Full-dose Anticoagulation Research Articles

A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

IntroductionThe vascular disrupting agent OXi4503, induces apoptosis in malignant myeloblasts, removes their endothelial cell protection, and sensitizes blasts to the cytotoxic effects of cytarabine. Cogle et al confirmed the safety and feasibility of intravenous (IV) OXi4503 up to doses of 7.81 mg/m2 (maximum tolerated dose [MTD] not reached) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (data on file). Based on these data, a Phase 1b dose-finding study was initiated to evaluate the safety and tolerability of combined therapy with OXi4503 and cytarabine for a similar patient population.MethodsThe primary objective of this ongoing study (NCT02576301) was to determine the MTD of OXi4503 in combination with intermediate-dose cytarabine in patients with relapsed/refractory AML or MDS. Pharmacokinetic/pharmacodynamic studies and a preliminary assessment of efficacy were secondary endpoints. Escalating doses of OXi4503 (based on a modified Fibonacci scheme and beginning at 3.75 mg/m2) were administered IV over 10 minutes on Days 1 and 4. Fixed dose cytarabine (1 g/m2) was administered IV over 2 hours on Days 1-5 and preceded infusion of OXi4503 on Days 1 and 4. Cycles were repeated every 28 days. Part 1 of the study was opened for patients with relapsed/refractory AML or MDS (following failure of at least 1 prior hypomethylating agent) who had good organ function, ECOG performance status of 0-2, and normal values for PT and INR (based on bleeding events observed with single-agent OXi4503). Key exclusion criteria included acute promyelocytic leukemia, absolute peripheral blood myeloblast count >20,000/mm3, uncontrolled hypertension, prolonged QTc, history of recent significant CV events, history of hemorrhagic stroke, and any requirement for full dose anti-coagulation.ResultsBetween December 2015 and May 2016, 7 patients with relapsed/refractory AML were enrolled (6 evaluable). Median age was 51.5 years (range 26-68), 50% were male, 83% and 17% had ECOG performance status scores of 1 or 2, respectively. Subjects had failed a median of 4.2 (range: 2-6) prior therapies and all patients had intermediate- or adverse-risk cytogenetics. Five of 6 patients (83%) received 1 cycle of therapy while 1 patient received 2 cycles. Four of 6 patients (67%) withdrew from the study for progressive disease (PD) and 1 patient withdrew with stable disease (SD). The final patient achieved a morphological complete remission (mCR) after 2 cycles and proceeded to donor lymphocyte infusion. One patient in the 3.75 mg/m2 cohort experienced a dose-limiting toxicity of hypofibrinogenemia, but no clinical evidence of bleeding. Following correction with cryoprecipitate, fibrinogen returned to normal and remained normal without further intervention. The most common (>10% incidence) Grade 3/4 treatment-emergent adverse events attributable to the combination of OXi4503 and cytarabine included neutropenic fever, anemia, platelet count decrease, neutrophil count decrease, fibrinogen decrease, AST increase, hypokalemia, and D-dimer increase.ConclusionsThe vascular disrupting agent OXi4503 (3.75 mg/m2) in combination with cytarabine (1 g/m2/day) is generally well tolerated with preliminary evidence of activity in heavily pretreated, refractory AML patients. This Phase 1b study continues to recruit patients into the second cohort, OXi4503 (4.68 mg/m2) plus cytarabine (1 g/m2/day), as the optimal dose combination has yet to be defined. DisclosuresNo relevant conflicts of interest to declare.

Prevention and treatment of venous thromboembolism in patients with solid brain neoplasms: results of a survey among Italian physicians.

The decision concerning the introduction of primary and secondary prophylaxis of venous thromboembolism (VTE) in patients with solid brain neoplasms and brain metastases is often challenging due to the concomitant increasedrisk of intracranial hemorrhage and to limited evidence from available literature. A standardized questionnaire composed of nine multiple-choice questions regarding primary VTE prevention in non-surgical patients during high-risk conditions and VTE secondary prevention in patients with a solid brain neoplasm or cerebral metastases was sent via electronic mail to all the members (n=2420) of the Italian Federation of the Internal Medicine Hospital Executives' Associations (FADOI) in June 2015. Three hundred and fifty two physicians (14.5%) returned it (participants' median age 51years; females 46.9%). The majority of respondents prescribe primary thromboprophylaxis (usually with heparin) in non-surgical patients with solid brain neoplasms and brain metastases in concomitance with high-risk conditions. Full-dose anticoagulation with either low-molecular-weight heparin or fondaparinux is the preferred option for acute VTE (69.6%), while a reduced dose is chosen by 21.0% of physicians. The presence of a highly vascular brain neoplasm histotype mandates the prescription of a reduced-dose antithrombotic regimen in a minority of respondents. Vena cava filter placement is an option for the treatment of acute VTE in more than 6% of respondents. Anticoagulants are often prescribed for both VTE primary prevention and treatment. In conclusion, physicians' managements are partially in contrast to recent guidelines, reinforcing the need for educational programs and other studies in this setting.

Impact of recent guideline changes on aspirin prescribing after knee arthroplasty.

