Therapeutic Doses Of Low Molecular Weight Heparin Research Articles

The Impact of Laboratory Sample Request Evaluation and the Use of Probability Testing for HIT By Trained Physician on the Decrease of Unnecessary Tests and Increase the Likelihood of Positivity

Introduction: Heparin-induced thrombocytopenia (HIT) is an extremely serious and potentially fatal condition that can develop in patients taking heparin-based medications, such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The laboratory tests for diagnosis of HIT is expensive and time consuming. Clinical assessment (4Ts) followed by testing for Heparin/platelet factor 4 antibody in intermediate and high risk patients is the standard algorithm of pretest for (HIT) which can be later confirmed by serotonin releasing assay if available. Materials and methods: We conducted a retrospective analysis of laboratory practice of pretest evaluation of samples submitted for HIT testing in a cohort of patients treated in a tertiary hospital in Saudi Arabia who had a clinical suspicion of HIT. The 4 T score was a pretest requisite to proceed for electronic request for HIT. It had to be performed by the requesting physicians of different medical specialties. The request then been evaluated by hematopathologist before proceeding. The test will be cancelled if: the 4T score calculated by attending physician is < 4 or if platelet count is normal with no evidence of significant drop in the last 4 days from request or the test was performed at least 2 days before the new request. Additional exercise was performed by two physicians in training after train them to standardize the calculation of the 4T scores without re evaluation by the hematopatologist. The sample proceeded for testing if it met the testing criteria of 4T score > 3 and passed the evaluation by the hematopathologist. All tested sample were performed by immunoglobulin G (IgG) antibodies via an ELISA (Asserachrom HPIA-IgG, Stago Diagnostica STA®) and Optic density ( OD) and was evaluated and considered positive if OD >0.39 with sub classification to low positive 0.4-1, moderate 1-2 and strong if >2. Over a period of 2 years, we received 449 samples for patients who were admitted to our hospital, received prophylactic or therapeutic doses of LMWH or UFH, and underwent an HIT test due to clinical suspicion ( > 50% drop in platelet count from baseline, or ≥ 2 consecutive platelet counts < 150,000 per mm 3 and was defined as possible HIT). The 4 T score was calculated in the hospital system by attending physicians referred to as (system 4T score) and recalculated by trained two physicians and referred to (re calculated 4T score). Descriptive statistics, paired samples statistics, correlations, and analysis of variance (ANOVA) were performed. Results: The test was labeled by the laboratory physician ( hematopathologist ) as not indicated and test was not performed in 156 (35%) for various reasons including low 4 T score <3 in 90 (57%), Normal platelet count > 150 at time of test ( and wrong calculated 4T score) in 28 (18%), duplication of test order in 10 (6.4%%), There was clear other cause of thrombocytopenia in 15 (10%), Bad sample quality 5 (3.2%%) and 8 (5%) for other reasons. The samples for HIT test were for 231(51%) males and 220 (49%) females with mean age 56.3 (1-102) years. The mean platelet count at time of request was 82.9 (2-384) per mm 3. Out of the total cohort 422 (95.1%) patients had received UFH and only 22 (4.9%) received LMWH. There is only 69/449 (15.4%) agreement between the two calculations (system and re calculated score) . Out of the tested samples 293, total positive tests 19 (6.5%), were 11 (3.8%) had low positive for HIT test, moderate positive in 6 (2%) and only 2 strongly positive for HIT. The calculated (system 4T score) of < 4 were 142 (32%) samples while the (re calculated 4T score) were 136 (30%) of which 60 ( 38%) of the cancelled tests by hematopathologist, of which 68 (23%) of tested samples were negative and 7 (37%) of positive tests could have been missed based on this calculation. There were 12 out of 19 had moderate and high score by calculation and positive HIT while there were 17 out of 19 had moderate and high score by system calculation. Conclusion: We are reporting improved detection of HIT and confirmed the value of applying the 4 T score for HIT testing with added value of pre test screening to exclude low probability and cancel samples with no clear indication of HIT due to presence of other causes of thrombocytopenia.The retrospective re calculation even with more trained physicians did not add a value compared to pretest evaluation and screening by hematopathologist which had resulted in cancelation or more than third of the requested tests.

