Heparin Monitoring with an Anti-Xa Protocol Compared to Activated Clotting Time in Patients on Temporary Mechanical Circulatory Support.

BACKGROUND: Temporary mechanical circulatory support (tMCS) devices are used for patients with severe cardiac or respiratory failure; however, these patients are at high risk for clotting and bleeding. The best method to monitor heparin in these patients has not been established. OBJECTIVE: To determine the risks for bleeding and clotting while monitoring heparin with either anti-Xa or activated clotting time (ACT) in tMCS patients. METHODS: A retrospective cohort study was conducted on tMCS patients who received heparin adjusted according to an anti-Xa or ACT protocol. The primary outcome was incidence of major bleeding. Pertinent secondary outcomes were individual components of the primary outcome, clotting events, and time to therapeutic range. RESULTS: There were 103 patients included in the study: 53 in the ACT group and 50 in the anti-Xa group. Overall, there were 30 (56.6%) patients with major bleeding in the ACT group, compared with 16 (32%) patients in the anti-Xa group (P = 0.017). An anti-Xa-based protocol was associated with a decreased hazard of major bleeding (hazard ratio = 0.388 [0.215-0.701]; P = 0.002) in the univariate analysis. In the multivariable analysis, an anti-Xa protocol remained associated with a significantly lower hazard of bleeding. Findings were similar when broken down into more discrete subgroups of the entire cohort, extracorporeal membrane oxygenation life support (ECMO), and non-ECMO groups. CONCLUSION AND RELEVANCE: Anti-Xa monitoring was associated with a lower hazard of bleeding during tMCS compared to an ACT-based protocol. Further studies should evaluate if anti-Xa monitoring should be preferentially used in tMCS.

Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins.

Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)-depleted plasma. UFH prevents tissue factor pathway inhibitor alpha (TFPIα) from inhibiting the procoagulant enzyme complex, prothrombinase, providing a possible mechanism for its procoagulant activity. The procoagulant potential of UFH and various low molecular weight heparins (LMWHs) were characterized for TFPIα dependence, using thrombin generation assays performed with antithrombin/HCII-depleted plasma. UFH, the LMWHs enoxaparin and dalteparin, and the low anticoagulant LMWH 2-O, 3-O desulphated heparin (ODSH) all promoted thrombin generation, but fondaparinux did not, and this activity was blocked by a TFPIα antibody. UFH, enoxaparin, and dalteparin were anticoagulant in reactions containing 1-2% normal plasma. In prothrombinase activity assays, UFH, enoxaparin, dalteparin and ODSH blocked prothrombinase inhibition by TFPIα, while again fondaparinux did not. In both the plasma and purified assays, LMWHs displayed greater procoagulant potential than UFH, even when normalized to saccharide concentration. These biochemical data reveal that UFH and LMWHs, but not fondaparinux, block prothrombinase inhibition by TFPIα, thereby producing their paradoxical procoagulant activity observed in the absence of antithrombin/HCII. The findings may help to understand the complex pathophysiology and treatment of patients that are simultaneously bleeding and clotting, such as those with disseminated intravascular coagulation.

Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices.

Left ventricular assist devices (LVADs) have increased the survival of patients with advanced heart failure fourfold. Despite these advances, significant bleeding and thrombotic complications occur. Hemorrhage requiring surgery has been reported in up to 30% of adults and 50% of children after LVAD placement. LVAD thrombosis and embolic stroke lead to significant long-term morbidity. Adults are treated with antithrombotic therapy to prevent thrombotic complications, but the amount and intensity of treatment differs between institutions. The goal international normalized ratio for warfarin therapy varies from 1.5 to 3.0. Some physicians manage adult LVAD patients without antiplatelet medication, whereas other adults are treated with aspirin as a single agent or combined with dipyridamole. In contrast, physicians typically manage children with LVADs using the Edmonton Anticoagulation and Platelet Inhibition Protocol, a detailed algorithm for anticoagulation and antiplatelet treatment modified based on thromboelastography results. LVAD implantation causes consumption of coagulation proteins, activation of fibrinolysis, and loss of high molecular weight von Willebrand protein multimers. How these changes in the coagulation system influence the risk of hemorrhage and initiation of thrombosis is unknown. Prospective, controlled studies are needed to determine the antithrombotic regimen that most effectively balances bleeding and thrombosis in LVAD patients.