BackgroundPrior to 2012, the American Academy of Orthopaedic Surgeons (AAOS) and American College of Chest Physicians (ACCP) differed in their recommendations for postoperative pharmacologic venous thromboembolism prophylaxis (VTEP) after total joint arthroplasty. More specifically, aspirin (ASA) monotherapy was not endorsed by the ACCP as an acceptable prophylaxis. In 2012, the ACCP supported ASA monotherapy compared with no prophylaxis. Our aim was to investigate the impact of the convergence of ACCP and AAOS recommendations on surgeon prescribing patterns after knee arthroplasty (KA).MethodsThis is a retrospective chart review. We collected data to assess preoperative VTE risk and examined VTEP prescriptions on postoperative day 1 (POD1) and at discharge (D/C) from 7/2008 to 12/2011 (pre-period) and 1/2012 to 7/2014 (post-period). Adult patients undergoing primary and revision KA were identified by ICD-9 procedure codes. Patients on preoperative full-dose anticoagulation and with hypercoagulability disorders were excluded.ResultsOf 368 records reviewed, 329 were included in the analysis. There were no differences between the two period groups for age, sex, BMI, estrogen therapy, malignancy, smoking status, prior VTE, bilateral procedures, or surgery within 3 months. On POD1, in the pre-period, 4.6 % were prescribed ASA monotherapy versus 44.4 % in the post-period (p < 0.001). On D/C, in the pre-period, 13.9 % were prescribed ASA versus 55.6 % in the post-period (p < 0.001).ConclusionsOur results indicate a statistically significant change in orthopedist prescribing patterns after guideline convergence. Furthermore, there was no apparent change in VTE risk between the two study groups when excluding patients necessitating full anticoagulation. Prior literature has shown that the divergence in guidelines influenced physicians away from ASA and toward more potent anticoagulants in order to avoid potential litigation. Once its role in VTEP was supported by the ACCP, it appears that ASA monotherapy was readily and rapidly incorporated into clinical practice. ASA may be favored over other VTEP agents for its lower bleeding risk profile and cost. This study highlights the profound impact clinical practice guidelines have on clinician prescribing patterns. Although prospective randomized trials are needed to compare the efficacy of ASA with other VTEP agents, ASA is now a predominant part of the VTEP armamentarium after KA.

US-Guided Paracentesis Complicated by Delayed Hemoperitoneum with Hemorrhagic Shock

Delayed hemoperitoneum is a rare complication of paracentesis, a generally safe procedure with overall complications occurring in less than one percent of cases. Vascular injuries are often addressed during or immediately following paracentesis. Regardless, life-threatening hemorrhage may arise following this well-tolerated procedure, especially in the setting of coagulopathy. We present a case of delayed hemorrhagic shock due to bleeding from a branch of the right inferior epigastric artery after ultrasound-guided paracentesis. A 67-year-old female with history of primary biliary cirrhosis and recent tibia-fibula fracture complicated by deep vein thrombosis on full-dose anticoagulation presented with abdominal distention and pain secondary to new-onset ascites. With her anticoagulation held, platelet count of 63 thousand/mcl and INR of 1.4, she underwent an ultrasound-guided paracentesis with removal of 5L of clear, yellow ascitic fluid. Afterward, anticoagulation was resumed and diuretics were initiated. The next day, she developed asymptomatic hypotension. Labs were notable for a hemoglobin drop from 11.6 mg/dL to 10.8mg/dL; INR 1.5. Despite aggressive volume resuscitation, she was transferred to the intensive care unit with multi-organ system failure. Repeat hemoglobin was 4.8mg/dL. Noncontrast computed tomography was notable for a large amount of ascites with intraperitoneal blood (Figure 1a). Urgent coil embolization of a pseudoaneurysm of the right inferior epigastric artery was performed (Figure 1b, 1c). Her course was complicated by ischemic hepatitis, acute kidney injury, disseminated intravascular coagulopathy, arrhythmia, and acute encephalopathy necessitating intubation and eventual withdrawal of life-sustaining measures.Figure 1Most hemorrhagic complications following paracentesis are due to abdominal wall trauma. Often iatrogenic and perhaps underreported, damage to the inferior epigastric artery can be fatal. Currently, there are no known guidelines to correct coagulopathies prophylactically or use vascular-flow imaging during ultrasound-guided paracentesis to prevent and identify bleeds. Given the infrequent occurrence of delayed hemoperitoneum, ultrasound-guided paracentesis with Doppler may allow for better visualization of abdominal wall vessels, especially in high-risk patients on anticoagulation.

The Treatment of Venous Thromboembolism in Patients with Cancer.

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. The treatment of VTE complications in cancer patients remains a difficult clinical task. Low-molecular-weight heparins (LMWH) are the cornerstone of VTE treatment in cancer patients, including the treatment of catheter-related thrombosis. LMWH dose adjustment is effective in treating recurrent thrombosis and in patients with bleeding or thrombocytopenia. The duration of treatment is dependent on several factors that need to be individually evaluated. The novel anticoagulants should be investigated more carefully before being routinely implemented in the treatment of cancer-associated VTE. Incidentally detected isolated sub-segmental pulmonary embolism is unlikely to require systematic full-dose anticoagulation. Whether the long-term use of LMWHs has the potential to prolong survival in subgroups of cancer patients requires further investigations.

Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist oral anticoagulants.

The acute phase of venous thromboembolism (VTE) treatment focuses on the prompt and safe initiation of full-dose anticoagulation to decrease morbidity and mortality. Immediate management consists of resuscitation, supportive care, and thrombolysis for patients with haemodynamically significant pulmonary embolism (PE) or limb-threatening deep-vein thrombosis (DVT). Patients with contraindications to anticoagulants are considered for vena cava filters. Disposition for the acute treatment of VTE is then considered based on published risk scores and the patient's social status, as the first seven days carries the highest risk for VTE recurrence, extension and bleeding due to anticoagulation. Next, a review of: immediate and long-term bleeding risk, comorbidities (i. e. active cancer, renal failure, obesity, thrombophilia), medications, patient preference, VTE location and potential for pregnancy should be undertaken. This will help determine the most suitable anticoagulant for immediate treatment. The non-vitamin K antagonist oral anticoagulants (NOACs), including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban as well as the direct-thrombin inhibitor dabigatran, are increasing the convenience of and options available for VTE treatment. Current options for immediate treatment include low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, apixaban, or rivaroxaban. LMWH or UFH may be continued as monotherapy or transitioned to treatment with a VKA, dabigatran or edoxaban. This review describes the upfront treatment of VTE and the evolving role of NOACs in the contemporary management of VTE.