Applications of rotational thromboelastometry in heparin monitoring in critical COVID-19 disease: Observations in the Maastricht Intensive Care COVID cohort

BackgroundCritically ill COVID-19 patients are at risk for venous thromboembolism (VTE). Therefore, they receive thromboprophylaxis and, when appropriate, therapeutic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). To monitor heparins in COVID-19 disease, whole-blood rotational thromboelastometry (ROTEM) may be a promising alternative to the aPTT and anti-Xa assays. ObjectiveTo evaluate the ROTEM INTEM/HEPTEM ratios in mechanically ventilated COVID-19 patients treated with UFH and therapeutic LMWH. Material and methodsA subcohort of mechanically ventilated COVID-19 patients of the prospective Maastricht Intensive Care Covid (MaastrICCht) cohort was studied. Anti-Xa, aPTT, and ROTEM measurements following treatment with UFH or therapeutic dose of LMWH (nadroparin) were evaluated using uni- and multivariable linear regression analysis and receiver operating characteristics. ResultsA total of 98 patients were included, of which 82 were treated with UFH and 16 with therapeutic LMWH. ROTEM-measured INTEM/HEPTEM CT ratio was higher in patients using UFH (1.4 [1.3–1.4]) compared to patients treated with LMWH (1.0 [1.0–1.1], p < 0.001). Both the aPTT and anti-Xa were associated with the CT ratio. However, the β-regression coefficient (95%CI) was significantly higher in patients on UFH (0.31 (0.001–0.62)) compared to therapeutic LMWH (0.09 (0.05–0.13)) for comparison with the anti-Xa assay. Furthermore, ROC analysis demonstrated an area under the curve for detecting UFH of 0.936(0.849–1.00), 0.851(0.702–1.000), and 0.645(0.465–0.826) for the CT ratio, aPTT, and anti-Xa, respectively. ConclusionThe ROTEM INTEM/HEPTEM CT ratio appears a promising tool to guide anticoagulant therapy in ICU patients with COVID-19 disease, but associations with clinical endpoints are currently lacking.

Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Advanced Pancreatic Cancer (APC) Receiving Chemotherapy

Introduction: APC is as a highly thrombogenic cancer where the score of 2 is assigned per Khorana score (KS). POTP is currently suggested to patients with KS of 2 and above by recent clinical practice guidelines. We conducted an updated meta-analysis to demonstrate the benefit of POTP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy. Methods: Comprehensive literature across MEDLINE and EMBASE databases were searched from inception through June 30, 2022, using search terms 'thromboprophylaxis’ OR 'anticoagulation’ OR 'low-molecular-weight heparin’ OR 'direct oral anticoagulants’ AND 'pancreas cancer'. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). I2 statistic and Cochran's Q- statistic were used to assess heterogeneity among the studies. Results: Two RCTs and a subgroup of another four RCTs including 1,091 patients with APC were included. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic doses of DOAC (rivaroxaban and apixaban) were used in the trials. The duration of anticoagulation ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2 statistic for heterogeneity was 35, suggesting some heterogeneity among RCTs. The VTE incidence was 30 (5.4%) in ATP group and 71 (13.2%) in control group with a RR of 0.42 (95% CI: 0.23 to 0.74, P = 0.003). The absolute RD was -0.08 (95% CI: -0.11 to -0.04, P < 0.0001) with an estimate of the number needed to treat (NNT) of 13 to prevent one VTE event. In a subset of patients treated with LMWH (n= 740, 4 studies), the pooled RR was significant at 0.32 (95% CI: 0.15 to 0.69, P = 0.003) whereas in patients who received DOACs (n=351, 2 studies), RR was statistically non-significant at 0.66 (95% CI: 0.36 to 1.22, P = 0.19). Conclusions: Although POTP in APC statistically significantly decreases VTE events (approximately with relative risk reduction of 59% and a NNT of 13), the VTE reduction seemed only statistically significantly observed in patients who had received "LMWH vs control” compared to patients who were treated with "DOAC vs control". One hypothesis could be that in the trials with LMWH, higher doses (therapeutic dose in FRAGEM and intermediate dose in CONKO-004) were utilized compared to the studies with DOAC where only prophylactic doses were utilized. Another possibility is that the compliance rates were poor in the CASSINI trial. More randomized trials are required to further define the high-risk subsets who may benefit from POTP as well as the optimal dosing and types of anticoagulation in such population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Molecular Weight Heparin Anti-Factor Xa Level Monitoring in a Healthcare System