Antithrombotic management of patients with deep vein thrombosis and venous stents: an international registry.

BACKGROUND: In patients with acute deep vein thrombosis (DVT) treated with catheter-based thrombolysis and venous stenting, poststenting anticoagulant management is uncertain. OBJECTIVES: To determine the type and duration of antithrombotic therapy used in patients who have received venous stents for treatment of acute lower extremity DVT. METHODS: We created an international registry of patients with leg DVT from 2005 to 2019 who received venous stents as part of their acute management. We collected data on baseline clinical characteristics and pre-venous and post-venous stent antithrombotic therapy. RESULTS: We studied 173 patients with venous stents: 101 (58%) were aged ≤50 years, 105 (61%) were female, and 128 (74%) had risk factors for thrombotic disease. DVT was iliofemoral in 150 (87%) patients, and catheter-based treatment was given within 7 days of diagnosis in 92 (53%) patients. After venous stenting, 109 (63%) patients received anticoagulant-only therapy with a direct oral anticoagulant (29%), warfarin (22%), or low-molecular-weight heparin (10%), and 59 (34%) received anticoagulant-antiplatelet therapy. In patients taking anticoagulant-only therapy, 29% received indefinite treatment; in patients on anticoagulant-antiplatelet therapy, 19% received indefinite treatment. Factors associated with combined anticoagulant-antiplatelet therapy vs anticoagulant-only therapy were use of thrombolytic, thrombectomy, and aspiration interventions (odds ratio [OR], 5.11; 95% CI, 1.45-18.05); use of balloon angioplasty (OR, 2.62; 95% CI, 1.20-5.76); and immediate stent restenosis (OR, 7.2; 95% CI, 1.45-5.89). CONCLUSION: Anticoagulant therapy without concomitant antiplatelet therapy appears to be the most common antithrombotic strategy in patients with DVT and venous stenting. More research is needed to determine outcomes of venous stenting in relation to antithrombotic therapy.

Lack of efficacy of pyridoxine (vitamin B6) treatment in acquired idiopathic sideroblastic anaemia, including refractory anaemia with ring sideroblasts.

Pyridoxine, or vitamin B6, is commonly used to treat acquired idiopathic sideroblastic anaemia (AISA, including refractory anaemia with ring sideroblasts), but the efficacy of this therapy in an unselected AISA population (i.e. patients without confirmed ALAS2 or other pyridoxine-responsive germline mutations) has not been established. We reviewed clinical data from 231 patients with AISA and found that 42% of 203 evaluable patients had been treated with pyridoxine. Only 6.8% of pyridoxine-treated patients experienced a haemoglobin improvement (≥ 1.5 g/dL) meeting 2006 International Working Group for Myelodysplastic Syndromes standardised response criteria. As some patients received combination therapy with erythropoietin or other agents, improvement could be attributed to pyridoxine monotherapy in only one patient (1.4%). Smaller, less meaningful increments in haemoglobin levels of 0.5 g/dL were observed in 13.5% of patients. Response to therapy did not correlate with International Prognostic Scoring System (IPSS) risk group or multilineage vs unilineage dysplasia. New symptomatic peripheral neuropathy was noted in 2.3% of patients treated with pyridoxine. In this large series of unselected patients with sideroblastic anaemia, pyridoxine therapy was ineffective and was associated with a risk of adverse effects. Pyridoxine therapy should be reserved for patients with known or suspected pyridoxine-responsive mutations.