Overuse of Bridging Anticoagulation for Patients With Venous Thromboembolism: First, Do No Harm.

Patients receiving anticoagulation for venous thromboembolism (VTE) have varying risks of recurrence on cessation of the therapy. Time from the most recent thrombotic event is perhaps the most important determinant of short-term VTE recurrence because patients who stop anticoagulation therapybefore the stabilizationof an active thrombus are particularly prone to propagation and embolization. If use of anticoagulation is stopped during the first 4 weeks of treatment, the risk of recurrent VTE is 0.3% to 1.3% per day, dropping to 0.03% to 0.2% per day over the next 4 to 12 weeks.1 After 3months, many patients can safely discontinue anticoagulation therapy, particularly if the thrombotic event occurred in the setting of a reversible precipitant. The importanceofdetermining the time frameof themost recent thrombotic episode is reflected in the currentAmerican College of Chest Physicians (ACCP) guidelines,2 which suggest stratifying patients who are receiving anticoagulation therapy for a history of VTE are at high risk for recurrence during anticoagulant cessation if the thrombosis occurredwithin the previous 3 months, intermediate risk if the thrombosis occurred within the past 3 to 12 months, and low risk if the event occurredmorethan12monthsearlier.Hypercoagulabilitycanalso tippatients intohigher-risk categories: theACCPguidelines include as high-risk thrombophilias homozygous prothrombotic mutations; protein C, S, or antithrombin deficiency; antiphospholipid antibodies; or multiple thrombophilic traits. Intermediate-riskthrombophilias includecancer, recurrentVTE, andsingleprothromboticmutations.Thisparadigmismoreconservative thanother suggested schemas that donot categorize all patientswithVTE in thepreceding3monthsashigh riskand give lowerpriority to laboratory-based thrombophilias that are not associated with recurrent VTE.1 In recent years, the literature3,4 has highlighted the bleeding risk conferred by use of full-dose anticoagulants following surgicalprocedures,particularlywhenthemedication isstarted in the first 2 to 3 days after surgery. Yet, for patients with prior VTE, the postoperative setting is a particularly high-risk time for recurrence since surgery itself is a potent VTE precipitant. Giventhisclinical landscape, thearticlebyClarkandcolleagues5 in this issue of JAMA Internal Medicine is a welcome addition totheliterature.Leveragingalargeadministrativedatabasefrom an integratedhealth care system, these authors identified 1812 procedures in 1178 patients receiving warfarin for VTE who stoppeditsuse intheperiprocedural setting.Bridgetherapywas identified by the purchase of parenteral anticoagulants by patientsandbyreviewofperiproceduralplansdocumented inanticoagulationclinic records.Bleedingandthromboticeventsoccurring within 30 days of the procedure were adjudicated via manual review of the medical records. Patient risk was stratified in accordance with current ACCP guidelines.2 However, since bridgingwas not standardized, approximately one-third of patients in the lowand intermediate-risk strata received bridgetherapy,andfewerthantwo-thirdsofpatients inthehighrisk stratum received bridge therapy. Consistentwithprior studies,4 2.7%of thepatientswhoreceived bridge therapy developed clinically relevant bleeding compared with only 0.2% of those who did not receive bridge anticoagulationtherapy.More important,only3patients (0.2%) who did not receive bridge therapy developed recurrent VTE. None of the 21 high-risk patients and only 1 of the 215 intermediate-riskpatientswhodidnot receivedbridge therapyhad recurrentVTE.Toputthesefindings instarkterms,bridgetherapy, despite being administered to only one-third of patients overall, ledtoapproximately14incrementalclinicallyrelevantbleeding events,whereas therewereonly 3 thrombotic events in the remaining two-thirds of the cohort who did not receive bridge therapy, with no signal that the current ACCP risk-stratificationschemasuccessfully identifiedpatientsathighenoughrisk for thrombosis to justifybridgetherapy.Althoughthisstudywas not powered to assess mortality (with no deaths in the entire cohort), we know from other studies that approximately 10% ofVTEpatientswhohavemajor bleedingdie,6,7 comparable to the case fatality rate from recurrent VTE.7,8 In contrast to patientswho experience cardioembolism, survivors of recurrent deep vein thrombosis or pulmonary embolism rarely have serious permanent sequelae. The present study is not without its limitations, particularly the lackof discriminationbetween full-dose andprophylactic-dose parenteral anticoagulants used as bridge therapy and the absence of information on the timing of anticoagulation therapy. Nevertheless, it is likely that the imbalance between bleeding and thrombotic events between subgroups would have been even more dramatic had all patients in the bridge therapygroup received full-doseparenteral anticoagulants in the immediatepostoperative setting.As such,we support theauthors’ contention that themajority—indeed thevast majority—of patients receiving anticoagulants for a history of VTE shouldnot be given therapeutic-dosebridge therapy, and that revision of the ACCP risk-stratification recommendations is warranted. There are undoubtedly some patients at such high risk for recurrent VTE that bridge therapy is a necessary evil, such as those with acute VTE in the preceding month and thosewith a prior pattern of brisk VTE recurrence during short-term interruption of anticoagulation therapy. Related article page 1163 Risks DuringWarfarin Interruption for Invasive Procedures Original Investigation Research

Current management of isolated soleal and gastrocnemius vein thrombosis.

