Heparin-induced thrombocytopenia and COVID-19

Heparin-induced thrombocytopenia (HIT) has not been included as a possible cause of thrombocytopenia in Coronavirus Disease 2019 (COVID-19) patients. We report a case of HIT in a patient with COVID-19 treated with heparin. A 78-yearold man was admitted to our hospital for acute respiratory failure and acute renal failure due to SARS-CoV-2 infection; in intensive care unit, one 5000IU heparin dose (day 0, platelet count 305000/μL). On day 2, haemoglobin started to decrease and heparin was stopped. On day 10, platelet count was 153000/μL and 5000IU calcium heparin subcutaneously twice daily was started. The platelet further decreased, reaching 49000/μL on day 17, and the patient was investigated for suspected HIT: an IgG specific chemiluminescence test for heparin- PF4 antibodies was positive and a femoral DVT was found at ultrasound. Argatroban was started, platelet count increased without any bleeding and thrombosis complication. Our experience shows that HIT may develop in heparin treated COVID-19 patients and should be included among the possible cause of thrombocytopenia in such patients.

A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment

Introduction: Defibrotide is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States and Canada and for patients aged >1 month with severe hepatic VOD/SOS post-HCT in the European Union. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. Defibrotide has been shown in vitro to reduce endothelial cell (EC) activation and promote EC-mediated fibrinolysis. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. In a phase 3 study of patients with VOD/SOS post-HCT, rates of bleeding-related adverse events (AEs) with defibrotide were generally similar to matched historic controls (Richardson PG, et al. Blood. 2016;127[13]:1656-1665). To broaden our understanding of the risk of bleeding events associated with defibrotide treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with defibrotide treatment in studies outside of the VOD/SOS and HCT setting, using published literature. Methods: PubMed and Embase were searched from database inception through July 24, 2018 for studies using defibrotide (controlled trials with ≥1 arm assessing an intervention of interest, observational/retrospective studies, retrospective or post hoc analyses, and case series with ≥10 patients). Studies of patients with VOD/SOS or HCT, case reports with <10 patients, and reviews were excluded. Publications were evaluated for the presence of data on endpoints of interest, which included any bleeding-related event and overall safety or efficacy summaries; all studies with available data were included in the analysis. Overall bleeding rate was estimated for defibrotide and controls using the Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software). The risk ratio of bleeding was calculated using the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software). Overall bleeding rate and risk ratio of bleeding were calculated from studies that used the IV defibrotide formulation; studies using oral or intramuscular formulations were excluded from these calculations. Results: A total of 1,857 records were identified in the search; 124 studies reported on defibrotide and 19 contained data related to bleeding and were included in the analysis. Of the 19 included studies, 2 had >1,000 patients. An IV defibrotide formulation was used in 12 studies; the other 7 used intramuscular or oral delivery or more than one method of defibrotide administration. The most common indications were prevention of deep vein thrombosis (11 of 19) and treatment of thrombosis (3 of 19). Most studies (14 of 19) had 2 treatment arms; among these studies, heparin was the most common comparator (11 of 14). For the other 5 of 19 studies, 4 studies were single-arm and 1 study had 3 arms. The majority of studies (16 of 19) were conducted in adults; the other 3 studies did not specify patients' age. The most commonly administered defibrotide dose was 800 mg daily (14 of 19 studies). Bleeding rate and risk ratio of bleeding were calculated based upon data from the 12 studies that used IV defibrotide. Rates of bleeding events reported in the 12 studies with IV defibrotide ranged from 0% to 10% in individual studies and the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.03). In 10 studies with control treatments (9 calcium heparin, 1 urokinase), rates of bleeding events ranged from 1% to 37%, with 7 studies having rates ≥10%. Across the 10 control studies, the estimated overall bleeding rate for controls was 11% (95% CI: 0.05-0.20). Among the 8 studies with available data on IV defibrotide and controls (7 calcium heparin, 1 urokinase), the risk ratio for bleeding events with IV defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P <0.00001; Figure). Conclusions: This meta-analysis of defibrotide use outside of the VOD/SOS setting suggests that the bleeding risk with defibrotide is low, and there is comparable risk of bleeding with defibrotide treatment versus controls such as heparin or urokinase. Important limitations of this analysis include variations in AE reporting across studies and the use of a defibrotide dose that is lower than the currently approved recommendation in the majority of studies. Disclosures Tappe: Jazz Pharmaceuticals: Employment, Equity Ownership. Aggarwal:Jazz Pharmaceuticals: Consultancy. Topaloglu:Jazz Pharmaceuticals: Consultancy. Iacobelli:Massimo Iacobelli: Consultancy. OffLabel Disclosure: The abstract describes a meta-analysis of defibrotide (indicated for VOD/SOS) in the non-VOD/SOS setting. As this analysis drew data from existing literature, no patients were administered defibrotide for off-label indications in the course of this analysis.

