Primary Hypercoagulable State Research Articles

Effectiveness and Safety of Rivaroxaban Versus Warfarin for Treatment of Venous Thromboembolism in Patients with Known Primary Hypercoagulable States

Background: The efficacy and safety of rivaroxaban versus enoxaparin/vitamin K antagonist (VKA) for treatment and secondary prevention of venous thromboembolism (VTE) was demonstrated in the EINSTEIN clinical trial program. As screening for primary hypercoagulable states was not required as part of the EINSTEIN trial program protocol, fewer than 500 total patients with a known primary hypercoagulable state were identified.Objective: To assess the effectiveness and safety of rivaroxaban versus warfarin for treatment and secondary prevention of VTE in patients with a known primary hypercoagulable state in a large, real-world population.Methods: US MarketScan claims data from January 2012-September 2015 were utilized. We identified adult patients with a primary International Classification of Diseases-9th Revision (ICD-9) discharge diagnosis code for deep vein thrombosis (DVT) (ICD-9=451.1, 451.2, 453.40, 453.41, 453.42, 453.8, 453.9) or pulmonary embolism (PE)(ICD-9=415.1x), diagnosed during a hospitalization or emergency department visit (the index event), with ≥180-days of continuous medical and prescription benefits prior to the index event (baseline), a documented diagnosis for a primary hypercoagulable state (ICD-9=289.81) during baseline or the index VTE encounter and newly-initiated on rivaroxaban or warfarin within 30-days of the index VTE event. Patients with a claim for an anticoagulant before the index event were excluded. Effectiveness and safety endpoints included recurrent VTE, any major bleeding (identified per the Cunningham algorithm), intracranial hemorrhage (ICH) and gastrointestinal bleeding (GIB). Patients were followed for a maximum of 12-months from the index event or until occurrence of an endpoint, switch or discontinuation (14-day permissible gap) of index oral anticoagulation or insurance disenrollment. Rivaroxaban users were 1:1 propensity-score matched to warfarin users. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (differences >0.1 indicating imbalance). Cox regression was performed and results reported as hazard ratios (HRs) with 95% confidence intervals (CIs).Results: We matched 403 rivaroxaban and 403 warfarin users with a known primary hypercoagulable state and experiencing a VTE. Mean±standard deviation (SD) duration of patient follow-up was 0.5±3 years. All baseline covariates had a standardized difference <0.1 after matching. Mean±SD age of the population was 50±14 years; PE (with or without DVT) was present in 53% of patients, 50% of patients were female and 12% had a hospital admission within 180-days of their qualifying VTE event. Rivaroxaban use was associated with a 30% non-significant relative reduction in the hazard of recurrent VTE and a non-significant 45% relative reduction in the hazard of major bleeding as compared to warfarin (Table). Only 2 patients experienced an ICH (both warfarin users). Rivaroxaban users had a non-significant 53% relative reduction in the hazard of GIB versus warfarin.Conclusion: Our study results suggest rivaroxaban's relative effectiveness and safety versus warfarin is maintained when treating VTE patients with known primary hypercoagulable states in routine practice. These real-world study findings are consistent with that of the overall EINSTEIN clinical trial program and its subgroup analysis of patients with primary hypercoagulable states. [Display omitted] DisclosuresColeman:Boehringer Ingelheim: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bayer AG: Consultancy, Honoraria, Research Funding. Turpie:Bayer HealthCare Pharmaceuticals: Consultancy; Janssen Research and Development: Consultancy, Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding.

Patients Undergoing Primary Total Joint Arthroplasty with Primary Hypercoagulable States.

ObjectiveTo analyze perioperative complications, resource consumption, and inpatient mortality of patients who receive total joint arthroplasty (TJA) with a concomitant diagnosis of a primary hypercoagulable state (PHS). The following questions were posed in the present paper. First, do patients undergoing TJA with PHS have increased risk of deep venous thrombosis (DVT), pulmonary embolism (PE), and periprosthetic joint infection (PJI)? Second, what other in‐hospital complications are more likely among PHS patients undergoing TJA? Third, do TJA patients with PHS usually consume greater in‐hospital resources? Fourth, do PHS patients suffer higher mortality rates compared to non‐PHS patients? Finally, have PHS patients received proper anticoagulant management in past arthroplasties?MethodsThe National Inpatient Sample (NIS) database for the years between 2003 and 2014 was searched to identify patients undergoing primary TJA. Patients with PHS were identified with the ICD‐9‐CM code 289.81. The χ2‐test, the Pearson test, and adjusted multivariate regression analysis were performed to evaluate the difference and odds ratios between the positive and negative diagnosis groups.ResultsFrom 2003 to 2014, a total of 2,044,356 patients were identified in the NIS as undergoing primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) in the United States. A total of 4664 patients (0.2%) were identified as having PHS. Compared with the non‐PHS group, TJA patients with PHS had a higher risk of DVT (THA: odds ratio [OR] = 8.343, 95% CI: 5.362–12.982, P < 0.001; TKA: OR = 4.712, 95% CI: 3.560–6.238, P < 0.001) but did not have increased risk of PE (THA: OR = 1.306, 95% CI: 0.48–3.555, P = 0.602; TKA: OR = 1.143, 95% CI: 0.687–1.903), and only PHS patients in the THA group had higher risks of inpatient mortality (OR = 3.184, 95% CI: 1.348–7.522, P = 0.008) and periprosthetic joint infection (OR = 3.343, 95% CI: 1.084–10.879, P = 0.036). In addition, PHS patients had extended length of stay, higher total costs, and increased risks of certain other complications, such as peripheral vascular disease, hemorrhage, and thrombophlebitis.ConclusionIn the present study, PHS patients had higher risks of DVT, greater in‐hospital resource consumption, and certain other perioperative complications. However, PHS was not associated with increased risk of PE in TJA patients in the United States between 2003 and 2014. While potential hazards of PHS have already been recognized, the present study revealed additional concerns and demonstrated that further improvements in the perioperative management of patients with hereditary hypercoagulable disorders are essential.