Thrombi of the soleal and gastrocnemius veins of the leg remain incompletely characterized in terms of the appropriate treatment algorithm to follow. Although they are anatomically located below the level of the fascia, making them "deep" vein thrombi, their natural history is unclear with respect to propagation and embolization. Varying treatment suggestions have been proposed, from full-dose anticoagulation to "watchful waiting" with repeated duplex examination, with none rising to the level of accepted scientific evidence. Herein, we present the current literature citing the differing opinions and data that have confused the subject.

Venous thromboembolism in cancer patients.

Venous thromboembolism (VTE) is a common complication in cancer patients. This review summarizes some of the most current knowledge of the epidemiology, risk factors, risk models, prophylaxis, and treatment of VTE in cancer patients. A literature search was conducted using PubMed; the search terms were venous thromboembolism, anticoagulation, and cancer. The bibliographies of pertinent studies and review articles were reviewed for additional references. Venous thromboembolism is the second leading cause of death in patients with cancer. Cancer patients with VTE have poorer outcomes compared with noncancer patients with VTE. Many risk factors have been identified for VTE in patients with cancer that are patient-related, cancer-related, or treatment-related. Several biomarkers have been identified as potentially predictive of VTE risk. Risk assessment models such as the Khorana Risk Score stratify cancer patients with low, intermediate, and high risk of developing VTE based on baseline clinical and laboratory variables. Currently, enoxaparin is the preferred anticoagulant for initial VTE treatment in cancer patients. Low molecular weight heparin (LMWH) is recommended for both initial and long-term management of cancer-related VTE. Because the optimal duration of anticoagulation in cancer patients with VTE is unknown, the decision to extend anticoagulation requires weighing the risk of recurrent thrombosis against the risk of major bleeding. Patients with recurrent VTE can be bridged with LMWH, transitioned to full-dose LMWH or treated with LMWH dose escalation. While there is insufficient data to determine whether anticoagulation should be held in the setting of thrombocytopenia, full-dose anticoagulation is typically considered unsafe when platelets are < 50 000/μL. Inferior vena cava filters are currently recommended only for patients with acute VTE and contraindications to anticoagulation. Although management of catheter-associated thrombosis has not been well studied in cancer patients, it is recommended that cancer patients with catheter-associated thrombosis be treated with therapeutic anticoagulation for ≥ 3 months. Venous thromboembolism prophylaxis with UFH, LMWH, or fondaparinux is recommended in all hospitalized nonsurgical cancer patients and cancer patients undergoing major cancer surgery. Primary thromboprophylaxis is only currently recommended in high-risk ambulatory cancer patients such as multiple myeloma patients receiving thalidomide- or lenalidomide- based therapy. Cancer-associated thrombosis is a common problem. As we begin to better understand the risk factors and biomarkers for cancer-associated VTE, we can further refine and develop risk-assessment models to determine those patients who would most likely benefit from anticoagulation. While LMWH products are generally preferred in cancer-related VTE, more research will continue to evolve our understanding of treatment and thrombopprophylaxis in cancer-associated VTE.

Management of Cancer-Associated Venous Thromboembolism in Patients with Concomitant Thrombocytopenia: A Survey of Canadian Practitioners

INTRODUCTION: Both venous thromboembolism (VTE) and thrombocytopenia are common in cancer patients. The management of cancer-associated thrombosis (CAT) in the context of thrombocytopenia remains an important area of clinical equipoise; a paucity of evidence to support management strategies implies that guidelines and consensus statements rely on expert opinion. We aimed to characterize the practices of Canadian practitioners in the treatment of CAT in thrombocytopenic patients. METHODS: In May to July 2014, we conducted an electronic survey of Canadian practitioners likely to participate in the management of CAT. The survey was comprised mainly of open- ended questions. An estimated 300 members of the Canadian Hematology Society and Thrombosis Canada were invited to complete the survey. RESULTS: Respondents: 31 practitioners participated in the survey. 17 (55%) were board- certified hematologists, 10 (32%) were internists, and 3 (10%) were general practitioners. 14 (45%) had been in practice for &lt; 5 years, and 15 (48%) had been practicing for &gt;15 years. The majority of respondents, 27 (87%), worked in tertiary-care centers or university-affiliated institutions. 17 (55%) had self-reported expertise in thrombosis. Regarding frequency of encounters, 10 (32%) of participants reported seeing &gt; 20 patients with CAT and thrombocytopenia per year, while 8 (26%) reported seeing &lt;5 such patients per year. Management strategies: The median (IQR) platelet count above which respondents reported administering VTE prophylaxis, to patients in whom this would otherwise be indicated, was 25 (20, 30) . The median (IQR) platelet count above which respondents would administer full-dose anticoagulation for treatment of established CAT was 50 (40, 50); for reduced-dose anticoagulation, this threshold was 30 (20, 50). For patients with CAT and thrombocytopenia, 21 (68%) reported the use of sub-therapeutic doses of anticoagulation as a management strategy. A majority of respondents, 20 (65%), reported that there were cases in which they elect to withhold all anticoagulation due to thrombocytopenia in patients with acute CAT, in the absence of bleeding. 20 (65%) respondents reported using platelet transfusions to achieve a higher platelet count target than would otherwise be indicated in order to facilitate anticoagulation in patients with CAT and concomitant thrombocytopenia; the median platelet count target in such cases was 35 (30, 50). 14 of 20 respondents reporting the use of platelet transfusions for this purpose employed this transfusion strategy to facilitate full-dose anticoagulation, while a minority (n=6) administered reduced dose anticoagulation in this setting. Those who were newer to practice (&lt; 5 year in practice) and those who reported treating higher volumes of patients with CAT and thrombocytopenia (&gt;10 patients per year) were more likely to employ prophylactic platelet transfusions to facilitate the administration of anticoagulation (86% vs. 47%, p= 0.03, for newer to practice; 87% vs. 44%, p= 0.03, for those treating &gt;10 patients per year) The use of three case studies, for which participants were asked to outline a management strategy, revealed considerable variability in practice (Figure 1). CONCLUSIONS: While most respondents' practices were somewhat consistent with published consensus statements and recommendations, strategies for anticoagulation of CAT in thrombocytopenic patients were highly variable among Canadian practitioners. High quality studies are required to establish an evidence-based approach to this uncommon clinical entity. Figure 1. Initial management approach of respondents for 3 cases of CAT with thrombocytopenia. LE-DVT= lower extremity deep vein thrombosis; PE= pulmonary embolism; UE-DVT= upper-extremity deep vein thrombosis; IVC= inferior vena cava. Figure 1. Initial management approach of respondents for 3 cases of CAT with thrombocytopenia. LE-DVT= lower extremity deep vein thrombosis; PE= pulmonary embolism; UE-DVT= upper-extremity deep vein thrombosis; IVC= inferior vena cava. Disclosures Kuo: Novartis Canada: Honoraria; Alexion: Honoraria.

