Vaccine-induced immune thrombotic thrombocytopenia post dose 2 ChAdOx1 nCoV19 vaccination: Less severe but remains a problem.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but established complication of 1st dose ChAdOx1 nCoV19 vaccination (AZD1222), however this complication after dose 2 remains controversial. OBJECTIVES: To describe the clinicopathological features of confirmed cases of VITT post dose 2 AZD1222 vaccination in Australia, and to compare this cohort to confirmed cases of VITT post 1st dose. METHODS: Sequential cases of clinically suspected VITT (thrombocytopenia, D-Dimer > 5x upper limit normal and thrombosis) within 4-42 days of dose 2 AZD1222 referred to Australia's centralised testing centre underwent platelet activation confirmatory testing in keeping with the national diagnostic algorithm. Final classification was assigned after adjudication by an expert advisory committee. Descriptive statistics were performed on this cohort and comparative analyses carried out on confirmed cases of VITT after 1st and 2nd dose AZD1222. RESULTS: Of 62 patients referred, 15 demonstrated presence of antibody mediated platelet activation consistent with VITT after dose 2 AZD1222. Four were immunoassay positive. Median time to presentation was 13 days (range 1-53) platelet count 116x10^9/L (range 63-139) and D-dimer elevation 14.5xULN (IQR 11, 26). Two fatalities occurred. In each, the dosing interval was less than 30 days. In comparison to 1st dose, dose 2 cases were more likely to be male (OR 4.6, 95% CI 1.3-15.8, p = 0.03), present with higher platelet counts (p = 0.05), lower D-Dimer (p = 01) and less likely to have unusual site thromboses (OR 0.14, 95% CI 0.04-0.28, p = 0.02). CONCLUSIONS: VITT is a complication of dose 2 AZD1222 vaccination. Whilst clinicopathological features are less severe, fatalities occurred in patients with concomitant factors.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

Cannula provoked upper extremity superficial vein thrombophlebitis: are we overtreating?

Cannula provoked upper extremity superficial vein thrombophlebitis (UESVT) is common. Retrospective audit of 93 consecutive patients, 51% male, median age 57 years (range 20-91), with symptomatic UESVT revealed varied management including symptomatic management (37%), prophylactic (37%) and higher dose anticoagulation (27%). There was 2% (95% confidence interval (CI) 0-7.6) thrombus extension and 1% (95% CI 0-5.9) major bleeding, both limited to cancer. We argue anticoagulation is unnecessary in most UESVT patients.

New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease and, globally, more than an estimated 10 million people have it yearly. It is a chronic and recurrent disease. The symptoms of VTE are non-specific and the diagnosis should actively be sought once considered. The mainstay of VTE treatment is anticoagulation, with few patients requiring additional intervention. A working group of experts in the area recently completed an evidence-based guideline for the diagnosis and management of DVT and PE on behalf of the Thrombosis and Haemostasis Society of Australia and New Zealand (www.thanz.org.au/resources/thanz-guidelines). MAIN RECOMMENDATIONS: The diagnosis of VTE should be established with imaging; it may be excluded by the use of clinical prediction rules combined with D-dimer testing. Proximal DVT or PE caused by a major surgery or trauma that is no longer present should be treated with anticoagulant therapy for 3 months. Proximal DVT or PE that is unprovoked or associated with a transient risk factor (non-surgical) should be treated with anticoagulant therapy for 3-6 months. Proximal DVT or PE that is recurrent (two or more) and provoked by active cancer or antiphospholipid syndrome should receive extended anticoagulation. Distal DVT caused by a major provoking factor that is no longer present should be treated with anticoagulant therapy for 6 weeks. For patients continuing with extended anticoagulant therapy, either therapeutic or low dose direct oral anticoagulants can be prescribed and is preferred over warfarin in the absence of contraindications. Routine thrombophilia testing is not indicated. Thrombolysis or a suitable alternative is indicated for massive (haemodynamically unstable) PE. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Most patients with acute VTE should be treated with a factor Xa inhibitor and be assessed for extended anticoagulation.

Weight-Based Enoxaparin for Venous Thromboembolism in Obesity Gives Similar Anti-Xa Levels to Patients <100 kg, with No Increase in Major Bleeding.