Adequacy of hemostatic resuscitation improves therapeutic efficacy of recombinant activated factor VII and reduces reexploration rate for bleeding in postoperative cardiac surgery patients with refractory hemorrhage.

Background: Excessive bleeding and surgical reexploration are common complications that increase the risk of multi-organ failure and prolonged hospitalization after cardiac surgery. Off-label use of recombinant activated factor VII (rFVIIa) is a recommended treatment for refractory bleeding. Objective: The objective of the study is to determine if the adequacy of hemostatic resuscitation enhances the efficacy of rFVIIa. Methods: This retrospective, observational, cohort study included patients who received rFVIIa for refractory postoperative bleeding after cardiac surgery. Patients were divided into two groups based on the presence or absence of adequate coagulation resuscitation before rFVIIa administration, defined as international ratio (INR) ≤1.5, platelet count ≥100 K/mL, and fibrinogen ≥200 mg/dL. The failure of rFVIIa treatment was defined as surgical reexploration within 24 h, thoracostomy drainage >400 mL/h within 6 h or transfusion of additional blood products or another rFVIIa dose within 6 h after initial rFVIIa dose. Results: Of the 3833 patients, screened who underwent cardiothoracic surgery procedures, 58 patients received rFVIIa for refractory postoperative bleeding. Successful hemostasis with rFVIIa was more likely in patients who were adequately resuscitated compared with those who were not (20 [71.4%] vs. 10 [33.3%], respectively; P = 0.0046). Multiple logistic regression analysis indicated that patients who were adequately resuscitated before rFVIIa were less likely to fail treatment (odds ratio, 0.16; 95% confidence interval [0.04-0.62]; P = 0.007). Conclusions: The therapeutic efficacy of rFVIIa is dependent on the adequacy of hemostatic resuscitation; restoration of normal serum fibrinogen, INR, and platelet counts >100 K/mL may provide an adequate substrate for rFVIIa to be effective in managing refractory postoperative cardiac surgical bleeding.

Reduced Prothrombinase Inhibition by Tissue Factor Pathway Inhibitor Contributes to the Factor V Leiden Hypercoagulable State.

Activated factor V (FVa) and factor X (FXa) form prothrombinase, which converts prothrombin to thrombin. The α isoform of tissue factor (TF) pathway inhibitor (TFPI) dampens early procoagulant events, partly by interacting with FV. FV Leiden (FVL) is the most common genetic thrombophilia in Caucasians. Thrombosis risk is particularly elevated in women with FVL taking oral contraceptives, which produce acquired TFPIα deficiency. In mice, FVL combined with 50% reduction in TFPI causes severe thrombosis and perinatal lethality. However, a possible interaction between FVL and TFPIα has not been defined in humans. Here, we examined this interaction using samples from patients with FVL in thrombin generation and fibrin formation assays. In dilute TF- or FXa-initiated reactions, these studies exposed a TFPI-dependent activation threshold for coagulation initiation that was greatly reduced by FVL. The reduced threshold was progressively overcome with higher concentrations of TF or FXa. Plasma assays using anti-TFPI antibodies or a TFPI peptide that binds and inhibits FVa demonstrated that the decreased activation threshold resulted from reduced TFPIα inhibition of prothrombinase. In assays using purified proteins, TFPIα was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL than with FV. Thus, FVL reduces the threshold for initiating coagulation, and this threshold is further reduced in situations of low TFPIα concentration. Individuals with FVL are likely prone to thrombosis in response to weak procoagulant stimuli that would not initiate blood clot formation in individuals with FV.

The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia.

