Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

A journey through anticoagulant therapies in the treatment of left ventricular thrombus in post-COVID-19 heparin-induced thrombocytopenia: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

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.

Using Nonheparin Anticoagulant to Treat a Near-Fatal Case With Multiple Venous Thrombotic Lesions During ChAdOx1 nCoV-19 Vaccination-Related Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. PATIENT: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5-2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients.

COVID-19 is a disease with a variable clinical course ranging from mild symptoms to critical illness, organ failure, and death. Prospective biomarkers may help to predict the severity of an individual's clinical course and mortality risk. We analyzed asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in blood samples from 31 patients hospitalized for COVID-19. We calculated associations of ADMA and SDMA with mortality and organ failure, and we developed a predictive algorithm based upon these biomarkers to predict mortality risk. Nine patients (29%) experienced in-hospital death. SDMA and ADMA serum concentrations were significantly higher at admission in COVID-19 patients who died than in survivors. Cut-offs of 0.90 µmol/L for SDMA (AUC, 0.904, p = 0.0005) and 0.66 µmol/L for ADMA (AUC, 0.874, p = 0.0013) were found in ROC analyses to best discriminate both subgroups of patients. Hazard ratio for in-hospital mortality was 12.2 (95% CI: 2.2-31.2) for SDMA and 6.3 (1.1-14.7) for ADMA above cut-off. Sequential analysis of both biomarkers allowed discriminating a high-risk group (87.5% mortality) from an intermediate-risk group (25% mortality) and a low-risk group (0% mortality). Elevated circulating concentrations of SDMA and ADMA may help to better identify COVID-19 patients with a high risk of in-hospital mortality.

Comparison of different anticoagulation strategies for renal replacement therapy in critically ill patients with COVID-19: a cohort study.

BACKGROUND: Critically ill coronavirus disease 2019 (COVID-19) patients have a high risk of acute kidney injury (AKI) that requires renal replacement therapy (RRT). A state of hypercoagulability reduces circuit life spans. To maintain circuit patency and therapeutic efficiency, an optimized anticoagulation strategy is needed. This study investigates whether alternative anticoagulation strategies for RRT during COVID-19 are superior to administration of unfractionated heparin (UFH). METHODS: Retrospective cohort study on 71 critically ill COVID-19 patients (≥18 years), admitted to intensive care units at a tertiary health care facility in the southwestern part of Germany between February 26 and May 21, 2020. We collected data on the disease course, AKI, RRT, and thromboembolic events. Four different anticoagulatory regimens were administered. Anticoagulation during continuous veno-venous hemodialysis (CVVHD) was performed with UFH or citrate. Anticoagulation during sustained low-efficiency daily dialysis (SLEDD) was performed with UFH, argatroban, or low molecular weight heparin (LMWH). Primary outcome is the effect of the anticoagulation regimen on mean treatment times of RRT. RESULTS: In patients receiving CVVHD, mean treatment time in the UFH group was 21.3 h (SEM: ±5.6 h), in the citrate group 45.6 h (SEM: ±2.7 h). Citrate anticoagulation significantly prolonged treatment times by 24.4 h (P = .001). In patients receiving SLEDD, mean treatment time with UFH was 8.1 h (SEM: ±1.3 h), with argatroban 8.0 h (SEM: ±0.9 h), and with LMWH 11.8 h (SEM: ±0.5 h). LMWH significantly prolonged treatment times by 3.7 h (P = .008) and 3.8 h (P = .002), respectively. CONCLUSIONS: UFH fails to prevent early clotting events in the dialysis circuit during COVID-19. For patients, who do not require effective systemic anticoagulation, regional citrate dialysis is the most effective strategy. For patients, who require effective systemic anticoagulation, the usage of LMWH results in the longest circuit life spans. The proposed anticoagulatory strategies are safe, can easily be monitored, and allow an individualized treatment.

Rapid Resolution of Non-Effusive Feline Infectious Peritonitis Uveitis with an Oral Adenosine Nucleoside Analogue and Feline Interferon Omega.