In trials assessing venous thromboembolism (VTE) treatment, obese patients are under-represented or excluded. The main objective of this article is to examine the safety of weight-based enoxaparin dosing in obesity, as assessed by anti-factor Xa (anti-Xa) activity, bleeding, and recurrence. A 5-year retrospective audit of patients with acute VTE, weighing > 100 kg, prescribed enoxaparin 1 mg/kg twice daily, with an anti-Xa level 2 to 6 hours post-dose. The primary outcome was anti-Xa levels, and the secondary outcomes were bleeding and recurrence. Results were compared with patients weighing < 100 kg (n = 64), and obese patients prescribed doses < 1 mg/kg (n = 28). One-hundred sixty-six patients weighing > 100 kg with VTE were identified, with 64 excluded for not fulfilling criteria. The remaining 102 patients had a median weight of 130 kg (range: 105-222 kg). The median peak anti-Xa level was 0.93 U/mL, with 56% of levels being in the proposed therapeutic range (0.5-1.0 U/mL), 40% > 1.0 U/mL, and 4% < 0.5 U/mL. The median anti-Xa levels and distribution were not significantly different between patients > 100 kg and patients < 100 kg, while obese patients prescribed < 1 mg/kg were more frequently subtherapeutic (21%). Regardless of weight, the majority of patients with moderate renal impairment (eGFR 30-59 mL/min) had an anti-Xa level > 1.0 U/mL (61%). In the obese patients, there was no major bleeding or recurrence within 30 days. In comparison, patients weighing < 100 kg, despite similar peak anti-Xa levels, had higher rates of bleeding and recurrence. This was likely due to their older age and comorbidities, particularly renal impairment and cancer. These data support weight-based dosing of enoxaparin in obesity with no maximum dose, ensuring therapeutic drug levels, with anti-Xa levels suggested in obese patients with clinical risk factors for bleeding.

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases.

Certain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

An update of consensus guidelines for warfarin reversal.

• Despite the associated bleeding risk, warfarin is the most commonly prescribed anticoagulant in Australia and New Zealand. Warfarin use will likely continue for anticoagulation indications for which novel agents have not been evaluated and among patients who are already stabilised on it or have severe renal impairment. • Strategies to manage over-warfarinisation and warfarin during invasive procedures can reduce the risk of haemorrhage. • For most warfarin indications, the target international normalised ratio (INR) is 2.0-3.0 (venous thromboembolism and single mechanical heart valve excluding mitral). For mechanical mitral valve or combined mitral and aortic valves, the target INR is 2.5-3.5. • Risk factors for bleeding with warfarin use include increasing age, history of bleeding and specific comorbidities. • For patients with elevated INR (4.5-10.0), no bleeding and no high risk of bleeding, withholding warfarin with careful subsequent monitoring seems safe. • Vitamin K1 can be given to reverse the anticoagulant effect of warfarin. When oral vitamin K1 is used for this purpose, the injectable formulation, which can be given orally or intravenously, is preferred. • For immediate reversal, prothrombin complex concentrates (PCC) are preferred over fresh frozen plasma (FFP). Prothrombinex-VF is the only PCC routinely used for warfarin reversal in Australia and New Zealand. It contains factors II, IX, X and low levels of factor VII. FFP is not routinely needed in combination with Prothrombinex-VF. FFP can be used when Prothrombinex-VF is unavailable. Vitamin K1 is essential for sustaining the reversal achieved by PCC or FFP. • Surgery can be conducted with minimal increased risk of bleeding if INR ≤ 1.5. For minor procedures where bleeding risk is low, warfarin may not need to be interrupted. If necessary, warfarin can be withheld for 5 days before surgery, or intravenous vitamin K1 can be given the night before surgery. Prothrombinex-VF use for warfarin reversal should be restricted to emergency settings. Perioperative management of anticoagulant therapy requires an evaluation of the risk of thrombosis if warfarin is temporarily stopped, relative to the risk of bleeding if it is continued or modified.

Venous thromboembolism in pregnancy: diagnosis, management and prevention.

A pregnant woman has a two- to five-fold higher risk of venous thromboembolism (VTE) than a non-pregnant woman of the same age and, in developed countries, she is more likely to die from fatal pulmonary embolism (PE) than from obstetric haemorrhage. The increased VTE risk is mediated through normal physiological changes of pregnancy including alterations in haemostasis that favour coagulation, reduced fibrinolysis and pooling and stasis of blood in the lower limbs. Thrombophilia, smoking, obesity, immobility and postpartum factors such as infection, bleeding and emergency surgery (including emergency caesarian section) also increase the risk of pregnancy-related VTE. The diagnosis of VTE can be safely established with acceptable radiation exposure to the fetus using readily available imaging modalities such as ultrasound, ventilation perfusion lung scanning and computed tomographic pulmonary angiography. However, the optimal diagnostic strategies still remain to be determined. If there is no contraindication to anticoagulation, commencing treatment prior to objective confirmation should be strongly considered. For the mother and fetus, effective and safe treatment is readily available with low-molecular-weight heparin (LMWH), but optimal dosing of these agents in pregnancy remains controversial. Emerging data support antepartum LMWH prophylaxis for women with previous VTE if the event was unprovoked or in the presence of thrombophilia. On the other hand, women with prior provoked VTE and no thrombophilia or women with asymptomatic thrombophilia (but a family history of VTE) can safely be managed with antepartum surveillance. Postpartum prophylaxis is recommended for women with prior VTE or thrombophilia (and a family history of VTE).

Does this patient have pulmonary embolism?

CONTEXT: Experienced clinicians' gestalt is useful in estimating the pretest probability for pulmonary embolism and is complementary to diagnostic testing, such as lung scanning. However, it is unclear whether recently developed clinical prediction rules, using explicit features of clinical examination, are comparable with clinicians' gestalt. If so, clinical prediction rules would be powerful tools because they could be used by less-experienced health care professionals to simplify the diagnosis of pulmonary embolism. Recent studies have shown that the combination of a low pretest probability (using a clinical prediction rule) and a normal result of a D-dimer test reliably excludes pulmonary embolism without the need for further testing. OBJECTIVE: To evaluate and demonstrate the accuracy of pretest probability assessment for pulmonary embolism using clinical gestalt vs clinical prediction rules. DATA SOURCES: The MEDLINE database was searched for relevant articles published between 1966 and March 2003. Bibliographies of pertinent articles also were scanned for suitable articles. STUDY SELECTION: To be included in the analysis, studies were required to have consecutive, unselected patients enrolled; participating physicians in the studies, blinded to the results of diagnostic testing, had to estimate pretest probability of pulmonary embolism; and validated diagnostic methods had to be used to confirm or exclude pulmonary embolism. DATA EXTRACTION: Three reviewers independently scanned titles and abstracts for inclusion of studies. An initial MEDLINE search identified 1709 studies, of which 16 involving 8306 patients were included in the final analysis. DATA SYNTHESIS: A clinical gestalt strategy was used in 7 studies, and in the low, moderate, and high pretest categories, the rates of pulmonary embolism ranged from 8% to 19%, 26% to 47%, and 46% to 91%, respectively. Clinical prediction rules were used in 10 studies, and 3% to 28%, 16% to 46%, and 38% to 98% in the low, moderate, and high pretest probability groups, respectively, had pulmonary embolism. CONCLUSIONS: The clinical gestalt of experienced clinicians and the clinical prediction rules used by physicians of varying experience have shown similar accuracy in discriminating among patients who have a low, moderate, or high pretest probability of pulmonary embolism. We advocate the use of a clinical prediction rule because it has shown to be accurate and can be used by less-experienced clinicians.

The sensitivity and specificity of a red blood cell agglutination D-dimer assay for venous thromboembolism when performed on venous blood.

BACKGROUND: Studies evaluating the accuracy of the SimpliRED D-dimer assay for venous thromboembolism (VTE) have used a capillary fingerstick blood sample, which requires the test to be performed immediately at the bedside. Initial studies showed a sensitivity for VTE of 90% to 95% when the assay was performed by a finite number of experienced health care workers. However, because of the test's subjectivity, misinterpretation of the result is possible when performed by inexperienced staff. Recent reports by other investigators indicated a low sensitivity of this assay for VTE and noted a reduction in sensitivity (84%) for pulmonary embolism. OBJECTIVE: To determine the sensitivity and specificity of the D-dimer test performed in the laboratory by experienced technologists on venous whole-blood samples in routine collection tubes. If D-dimer testing results accurately detect VTE when performed in this manner, concerns about the sensitivity of this assay would be solved. METHODS: One hundred forty-eight consecutive patients with suspected VTE underwent D-dimer testing at the bedside using a fingerstick sample and venous blood collected into a plain tube. Venous blood was also collected into tubes containing tri-potassium EDTA, sodium citrate, or a combination of lithium and heparin for D-dimer testing in the laboratory. In addition, the EDTA tube was refrigerated overnight at 4 degrees C for retesting at approximately 24 hours. The presence or absence of VTE was determined by means of objective results of testing and a 3-month follow-up. RESULTS: Thirty-four subjects (23%) had confirmed VTE (25 with deep vein thrombosis; 9 with pulmonary embolism). All laboratory venous blood D-dimer results showed sensitivities of 97%, specificities of 61% to 64%, and negative predictive values of 99%, compared with 88%, 71%, and 95%, respectively, when the results were obtained by means of fingerstick at the bedside. CONCLUSIONS: The SimpliRED D-dimer assay performed in the laboratory on venous blood, collected into any of 3 routine laboratory tubes, is sensitive and moderately specific for VTE. Based on this study, immediate bedside testing (particularly by inexperienced personnel) under suboptimal conditions is unnecessary. Furthermore, the high sensitivity of refrigerated EDTA samples allows specimens to be stored or transported (on ice at 4 degrees C) for testing for 24 hours after collection.