Purpose: Low molecular weight heparin (LMWH) is widely used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Routine monitoring of therapeutic effects through anti-Xa levels is not recommended but may be beneficial in patients with altered pharmacokinetics including pregnancy, weight extremes, or renal impairment. Levels should be drawn approximately four hours after the third dose to measure peak anti-Xa activity after achieving steady state. Untimely monitoring results in excessive testing, increased laboratory costs, and unwarranted dose adjustments compromising patient safety and efficacy. The purpose of this performance improvement project was to evaluate the appropriateness of monitoring LMWH anti-Xa levels and identify opportunities to optimize ordering within a healthcare system. Methods: A random sample, retrospective chart review of patients at a multi-site hospital system over a 3 year period was conducted. Inclusion criteria were adult inpatients with at least one anti-Xa level ordered. Data collection included the anticoagulant agent, dose, indication, and administration time; indication for anti-Xa level monitoring, and anti-Xa sample collection time relative to the dose of the anticoagulant administered. Data was collected to assess if the dose was appropriately adjusted in patients who received an anticoagulant dose adjustment following anti-Xa level monitoring. Baseline characteristics collected included patient's creatinine clearance (CrCl), weight, and COVID-19 status. Primary outcomes of this study consisted of ordering trends for anti-Xa levels including indication and corresponding dose adjustments. Secondary outcomes included anti-Xa levels ordered at the appropriate time window and incidence of bleeding or thrombosis following inappropriate dose adjustments. Results: A total of 220 patients with anti-Xa level monitoring were reviewed. An appropriate indication for anti-Xa level monitoring was identified in 28% of patients. Of the 49 patients that warranted anticoagulant dose adjustments following anti-Xa levels, 45 patients (92%) received appropriate dose adjustments. Anti-Xa levels were drawn after the third therapeutic dose of LMWH in 146 patients and 84 of these patients had levels drawn 3-5 hours post-dose. Therefore, 54% of levels drawn were within the appropriate time frame. A total of 4 patients had documentation of bleeding and 1 patient had thrombosis following an inappropriate dose adjustment of LMWH. Conclusion: Appropriate anti-Xa level monitoring in patients with altered pharmacokinetics resulted in justified LMWH dose adjustments and ensured therapeutic concentrations were attained. In patients who received appropriate monitoring and subsequent dose adjustments, there were no adverse events noted. The results of this performance improvement project will be reviewed with pertinent stakeholders and a multi-disciplinary approach will be utilized to develop a protocol for LMWH anti-Xa level monitoring.

P11.01.B Lower-extremity deep vein thrombosis and bleeding complications in primary brain tumor patients: A prospective study