Abstract WP374: 30 Days Unplanned Readmission (30-DR) in Cerebral Vein Thrombosis: US National Retrospective Analysis

Introduction: Thrombosis of the cerebral veins and/or dural sinuses (CVST) results in 0.5% to 1% of all strokes. CVST has a lower mortality rate compared to arterial stroke; however it predisposes to certain complications, which lead to frequent hospital readmissions. Objective: To study the readmission rate, reasons for readmissions and predictors of intracranial hemorrhage (ICH). Method: Using the Nationwide Readmission Database (NRD) from 2013 -2014 patients with a primary discharge diagnosis of CVST (ICD 9 CM code: 437.6, 325, and 671.5) were identified. Their post-hospitalization course was tracked using the variable “NRD_visitlink,” and the time between re-admissions was calculated by subtracting the variable “NRD_DaysToEvent”. SAS 9.4 was used for data analysis with categorical and continuous variables tested using the Rao Scott Chi-square test and Student’s t-test, respectively. Multivariate logistic regression models were used for categorical dependent variable. Result: A total of 3,611 (weighted) Index discharges of CVST were identified. After excluding elective readmissions, 11.32%, 17.04% and 21.81% were the observed readmission rates at 30, 90 and 180 day-follow-up periods respectively. The common causes of 30-day readmission (30-DR) were complications of the puerperium (8.76%), ICH (6.13%), migraine (4.23%), ischemic stroke (2.86%), sepsis (2.30%) and hypertensive complications (1.83%). Epilepsy related readmissions were observed only in the 90-day (1.95%) and 180-day (2.51%) follow up periods. The mean 30-DR cost was lower vs. Index admission (Mean ± SE $ 12,439±1139 vs. $ 16314±652; P value &lt;0.0001) while the length of stay (LOS) during readmission was also lower compared to Index LOS (Mean ± SE 5.0±0.4 vs. 6.4±0.2 ;&lt; 0.0001). After adjusting age and gender, multivariate predictors of increase risk of ICH readmission were hypertension (OR 4.79 CL 1.38-16.59; P=0.0068), primary hypercoagulable state (OR 3.34, CL 1.12-9.99; P=0.0306), meningitis (OR 17.77 CL 2.51-125.96, P=0.0041) and chronic kidney disease (OR 3.80CL 1.04-13.85, P=0.0434). Conclusion: Puerperal complications, ICH, epilepsy and sepsis are the most common complications prompting re-hospitalization in patients diagnosed with CVST.

Effectiveness and safety of outpatient rivaroxaban versus warfarin for treatment of venous thromboembolism in patients with a known primary hypercoagulable state

IntroductionScreening for primary hypercoagulable states (PHSs) in venous thromboembolism (VTE) patients was not mandated in the EINSTEIN trials; and therefore, few patients with a known PHS were available for analysis. We sought to assess the effectiveness and safety of rivaroxaban versus warfarin for treatment of VTE in patients with a known PHS. MethodsUsing MarketScan claims data from 1/2012-9/2015, we identified adults with a primary diagnosis of VTE during a hospitalization/emergency department visit (the index event), with ≥180-days of continuous insurance coverage prior to the index event, a documented diagnosis for a PHS and newly-initiated as an outpatient on rivaroxaban or warfarin within 30-days of the index VTE. Rivaroxaban and warfarin users were 1:1 propensity-score matched. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (<0.1 considered well-balanced). Patients were followed up to 12-months from the index event or until occurrence of an endpoint, switch/discontinuation of index oral anticoagulation or insurance disenrollment. Rates of recurrent VTE and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). ResultsWe matched 403 rivaroxaban and 403 warfarin patients with VTE and a known PHS. All baseline covariates had a standardized difference < 0.1. Rivaroxaban use was associated with a non-significant reduction in recurrent VTE (HR = 0.70, 95%CI = 0.33–1.49) and major bleeding (HR = 0.55, 95%CI = 0.16–1.86) versus warfarin. ConclusionsIn routine practice, the effectiveness and safety of rivaroxaban versus warfarin in VTE patients with a known PHS appears to be similar to that observed in the EINSTEIN trial program.

