Heparin resistance in severe thermal injury:a prospective cohort study

Background:Low molecular-weight heparin(LMWH)is routinely administered to burn patients for thromboprophylaxis.Some studies have reported heparin resistance,yet the mechanism(s)and prevalence have not been systematically studied.We hypothesized that nucleosomes,composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps(NETs or NETosis),neutralize LMWH resulting in suboptimal anticoagulation,assessed by reduction in anti-factor Xa activity.Methods:Blood was sampled from>15%total body surface area(TBSA)burn patients receiving LMWH on days 5,10 and 14.Peak anti-factor Xa(AFXa)activity,anti-thrombin(ATIII)activity,cellfree DNA(cfDNA)levels and nucleosome levels were measured.Mixed effects regression was adjusted for multiple confounders,including injury severity and ATIII activity,and was used to test the association between nucleosomes and AFXa.Results:A total of 30 patients with severe burns were included.Mean TBSA 43%(SD 17).Twentythree(77%)patients were affected by heparin resistance(defined by AFXa activity<0.2 IU/mL).Mean peak AFXa activity across samples was 0.18 IU/mL(SD 0.11).Mean ATIII was 81.9%activity(SD 20.4).Samples taken at higher LWMH doses were found to have significantly increased AFXa activity,though the effect was not observed at all doses,at 8000 IU no samples were heparin resistant.Nucleosome levels were negatively correlated with AFXa(r=−0.29,p=0.050)consistent with the hypothesis.The final model,with peak AFXa as the response variable,was adjusted for nucleosome levels(p=0.0453),ATIII activity(p=0.0053),LMWH dose pre-sample(p=0.0049),drug given(enoxaparin or tinzaparin)(p=0.03),and other confounders including severity of injury,age,gender,time point of sample.Conclusions:Heparin resistance is a prevalent issue in severe burns.Nucleosome levels were increased post-burn,and showed an inverse association with AFXa consistent with the hypothesis that they may interfere with the anticoagulant effect of heparin in vivo and contribute to heparin resistance.Accurate monitoring of AFXa activity with appropriate therapy escalation plans are recommended with dose adjustment following severe burn injury.

A Review of an Unorthodox Argatroban Infusion Rate for Anticoagulation in a Patient Case

Argatroban is an intravenous DTI （direct synthetic thrombin inhibitor） that is not routinely used for anticoagulation; thus, expertise surrounding its use is very limited. Therefore, this case reviews an unusually high argatroban infusion rate, which was needed to prevent further emboli formation in a patient. In this case, a 61-year-old Caucasian male patient exhibited heparin resistance during an intraoperative vascular procedure as measured by activated clotting time and PTT （partial thromboplastin time）. The patient had multiple occlusions in his right lower extremities and underwent embolectomies of the right popliteal and posterior tibial arteries. The clinical pharmacist was consulted to manage the argatroban infusion once heparin was discontinued. The therapeutic window required a PTr of 1.5-3 times the patient baseline （35-75 s）. The patient was reported to be 89 kg with a baseline PTT of 24.7 s and INR （international normalized ratio） of 0.98. The starting dose ofargatroban was initiated by the pharmacist at 2 mcg/kg/min （10.7 mL/h） as the patient did not have hepatic failure or sepsis. The patient was maintained on argatroban in the therapeutic PTT window for more than 72 h; however, frequent and aggressive dose increases, to a final rate of 7.5 mcg/kg/min （40 mL/h）, were needed to maintain the therapeutic PTT level. From the case, the cause of heparin resistance still has not been determined despite a hematologic work-up; however, this patient required an unusually high infusion rate of argatroban to maintain a therapeutic PTT during the hospital course before being changed to an anticoagulation regimen for discharge.

Potential mechanisms of resistance to current antithrombotic strategies in Multiple Myeloma

Multiple Myeloma(MM)is a common haematological malignancy that is associated with a high rate of venous thromboembolism(VTE)with almost 10% of patients suffering thrombosis during their disease course.Recent studies have shown that,despite current thromboprophylaxis strategies,VTE rates in MM remain disappointingly high.The pathophysiology behind this consistently high rate of VTE is likely multifactorial.A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients,however,the optimal method of clinically evaluating this is unclear at present,though some groups have attempted its characterisation with thrombin generation testing(TGT).In addition to testing for heparin resistance,TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels.Apart from these thrombin-mediated processes,other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance,endothelial toxicity secondary to chemotherapy agents,tissue factor abnormalities and the effect of immunoglobulins/“M-proteins”on both the endothelium and on fibrin fibre polymerisation.It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.