Abstract Background Primary brain tumor patients have a high risk of venous thromboembolism (VTE). Bleeding risk with prophylactic and therapeutic anticoagulation is an important concern in these patients, and data on the management of asymptomatic VTE events in this population are lacking. The aim of this prospective study is to investigate risk and risk factors for asymptomatic lower-extremity deep-vein thrombosis (LE-DVT) in patients with primary brain tumors, and to estimate the rate of bleeding complications on full, prophylactic or no anticoagulation. Material and Methods We included consecutive patients with primary brain tumours undergoing surgery. Screening for asymptomatic LE-DVT by compression ultrasound (CUS) was performed pre-operatively and postoperatively within 2 months after surgery. Telephone follow-up was done 6 and 12 months after surgery. The protocol pre-specified therapeutic doses of low-molecular-weight heparin (LMWH) in case of detection of an asymptomatic LE-DVT. Results Fifty patients were included (female: 34%, median age 58 years, WHO grade IV tumors: 78%, prophylactic-dose LMWH at baseline: 12%). During a median observation period of 9.1 months, LE-DVT was detected in 9 patients (18%). LE-DVTs included two asymptomatic events (4%) at pre-operative screening, five asymptomatic events (10%) at postoperative screening, and two symptomatic events (4%, both 4-level LE-DVT) at telephone follow-up. This corresponded to a 12-month cumulative incidence of LE-DVT of 14.9% (95%CI: 6.4-26.6). At postoperative screening, n=10 patients were on prophylactic-dose LMWH, and one of these patients had an LE-DVT event detected by screening. The two patients with symptomatic LE-DVT were not on thromboprophylaxis at the time of event. Among a variety of investigated potential risk factors, only higher age (Odds Ratio (OR) per 5 years increase=1.46, 95%CI: 1.01-2.13, p=0.05), higher neurologic assessment in neuro-oncology (NANO) scale (OR per 1 point increase=1.59, 1.00-2.54, p=0.05), higher serum Galectin-3 levels (OR per 1ng/ml increase=1.20, 1.01-1.42, p=0.041) but not D-Dimer (OR per 1mg/L increase=1.89, 0.75-4.77, p=0.178) emerged as significant predictors of any LE-DVT. Six patients (12%) developed bleeding events, including n=3 operative intracranial bleedings without LMWH, n=1 spontaneous ventricular hemorrhage without LMWH, n=1 minor subcutaneous bleeding without LMWH, and 1 intracerebral hematoma during therapeutic-dose LMWH initiated for asymptomatic distal LE-DVT. Conclusion In our study we detected a high-frequency of asymptomatic LE-DVT in patients with primary brain tumours. Conversely, symptomatic LE-DVT risk was low, which may be related to prior screening. Patients with primary brain tumors appear to have LE-DVT risk factors specific to this entity. Prophylactic-dose LMWH did not show any adverse safety signals regarding bleeding.

Outcomes of Open Surgery for Retroperitoneal Hematoma in Covid-19 Patients: Experience from a Single Centre.

Background: Spontaneous retroperitoneal hematoma is a severe and potentially fatal complication that appears in the course of anticoagulation therapy. Therapeutic doses of low molecular weight heparin (LMWH) are used for the prevention of thrombosis in patients seriously ill with Covid-19. Methods: We describe 27 (0.14%) patients with retroperitoneal hematomas who required emergency surgery out of 19108 patients with Covid-19 who were hospitalized in Batajnica COVID Hospital between March 2021 and March 2022. All the patients were on therapeutic doses of LMWH. The existence of retroperitoneal hematoma was confirmed by abdominal ultrasound and computed tomography scans. Results: Open surgery was performed on 27 patients with spontaneous retroperitoneal hematomas (12 female and 15 male). The mean age of the study population was 71.6+-11.9 years. D-dimer was significantly elevated two days before the surgery in comparison with the values on the day of surgery (p=0.011). Six patients (22.23%) survived, while 21 (77.77%) patients died. Conclusion: Bleeding in Covid-19 patients treated by LMWH is associated with an increased risk of developing retroperitoneal hematoma. Open surgery for retroperitoneal hematoma in Covid-19 patients on anticoagulation therapy is a procedure associated with a high rate of mortality.

