Aneel A. Ashrani

Is Diabetes Mellitus an Independent Risk Factor for Venous Thromboembolism?: A Population-Based Case-Control Study

Objective—Although diabetes mellitus is reported as a risk factor for venous thromboembolism (VTE), persons with diabetes are frequently hospitalized for medical illness or surgery, or confined to a nursing home, all major VTE risk factors. Consequently, we tested diabetes for an independent association with incident VTE. Methods and Results—Using Rochester Epidemiology Project resources, we identified all Olmsted County, Minn residents who met objective criteria for incident VTE over the 25-year period, 1976 to 2000 (n=1922), and 1 to 2 resident controls per case, matched on age, gender, and length of medical history (n=2115). Complete medical histories in the community were reviewed for previously identified independent VTE risk factors and diabetes-related variables. We tested diabetes and diabetes complications (retinopathy, nephropathy or neuropathy, and ketoacidosis) as potential VTE risk factors, both alone and after adjusting for VTE risk factors. Univariately, diabetes by clinical diagnosis or by stricter criteria (fasting ambulatory blood glucose ≥140 mg/dL or antidiabetic drug therapy), and diabetes complications, were associated with overall incident VTE. However, after controlling for hospitalization for major surgery or medical illness and nursing home confinement, diabetes was no longer associated with VTE. Conclusion—Diabetes mellitus and diabetes complications are not independent risk factors for incident VTE.

Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study

To test recommended anticoagulation measures as predictors of 180-day venous thromboembolism (VTE) recurrence, we identified all Olmsted County, MN residents with incident VTE over the 14-year period of 1984-1997, and followed each case (N = 1166) forward in time for VTE recurrence. We tested the activated partial thromboplastin time (APTT), international normalized ratio (INR), and other measures of heparin and warfarin anticoagulation as predictors of VTE recurrence while controlling for baseline and time-dependent characteristics using Cox proportional hazards modeling. Overall, 1026 (88%) and 989 (85%) patients received heparin and warfarin, respectively, and 85 (8%) developed VTE recurrence. In multivariable analyses, increasing proportions of time on heparin with an APTT ≥ 0.2 anti-X(a) U/mL and on warfarin with an INR ≥ 2.0 were associated with significant reductions in VTE recurrence, while the hazard with active cancer was significantly increased. Time from VTE onset to heparin start, duration of overlapping heparin and warfarin, and inferior vena cava (IVC) filter placement were not independent predictors of recurrence. At a heparin dose ≥ 30 000 U/d, the median proportion of time with an APTT ≥ 0.2 anti-X(a) U/mL was 92%, suggesting that routine APTT monitoring and heparin dose adjustment may be unnecessary. In summary, lower-intensity heparin and standard-intensity warfarin anticoagulation are effective in preventing VTE recurrence.

Iliopsoas haemorrhage in patients with bleeding disorders – experience from one centre

Summary.  Iliopsoas haemorrhage in patients with bleeding disorders is a potentially life‐threatening condition, with significantly associated morbidity. Despite its clinical importance, little has been published on the frequency, complications or outcomes of this entity since the advent of modern therapies for haemophilia. In a retrospective review of 297 patients with bleeding disorders followed at our centre, we identified 46 episodes of iliopsoas haemorrhage in 31 patients. Patients presented primarily with thigh, hip and/or groin pain, and frequently had flexion hip contracture, femoral nerve paresthesia, and >2 g dL−1 haemoglobin drop. The duration of symptoms prior to seeking medical attention was 3.8 ± 4 days. Nineteen of 155 patients (12.3%) with haemophilia A had 28 episodes of iliopsoas bleed; 52.6% of these patients had severe haemophilia. Of these 19 patients with haemophilia A who had iliopsoas haemorrhage, seven (36.8%) had an inhibitor to factor VIII (FVIII), and accounted for one‐half of the bleeding episodes. Nine of 66 patients (13.6%) with haemophilia B had 15 episodes of iliopsoas haemorrhage; 22.2% of these patients had severe haemophilia, including one patient with an inhibitor to FIX who had two iliopsoas bleeds. The mean duration of therapy was 18.7 ± 11.9 days, and the duration of hospitalization was 12.3 ± 9.1 days. The length of hospital stay was significantly longer in patients with inhibitors, when compared with patients without inhibitors (19.1 ± 5.8 days vs. 7.6 ± 7.8 days; P < 0.0001) with higher factor consumption, although the total duration of therapy was not significantly different. Patients with inhibitors were over‐represented in the cohort of haemophiliacs with iliopsoas bleed. Patients with inhibitors who had iliopsoas bleeds remained hospitalized longer, although the duration of therapy was the same as patients with no inhibitors. There was a low frequency of recurrent bleed (2.8%).