Management and outcomes of cancer-associated venous thromboembolism in patients with concomitant thrombocytopenia: a retrospective cohort study.

Venous thromboembolism (VTE) and thrombocytopenia are both more common in cancer patients than in general populations. Both the outcomes and optimal management of cancer-associated VTE in thrombocytopenic patients are unknown. The objective of thecurrent study is to describe a cohort of patients presenting with acute cancer-associated VTE with concomitant thrombocytopenia, including management patterns and outcomes. We conducted a retrospective cohort study of all cancer patients admitted to a regional cancer centre and the main university hospital's hematology service in Edmonton, Alberta, from 2005-2011, who had thrombocytopenia at the time of acute VTE. We report rates of recurrent symptomatic thromboembolism, major and clinically relevant non-major bleeding, within the initial 3months following VTE diagnosis. Seventy-four patients were identified as eligible and reviewed. Seventeen (23.0%) patients did not receive any antithrombotic therapy, 30 (40.5%) received a minimum of 3months of full-dose anticoagulation, and 27 (36.5%) received partial treatment, which was either dose-reduced, interrupted, or shortened in duration. Twenty-three (31.1%) experienced recurrent thromboembolism and 13 (17.6%) had bleeding events, of which 3 (4.1%) were major. In conclusion,patients with acute cancer-associated VTE and concomitant thrombocytopenia were managed heterogeneously at our institution, without a predominant strategy. There was a high rate of short-term complications, including recurrent thromboembolism and hemorrhage in this cohort. Future research should focus on determining the optimal management strategy in this challenging clinical scenario.

Cerebral venous thrombosis after embolization of pediatric AVM with jugular bulb stenosis or occlusion: Management and prevention

PurposeThrombosis of cerebral arteriovenous malformation after embolization is rare, but can involve the normal venous network with extensive venous thrombosis. We report angioarchitecture findings, our management and prevention strategy for this complication in pediatric AVMs. MethodsIn this 5.5-year retrospective series, we reviewed records of 13 patients under 15 years who were anticoagulated after embolization. In our initial experience 4 children who didn't receive any prophylactic anticoagulation presented with extensive venous thrombosis after embolization (group 1). Following this, nine children with similar angioarchitecture and embolization modalities were treated with prophylactic anticoagulation immediately after embolization (group 2). We analyzed the type of AVM, angioarchitecture, dose of prophylactic anticoagulant, efficacy/complications of treatment and late outcome. ResultsAll patients in group 1 had severe jugular bulb stenosis/occlusion associated with cerebral venous dilatation. In group 2 with similar angioarchitecture, only three patients (33%) developed extensive thrombosis. In both groups, thrombosis occurred within two days of treatment in six children and two weeks in one child. The diagnosis was suspected on intracranial hypertension in five patients and occulomotor disorder in one. One was asymptomatic. All children were treated with therapeutic doses of LMWH (anti-Xa: 0.5–1). No hemorrhagic complications occurred. Good venous remodeling was observed in all but one patient. ConclusionAnticoagulation in extensive venous thrombosis after AVM embolization in children appears to be safe and effective. In cases with angioarchitectural features of dilatation of the cerebral venous network and occlusion/severe stenosis of the jugular bulbs, full dose anticoagulation may be required to prevent thrombosis.

Outcomes of patients requiring insertion of an inferior vena cava filter

Data regarding inferior vena cava (IVC) filter use and complications are scarce. This study evaluates the safety and efficacy of IVC filters over a 4-year period at two adult tertiary care hospital sites. A retrospective observational study was conducted of consecutive admitted patients who underwent insertion of an IVC filter between 1 January 2007 and 31 December 2010. The main objective of the study was to evaluate the safety and efficacy of IVC filters. We identified 338 patients with an attempted filter insertion who were followed for a median 16.3 months. Ninety-one percent of filters inserted were for an appropriate indication. Sixty-eight patients (20% of all patients) had one or more filter-related complication. Despite a median time after filter insertion to start anticoagulation of 2 days (interquartile range 3 days) for prophylactic and 6 days (interquartile range 7 days) for full dose, 38 patients (11% of all patients) had one or more thrombotic complications during follow-up. In a subgroup of patients with complete anticoagulation information available, thrombotic complications occurred in 18, 16, and 8% of patients receiving no, prophylactic, or full dose anticoagulation after IVC filter insertion, respectively (NS; P = 0.13). IVC filter use in our study was associated with a substantial rate of complications including thrombotic complications. This study highlights the need for further research regarding the safety and efficacy of IVC filters and the role for early initiation of anticoagulation.