This is the first report of a successful treatment of a non-effusive feline infectious peritonitis (FIP) uveitis case using an oral adenosine nucleoside analogue drug and feline interferon omega, and alpha-1 acid glycoprotein (AGP) as an indicator of recovery. A 2-year-old male neutered Norwegian Forest Cat presented with uveitis, keratic precipitates, mesenteric lymphadenopathy and weight loss. The cat was hypergammaglobulinaemic and had a non-regenerative anaemia. Feline coronavirus (FCoV) RNA was detected in a mesenteric lymph node fine-needle aspirate by a reverse-transcriptase polymerase chain reaction-non-effusive FIP was diagnosed. Prednisolone acetate eye drops were administered three times daily for 2 weeks. Oral adenosine nucleoside analogue (Mutian) treatment started. Within 50 days of Mutian treatment, the cat had gained over one kilogram in weight, his globulin level reduced from 77 to 51 g/L and his haematocrit increased from 22 to 35%; his uveitis resolved and his sight improved. Serum AGP level reduced from 3100 to 400 µg/mL (within normal limits). Symmetric dimethylarginine (SDMA) was above normal at 28 µg/dL, reducing to 14 µg/dL on the cessation of treatment; whether the SDMA increase was due to FIP lesions in the kidney or Mutian is unknown. Mutian treatment stopped and low-dose oral recombinant feline interferon omega begun-the cat's recovery continued.

Emergent Carotid Artery Stenting Following Intravenous Alteplase Infusion After Rapid Negative Diagnosis for COVID-19 by Loop-Mediated Isothermal Amplification Assay.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, a rapid screening method for COVID-19 detection is needed to decide the appropriate strategy to treat stroke patients. In acute ischemic stroke treatment, the efficacy and safety of emergent carotid artery stenting (eCAS) for hyperacute ischemic stroke (hAIS) due to internal carotid artery stenosis (ICS) have not been sufficiently established. CASE DESCRIPTION: A 71-year-old man with hAIS caused by severe ICS was treated via intravenous alteplase infusion. The patient underwent screening for COVID-19 by the loop-mediated isothermal amplification (LAMP) assay shortly after arrival at our institution. The LAMP result was obtained within 90 minutes, during intravenous alteplase infusion, and turned out to be negative. The symptom of hemiplegia worsened during alteplase infusion, and he, therefore, underwent eCAS after administration of aspirin (200 mg). Recanalization was achieved successfully by eCAS, and dual antiplatelet therapy and argatroban were administrated following eCAS. Hemorrhagic complications or restenosis/occlusion of the carotid artery were not observed. He was discharged without neurologic deficits 15 days following eCAS. Because of the rapid negative diagnosis for COVID-19 using the LAMP method, eCAS could be performed following standard procedures, along with infectious defense, without delay. CONCLUSIONS: This case report suggests that eCAS for hAIS due to ICS following intravenous alteplase can be an effective treatment, along with appropriate antiplatelet medication and management in select patients. During the COVID-19 pandemic, the LAMP assay for COVID-19 detection might be a suitable diagnostic strategy preceding stroke treatment because of the rapid turnaround time.

Thrombin Inhibition by Argatroban: Potential Therapeutic Benefits in COVID-19.

Thrombin is a trypsin-like serine protease with multiple physiological functions. Its role in coagulation and thrombosis is well-established. Nevertheless, thrombin also plays a major role in inflammation by activating protease-activated receptors. In addition, thrombin is also involved in angiogenesis, fibrosis, and viral infections. Considering the pathogenesis of COVID-19 pandemic, thrombin inhibitors may exert multiple potential therapeutic benefits including antithrombotic, anti-inflammatory, and antiviral activities. In this review, we describe the clinical features of COVID-19, the thrombin's roles in various pathologies, and the potential of argatroban in COVID-19 patients. Argatroban is a synthetic, small molecule, direct, competitive, and selective inhibitor of thrombin. It is approved to parenterally prevent and/or treat heparin-induced thrombocytopenia in addition to other thrombotic conditions. Argatroban also possesses anti-inflammatory and antiviral activities and has a well-established pharmacokinetics profile. It also appears to lack a significant risk of drug-drug interactions with therapeutics currently being evaluated for COVID-19. Thus, argatroban presents a substantial promise in treating severe cases of COVID-19; however, this promise is yet to be established in randomized, controlled clinical trials.