Successful liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor

Summary.  We present the case of a 61‐year‐old man with severe haemophilia A and a high‐titre factor VIII inhibitor who underwent successful orthotopic liver transplantation (OLT) for hepatocellular carcinoma. Postoperatively, a modest early anamnestic response to FVIII was followed by immunological tolerance to FVIII. This case illustrates the technical feasibility of OLT in some patients with high‐titre inhibitors to FVIII, and suggests that immune tolerance may be induced by endogenously produced FVIII from the transplanted organ.

Risk Factors and Underlying Mechanisms for Venous Stasis Syndrome: A Population-Based Case-Control Study

Abstract Venous stasis syndrome may complicate deep vein thrombosis (DVT; i.e. post-phlebitic syndrome), but, in most cases, venous stasis syndrome is not post-phlebitic. The objective of this study was to determine the risk factors (including prior DVT) for venous stasis syndrome, and to assess venous outflow obstruction and venous valvular incompetence as possible mechanisms for venous stasis syndrome. This was a case–control study nested within a population-based inception cohort. The study population consisted of 232 Olmsted County, MN residents with a first lifetime venous thromboembolism (VTE) and 133 residents without VTE. Measurements included a questionnaire and physical examination for venous stasis syndrome; strain gauge outflow plethysmography, venous continuous wave Doppler ultrasonography and passive venous drainage and refill testing for venous outflow obstruction and venous valvular incompetence. Altogether, 161 (44%), 43 (12%), and 136 (38%) subjects respectively, had venous stasis syndrome, venous outflow obstruction and venous valvular incompetence. Independent risk factors for venous stasis syndrome included increasing patient age and body mass index (BMI), prior DVT, longer time interval since DVT, and varicose veins. Both venous outflow obstruction (p = 0.003) and venous valvular incompetence (p < 0.0001) were strongly associated with venous stasis syndrome. Increasing age and prior DVT were significantly associated with venous outflow obstruction, while prior DVT, varicose veins and venous stasis syndrome diagnosed prior to the incident DVT were significantly associated with venous valvular incompetence. The risks of venous outflow obstruction, venous valvular incompetence and venous stasis syndrome were higher with left leg DVT. In conclusion, increasing patient age and BMI, prior DVT (particularly left leg DVT), longer time interval since DVT and varicose veins are independent risk factors for venous stasis syndrome. Venous stasis syndrome related to DVT is due to venous outflow obstruction and venous valvular incompetence, while venous stasis syndrome related to older age and to varicose veins is due to venous outflow obstruction and to venous valvular incompetence, respectively.

Reasons for the persistent incidence of venous thromboembolism

Reasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981-2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981-2010, did not change significantly. Over the time period, 1988-2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981-2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one-third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient.