Assessment of the Outcomes Associated with Periprocedural Anticoagulation Management in Children with Acute Lymphoblastic Leukemia

To report the outcomes of an institutional protocol for periprocedural anticoagulant (AC) management in children with acute lymphoblastic leukemia (ALL). Children being treated for ALL who received full-dose (therapeutic) anticoagulation before undergoing at least 1 lumbar puncture (LP) were included in this retrospective cohort study. The main outcome was the risk of traumatic LP; exploratory analysis included the risks of symptomatic spinal hematoma and progression/recurrence of the thrombotic event. Analyses were conducted using logistic regression analysis with a generalized estimating equation approach. Twenty-two children with ALL receiving an AC underwent a total of 396 LPs. Although traumatic LP was associated with full-dose AC therapy in univariable analysis, a multiple logistic regression model controlling for other risk factors for traumatic LP showed that AC therapy was not significantly associated with the risk of traumatic LP when the ACs were held as per the institutional protocol. No patient developed symptomatic spinal hematoma. Exploratory analysis revealed that AC dose, a likely marker of thrombus burden, was significantly associated with progression/recurrence of the thrombotic event in univariable analysis. In our cohort, recent AC therapy was not statistically associated with an increased risk of bleeding after LP when following a specific protocol for periprocedural AC management. The risk associated with the progression/recurrence of thromboembolic events requires further evaluation.

Review of Management and Outcomes in Women with Thrombophilia Risk during Pregnancy at a Single Institution

Pregnancy is a hypercoagulable state associated with an increased risk of venous thromboembolic disease (VTE). We retrospectively studied 38 Caucasian pregnant women with thrombophilia risk and compared their obstetric outcomes with a matched cohort without known thrombophilia risk during the period between January 2007 and December 2010. There were (2) cases with factor V Leiden, (6) prothrombin gene mutation, (1) antithrombin III deficiency, (2) protein C deficiency, (3) protein S deficiency, (10) MTHFR mutation, (7) anti-cardiolipin antibodies, and (1) lupus anticoagulant. Patients without thrombophilia who presented with recurrent unprovoked VTE were considered as high risk (6 cases). Most patients received anticoagulation (34/38) with aspirin only (6), enoxaparin (27), and warfarin (1). Twenty-six out of thirty-eight pregnant women (68.4%) with an increased risk of thrombophilia experienced one or more obstetric complications defined as hypertension, preeclampsia, placenta abruptio, VTE, and oligohydramnios, compared with 15 out of 40 (37.5%) pregnant women in the control group (OR 3.6; 95% CI 1.42, 9.21, P < 0.001). The incidence of obstetric complications was significantly higher in the thrombophilia group compared to the controls. However, these complications were the lowest among patients who received full-dose anticoagulation. Our study suggests that strict application of anticoagulation therapy for thrombophilia of pregnancy is associated with an improved pregnancy outcome. The study was registered in the Australian and New Zealand Clinical Trials Registry under ACTRN12612001094864.

Venous Thromboembolism in Cancer Patients

Objective: Venous thromboembolism (VTE) is a common complication in cancer patients. This review summarizes some of the most current knowledge of the epidemiology, risk factors, risk models, prophylaxis, and treatment of VTE in cancer patients. Methods: A literature search was conducted using Pub Med; the search terms were venous thromboembolism, anticoagulation, and cancer. The bibliographies of pertinent studies and review articles were reviewed for additional references. Results: Venous thromboembolism is the second leading cause of death in patients with cancer. Cancer patients with VTE have poorer outcomes compared with noncancer patients with VTE. Many risk factors have been identified for VTE in patients with cancer that are patient-related, cancer-related, or treatment-related. Several biomarkers have been identified as potentially predictive of VTE risk. Risk assessment models such as the Khorana Risk Score stratify cancer patients with low, intermediate, and high risk of developing VTE based on baseline clinical and laboratory variables. Currently, enoxaparin is the preferred anticoagulant for initial VTE treatment in cancer patients. Low molecular weight heparin (LMWH) is recommended for both initial and long-term management of cancer-related VTE. Because the optimal duration of anticoagulation in cancer patients with VTE is unknown, the decision to extend anticoagulation requires weighing the risk of recurrent thrombosis against the risk of major bleeding. Patients with recurrent VTE can be bridged with LMWH, transitioned to full-dose LMWH or treated with LMWH dose escalation. While there is insufficient data to determine whether anticoagulation should be held in the setting of thrombocytopenia, full-dose anticoagulation is typically considered unsafe when platelets are < 50 000/μL. Inferior vena cava filters are currently recommended only for patients with acute VTE and contraindications to anticoagulation. Although management of catheter-associated thrombosis has not been well studied in cancer patients, it is recommended that cancer patients with catheter-associated thrombosis be treated with therapeutic anticoagulation for ≥ 3 months. Venous thromboembolism prophylaxis with UFH, LMWH, or fondaparinux is recommended in all hospitalized nonsurgical cancer patients and cancer patients undergoing major cancer surgery. Primary thromboprophylaxis is only currently recommended in high-risk ambulatory cancer patients such as multiple myeloma patients receiving thalidomide-or lenalidomide- based therapy. Conclusion: Cancer-associated thrombosis is a common problem. As we begin to better understand the risk factors and biomarkers for cancer-associated VTE, we can further refine and develop risk-assessment models to determine those patients who would most likely benefit from anticoagulation. While LMWH products are generally preferred in cancer-related VTE, more research will continue to evolve our understanding of treatment and thrombopprophylaxis in cancer-associated VTE.