Exposure to Agent Orange (AO) and the contaminating chemical 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been associated with the development of chronic lymphocytic leukemia (CLL). Of the 195 veterans diagnosed with CLL from 2001 to 2010 in a retrospective cohort from the Minneapolis Veterans Affairs Medical Center, 33 (17%) were exposed to AO. Prognostic factors including Rai stage, lymphocyte doubling time and cytogenetics did not differ between exposed and unexposed patients. Exposed patients were younger at diagnosis (61 vs. 72 years, p < 0.0001) and time to CLL treatment was shorter (9.6 vs. 30.2 months, p = 0.02). Overall survival did not differ between exposed and unexposed patients on Kaplan-Meier analysis, but when adjusted for age, AO exposure had a hazard ratio of death of 1.8 compared to non-exposure (95% confidence interval 0.7-4.5, p = 0.24). The high estimate of the mortality hazard combined with the relatively low numbers in the exposure group suggests that further examination in a larger patient population is warranted.

Management of the bleeding patient receiving new oral anticoagulants: a role for prothrombin complex concentrates.

Ease of dosing and simplicity of monitoring make new oral anticoagulants an attractive therapy in a growing range of clinical conditions. However, newer oral anticoagulants interact with the coagulation cascade in different ways than traditional warfarin therapy. Replacement of clotting factors will not reverse the effects of dabigatran, rivaroxaban, or apixaban. Currently, antidotes for these drugs are not widely available. Fortunately, withholding the anticoagulant and dialysis are freqnently effective treatments, particularly with rivaroxaban and dabigatran. Emergent bleeding, however, requires utilization of Prothrombin Complex Concentrates (PCCs). PCCs, in addition to recombinant factor VIIa, are used to activate the clotting system to reverse the effects of the new oral anticoagulants. In cases of refractory or emergent bleeding, the recommended factor concentrate in our protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer an activated PCC (aPCC) [FELBA] due to reported benefit in human in vitro studies. Based on human clinical trial evidence, the 4-factor PCC (Kcentra) is suggested for patients with refractory rivaroxaban- or apixaban-associated hemorrhage. If bleeding continues, recombinant factor VIIa may be employed. With all of these new procoagulant agents, the risk of thrombosis associated with administration of factor concentrates must be weighed against the relative risk of hemorrhage.

Monitoring anticoagulation in patients with an unreliable prothrombin time/international normalized ratio: factor II versus chromogenic factor X testing.

The international normalized ratio (INR) can be unreliable in patients with lupus anticoagulants (LACs) or other conditions affecting baseline testing. Alternative methods to assess anticoagulation on warfarin through measures of vitamin K-dependent factor activity by clot based or chromogenic assays may be necessary. In this patient population, the ideal method is unknown. Thirty-six patients stable on warfarin with LAC or unreliable INR testing had an INR, a prothrombin time-based clotting assay for factor II (FII) activity, and a chromogenic assay for factor X (CFX) activity were performed simultaneously. Eighty-nine sets of measurements were obtained of which 83 sets included all three assays. CFX and FII levels were well correlated (r = 0.92) in all patients and in 26 patients with a documented antiphospholipid antibody (r = 0.93). Parallel testing was seen in 99% of FII assays. Sixty-one percent of CFX and 57% of FII were within the therapeutic range. In 32 CFX and FII pairs wherein assessment of anticoagulation was discordant, 16 CFX agreed with INR and 13 FII agreed with INR (McNemar's, χ = 0.14, P = 0.7). The number of times tests were discrepant was not statistically different between CFX and FII (P = 0.36). CFX and FII activity are well correlated in patients that require alternative monitoring of warfarin. Either test can be used in this population.

New anticoagulants: A concise review.

During the last 2 years, two new oral anticoagulants, dabigatran and rivaroxaban, have been approved in the United States. Phase II and Phase III clinical trials of dabigatran, rivaroxaban, and apixaban are summarized. Approach to perioperative management depends on the half-life of the medication, risk of surgical bleeding, and the patient's renal function. No reversal agent is available for any of the new oral anticoagulants. Management of bleeding patients is based on local measures and consideration of antifibrinolytic therapy and activated factor VII or prothrombin complex concentrate infusion based on healthy volunteer and animal studies. The new oral anticoagulants provide additional options to prevent venous thromboembolism in patients after orthopedic surgery or stroke in patients with atrial fibrillation but present unique challenges compared to warfarin.