Salvaging Digital Replantation and Revascularisation: Efficiency of Heparin Solution Subcutaneous Injection

Background. Distal digital replantation and revascularisation remains one of the demanding microsurgical procedures due to the difficulty of vascular anastomosis. Venous congestion is the most commonly encountered problem after replantation due to the difficulty of venous anastomosis in traumatic injuries. Heparin, among other drugs, is commonly used to facilitate venous drainage and prevent thrombosis. However, systemic heparin can be contraindicated in some patients. The senior author has experience of subcutaneous heparin injection for venous congestion in thirteen patients. Methods. An amount of 1 ml of calcium heparin (25,000 U) was mixed in 2.4 ml of normal saline making a solution that has 1000 U per 0.1 ml. 1000 U (0.1 ml) of the solution was injected directly into the congested replanted digits. This was repeated twice daily until venous congestion improved. Results. All the congested replanted digits survived without systemic side effects. There were no local side effects of the treatment. The PT and APTT have shown slight increase but they remained within the normal range. Haemoglobin levels have dropped slightly but no patients were at any risk of developing anaemia or needed blood transfusion. Conclusions. Subcutaneous heparin injections can salvage the replanted digits when venous congestion is a warning flag for replantation failure. It is safe and very efficient in patients where systemic heparin cannot be administered. However, this article shows the results in only thirteen patients which is a small number to show the efficacy, safety, and side effects.

Diagnosis and Management of Deep Vein Thrombosis

Awareness of deep venous thrombosis has increased considerably in the last decade including recognition of the importance of thromboprophylaxis for acutely ill hospital inpatients as preventative therapy. Combinations of a pre-test probability score plus a D-Dimer analysis can identify those patients where the chances of DVT are very low and radiological investigation can be obviated. The gold standard for diagnosis is still either ascending venography or venous Doppler ultrasound. Low molecular weight heparin has taken over from unfractionated calcium heparin as the initial treatment of choice. There are many challenges in management, especially deciding the optimum duration of anticoagulant treatment in order to balance the risks of drug induced bleeding against recurrent venous thromboembolic events.

Low-Molecular-Weight Heparin and Calcium Heparin in Thrombosis Prophylaxis in Patients with Percutaneous Arterial and Venous Ports for Colorectal Liver Metastases

Study Objective The evaluation of low-molecular-weight heparin use to prevent arterial and venous thrombosis in patients with indwelling arterial Port-a-Cath implants. Methods From 1996 to March 2003 we placed 370 indwelling hepatic arterial catheters with a minimally invasive approach. The left distal subclavian artery was approached from beneath the left clavicle, then an angiographic study of the tumoral vascular district was performed and the gastroduodenal artery was occluded by an embolus. A polyurethane catheter was introduced distally into the hepatic artery and connected to a reservoir through a 3-4 cm long subcutaneous tunnel. In 90 patients a venous Port-a-Cath was placed for concurrent systemic chemotherapy. All 370 patients received regional chemotherapy and were treated with calcium heparin at a dose of 5000 IU twice a day and with low-molecular-weight heparin at prophylactic doses (dalteparin 2500 IU or nadroparin 3000 IU) during catheter permanence to prevent hepatic artery thrombosis. Intra-arterial trans-port radionuclide scans using technetium-99m-labeled micro-aggregated albumin were performed monthly to check the infusion distribution and hepatic artery patency. In the presence of anomalous patterns, thrombosis, pulmonary embolism or other complications, angiography and/or other diagnostic studies were performed to determine the cause of the vascular event and the local or systemic symptoms. The mean arterial and venous Port-a-Cath permanence times were 6 and 8 months, respectively. Results We observed episodes of hepatic artery thrombosis in 4.3% of patients. Three of these 17 patients were successfully treated by intra-arterial thrombolysis using urokinase. No venous thrombosis occurred as a consequence of regional and/or systemic chemotherapy, no episodes of arterial thrombosis were registered during arterial catheter permanence, nor did any hemorrhagic complications related to anti-coagulant therapy occur. Five patients treated with low-molecular-weight heparin required treatment suspension due to a platelet count of <40,000/dL. Conclusion Our experience suggests that low-molecular-weight heparin and/or calcium heparin at prophylactic doses could be useful in the prevention of arterial and venous thrombosis in patients with indwelling arterial catheters or venous Port-a-Cath treated with regional or systemic chemotherapy for hepatic metastases from colorectal cancer. The homogeneity of the patient group and the use of analogous chemotherapeutic drugs (fluoropyrimidines) avoided statistical contamination related to differences between kinds of cancer and between the chemotherapeutic agents used.