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Introduction: 28 y/o African American female, G5P2A3, no significant PMH, presented to ED3 with Right Lower Extremity (RLE) and Right Upper Extremity(RUE) pain, attributed to a motor vehicle crash 12 days prior, from which patient had no significant injury. 14 days prior to admission, home pregnancy test was positive. At time of MVC, ED1 observed fetal heart tones, beta-HCG of 79000. 6 days prior to admission, pain in RUE, fevers, chills and vaginal bleeding. ED2 visit revealed fetal demise, and discharged home with OB/Gyn follow-up. Pt then developed foul smelling clots, dyspnea on exertion, headache, chills, and presented to the ED3. Admitted to ICU with severe sepsis. Treated with IV drugs vancomycin, pip/tazo, clindamycin, and gentamicin. OB/GYN exam revealed no retained products, some cervical motion tenderness, negative vaginal u/s, beta-HCG of 1616. Right shoulder CT revealed inflammatory/infectious process, confirmed with MRI. Contrast CT right hip also concerning for metastatic septic process. CT chest confirmed septic pulmonary emboli. Blood cultures positive in 12 hours, with GPC's in clusters, found to be MRSA. Vaginal and urine cultures were also positive for MRSA. Transthoracic Echocardiogram (TTE) and Transthoracic Echocardiogram (TEE) were negative for endocarditis. TTE with Bubble study however revealed a small right to left atrial shunt, suggestive of patent foramen ovale. Pt continued to spike temperatures on therapeutic antibiotics. CT abd/pelvis with contrast revealed right internal iliac vein thrombus. Pt was started on full dose anticoagulation with enoxaparin for presumed septic pelvic thrombophlebitis. I&D of right shoulder and hip performed on day 7 after admission, with MRSA growth from right shoulder. Pt defervesced and was sent home in good condition, on antibiotics and anticoagulation, with scheduled repeat scans of pelvis to assess the internal iliac vein thrombus. Discussion: This case represents a very rare case of post-spontaneous abortion MRSA septicemia with septic pelvic thrombophlebitis (SPT), septic pulmonary emboli, and pyomyositis. Our theory for this case is possible MVC/trauma/stress induced miscarriage, leading to infected products of conception. Our suspicion is that deep pelvic vein septic thrombophlebitis developed, leading to septic pulmonary emboli. Although the frank bacteremia with MRSA on its own could lead to disseminated abscesses, the presence of a PFO seen on TTE may also have contributed. Our conclusion of SPT arose from persistent febrile episodes, with negative TEE for endocarditis, in a patient with an obvious endovascular source. SPT can present as either ovarian vein thrombophlebitis (OVT) or deep septic pelvic thrombophlebitis. Although OVT presents with abdominal pain, deep SPT generally does not. Much of the literature surrounding SPT stems from papers in the 1970's and earlier. Post-partum persistent fever 4-5 days after initiation of therapeutic antibiotics for infected individuals, elicits the consideration of SPT. Early on, the treatment was surgical ligation of the involved pelvic vessels, be it the ovarian vein, or deep pelvic veins. Studies found that patients with SPT could be treated with anticoagulation, preventing surgical intervention, and defervescence could be obtained. A more recent study in 1999 has questioned whether anticoagulation is necessary as anticoagulation had no impact on defervescence, however, this study included only 15 patients. Our review of the literature showed other studies in which patients were safely treated with anticoagulation, achieving defervescence, which led us to choose enoxaparin for treatment in this case. Deep SPT historically has been a diagnosis of exclusion due to poor imaging modalities. With improving imaging modalities, it is becoming easier to diagnose SPT, however this does not preclude the high degree of suspicion for SPT required on clinicians behalf in post-partum patients with persistent fever.

Anticoagulants for Cerebral Venous Thrombosis

See related article, p 8. Evidence relating to efficacy and safety of anticoagulants for CVT is only partially available from studies in the peer reviewed medical literature and from the corresponding authors of those studies. Consequently, this article is an opinion piece rather than a systematic review. Cerebral venous thrombosis (CVT) accounts for ≈0.5% of strokes and may occur at any age.1 Risk factors include pregnancy, oral contraceptives, head trauma, malignancy, infection, anemia, and dehydration. In older reports, the incidence of CVT was 3 to 4 per 1 million people per year in Europe and the United States.2 However, a survey published in 2012 found an incidence of CVT of 13.2 per 1 million people per year.3 With modern brain imaging technology, more cases are being discovered that probably would have resolved without medical intervention. Relative to pre-1990 clinical outcomes data, the average prognosis has dramatically improved.4,5 A Cochrane review of anticoagulant therapy for CVT4 based the recommendation in favor of using anticoagulation treatment (full-dose unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH] followed by a vitamin K antagonist [VKA]) on 2 small randomized placebo-controlled trials (RCTs, n=79). These trials demonstrated a non-statistically significant reduction in deaths with anticoagulation (risk ratio, 0.33; 95% confidence interval [CI], 0.08–1.28). Subsequently, the European Federation of Neurological Sciences6 and the American Heart Association/American Stroke Association7 issued clinical practice guidelines calling for full-dose heparin acutely followed by VKAs for ≥3 months. The efficacy and safety of anticoagulants for CVT have not been comprehensively reviewed, with the inclusion of observational studies and the RCTs excluded from the Cochrane review. This review will evaluate published reports from 1990 to 2013 regarding the efficacy and safety of full-dose heparin (UFH or LMWH) during initial hospitalization and subsequent VKA treatment …

Evidence Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Reply by David K. Cundiff