C36. Deep Vein Thrombosis in A Patient with Thrombocytopenia : Case Report

Abstract Background Deep vein thrombosis (DVT) is a common but elusive illness that can result in suffering and death if not recognized and treated effectively. Overall, 43% of patients with thrombocytopenia were hospitalized, but just 2% of patients had DVT. Case Summary A 48-year-old male patient presented with a complaint left leg pain accompanied by edema leg 8 days before admission. The patient is a smoker, the patient has a history of diabetes since one year ago, In the laboratory results showed platelet count 23,000/mm3, D-dimer above 4000 ng/ml. Anti-dengue IgM and IgG were negative. Doppler examination revealed a thrombus in the common femoral and popliteal veins of the left leg. Patient was treated with low molecular weight heparin (LMWH) Subcutan fondaparinux 5 mg once daily for up to 7 days without bleeding and continued with Rivaroxaban 20 mg once daily, The patient was discharged on day 14. Discussion Platelet count below 50 x109/L significantly reduces the risk of DVT. Some known risk factors for DVT still appear to apply in patients with thrombocytopenia, and therefore patients with thrombocytopenia would benefit from DVT risk stratification based on platelet count and comorbidity. Patients having thrombocytopenia with DVT were treated safely with anticoagulants without increased occurrence of bleeding. The majority of cases were given therapeutic doses of LMWH.

C36. Deep Vein Thrombosis in A Patient with Thrombocytopenia : Case Report

Abstract Background Deep vein thrombosis (DVT) is a common but elusive illness that can result in suffering and death if not recognized and treated effectively. Overall, 43% of patients with thrombocytopenia were hospitalized, but just 2% of patients had DVT. Case Summary A 48-year-old male patient presented with a complaint left leg pain accompanied by edema leg 8 days before admission. The patient is a smoker, the patient has a history of diabetes since one year ago, In the laboratory results showed platelet count 23,000/mm3, D-dimer above 4000 ng/ml. Anti-dengue IgM and IgG were negative. Doppler examination revealed a thrombus in the common femoral and popliteal veins of the left leg. Patient was treated with low molecular weight heparin (LMWH) Subcutan fondaparinux 5 mg once daily for up to 7 days without bleeding and continued with Rivaroxaban 20 mg once daily, The patient was discharged on day 14. Discussion Platelet count below 50 x109/L significantly reduces the risk of DVT. Some known risk factors for DVT still appear to apply in patients with thrombocytopenia, and therefore patients with thrombocytopenia would benefit from DVT risk stratification based on platelet count and comorbidity. Patients having thrombocytopenia with DVT were treated safely with anticoagulants without increased occurrence of bleeding. The majority of cases were given therapeutic doses of LMWH.

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19

Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. To evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US. Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data. Of 257 patients randomized, 253 were included in the analysis (mean [SD] age, 66.7 [14.0] years; men, 136 [53.8%]; women, 117 [46.2%]); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk [RR], 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71). In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients. ClinicalTrials.gov Identifier: NCT04401293.

Potential benefits of anticoagulant doses of low molecular weight heparin in COVID-19: An observational retrospective study

Hypercoagulability is a common complication of the systemic inflammation related to coronavirus disease 2019 creating debate within the critical care community on the therapeutic utility of Low Molecular Weight Heparin (LMWH). We collected data on consecutive patients with COVID-19 admitted to the Emergency Department of Castel San Giovanni Hospital, between February 29th and April 7th, 2020. Exclusion criteria were age &lt;18 years, hospital stay &lt;7 days, patients on dialysis and patients who had been transferred to other centers for which we could not collect data. Of the 257 patients included in the study, 49 (19.1%) died during hospitalization. We considered a wide set of variables as independent variables (age, sex, comorbidities and in-hospital treatments). We used a multivariate logistic regression model and, being heparin the only one therapy affecting survival rate, we compared prophylactic LMWH (p-LMWH) and Therapeutic LMWH (T-LMWH) groups. Kaplan Meier curve showed a higher survival probability in the T-LMWH and the difference between the two groups was statistically significant according to the log-rank or Mantel- Haenszel test (p&lt; 0.0001). In a stratified analysis by ventilation type, the subgroup of patients who benefited from therapeutic LMWH was that in non-invasive mechanical ventilation. Using a multivariate analysis and adjusting for the drugs intake, TLMWH was the only therapy impacting on survival (HR 0.293, p &lt;0.001). No fatal bleeding was observed. Therapeutic dose of LMWH in patients admitted to hospital with COVID-19 pneumonia was 70 associated with a decrease risk of intra-hospital mortality.