Pulmonary thromboembolism in an emergency hospital: Are our patients different?

Pulmonary thromboembolism (PTE) represents a medical emergency and is the third most common cause of mortality after myocardial infarction and stroke. The purpose of this study was to describe the characteristics and management of patients with PTE admitted in a referral emergency hospital in Romania. We retrospectively reviewed all cases of PTE diagnosed in one of the largest emergency hospitals in Bucharest during a 2-year period (January 2014 - December 2016). Patients with acute PTE were identified by a database search of the diagnostic codes of all discharge diagnoses. Demographic, clinical and paraclinical tests data was retrieved from medical records. 221 patients (48.87% male, mean age 61.76 years (range 21-94 years)) were diagnosed with PTE in our hospital (0.31% of all hospitalizations). Dyspnea was the most frequent symptom reported (78.9%), followed by pleuritic chest pain (23.9%) and unilateral leg pain (15.8%). Upon presentation, 12.6% of patients had high-risk PTE. Up to 72.8% of patients had at least one thrombotic risk factor, while cancer (14%) was the most frequent amongst them. The mean length of hospitalization was 10.3 ± 4.6 days. Unfractioned heparin (UFH) was the preferred anticoagulant during hospital stay (73.7%, p < 0.001). Vitamin K antagonists (AVK) were the preferred anticoagulant (71.7%, p < 0.001) after discharge, whereas non-antivitamin K oral anticoagulants (NOAC) were recommended in 26.3% of patients. Thrombolysis was used in 18 (8.4%) cases. Mortality was 0.9%. Younger patients more frequently associated thrombophilia or a previous thromboembolic event and clinical signs of DVT at presentation. Older patients associated more frequently a history of hospitalization for heart failure or atrial fibrillation during the previous 3 months and a history of cancer. The clinical presentation in older patients was more severe, with higher PESI scores (103.6 ± 33.4 vs. 55.5 ± 17.9, p<0.001) and a longer hospital stay (10.7 ± 4.7 vs. 9.2 ± 3.9, p = 0.03). The type of anticoagulant treatment did not differ depending on age. In our emergency hospital, PTE is a relatively rare cause of hospitalization; the rate is, however, comparable with other major hospitals. Dyspnea and pleuritic chest pain was the clinical presentation dyad. UFH was the preferred anticoagulant for in-hospital treatment while AVK was the preferred option for long term treatment and recurrence prophylaxis; however an increasing number of patients are prescribed NOAC. In older patients clinical severity was higher upon presentation, hospitalization duration was increased and cancer was more frequently associated. Younger patients associated more frequently a primary hypercoagulable state and recurrent thromboembolism. Mortality rate was low during hospitalization, comparable with that seen in other studied populations.

Challenges of Anticoagulation Therapy in Pregnancy.

Thrombotic complications in pregnancy represent a major cause of morbidity and mortality. Pregnancy is a primary hypercoagulable state due to enhanced production of clotting factors, a decrease in protein S activity, and inhibition of fibrinolysis. These physiologic changes will yield a collective rate of venous thromboembolism (VTE) of about 1-2 in 1000 pregnancies for the general obstetric population, which represents a five- to tenfold increased risk in pregnancy compared to age-matched non-pregnant peers. A select group of women, however, will carry a significantly higher rate of thrombosis due to primary thrombophilia, either inherited or acquired. This introduces a population of women who may benefit from prophylactic anticoagulation, either antepartum or postpartum. The coagulation changes that occur in preparation for the hemostatic challenges of delivery endure for several weeks postpartum. In fact, daily risk for pulmonary embolism (PE) is the highest postpartum. Use of anticoagulation in pregnancy introduces particular risk at the time of delivery, where bleeding and clotting risk collide. Altered metabolism rates of anticoagulants in pregnant women often necessitate closer monitoring than is required outside of pregnancy in order to ensure efficacy and safety. Heparin products are the mainstay of treating VTE in pregnancy, chiefly because they do not cross the placenta. In women with mechanical heart valves, the ideal anticoagulation regimen remains controversial as heparin use has shown inferior outcomes for preventing thromboembolic complications compared to warfarin, but warfarin carries risk for fetal embryopathy. Other populations where a heparin alternative is necessary include women with a history of heparin-associated thrombocytopenia (HIT) or other heparin intolerance. Further challenging the management of anticoagulation in pregnancy is the dearth of randomized clinical trials. The evidence governing treatment recommendations is largely based on expert guidelines, observational studies, or extrapolation from non-pregnant cohorts. A careful critique of a woman's history, as well as the available data, is essential for optimal management of anticoagulation in pregnancy. Such decisions should involve a multidisciplinary team involving obstetrics, hematology, cardiology, and anesthesia.

Outcomes of Isolated Pediatric Small Intestine Transplants Using Vascular Homografts

Introduction: Pediatric intestinal transplantation has changed recently with more isolated small intestine transplants being performed in small children instead of combined liver-intestine transplants. Consequently, surgical techniques have changed, requiring a frequent use of vascular homografts of small caliber, the impact of which on outcomes is unknown. Methods: Among 106 pediatric intestine and multivisceral transplants performed at our center since 2003, 39 recipients of an isolated small intestine graft were reviewed. Four patients transplanted between 2003 and 2005 with insufficient medical records and two patients with follow-up <1 year were excluded. The remaining 33 pts, including 4 retransplants (16M, 17F, median age 3.3 y [range 1.2-17.2], median weight 14.2 kg [8.1-56]) were included in this study. Grafts were monitored with Doppler of the stoma and angiography when necessary. Patients with hypercoagulable state received systemic anticoagulation from the time of graft reperfusion. Outcome parameters were thrombotic complications and graft survival. Results: 25/33 grafts (76%) were reperfused “centrally” (aorta and vena cava), 24 of them via vascular homograft. The other 8 grafts were reperfused via native superior mesenteric artery and vein. Overall, 28/33 (85%) patients required both arterial and venous homografts from the same donor (donor's median age 1.1 y [2mo-23 y], median weight 10 kg [14.7-48.5]), mainly iliac or carotid artery and iliac or innominate vein, respectively. Post-transplant, there were 3 acute thromboses at the anastomosis of the arterial homograft (2 central and one mesenteric) on post-operative day 0, 2 and 13 and one venous homograft thrombosis on POD 7 requiring urgent percutaneous thrombolysis and/or operative thrombectomy resulting in 2 peri-operative graft salvages and 2 graft losses. Three out of 4 thromboses occurred in patients with primary hypercoagulable state, including the 2 graft losses. Overall, at a median of 4.1 years (1–10.2) from transplant, 29/33 (88%) patients are alive with 26/33 (79%) functioning grafts. Conclusion: In our series 2/33 (6%) pediatric isolated intestine grafts were lost due to thrombotic complications of the vascular homograft in patients with hypercoagulable state. The procurement of intact, size-matched donor vessels and post-transplant anticoagulation are critical.

IMPACT OF HEREDITARY CAUSES OF THROMBOSIS ON ISCHEMIC STROKE BETWEEN THE YEARS 2008 THROUGH 2012: NATIONWIDE INPATIENT SAMPLE DATA ANALYSIS

Background: Ischemic Stroke (IS) is associated with traditional risk factors of diabetes, hypertension, hyperlipidemia and smoking. However, impact of hereditary causes of thrombosis (HT) on IS is largely unknown. HT includes primary hypercoagulable state, activated protein C resistance,

Abstract WP157: Stroke Risk Factors for Women With Preeclampsia in New York State, 2008-2012: a Case Control Study

Introduction: Pregnancy-associated stroke (PAS) remains among the leading causes of maternal morbidity and mortality. Up to 20% of women with PAS have preeclampsia or eclampsia (PEC). However, PEC is relatively common (∼3.4% of pregnancies), while PAS is rare (∼20 per 100,000 deliveries). It is not clear what risk factors differentiate women with PEC who develop PAS. Hypothesis: Identifying risk factors for stroke in women with PEC could help identify women at highest risk for PAS. Methods: We used the 2008-2012 New York State Department of Health Statewide Planning and Research Cooperative System (SPARCS) inpatient sample database to identify pregnant or postpartum women (APR MDC 14) aged 12-50 with mild to severe preeclampsia (642.4x-642.5x) or eclampsia (642.6x). We compared non-stroke PEC patients (controls) to those with ischemic (ICD-9 433.xx, 434.xx, 436), ICH (ICD-9 431), SAH (ICD-9 430), and non-specified pregnancy-related strokes, including post-partum stroke (ICD-9 671.7, 674.0-674.4). Risk factors included delivery type (C-section vs vaginal), age, multigravida, primary hypercoagulable state, pre-existing diabetes, obesity and migraine. The associations between risk factors and stroke were evaluated using generalized estimating equation logistic regression adjusting for patients’ re-hospitalizations to calculate odds ratios and 95% confidence intervals (OR, 95%CI) for stroke . Results: There were 85 stroke cases and 41,634 PEC controls without stroke. A majority of strokes in PEC patients occurred postpartum (n=76, 89.4%). Stroke patients were more likely to have eclampsia (OR: 24.7, 95%CI: 15.6-39.3) or severe pre-eclampsia (OR: 1.6, 95%CI: 1.0-2.5) compared to non-stroke patients. In multivariable analyses, being multigravida (OR: 1.4, 95%CI 1.3-1.6), primary hypercoagulable state (OR:2.1, 95%CI 1.8-2.4) and migraine (OR 2.3, 95%CI 2.1-2.5) were also risk factors for stroke. Conclusions: Women with eclampsia were at at the highest risk for pregnancy-associated stroke. Several other risk factors for stroke in women with preeclampsia may also help identify women who warrant closer monitoring for neurological symptoms in the peripartum period.

Abstract WMP59: Multiple Scattered Tiny Cerebral Infarctions Are Unlikely Cardiogenic

Background: Embolic ischemic strokes are commonly considered to be cardiogenic. In clinical practice, however,patients with a pattern of multiple tiny ischemic foci on MRI often have no cardiac source. To identifying its etiology may help selecting the right therapy to treat or prevent recurrent strokes. Methods: From 1/2010 to 12/2013, records and MRI imaging of 2984 consecutive stroke patients were reviewed. Patients with the following DWI MRI findings were included: 1) ≥3 high intensity lesions in three different arterial territories, 2) each ≤15mm in size and ≤2 sections in thickness. Other data reviewed include general demographics, clinical features and lab results. Patients with known cardiac embolism, aortic arch plaques or aneurysms and recent surgery were excluded. Images of follow-up MRI were reviewed. Results: Among 2984 cases reviewed, 71 patients had multiple tiny DWI lesions. In order to rule out artery to artery emboli, patients with lesions from the same artery territory or watershed region were excluded. Only 43 met all criteria. Their median age was 65 and 23(53.5%) were male. Extremity weakness and slurred speech were the most common presenting symptoms. The median number of DWI lesions in each brain was 13. Common disorders identified include: infection (81.4%), hyperlipidemia(58.1%), moderate chronic kidney disease(39.5%), previous history of stroke (48.8%). Four (9.3%) had large B cell lymphoma and 2 had lung cancer. The quantity of DWI lesions was related to hyperglycemia, hyperlipidemia and impaired GFR. Patients with primary hypercoagulable state more likely had multiple lesions (median 39). On discharge, 5 (11.6%) patients were prescribed dual antiplatelet therapy and 11 (25.6%) were given oral anticoagulants. Conclusions: To our knowledge, this was the first review of this type of specific DWI findings with clinical correlation. Multiple tiny or ‘Star-like’ type of lesions on DWI MRI were likely caused by infection, hyperlipidemia CKD and leukemia. They are unlikely cardiogenic and its recurrent rate was high. Recognizing the pattern of these tiny lesions will help clinicians refocus on the work up of stroke, strategies of treatment and stroke prevention strategy.

National Epidemiology of Inpatient Venous Thromboembolism in Patients with Hematologic Malignancies in United States from 1993 to 2012

▪Background: Venous thromboembolism (VTE) is an important cause of morbidity and mortality in patients with hematologic malignancies (HMs). The national burden of inpatient VTE in patients with HMs is not known.Methods: We used the National Inpatient Sample (NIS), one of the largest publicly-available inpatient dataset in United States (U.S.), which represents a 20% stratified random sample of discharges from all hospitals, excluding rehabilitation and long-term acute care hospitals. The NIS is drawn from all States participating in Healthcare Cost and Utilization Project, representing more than 95 percent of the U.S. population. Discharge weights are used to generate national estimates. Patients with HMs were identified using ICD9 codes published by NIS and VTE was defined by ICD9 codes 451 - 453 and 415.1. Annual rates of inpatient VTE were calculated from 1993 to 2012 by HM type. Multivariate odds of inpatient VTE was determined by logistic regression controlling for confounders (age, sex, Charlson co-morbidity index, metastasis, chemotherapy, transfusion of blood products, major operating room procedure, primary hypercoagulable state, disseminated intravascular coagulation, heparin induced thrombocytopenia and thrombosis, antiphospholipid syndrome, obesity and calendar year). The malignancies with non-specific designation (e.g. unspecified leukemia) or with less than 1000 patients (weighted number) were excluded from results.Results: 8.42million hospitalized patients (weighted number) with HMs were identified, and 335,240had VTE (3.98%). In patients with HMs, rates of inpatient VTE increased from 2.59% to 5.22% between 1993 and 2012 (p<0.01). A detailed analysis of VTE rates for various HMs is presented in Table 1. The HMs with highest odds of inpatient VTE are peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL) and primary central nervous system (CNS) lymphoma (OR 1.56, 1.53, and 1.39, p<0.05) as compared to all other HM. Among leukemias, hairy cell leukemia had higher odds of VTE (OR 1.19, p<0.05). The HMs with the least odds of VTE were acute lymphoid leukemia, chronic monocytic leukemia and plasma cell leukemia (OR 0.65, 0.66 and 0.71, p<0.05). The HMs with the highest rates of VTE were PTCL, large cell lymphoma and ALCL (6.96%, 6.35% and 6.27%). The HMs with lowest rate of VTE were megakaryocytic leukemia, acute lymphoid leukemia and acute monocytic leukemia (1.42%, 2.04%, and 2.73%).Conclusions: Our study provides national estimates of inpatient VTE in HM, which are increasing over the last 20 years. Certain HMs have higher rates and odds of VTE as compared to others. Identification of these differences provides valuable information for the use of prophylaxis in HM with high risk of VTE.Table 1Multivariate Odds and Rates of Inpatient Venous Thromboembolism in Patients with Hematologic Malignancies (Total weighted N = 8.42 million)Hematologic malignancyInpatient VTE rate (%)Adjusted OR (95% CI) of inpatient VTE compared to all other HMHodgkin's diseaseHodgkin's disease - lymphocyte rich3.861.15 (0.82 - 1.61)Hodgkin's disease - nodular sclerosing4.041.3 (1.18 - 1.43)Hodgkin's disease - mixed cellularity4.021.22 (0.89 - 1.68)Hodgkin's disease - lymphocyte depleted3.881.14 (0.73 - 1.77)Non-hodgkin's lymphomaNodular lymphoma4.891.2 (1.13 - 1.28)Mycosis fungoides4.831.25 (1.16 - 1.35)Sezary's disease3.991.08 (0.72 - 1.62)Peripheral t-cell lymphoma6.961.56 (1.32 - 1.85)Burkitt's lymphoma3.441.05 (0.97 - 1.15)Marginal zone lymphoma5.571.07 (0.91 - 1.26)Mantle cell lymphoma4.911.03 (0.92 - 1.15)Primary CNS lymphoma6.181.39 (1.18 - 1.64)Anaplastic large cell lymphoma6.271.53 (1.21 - 1.94)Large cell lymphoma6.351.36 (1.22 - 1.51)SarcomaMyeloid sarcoma4.241.14 (0.9 - 1.44)Myeloma and leukemiaMultiple myeloma4.571.14 (1.1 - 1.18)Plasma cell leukemia2.850.71 (0.5 - 1)Lymphoid leukemia - acute2.040.65 (0.61 - 0.69)Lymphoid leukemia - chronic3.430.76 (0.73 - 0.78)Myeloid leukemia - acute3.710.97 (0.93 - 1)Myeloid leukemia - chronic2.930.72 (0.68 - 0.76)Monocytic leukemia - acute2.730.75 (0.59 - 0.96)Monocytic leukemia - chronic2.740.66 (0.44 - 0.98)Erythrocytic leukemia - acute2.950.81 (0.5 - 1.32)Megakaryocytic leukemia1.420.48 (0.23 - 1.02)Hairy cell leukemia4.721.19 (1.07 - 1.32) DisclosuresNo relevant conflicts of interest to declare.

Antithrombin Concentrate Use in Children: A Multicenter Cohort Study

To describe the off-label use of antithrombin concentrate in tertiary care pediatric hospitals across the US. This is a retrospective, multicenter, cohort study of 4210 admissions of children younger than 18 years of age who received antithrombin concentrate between 2002 and 2011 within the Pediatric Health Information System administrative database. An on-label admission was defined as an admission with an International Classification of Diseases diagnostic code for a primary hypercoagulable state; admissions without this code were classified as off-label. During the 10-year study period, off-label use of antithrombin concentrate increased 5-fold. Overall, 97% of study subjects received antithrombin off-label. Neonates younger than 30 days of age comprised the largest age group (45.7%) of use; 87% of patients had at least one complex chronic condition, with congenital heart/lung defects being the most prevalent primary diagnosis (36.3%). Extracorporeal membrane oxygenation was the most common procedure associated with antithrombin use (43.7%). The off-label use of antithrombin concentrate is increasing rapidly, particularly in critically ill children receiving extracorporeal membrane oxygenation, with few parallel studies to substantiate its safety or efficacy. Further preclinical and controlled clinical studies are critical to expanding our knowledge of this drug. In the meantime, antithrombin concentrate should be used judiciously by clinicians and following guidelines instated by hospitals.

Right heart thrombus entrapped in patent foramen ovale with pulmonary embolism in a patient with primary hypercoagulable state

Tromboembolik hastalik erken tani konulmadiginda hayati tehdit eden ciddi bir patolojidir. Pulmoner arterde masif okluzyon olusturdugunda, kalp yetmezligi de gelismisse genc insanlarda bile olume neden olabilir. Sag veya sol atriyumda trombus olmasi ise bu hastaligin morbidite ve mortalitesinde artisa sebep olur. Bu yazida patent foramen ovalenin tuzakladigi trombusu olan, masif pulmoner tromboemboli ve sag kalp yetmezligi gelisen 32 yasinda bir erkek olgu sunulmustur. Transtorasik ekokardiyografide interatriyal septuma yapisik sag atriyal trombusu olan hastaya masif pulmoner tromboemboli tanisi konulduktan sonra doku plazminojen aktivatoru (2 saatte 100 mg) infuzyonu uygulandi. Tedaviden 2 gun sonra yapilan ekokardiyografide sag atriyumdaki trombusun tamamen kayboldugu ve sag ventrikul boyutlarinda kuculme oldugu goruldu. Yapilan genetik incelemede, faktor V Leiden ve trombofili gen mutasyonu saptandi. Hastanin serum homosistein seviyeleri yuksek bulundu.

Recurring extracorporeal circuit clotting during continuous renal replacement therapy resolved after single‐session therapeutic plasma exchange

We report a case of a 17-year-old white male with multiple fractures and multiorgan failure who developed oliguric acute renal failure requiring continuous renal replacement therapy. Repeated clotting of the extracorporeal circuit (ECC) prevented delivery of a minimally acceptable dose of renal replacement therapy despite adequate anticoagulation and dialysis catheter exchanges. Evaluation for a primary hypercoagulable state was negative, but his fibrinogen was elevated (1,320 mg/dL, normal range: 150-400 mg/dL), which is likely induced by his severe inflammatory state. A single session of therapeutic plasma exchange (TPE) with albumin and normal saline replacement was performed with subsequent drop in fibrinogen to 615 mg/dL. No further episodes of premature ECC clotting occurred, suggesting plasma factor(s) removed may have contributed to the clinical hypercoagulable state. TPE may play an adjunctive role in select cases of recurrent ECC clotting refractory to current anticoagulation techniques.

Hypercoagulable state, pathophysiology, classification and epidemiology

Hypercoagulable state is not a uniform disease. It is a complex condition with an abnormal propensity for thrombosis that may or may not lead to thrombosis, depending on complex gene-gene and gene-environment interactions. The prevalence of the hypercoagulable state depends on the ethnicity and clinical history of the population being studied. The consequences of a hypercoagulable state due to thrombosis of veins and arteries are the most important cause of sickness and death in developed countries at present. Primary hypercoagulable state is an inherited condition caused by the reduced level of natural anticoagulants due to a qualitative defect or quantitative deficiency of an antithrombotic protein, or increased concentrations or function of coagulation factors. Most of the inherited abnormalities recognized to date have little or no effect on arterial thrombosis and are associated primarily with venous thromboembolism. Arterial thrombosis usually develops as a complication of atherosclerosis and patients usually have more than one traditional risk factor. Secondary hypercoagulable states generally occur as a result of a large number of transient or permanent acquired conditions that increase the tendency for formation of blood clots. New epidemiological data and clinical trials suggest that many acquired risk factors in the pathophysiology of arterial and venous thrombosis overlap and coexist for both disorders.

Outcomes during and after Pregnancy in Patients with Primary Hypercoagulable States.

Pregnant women with primary hypercoagulable states have an increased risk of recurrent fetal loss, fetal growth retardation, preclampsia, and placental abruption, as well as thromboembolism in both the antepartum and postpartum periods. Conditions that have been associated with adverse pregnancy outcomes include inherited gene mutation disorders such as Factor V Leiden G1691A (FVL); prothrombin gene mutation G20210A (PGM); hyperhomocysteinemia with C677T mutation (MTHFR); deficiencies of protein S (PS), protein C (PC), antithrombin III (ATIII); and anticardiolipin antibodies/lupus anticoagulants (LA). Screening by obstetricians for these disorders has led to an increase in diagnosis yet there are no established guidelines and therapeutic interventions are variable. A retrospective chart review was conducted on 59 women and 197 pregnancies (1–12 per pt) in whom primary hypercoagulable state was diagnosed: FVL (n=7), PGM (n=11), MTHFR (n=3), ATIII (n=2), PC (n=1), PS (n=8), LA (n=10), and those with more than one thrombophilic risk (TR) (n=12) or lupus (n=2). Of the 197 pregnancies, only 106 (54%) were carried to term in 50 pts (85%). Of the remaining 91 pregnancies, there were 16 terminations, 5 ectopic pregnancies and 4 preterm live births. 66 fetal losses occurred: 45 in the first trimester (26 with single TR/19 with >1 TR), 19 in the 2nd–3rd trimester (14 with single TR/5 with > 1 TR) and 2 unknown. See Table for risk of fetal loss by class of hypercoagulable state. Venous thromboembolism occurred in 8/106 (8%) of term pregnancies, including 5 postpartum. Of women with previous fetal losses, management with anticoagulation (A/C) subsequently was utilized in 20 pregnancies: 9 low molecular weight heparin (LMWH), 6 LMWH+aspirin (ASA), 3 heparin (H), 1 ASA, and 1 H+ASA. 18/20(90%) of these pregnancies resulted in live term births; 1 loss due to intracranial hemorrhage at 27 weeks in a patient on L+ASA. Compared to 146 pregnancies untreated with A/C, successful completion of pregnancy was significantly greater on A/C, 90% vs. 58% (p=0.006).Conclusions: Fetal losses secondary to TR occurred in both the first and late trimesters in high proportion of pregnancies in women with hypercoagulable states. Outcomes may be improved with the use of A/C therapy.Table -Risk of Fetal Loss by Class of Hypercoagulable StateLAPGMMTHFRPSFVLATIIIFVL/otherTrimester19/38 (24%)7/44 (16%)3/9 (33%)3/27 (11%)1/27 (4%)2/5 (40%)17/42 (40%)Trimester 2–35/38 (13%)1/36 (3%)0%5/16 (31%)2/27 (7%)1/5 (20%)4/44 (9%)

The Spectrum of Hypercoagulable States in Minority Patients with Unexplained Thrombosis.

The association of genetic risk factors with hypercoagulable states in minority populations has not been well defined. With an estimated prevalence of anywhere between 2-15% in healthy individuals, activated protein C resistance (APCR/Factor V Leiden) is considered to be the most common risk factor for venous thromboembolism( VTE) in the white population. It has also been postulated that this mutation is extremely rare in non-white populations. The prevalence of the prothrombin gene mutation G20210A in the white population is estimated at 0.7–4%, protein C and S deficiencies at 2% each and antithrombin III deficiency at 0.1–0.5% but unknown in Blacks with VTE though case control studies have identified protein C and protein S deficiencies in this population. This study is a retrospective review of all patients with thrombophilia registered at the Hemophilia Treatment Center between 1999–2005. 45/164(27%) of patients with thrombophilia were identified to be from minority groups. Of these minority patients 23/45(51%) had an identifiable primary hypercoagulable state. This group included 7/23(30%) males and 16/23(70%) females. The mean age of the patients was 35 years (range 12–80 years ). 4/23( 17%) were smokers and only 4/23(17%) had a family history of thrombosis with no documented hypercoagulable states in any family members. The majority of the patients were of African American descent 16/23(69%), 5/23(22%) were Hispanic and 2/23(9%) were Asians. 16/23(69%) of the patients had documented deep venous thrombosis/pulmonary embolus, 1/23(4%) had arterial thrombosis, 3/23(13%) had fetal loss, and 2/23(9%) were asymptomatic. APCR was the most common diagnosis in 8/23(35%) of the patients, followed by antiphospholipid antibody syndrome in 7/23(30%) of the patients. Protein S deficiency was diagnosed in 5/23(22%), hyperhomocysteinemia in 4/23(17%), Protein C deficiency in 1/23(4%), antithrombin III in 1/23(4%), and prothrombin gene mutation in 1/23(4%) of the patients. 4/23(17%) of the patients were found to have two coexisting hypercoagulable diagnoses. Recurrent VTE occurred in 7/23(30%) of the patients.Conclusion: Primary hypercoagulable states are not rare in minorities. In this study, APCR was found to be the most common identified abnormality, followed by antiphospholipid antibody and protein S deficiency. Similar to the white population, thrombophilia in minorities occurred more commonly in young female patients. Work up for primary hypercoagulable states should be considered in minority patients with unexplained thrombosis. Further studies are warranted to determine the true prevalence of hypercoagulable states in minority populations.

Quality of evidence underlying the management of thrombophlebitis

Objective: Superficial thrombophlebitis (ST) is commonly associated with varicose veins, although it may occur anywhere else in the body. The aim of this study was to review the quality of the evidence underlying the management of ST. Methods: Review of the literature on the management of ST over a 20-year period carried out using Medline and manual searching. The current management of ST was then divided into levels of evidence as defined by the US Agency for Health Care Policy and Research. Results: Superficial thrombophlebitis of varicose veins of the lower limb can be treated by saphenofemoral ligation with stripping of the proximal vein and surgical excision of the thrombosed segment (levels Ib and III). In the presence of deep vein thrombosis, oral anticoagulant (OC) is recommended (levels Ib and IIa). Hypercoagulable state should be investigated if ST occurs in the absence of varicose veins. In primary hypercoagulable state, disconnection of the saphenofemoral junction should be performed in patients at high risk of pulmonary embolism. Oral anticoagulant should be instituted after the first thrombotic event (level III). In secondary hypercoagulable state, OC with treatment of the underlying cause is recommended (level IV). Conclusions: The quality of evidence supporting the management of ST varies considerably. Further randomized studies are required to support some of the current management methods.

Primary thrombophilia in Mexico III: A prospective study of the sticky platelet syndrome.

During an 18-month period, 10 consecutive Mexican mestizos with a dinical marker associated with a primary hypercoagulable state were studied. The assessment of the sticky platelet syndrome (SPS) was done by the method described by Mammen. In addition, the activated protein C resistance phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen activator inhibitor type 1, IgG and IgM isotypes of anti-phospholipid antibodies, homocysteine levels, the factor V gene Leiden mutation, the 677 C->T mutation in the 5,10-methylen-tetrahydrofolate-reductase (MTHFR), and the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene were studied. Six patients with the SPS were identified: only one displayed this as the single thrombophilic abnormality; in five others, additional thrombosis-prone conditions were found: heterozygosity for the MTHFR 677 gene mutation in five cases; and, in one case each, heterozygosity for the factor V Leiden mutation, heterozygosity for the factor II G20210A mutation, and antiphospholipid antibodies in another. Four of the six patients had a family history of thrombophilia. All patients were treated with aspirin and no new vasoocclusive episodes have been recorded. SPS in not an infrequent finding in Mexican mestizo thrombophilic patients and may contribute to thrombophilia.

Hypercoagulable states: molecular genetics to clinical practice

Summary Several physiological antithrombotic proteins—including antithrombin, protein C, protein S, tissue factor pathway inhibitor, and components of the fibrinolytic system—act as inhibitors at strategic sites in the coagulation cascade to maintain normal blood fluidity under normal circumstances. The molecular basis of specific inherited hypercoagulable states has been recently elucidated. With the description of resistance to activated protein C, which is the commonest coagulation defect associated with thrombophilia, a specific primary hypercoagulable state can be identified in over 50% of patients with thrombophilia. Although the prevalence in the normal population of some "prothrombotic" mutations is remarkably high, most affected individuals do not have clinical thrombotic complications, so it is likely that clinically apparent hypercoagulable states result from multigene interactions, and that clinical episodes of thrombosis are precipitated by acquired prothrombotic insults in patients with an inherited predisposition to thrombosis.