HomeStrokeVol. 44, No. 11Evidence Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Reply by David K. Cundiff Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEvidence Basis for Anticoagulants for Cerebral Sinus Venous Thrombosis? Reply by David K. Cundiff David K. Cundiff, MD, Independent Researcher David K. CundiffDavid K. Cundiff 333 Orizaba Avenue, Long Beach, CA 90814 Search for more papers by this author Originally published1 Oct 2013https://doi.org/10.1161/STROKEAHA.113.003244Stroke. 2013;44:e151Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 Not only did the International Study on Cerebral Venous Thrombosis (ISCVT) articles fail to provide evidence against the hypothesis that anticoagulants reduce morbidity and mortality in patients with CVT, but they provided solid evidence against using anticoagulants for CVT.I agree with the ISCVT authors that in observational studies, risk factors present in treated and untreated patients may confound any outcome comparison. Unfortunately, the ISCVT articles published so far have not compared anticoagulated versus unanticoagulated cohorts with respect to the prevalence of risk factors (eg, baseline intracerebral hemorrhage [ICH], presentation with stupor or coma, age, etc) in relationship to clinical outcomes (eg, death and disability). Surely, clinicians will welcome the imminent publication of these data mentioned by Dr Ferro and Canhão.The ISCVT authors said that insufficient variation existed for an appropriate comparison of patients who were anticoagulated (n=520 treated with full-dose heparin) versus unanticoagulated (n=104, including no antithrombotic drug=23, antiplatelet agents=50, low dose heparin=23, vitamin K antagonists=28, and thrombolysis=3) due to lack of statistical power. I disagree. They used exactly this comparison to try to show a possible benefit of full-dose heparin on death and dependency at the end of outpatient follow-up (an inappropriate clinical outcome in relation to full-dose heparin in hospital): “We found a nonsignificant difference in outcome in favor of the patients who were anticoagulated in therapeutic doses in the acute phase (66/520 [12.7%] dead/dependent versus 19/104 [18.3%]; HR 0.73; 95% CI, 0.44 to 1.21).”1 Consequently, the ISCVT authors have no basis to object to my appropriate hospital mortality comparison of fully heparinized patients relative to those not fully heparinized (full-dose heparin, 25/520 [4.8%] dead versus no full-dose heparin, 2/104 [1.92%]; odds ratio [OR] 2.5; 95% confidence interval, 0.58–10.7; P=0.20).2,3The ISCVT authors challenged my inference that the only patient who died who received no antithrombotic drug was the only patient first diagnosed with CVT at autopsy. I stand corrected. They clarified that a 37-year-old woman had ICH at presentation and received full-dose heparin. CVT was confirmed in this patient only at autopsy. Despite an autopsy, it was not known if the ICH had increased from baseline.2 Indeed, of the 25 patients who received full-dose heparin and died, 16 patients had documented new brain lesions after receiving heparin. However, out of 104 patients who did not receive full-dose heparin, 1 patient who received no antithrombotic drug died. She died of sepsis (ICH but no herniation). The only nonheparinized patient who died of brain herniation and ICHs had received an antiplatelet drug.2Finally, about the implications for anticoagulation treatment of Hillary Clinton, I agree with the ISCVT authors that headache alone, as clinical presentation, forecasts a very good prognosis at any age. My point is that the ISCVT data indicate an alarming risk of fatal bleeding with anticoagulants, especially in patients ≥65 years. Of 41 patients who were ≥65 years who received full-dose heparin, 4 died in hospital, 3 of whom presented with ICH. Of 37 patients who were ≥65 years and were given vitamin K antagonists during follow-up, 2 died of bleeding complications.Currently, the American Heart Association/American Stroke Association guidelines recommending anticoagulants for CVT make it risky for physicians treating CVT patients to avoid heparin and oral anticoagulants. If an unanticoagulated patient deteriorates or dies, as some will, the doctor may face a malpractice suit. However, the ISCVT data should guide physicians to avoid full-dose anticoagulants or other antithrombotic drugs for CVT.David K. Cundiff, MD, Independent Researcher333 Orizaba AvenueLong Beach, CA 90814DisclosuresNone.FootnotesStroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited.

Real-time ultrasound guidance reduces total and major vascular complications in patients undergoing pulmonary vein antral isolation on therapeutic warfarin

Vascular complications are a known risk of catheter-based pulmonary vein antral isolation (PVAI). Procedure-related thromboembolic events necessitate full-dose anticoagulation, which worsens outcomes in the event of vascular access injury. Real-time ultrasound allows direct visualization of vascular structures. We hypothesized that ultrasound use with venipuncture reduces vascular complications associated with PVAI. Retrospective analysis of all adverse events occurring with PVAI was performed during two periods: 2005-2006 when ultrasound was not used and 2008-2010 when ultrasound was routinely employed. All patients received full-dose IV heparin during PVAI. In the no ultrasound cohort, only 14 % underwent PVAI without stopping warfarin, while 91 % of patients in the ultrasound cohort were on continued warfarin. Only patients deemed at high risk for thromboembolism with a periprocedural international normalized ratio (INR) less than 2 were bridged with subcutaneous low-molecular-weight heparin. Ultrasound reduced total vascular complications (1.7 vs. 0.5 %, p < 0.01) and decreased the incidence of major vascular complications by sevenfold. Warfarin with INR ≥ 1.2 on the day of PVAI was associated with more vascular complications (4.3 vs. 1.2 %, p < 0.01). Ultrasound guidance overcame the risk associated with warfarin therapy. Vascular complications in anticoagulated patients with INR ≥ 1.2 using ultrasound guidance were two- and ninefold lower than those in patients not using ultrasound with an INR < 1.2 (0.5 vs. 1.2 %, p < 0.05) and INR ≥ 1.2 (0.5 vs. 4.3 %, p < 0.01), respectively. Ultrasound-guided venipuncture improves the safety profile of PVAI, reducing vascular complications in patients on warfarin to levels below those with no ultrasound and off warfarin.