Anticoagulant treatment of venous thromboembolism in pregnant women

Venous thromboembolism (VTE), in particular pulmonary embolism (PE), remains the leading cause of death among pregnant women. Low-molecular-weight heparin (LMWH), with preference for therapeutic doses given twice daily according to European guidelines, is the drug of choice for the treatment of VTE in pregnancy and the puerperium. The recommended therapeutic dose is calculated on early pregnancy body weight. Evidence to support anti-Xa monitoring in pregnancy is weak. Unfractionated heparin (UFH) with multiple activated partial thromboplastin time measurements is still used in the acute treatment of high-risk PE. American experts have suggested considering initial outpatient therapy over hospital admission also in pregnant women with low-risk acute VTE, but European experts suggest adopting such a strategy selectively, for example in isolated distal leg thrombosis. Scheduled delivery with prior discontinuation of anticoagulant therapy in pregnant women who received a therapeutic dose of LMWH is suggested with the restart of therapy 4–6 h after a vaginal birth and 6–12 h after a cesarean delivery. It is recommended that UFH, LMWH, warfarin, acenocoumarol, or fondaparinux, but not direct-acting oral anticoagulants, should be used in breastfeeding women. This review summarizes the key messages from current guidelines mainly based on low-quality evidence and expert consensus.

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

BackgroundDisseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.ObjectiveThe aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.MethodsWe used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.ResultsSeven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.ConclusionStudies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.

Comparison of standard prophylactic and preemptive therapeutic low molecular weight heparin treatments in hospitalized patients with COVID-19.

Anticoagulant treatment approach in patients with COVID-19 is not well studied and not standardized. We aimed to compare the effects of standard prophylactic and pre-emptive therapeutic Low-Molecular-weight Heparin (LMWH) treatment approaches on mortality in patients with COVID-19. This retrospective and single-centre study includes patients aged ≥ 18 years, who were diagnosed with COVID-19 and treated with LMWH during the hospital stay. Therapeutic dose of LMWH was defined as 1 mg/kg subcutaneously twice daily and prophylactic dose of LMWH was defined as 40 mg subcutaneously once daily. Among the 336 patients diagnosed with COVID-19 pneumonia, 115 patients, who received LMWH were included in the study. The mean age was 58.6 ± 13.3 and 58 (50.4 %) of the patients were male. Sixty-nine (60 %) of the patients were treated with prophylactic and 46 (40 %) therapeutic LMWH.In-hospital mortality was not different between patients treated therapeutic LMWH and prophylactic LMWH by the multivariate regression analysis (OR=2.187, 95% CI 0.484-9.880, p=0.309) and the propensity score modelling (OR=1.586, 95% CI 0.400-6.289, p=0.512.)CONCLUSION: Clinicians should consider the potential risks and benefits of standard prophylactic and pre-emptive therapeutic LMWH. Therefore, anticoagulant therapy should be individualized in patients with COVID-19 (Tab. 3, Ref. 28).

Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection.

