HIT occurs in association with Covid-19 infections even in the absence of prior exposure and may not be easily recognized without a high index of suspicion. Case Summary: A 33-year-old previously healthy male was initially evaluated for low grade fever, dyspnea without hypoxia and cough. A Covid-19 PCR swab was negative despite a recent exposure. He was treated with azithromycin. However, his symptoms did not improve, he then developed right leg swelling and hypoxia, so he was re-evaluated. CTA of the chest showed bilateral pulmonary emboli and ground-glass opacities at the lung bases. Venous Duplex Ultrasound showed non-occlusive thrombus in the deep veins of right lower extremity. He was hospitalized and placed on oxygen and heparin. Covid-19 swab was negative again. Laboratory tests before heparin showed a decreased platelet count of 64,000 k/ul, elevated prothrombin time of 16.4 seconds, normal aPTT at 30.8 seconds, decreased serum fibrinogen at 120 mg/dl and markedly elevated D-dimer at 59,966 ng/ml. Lupus anticoagulant and anti-phospholipid antibody tests were negative. On heparin at the desired therapeutic aPTT target range, the right leg became significantly swollen and painful by day five. Platelet count had decreased further to 39,000 k/ul. Repeat doppler examination of the right leg now showed more severe and extensive deep venous thrombosis. D-dimer had increased to 125,133 ng/ml. The HIT 4T score was 4, suggesting intermediate probability. Rapid HIT immunoassays on 2 separate samples were positive. Heparin was discontinued and he was placed on argatroban. Serotonin release assays on 2 separate samples came back positive. Suspicion for Covid-19 infection remained high and so a Covid-19 serology sample was obtained which was positive for IgG. A repeat nasopharyngeal swab at this time turned positive. He did not receive any COVID specific treatments. As viability of his leg appeared threatened, he underwent right iliofemoral vein thrombectomy with arteriovenous fistula creation. He improved on argatroban and was transitioned to apixaban with gradual normalization of hemostasis laboratory parameters, improvement in hypoxemia and fading clinical symptoms, he was discharged home on day 15. Conclusion: Current consensus guidelines for thromboprophylaxis and treatment of thromboembolism in hospitalized patients with Covid-19 infection recommend heparins as primary therapy to reduce morbidity and mortality. However, our report in addition to the two previous reports of HIT in Covid-19 patients illustrate that HIT can be a complication in the setting of Covid-19 infection. Further, our report also highlights that HIT with thrombosis can occur in a spontaneous manner in the absence of prior heparin exposure, which has been so far studied only in bacterial infection with the hypothesis that Platelet factor 4 (PF4) can bind to negatively charged polysaccharides on the surface of bacteria, triggering an immune response. Disclosures: No relevant conflicts of interest to declare.

Caution in Using the Activated Partial Thromboplastin Time to Monitor Argatroban in COVID-19 and Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT).

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.

Laboratory methods for monitoring argatroban in heparin-induced thrombocytopenia.

INTRODUCTION: The Summary of Product Characteristics for the direct thrombin inhibitor argatroban states monitoring should be by activated partial thromboplastin time (APTT), with a target range of 1.5-3.0 times the patients' baseline APTT. APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Previous studies have shown sensitivity differences of APTT reagents to argatroban. Some recent publications have favoured the use of anti-IIa methods to determine the plasma drug concentration of argatroban. This study aims to compare the anti-IIa assays: Hemoclot thrombin inhibitor assay (HTI) and Ecarin chromogenic assay (ECA) alongside the APTT. METHODS: Residual plasma of 25 samples from 8 patients (3 with COVID-19 and HIT: n = 18, 5 with HIT: n = 7) was tested at two sites: site A: Sysmex CS5100 by HTI and APTT (Actin FS and SynthASil), and also on Stago STA Compact Max: ECA and APTT (CK Prest); and site B: Stago STA R Max 2 by ECA and APTT (Cephascreen). RESULTS: Mean APTT ratio was 1.96 (Actin FS), 1.84 (SynthASil), 1.59 (CK Prest) and 2.48 (Cephascreen). Mean argatroban concentration by HTI was 0.60 µg/mL and by ECA was 0.65 µg/mL (site A) and 0.70 µg/mL (site B). There was a poor correlation to HTI in APTT ratios (range r2  = .0235-0.4181) with stronger correlations between ECA methods to HTI (r2  = .8998 site A, r2  = .8734 site B). CONCLUSION: This study confirms previous publications on the unsuitability of APTT and expands this by being multisited and included APTT reagents that use mechanical clot detection. Both anti-IIa methods are more suitable.

GFHT proposals on the practical use of argatroban - With specifics regarding vaccine-induced immune thrombotic thrombocytopaenia (VITT).

Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg × kg-1 × min-1, with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly advised to involve a health practitioner experienced in the management of difficult cases in haemostasis. The first laboratory assessment should be performed 4 h after the initiation of argatroban infusion, with further controls at 2-4-h intervals until steady state, and at least once daily thereafter. Importantly, full anticoagulation should be rapidly achieved in case of widespread thrombosis. Cerebral vein thrombosis (which is typical of VITT) should not call for an overly cautious anticoagulation scheme. Argatroban administration requires baseline laboratory assessment and should rely on an anti-IIa assay to derive argatroban plasma levels using a dedicated calibration, with a target range between 0.5 and 1.5 µg/mL. Target argatroban plasma levels can be refined based on meticulous appraisal of risk factors for bleeding and thrombosis, on frequent reassessments of clinical status with appropriate vascular imaging, and on the changes in daily platelet counts. Regarding the use of aPTT, baseline value and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient's/mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged: one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg × kg-1 × min-1 up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.