Impact of Venous Thromboembolism, Venous Stasis Syndrome, Venous Outflow Obstruction and Venous Valvular Incompetence on Quality of Life and Activities of Daily Living: A Nested Case-Control Study

The role of venous stasis syndrome (VSS) mechanisms (i.e. venous outflow obstruction [VOO] and venous valvular incompetence [VVI]) on quality of life (QoL) and activities of daily living (ADL) is unknown. The objective of this study was to test the hypotheses that venous thromboembolism (VTE),VSS,VOO and VVI are associated with reduced QoL and ADL. This study is a follow-up of an incident VTE case-control study nested within a population-based inception cohort of residents from Olmsted County, MN, USA, between 1966 and 1990. The study comprised 232 Olmsted County residents with a first lifetime VTE and 133 residents without VTE. Methods included a questionnaire and physical examination for VSS; vascular laboratory testing for VOO and VVI; assessment of QoL by SF36 and of ADL by pertinent sections from the Older Americans Resources and Services (OARS) and Arthritis Impact Measurement Scales (AIMS2) questionnaires. Of the 365 study participants, 232 (64%), 161 (44%), 43 (12%) and 136 (37%) had VTE, VSS, VOO and VVI, respectively. Prior VTE was associated with reduced ADL and increased pain, VSS with reduced physical QoL and increased pain, and VOO with reduced physical QoL and ADL.VVI was not associated with QoL or ADL. In conclusion,VSS and VOO are associated with worse physical QoL and increased pain. VOO and VTE are associated with impaired ADL. We hypothesize that rapid clearance of venous outflow obstruction in individuals with acute VTE will improve their QoL and ADL.

Lupus anticoagulant associated with transient severe factor X deficiency: a report of two patients presenting with major bleeding complications

Summary. Acquired factor X (FX) deficiency is rare, but has been reported in diverse disease states, including systemic amyloidosis and respiratory infections. FX deficiency associated with lupus anticoagulant (LA) and a bleeding diathesis has not been previously reported. We report two patients both of whom presented with a severe bleeding diathesis after a preceding respiratory infection due to isolated FX deficiency associated with a LA. The FX deficiency and LA were transient. We conclude that patients with LA may rarely present with severe acquired FX deficiency. This may be another mechanism whereby patients with antiphospholipid antibodies present with bleeding complications.

Pilot study to test the efficacy and safety of activated recombinant factor VII (NovoSeven) in the treatment of refractory hemorrhagic cystitis following high-dose chemotherapy [3]

Pilot study to test the efficacy and safety of activated recombinant factor VII (NovoSeven) in the treatment of refractory hemorrhagic cystitis following high-dose chemotherapy

Original ResearchPulmonary Vascular DiseaseRethinking Guidelines for VTE Risk Among Nursing Home Residents: A Population-Based Study Merging Medical Record Detail With Standardized Nursing Home Assessments

BACKGROUND Nursing home (NH) residents are at increased risk for both VTE and bleeding from pharmacologic prophylaxis. Construction of prophylaxis guidelines is hampered by NH-specific limitations with VTE case identification and characterization of risk. We addressed these limitations by merging detailed provider-linked Rochester Epidemiology Project (REP) medical records with Centers for Medicare and Medicaid Services Minimum Data Set (MDS) NH assessments. METHODS This population-based nested case-control study identified all Olmsted County, Minnesota, residents with first-lifetime VTE October 1, 1998, through December 31, 2005, while a resident of an NH (N = 91) and one to two age-, sex-, and calendar year-matched NH non-VTE control subjects. For each NH case without hospitalization 3 months before VTE (n = 23), we additionally identified three to four nonhospitalized NH control subjects. REP and MDS records were reviewed before index date (VTE date for cases; respective REP encounter date for control subjects) for numerous characteristics previously associated with VTE in non-NH populations. Data were modeled using conditional logistic regression. RESULTS The multivariate model consisting of all cases and control subjects identified only three characteristics independently associated with VTE: respiratory infection vs no infection (OR, 5.9; 95% CI, 2.6-13.1), extensive or total assistance with walking in room (5.6, 2.5-12.6), and general surgery (3.3, 1.0-10.8). In analyses limited to nonhospitalized cases and control subjects, only nonrespiratory infection vs no infection was independently associated with VTE (8.8, 2.7-29.2). CONCLUSIONS Contrary to previous assumptions, most VTE risk factors identified in non-NH populations do not apply to the NH population. NH residents with infection, substantial mobility limitations, or recent general surgery should be considered potential candidates for VTE prophylaxis.