ABSTRACTBACKGROUND: Venous thromboembolism or extensive thrombosis is relatively common in patients with severe COVID-19 infection and has been associated with increased mortality. During the current COVID-19 pandemic, several prophylactic doses and types of low-molecular-weight heparin (LMWH) are being used worldwide; however, there are no high-quality studies or recommendations for an optimal prophylactic LMWH dose.OBJECTIVES: Investigate the relationship between coagulation parameters and the LMWH dose, and mortality and ICU admission in hospitalized patients with severe COVID-19 pneumonia.DESIGN: Retrospective.SETTING: Tertiary care hospital.PATIENTS AND METHODS: Data on clinical features, coagulation parameters and anticoagulant medications of inpatients with severe COVID-19 were collected for the period between 11 March 2020 and 31 April 2020.MAIN OUTCOME MEASURES: Mortality and ICU admission for prophylactic dose LMWH (0.5 mg/kg twice daily) and therapeutic dose LMWH (1 mg/kg twice daily).SAMPLE SIZE: 154 cases.RESULTS: Ninety-eight (63.6%) patients were treated with the LMWH prophylactic dose and 56 (36.4%) patients were treated with the therapeutic dose. Forty-four (44.9%) of 98 patients using the prophylactic dose LMWH died, while 10 (17.9%) of 56 patients using the therapeutic dose LMWH died (P=.001). Mortality was 6.4-fold higher in the prophylactic dose LMWH users than in the therapeutic dose LMWH users (OR=6.5, 95% CI: 2.4–17.6, P<.001).CONCLUSIONS: Therapeutic dosing of LMWH may decrease mortality in patients with severe COVID-19 infected pneumonia. More aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.LIMITATIONS: Lack of information about bleeding complications. LMWH was not compared with other anticoagulant therapies. There was no comparison between our two groups on the APACHE score. Used different doses of LMWH in different clinics in our hospital. Single-center, retrospective study.CONFLICT OF INTEREST: None.

A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID-19.

Those who are infected with Severe Acute Respiratory Syndrome‐related CoronaVirus‐2 are theoretically at increased risk of venous thromboembolism during self‐isolation if they have reduced mobility or are dehydrated. Should patients develop coronavirus disease (COVID‐19) pneumonia requiring hospital admission for treatment of hypoxia, the risk for thromboembolic complications increases greatly. These thromboembolic events are the result of at least two distinct mechanisms – microvascular thrombosis in the pulmonary system (immunothrombosis) and hospital‐associated venous thromboembolism. Since pregnancy is a prothrombotic state, there is concern regarding the potentially increased risk of thrombotic complications among pregnant women with COVID‐19. To date, however, pregnant women do not appear to have a substantially increased risk of thrombotic complications related to COVID‐19. Nevertheless, several organizations have vigilantly issued pregnancy‐specific guidelines for thromboprophylaxis in COVID‐19. Discrepancies between these guidelines reflect the altruistic wish to protect patients and lack of high‐quality evidence available to inform clinical practice. Low molecular weight heparin (LMWH) is the drug of choice for thromboprophylaxis in pregnant women with COVID‐19. However, its utility in non‐pregnant patients is only established against venous thromboembolism, as LMWH may have little or no effect on immunothrombosis. Decisions about initiation and duration of prophylactic anticoagulation in the context of pregnancy and COVID‐19 must take into consideration disease severity, outpatient vs inpatient status, temporal relation between disease occurrence and timing of childbirth, and the underlying prothrombotic risk conferred by additional comorbidities. There is currently no evidence to recommend the use of intermediate or therapeutic doses of LMWH in thromboprophylaxis, which may increase bleeding risk without reducing thrombotic risk in pregnant patients with COVID‐19. Likewise, there is no evidence to comment on the role of low‐dose aspirin in thromboprophylaxis or of anti‐cytokine and antiviral agents in preventing immunothrombosis. These unanswered questions are being studied within the context of clinical trials.

Updated Meta-Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Advanced Pancreatic Cancer (APC) Receiving Chemotherapy

Introduction: Thrombosis is the second leading cause of death in cancer patients and patients with APC are categorized as high-risk of developing venous thromboembolism (VTE). Many trials had failed to demonstrate improvement in survival with PATP. Despite decreasing VTE events, PATP in solid cancer patients is not routinely recommended. We conducted an updated meta- analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy. Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Results: A total of 1,013 patients with APC from two RCTs and a subgroup of another three RCTs were included in our meta-analysis. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic dose of DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2statistic for heterogeneity was 60, suggesting some heterogeneity among RCTs. The VTE incidence was 28 (5.43%) in PATP group and 60 (12.07%) in control group with a RR of 0.44 (95% CI: 0.20 to 0.99, P = 0.05) and RD of -0.06 (95% CI: -0.11 to -0.01, P = 0.01). In fixed effects model, the pooled RR was 0.45 (95% CI: 0.29 to 0.70, P = 0.0003) and the absolute RD in VTE was -0.07 (95% CI: -0.10 to -0.03, P = 0.0002) with an estimate of the number needed to treat (NNT) of 15 to prevent one VTE event. MB events were reported in 9 (4.11%) patients in PATP group compared to 7 (3.27%) in control group according to an analysis of 2 RCTs. The pooled relative risk for MB was statistically non-significant at 1.25 (95% CI: 0.47 to 3.31, P = 0.65). Conclusions: In our study, PATP in APC may statistically significantly decrease VTE events, approximately with relative risk reduction of 55% and a NNT of 15, without increasing MB events. Proper selection of patients who are high risk for VTE in outpatient setting is important. More RCTs are required to further define high risk subsets of APC patients receiving chemotherapy who may benefit from PATP. Disclosures Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: Research: site co-investigator .

Human-Centered Design of a Low Molecular Weight Heparin Order Set to Reduce Medication Errors.

Inpatient anticoagulation medication errors for venous thromboembolism (VTE) therapy are common. Our VTE Team identified frequent dosing and duplicate order errors for therapeutic-dose low molecular weight heparin, which (lacking computerized physician order entry) was ordered using blank forms. To decrease such errors, a nonmandatory order form with weight-based dosing and prechecked orders discontinuing existing injectable anticoagulation was developed using human-centered design innovation principles/processes emphasizing end-user engagement in all phases: observation, exploring solutions, and rapid prototyping/feedback. Three physicians independently reviewed ordering errors the year before versus after implementation. Before implementation, 11% of orders contained any error versus 10.5% after implementation (p = .82); 6.2% had a dosing or duplicate therapy error versus 4.2% after implementation (all made when the form was not used; p = .19). No dosing or duplicate therapy errors were made when the form was used. Were the form mandatory, all such ordering errors would likely have been eliminated, leaving 11% before versus 6.3% after implementation orders with any error (p = .015), and 6.2% before versus 0% after implementation orders with duplicate or dosing therapy errors (p < .001). Human-centered design of an anticoagulation order form can reduce anticoagulation order errors; such principles can be applied to other health care innovations, including electronic order sets.

Platelet cut-off for anticoagulant therapy in thrombocytopenic patients with blood cancer and venous thromboembolism: an expert consensus.

Management of venous thromboembolism (VTE) in patients with haematologic malignancies and thrombocytopenia is clinically challenging due to the related risks. No prospective studies or clinical trials have been carried out and, therefore, no solid evidence on this compelling issue is available. Given this, an expert panel endorsed by the Gruppo Italiano Malattie Ematologiche dell'Adulto Working Party on Thrombosis and Haemostasis was set up to produce a formal consensus, according to the RAND method, in order to issue clinical recommendations about the platelet (PLT) cut-off for safe administration of low molecular weight heparin (LMWH) in thrombocytopenic (PLT <100×109/L) adult patients with haematologic malignancies affected by acute (<1 month) or non-acute VTE. In acute VTE, the panel suggests safe anticoagulation with LMWH at therapeutic doses for PLT between ≥50<100×109/L and at 50% dose reduction for PLT ≥30<50×109/L. In acute VTE for PLT <30×109/L, the following interventions are recommended: positioning of an inferior vena cava (IVC) filter with prophylactic LMWH administration and platelet transfusion. In non-acute VTE, anticoagulation with LMWH at therapeutic doses for PLT between ≥50<100×109/L or over and at 50% dose reduction for PLT ≥30<50×109/L is considered appropriate. The discontinuation of full or reduced therapeutic dose of LMWH is recommended for PLT <30×109/L, both in acute and non-acute VTE. We suggest using dose-adjusted LMWH according to PLT to optimise anticoagulant treatment in patients at high bleeding risk.

Treatment for superficial thrombophlebitis of the leg.

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach. We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy.

BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy.