Personal History Of Thrombosis Research Articles

Hormone replacement therapy in women with history of thrombosis or a thrombophilia.

Findings from the Women's Health Initiative (WHI) randomised placebo-controlled trial (RCT) were published at the beginning of this century. They suggested that hormone replacement therapy (HRT) use increased the risk of cardiovascular disease and venous thromboembolism including pulmonary embolism and deep vein thrombosis The findings led to a decline in HRT prescriptions and negative publicity about the use of HRT for women with significant menopausal symptoms. Subsequent studies have shown that the risk of thrombosis with HRT relates to whether estrogen is combined with a progestogen and the route of administration of estrogen. In healthy women with no background medical problems, transdermal hormone replacement is not associated with an increased risk of thrombosis. However, much less is known about the safety of various HRT preparations in women with a high background risk of thrombosis. These cases can often be challenging for clinicians with uncertainties around testing for thrombophilia, use of anticoagulation and striking a balance between the risks and benefits of prescribing HRT. This article will review the mechanism of thrombosis with differing types of HRT and present the evidence from the relevant trials. The article will also present the evidence that specifically relates to women with a personal history of thrombosis or thrombophilia (heritable and acquired) to enable clinicians to better individualise the risk assessment for each woman requesting HRT and understand the role of thrombophilia screening or concomitant anticoagulation in such situations.

Ordering Patterns, Cost, and Utility of Factor V Leiden Testing in an Academic Medical Center

Factor V Leiden (FVL) is one of the most common inherited thrombophilias. It is an autosomal dominant condition, and 99% of individuals with FVL are heterozygous for the variant. Heterozygotes have a mildly increased risk of venous thromboembolism (VTE) compared to non-carriers, with an estimated lifetime risk of 10%. An association between FVL and arterial thromboembolism remains controversial and is likely to be relatively small if present. Although anticoagulation guidelines for VTE published by the American College of Chest Physicians are not affected by the presence or absence of thrombophilia, testing is commonly ordered. FVL in particular is one of the most frequently ordered molecular genetic tests. This testing is costly and may represent an unnecessary healthcare expenditure if it does not affect clinical decision making. This was a retrospective chart review of FVL testing performed at the University of Kansas Medical Center from 7/6/21-7/5/2022. The purpose of the study was to determine FVL testing patterns, cost, impact on clinical decision making, and potential opportunities for quality improvement. FVL screening was obtained in 192 patients during the study period; 21% of testing was obtained inpatient, and 79% outpatient. Hematology ordered testing most frequently overall (46% of the time), followed by cardiology (13%), neurology (12%), and internal medicine (8%). Nineteen (10%) tests were positive, all of which were heterozygous on subsequent gene testing. Additional thrombophilia testing was performed 89% of the time, which was positive in 6 patients (3 with lupus anticoagulant, 3 with heterozygous prothrombin G20210A mutation). Of the 41 tests performed inpatient, 88% were ordered by non-hematology services, and hematology was consulted only 11% of the time prior to testing. Inpatient testing was ordered most frequently by neurology (42%), internal medicine (20%), cardiology and intensive care units (7% each). The most frequent indications for inpatient testing were arterial thrombosis (56%), first venous thrombosis (24%), and recurrent venous thrombosis (10%). Neither anticoagulation type nor duration was change based on results in any of the patients. Regarding outpatient testing, hematology ordered the majority of tests (55%), followed by cardiology (15%), internal medicine, family medicine and surgery (5% each). The most frequent indications were first venous thrombosis (39%), recurrent venous thrombosis (15%), family history without any personal history of thrombosis (11%), and arterial thrombosis (9%). When provoked or unprovoked venous thrombosis was the testing indication, neither duration nor type of anticoagulation was changed in any of the 86 patients. The average charge for FVL testing from hospitals in the Kansas City Area is $119, totaling an estimated $22,848 in charges for the time period reviewed. Given the lack of impact test results had on the duration or type of anticoagulation, the utility of FVL testing appears to be limited in our sample. In particular, FVL testing of inpatients, most often performed for arterial thrombosis by non-hematology services, had no notable impact on patient care. These results suggest that a quality improvement project restricting testing to the outpatient setting and to indications where results would change clinical decision making, would result in significant cost savings. The additional thrombophilia work-up often performed with FVL screening is even more costly, with an average charge of $2500 for protein c, protein s, prothrombin, and anti-thrombin III testing. In addition, given only 3.5% of those tested for additional thrombophilias were found to be positive, investigation into the utility of these tests may also be warranted. This analysis is limited by its retrospective nature and limited follow-up. Future studies based on this data will include quality improvement measures with subsequent re-analysis to determine the effect on test reduction and cost savings.

Relevance of Inherited Thrombophilia Screening in Adult Kidney Transplant Recipients

Thrombophilia has been implicated in posttransplant thrombosis. Data concerning the impact of thrombophilia on thrombotic risk in renal graft recipients are inconclusive. We evaluated whether identification of thrombophilia in patients during pretransplant laboratory screening was a predictor of posttransplant outcomes. We conducted a prospective single-center longitudinal study that included adult recipients who underwent kidney transplant from January 2011 to December 2017. Cardiovascular risk factors, personal history of thrombosis, and data concerning kidney transplant episodes were recorded. Before kidney transplant, all patients were systematically screened for thrombophilia. For thrombophilia screening for antithrombin, protein C, protein S deficiencies, and activated protein C resistance, reagents from Stago were used (Stachrom AT, Staclot Protein C, Staclot Protein S, and Staclot APCR). The endpoint was a thrombotic event within 2 years after kidney transplant. Among 75 end-stage renal disease candidates for kidney transplant, 46 kidney transplant recipients were screened for thrombophilia. Thirty-six of the patients were men. The median age was 37 years (interquartile range, 33-43 years). Renal replacement therapy (36 hemodialysis and 10 peritoneal dialysis) was started in all patients. Forty-five patients received a kidney from a living donor. Among the 46 patients, 4 (9%) had a thrombophilia abnormality (3 with protein C deficiency and 1 with activated protein C resistance). Thrombotic events occurred during the follow-up in 7 cases (15%) with no anterior thrombophilia abnormality; 2 of these concerned the kidney transplant. Only 1 patient had loss of kidney graft immediately after kidney transplant. There was no association between pretransplant thrombophilia and posttransplant thrombotic events. Our results suggest that the utility of universal, comprehensive preoperative thrombophilia testing is not beneficial to determine risk of postoperative thrombosis. Thrombophilia testing may be considered in a select population with a history of pretransplant thrombotic events.

Venous Thromboembolism Prophylaxis with Low-Molecular-Weight Heparin in Primary Central Nervous System Lymphoma

Background: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. Objectives: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. Patients: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005–2017 were included. Results: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0–1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. Conclusions: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.

Incidence of venous thrombosis after peg-asparaginase in adolescent and young adults with acute lymphoblastic leukemia.

Aim:There are limited data describing incidence of symptomatic venous thromboembolism (VTE) in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) patients receiving peg-asparaginase.Materials & methods:Single-institution retrospective analysis of 44 AYA ALL patients treated with peg-asparaginase. Rates of VTE and proposed risk factors were assessed.Results:18 patients (41%) had a symptomatic VTE following peg-asparaginase. The cumulative incidence rate was 25% (95% CI: 13–38%) within 30 days of the initial dose. Personal history of thrombosis was statistically significantly associated with an increased risk of VTE with HR of 2.73 (95% CI: 1.40–5.33, p = 0.003) after adjusting for gender.Conclusion:These data indicate a high rate of VTE in the AYA ALL population following treatment with peg-asparaginase.

Sonographic evolution of the superficial vein thrombosis of the lower extremity.

Superficial venous thrombosis (SVT) is a common clinical problem across various treatment settings. SVT shares risk factors with deep venous thrombosis (DVT) and carries a risk of thromboembolic complications, greater than previously expected. Little is known about the pathophysiology, resolution and recurrence of this disease. The objective of the present study was to describe the natural course of SVT, and factors correlated with the progression or resolution of the thrombus. We included 218 patients with a recent diagnosis of SVT that were consecutively referred to a thrombosis clinic from the Emergency Department (ED) between January 2016 and April of 2018. The resolution of the thrombus prior to discharge was correlated to gender (female 73.8% vs. male 57.5%, p = 0.015), presence of varicose veins (62.4% vs. 46.4, p = 0.026), absence of family or personal history of thrombosis (98% vs. 91.3%, p = 0.021). The factor most correlated to thrombus resolution prior to discharge was the result of the 2nd ultrasound (improvement 83.9% vs. 16.1%, p < 0.001) immediately after initiation of heparin treatment. In the multivariate analysis, a high thrombus burden in the early follow-up ultrasound was the most significant predictive variable with prior to discharge recanalization (B = 20.9, 95% CI 9.8-44.7; p < 0.001). The follow-up of SVT with duplex lower extremity ultrasound allows us to monitor the evolution and early identify residual thrombosis, as a marker of hypercoagulability and recurrence. This study offers new perspectives for future research, necessary to improve the management of this disease, to reduce long-term complications.

P073 RISK STRATIFICATION TO INCREASE VENOUS THROMBOEMBOLISM PROPHYLAXIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

Pediatric patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but are often overlooked for pharmacologic prophylaxis. We instituted a risk-stratification algorithm to identify high-risk patients and offer enoxaparin prophylaxis (EP) aimed at preventing VTE in hospitalized children with IBD flares. We performed a prospective observational quality improvement and patient safety initiative at a large pediatric tertiary care hospital from September 2012 to June 2017. Major risk factor was admission for IBD flare with colonic involvement. Minor risk factors were personal history of thrombosis, first-degree family history of VTE, known thrombophilia, persistent anti-phospholipid antibody >12 weeks, oral contraceptive use, smoking, obesity, thalidomide use, or central venous catheter. The algorithm was incorporated into the electronic medical record (EMR). 458 patients aged 1-27 years (mean 14.6 years, 58.4% male) were admitted 787 times. The electronic risk-stratification algorithm was applied to 234 (29.7%) admissions. Of those, 29 (12.4%) met high-risk criteria and received prophylactic enoxaparin. Forty-three admissions were not screened in the EMR but received VTE prophylaxis, indicating likely use of the posted paper algorithm. Patients assessed with the electronic tool were more likely to receive prophylactic enoxaparin than those who were not screened (p < 0.05). There were 8 total VTE events (7 venous, 1 arterial), 3 of whom were receiving EP. There were no bleeding complications in patients receiving EP. A standardized approach to risk-stratification and EP is important in preventing thrombotic events in pediatric patients with IBD. Risk assessment using our EMR algorithm increased the number of patients who receive thromboprophylaxis. EP is safe for children with active IBD flares.

P073 RISK STRATIFICATION TO INCREASE VENOUS THROMBOEMBOLISM PROPHYLAXIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

Objectives: Pediatric patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but are often overlooked for pharmacologic prophylaxis. We instituted a risk-stratification algorithm to identify high-risk patients and offer enoxaparin prophylaxis (EP) aimed at preventing VTE in hospitalized children with IBD flares. We performed a prospective observational quality improvement and patient safety initiative at a large pediatric tertiary care hospital from September 2012 to June 2017. Major risk factor was admission for IBD flare with colonic involvement. Minor risk factors were personal history of thrombosis, first-degree family history of VTE, known thrombophilia, persistent anti-phospholipid antibody >12 weeks, oral contraceptive use, smoking, obesity, thalidomide use, or central venous catheter. The algorithm was incorporated into the electronic medical record (EMR). 458 patients aged 1-27 years (mean 14.6 years, 58.4% male) were admitted 787 times. The electronic risk-stratification algorithm was applied to 234 (29.7%) admissions. Of those, 29 (12.4%) met high-risk criteria and received prophylactic enoxaparin. Forty-three admissions were not screened in the EMR but received VTE prophylaxis, indicating likely use of the posted paper algorithm. Patients assessed with the electronic tool were more likely to receive prophylactic enoxaparin than those who were not screened (p < 0.05). There were 8 total VTE events (7 venous, 1 arterial), 3 of whom were receiving EP. There were no bleeding complications in patients receiving EP. A standardized approach to risk-stratification and EP is important in preventing thrombotic events in pediatric patients with IBD. Risk assessment using our EMR algorithm increased the number of patients who receive thromboprophylaxis. EP is safe for children with active IBD flares.

Thrombin generation profile in non-thrombotic factor V Leiden carriers.

Factor V Leiden (FVL) mutation is the most common genetic risk factor for venous thromboembolism. In families with a history of thrombosis, FVL can be present in 18%. Thrombin generation test is commonly used as an evaluation tool of thrombotic risk. The objective of this study was to evaluate the thrombogenic potential of FVL in asymptomatic carriers and in patients with personal or familial history of thrombosis. This was a retrospective single center study including 160 patients. Among them, 43 had personal history of thrombosis and 117 had familial history of thrombosis. Thrombin generation (TG) was realized in frozen platelet poor plasma with 1 pM of tissue factor and 4µM of phospholipid. FVL mutation was associated with a global increase of TG. No difference was observed between patients with provoked thrombosis and patients with first-degree familial history of thrombosis (endogenous thrombin potential (ETP): 1501.0 ± 316.4nMmin and thrombin peak: 253.4 ± 71.5nM vs. 1520.4 ± 283.8nMmin and 268.6 ± 68.0nM). An increase of TG was observed in patients with unprovoked thrombosis (n = 23) and in patients with provoked thrombosis (n = 20) (ETP: 1819.5 ± 319.8nMmin and peak: 332.3 ± 55.8nM). In the unprovoked thrombosis group, patients with a pulmonary embolism had a higher ETP than patients with deep vein thrombosis (DVT) (2036 ± 343nMmin vs. 1707 ± 261nMmin). With a predictive score formula (s = 0.1315 × Age + 0.0105 × ETP) with a threshold of 22.1 as risk to develop an unprovoked thrombosis among patients with second-degree familial history. The results of our analysis suggest that measurement of thrombin generation in patients with FVL mutation may identify subjects with an increased risk of unprovoked thrombosis. Further studies are needed to examine the usefulness of predicting thrombotic presentation in asymptomatic carriers.

Low Molecular Weight Heparin (LMWH) for Venous Thromboembolism (VTE) Prophylaxis in Patients with Primary Central Nervous System Lymphoma (PCNSL)

Introduction: Venous thromboembolism (VTE) is a frequent, potentially lethal, complication in patients with cancer. Patients with brain tumors are at a particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma, involving the cranio-spinal axis. The incidence of VTE in patients with PCNSL is as high as 30-60% in various series, occurring mostly in the early period of therapy. Due to this high incidence, the policy in our medical center since the year 2005, is to treat with prophylactic low molecular weight heparin (LMWH) from the time of PCNSL diagnosis until the end of treatment. We aimed to evaluate the incidence of VTE in patients with PCNSL treated with prophylactic LMWH.Material and methods: All patients ≥18 years who were diagnosed and treated for PCNSL in Hadassah-Hebrew University Medical Center between the years 2005-2017 were included in the study. We retrospectively reviewed their medical records for demographic details and initial disease characteristics (age at diagnosis, sex, performance status, laboratory results such as LDH, cerebrospinal fluid content and location of the growth), for details of risk factors for VTE such as diabetes, smoking or heart failure, and for personal or familial history of thrombosis. Therapeutic details including chemotherapy protocol, response to treatment and supportive care were compiled. Specifically we noted if prophylactic LMWH was given, if any complications developed due to the LMWH treatment and whether a VTE event occurred.Results: Forty four patients were included in the study. Mean age at diagnosis was 60.2 years and there were 27 (61%) females. Three (6.8%) patients had a personal history of thrombosis and 13 (29%) had a history of diabetes or smoking. Thirty two (72%) had an ECOG performance study of 0-1 at diagnosis and seven (16%) had leptomeningeal involvement. Forty one (93%) of patients were treated with a systemic high dose methotrexate (HDMTX) based protocol (mean of 7.6 courses of HDMTX per patient) and thirty two (73%) patients were treated with systemic rituximab. All 44 patients were treated with prophylactic LMWH, mostly at a dose of 40 mg per day (41 patients, 93%). Of the 44 patients, five (11%) discontinued treatment; 2 due to side effects (abnormal liver function tests and subdural hematoma (SDH)) and 3 for an unknown reason. Three (7%) patients had a minor bleeding event (gum, conjunctival, Ommaya reservoir catheter tract). One patient (2.3%) had a major bleeding event (SDH) while on LMWH treatment which was found on routine MRI imaging of the brain as he was asymptomatic. No VTE events (0%) were recorded in patients treated with LMWH. Two patients had a VTE, however both patients were off LMWH treatment at the time of VTE (one stopped LMWH, the other was diagnosed with VTE concurrently with the diagnosis of PCNSL).Conclusions: In our group of 44 PCNSL patients, prophylactic use of LMWH was highly effective, with no VTE events. Two cases of VTE occurred in our patient group, both occurred while the patients were off LMWH treatment. Only one, asymptomatic, intracranial bleed was recorded, indicating the relative safety of this treatment in PCNSL patients. Further prospective studies should be done to support the routine use of this prophylactic strategy. DisclosuresNo relevant conflicts of interest to declare.

Procoagulant Profile in Primary Antiphospholipid Syndrome Is Not Dependent upon Increased Inflammatory Response

The association of systemic inflammation and thrombosis in antiphospholipid syndrome (APS) is a matter of debate. The "second hit" theory advocates that the immune-mediated activation of endothelial cells, platelets and monocytes is the stimulus which triggers the initial pathogenesis of APS, while a second stimulus would be necessary for the onset of thrombosis. According to the theory, inflammation and hypercoagulability are not necessarily correlated and the latter would be the result of other associated factors in APS. Further clinical evidences may support that theory, since patients with venous thromboembolism without antiphospholipids (VTE-non aPL) may present an inflammatory state without the aggressive and recurrent thrombotic presentation observed in APS and the presence of systemic autoimmune disease does not worsen the clinical course of thrombosis in APS. The aim of this study is to draw a parallel between the intensity of inflammatory and coagulation responses in thrombotic primary APS (t-PAPS), compared with thrombotic secondary APS (t-SAPS), spontaneous VTE-non aPL and healthy controls. Patients were consecutively selected in the outpatient unit of the Hematology and Hemotherapy Center at the University of Campinas. Clinical data were collected in medical records and interviews with the participants. The markers of inflammation: interleukin (IL)-6, IL-8, TNF-α were measured by commercial ELISA, and high-sensitive hs-CRP by BN ProSpec® Kit. The markers of hemostasis: soluble tissue factor (sTF), von Willebrand factor (vWF) and a desintegrin and metalloprotease thrombospondin motifs (ADAMTS)-13 were measured by commercial ELISA. One hundred and seventy-three patients were included, 71 had t-PAPS, 44 had t-SAPS and 58 had spontaneous VTE-non aPL; 143 patients were women, 57 were men, the median age of patients were 42 years (IQ 29-52). One hundred twenty one controls, without personal history of thrombosis, were included; 88 were women, 33 were men, their median age was 42 years old (IQ 30- 52). Serum levels of the inflammatory markers TNF-α, CRP and IL-6 were higher in the three groups of thrombotic disease (VTE-non aPL, t-PAPS and t-SAPS) compared to controls. IL-8 levels were increased only in patients with t-SAPS, compared to controls. The relative risk (RR) for elevated TNF-α values were 11.9 for VTE, 4.4 for t-PAPS and 6.0 for t-SAPS (p <0.001). RR for increased values of CRP were 1.9 for VTE, 3.5 for t-PAPS and 3.8 t-SAPS (p <0.05). RR for elevated IL-6 levels were 5.8 for VTE, 3.4 for t-PAPS and 4.1 for t-SAPS (p <0.001). Among the coagulation markers, the imbalance between VWF and ADAMTS13 was observed in patients, compared to controls, but levels of VWF and ADAMTS13 activity were similar among the three groups of patients. Compared to controls, higher levels of VWF were equally found in patients with VTE (RR = 1.015; 95% CI = 1.008-1.023), t-PAPS (RR= 1.008; 95% CI= 1.002-1.015) and t-SAPS (RR= 1.010; 95% CI= 1.003-1.018), whereas lower levels of ADAMTS-13 activity were detected in VTE (RR = 0.94; 95% CI = 0.92-0.97 and t-SAPS (RR = 0.98; 95% CI= 0.97-0.99). Patients with t-PAPS and t-SAPS presented higher levels of sTF, compared to controls and VTE (RR = 1.008; 95% CI = 1004-1012 and RR= 1.011; 95% CI= 1.007-1.015, respectively). sTF values in patients with VTE were similar to controls. The adjustment for confounders (age, sex, BMI and comorbidities such as hypertension, dyslipidemia and diabetes) did not influence the estimated relative risks. Among patients with APS, levels of sTF correlated weakly with the levels of TNF-α (r=0.308, P=0.001) and IL-6 (r=0.315, P=0.001). Other inflammatory and coagulation markers did not present any statistical correlation. In conclusion, we observed that t-PAPS patients have an exacerbated inflammatory response when compared to controls, but the level of inflammation is similar to that observed in patients with spontaneous VTE-non aPL and t-SAPS. Despite the similar levels of inflammation, the procoagulant profile in t-PAPS, detected by sTF, was higher than in non-immune thrombosis. The results suggest that inflammation in t-PAPS may not be distinct from that observed in other non-immune thrombotic disorders, whereas the exacerbation of procoagulant stimulus seems to be more evident in t-PAPS than in non-immune VTE. Furthermore, we postulate that risk factors beyond inflammation may be related to the hypercoagulability detected in t-PAPS. DisclosuresNo relevant conflicts of interest to declare.

Home parenteral nutrition‐associated thromboembolic and bleeding events: results of a cohort study of 236 individuals

Essentials Sparse or outdated studies focus on thrombotic and bleeding risk in home parenteral nutrition (HPN). 236 HPN patients followed at a single center for a total of 684 patient-years were evaluated. Rates of venous thrombosis and major bleeding, and prevalence of vena cava syndrome are provided. Anticoagulants might reduce thrombosis risk, but population-specific safety concerns remain. Background Home parenteral nutrition (HPN) is necessary for patients with intestinal failure. Recurrent catheter-related thrombosis (CRT) is common, leading to infectious complications, pulmonary embolism, vascular access loss and intestinal transplantation. The efficacy and safety of anticoagulants are unknown in this setting and based on sparse and low-quality observational data. Objectives Our aim was to estimate the incidence of thromboembolic, bleeding and anticoagulant-related complications in HPN patients, and evaluate risk factors for first venous thrombosis (VT). Methods This retrospective cohort study included all adult patients followed for long-term HPN at our center between 1986 and 2014. Primary outcomes were symptomatic objectively diagnosed VT, encompassing CRT and venous thromboembolism, and major bleeding. Secondary outcomes were vena cava syndrome and heparin-induced thrombocytopenia or hypersensitivity. Results A total of 236 patients were included (median HPN duration, 17 months) and 136 received anticoagulants at HPN onset (57.6%). Overall, the annual incidence of first VT was 11.4% (95% confidence interval [95% CI], 8.6-14.7%); VT was associated with a personal history of thrombosis (adjusted hazard ratio, 2.22; 95% CI, 1.06-4.64), whereas anticoagulation seemed to account only for a mild protection (adjusted hazard ratio, 0.72; 95% CI, 0.36-1.44). The annual incidence of major bleeding was 4.3% for patients on anticoagulants vs. 1.8% for those off anticoagulants. Vena cava syndrome developed in 20.7% of patients with VT. One patient had isolated heparin-induced thrombocytopenia (0.6%) and four had heparin hypersensitivity (2.5%). Conclusions Patients on HPN have a significant risk of venous thrombosis, major bleeding and vena cava syndrome. Anticoagulants might reduce thrombosis risk, but population-specific safety concerns remain.

Infections et thromboses veineuses en pédiatrie : analyse d’une série de 24 cas

Venous thromboembolism disease (VTE) is rare in children (5.3 of 10,000 hospitalized children). However, morbidity and mortality are high, especially when the child is already suffering from severe sepsis. We report an analytical study of 24 cases of deep venous thrombosis occurring in children during infection, recorded at the Montpellier University Hospital between 1999 and 2009. Many parameters were studied in each population (age, sex, familial and personal history of thrombosis, history of thrombophilia, the presence of a venous catheter, a causative organism, time to onset of thrombus, topography of lesions, acquired abnormalities of hemostasis, and thrombosis prophylaxis). The children were aged from 1 day of life to 16 years. Thromboses occurred in two clinical contexts: "contact" thrombosis (which appeared near the infection) and disseminated thrombosis. This is an early complication because in most of the cases, it appeared in the first 10 days of sepsis. Infection and coagulation appear to be closely related and the states of latent or decompensated disseminated intravascular coagulation are common. Nevertheless, it is not possible to predict the occurence of a thrombotic event. The presence of risk factors (venous catheters, acquired thrombophilia, or constitutional thrombophilia) may increase the thrombogenic potential of the infection. VTE should always be suspected and sought in case of an unfavorable clinical course, and routine prophylaxis of thrombosis during sepsis should be discussed.

Prevalence of hereditary antithrombin mutations is higher than estimated in patients with thrombotic events

Antithrombin is the major inhibitor of blood coagulation, primarily inactivating thrombin and factor Xa. Inherited antithrombin deficiency is associated with an increased risk of thromboembolism. Its prevalence is estimated to be about 0.2% in the general healthy population, whereas it is 2% in patients with a history of thrombosis. We previously demonstrated thrombosis patients receiving therapeutic dosage of low-molecular-weight heparin having a lower antifactor Xa activity than originally estimated. In those patients, mutations in the AT gene (SERPINC1) were detected despite normal antithrombin activity. Thus we concluded that prevalence of antithrombin mutations might be higher than previously calculated. The aim of the present study was to investigate the prevalence of hereditary antithrombin mutations by analyzing the antithrombin gene in patients with a history of thromboembolism. Mutation analyses were performed by direct sequencing of SERPINC1 in 150 patients (aged <40 years) with thromboembolism and normal antithrombin levels. Patients with thrombophilic defects [factor V Leiden (G1691A), prothrombin (G20210T) mutation, protein C deficiency, protein S deficiency, and antiphospholipid antibodies] were excluded. The results were compared with those of 150 healthy controls without any personal history of thrombosis. Mutation analyses of all seven antithrombin exons revealed five (3.5%) patients with antithrombin mutations: three different heterozygous missense mutations were found in exon 2 and one (in two patients) in exon 7. Prevalence of inherited antithrombin mutations in thrombosis patients is higher than previously estimated. Functional antithrombin tests are unable to detect all clinically relevant antithrombin defects.

Risk of recurrence of unusual site venous thromboembolism

The term unusual site venous thrombosis defines uncommon clinical manifestations of venous thromboembolism occurring in sites different from the lower limbs or the lungs, with peculiar pathophysiological features and clinical history. Information on long-term outcomes of unusual site thrombosis is generally scant, because most studies are small and usually retrospective. Recurrence rate of cerebral vein thrombosis is about 2/100 patient-years; the only identified predisposing factors have been male gender and personal history of thrombosis. Retinal vein occlusion showed a recurrence in the same eye of 2.5% and in the fellow eye of 11.9% within four years. Hypercholesterolemia, hypertriglyceridaemia and hyperhomocysteinaemia were significantly associated with recurrent events. Recurrence rates of splanchnic vein thrombosis are difficult to estimate given the heterogeneity of patient populations; higher recurrence rates are reported in the cirrhotic population (from 27% to 38.5%). Hormone therapy, myeloproliferative neoplasm or other prothrombotic states, and absence of anticoagulant therapy emerged as independent prognostic factors. Future studies should aim at better assessing the risk of recurrence in different patients subgroups and at identifying more accurate prognostic markers.

Management of Deep Vein Thrombosis of the Upper Extremity

Case 1: A 34-year-old previously healthy male office manager was admitted with acute onset of heaviness, pain, and functional impairment of his right arm. The arm was cyanotic and massively swollen (Figure 1). For the past weeks, he reported transient paresthesia of his right arm during overhead activities and was unable to perform repetitive or strenuous arm exercise. He had a fracture of the right clavicle after a ski accident 5 years previously. The fracture was managed conservatively. There was no personal or family history of thrombosis. Conventional phlebography confirmed axillary and subclavian vein thrombosis (Figure 2, top), and treatment with intravenous unfractionated heparin was started. Figure 1. Clinical presentation of case 1 with massive swelling and cyanosis of the right arm (left). One day after pharmacomechanical thrombolysis, signs of thrombosis have markedly improved (right). Figure 2. Baseline digital subtraction venogram from case 1 with extensive filling defects in the axillary subclavian veins (top). Control venogram after 15 hours of pharmacomechanical thrombectomy confirmed resolution of filling defects and restored venous flow (middle). Positional venography obtained during abduction of the right arm confirmed the venous thoracic outlet syndrome with residual stenosis of the subclavian vein at the costoclavicular junction (white arrow, bottom). Case 2: A 55-year-old man with lung cancer presented with swelling, heaviness, and pain in his left arm 1 week after completion of chemotherapy administered via a left-sided indwelling central venous catheter. Axillary and subclavian vein thrombosis was confirmed by ultrasonography. Low-molecular-weight heparin (LMWH) was initiated, and the catheter was removed 3 days later because it was no longer functional. At 1 week, pain and functional impairment had not improved, and the circumference of the left upper arm had increased by 2 cm. Case 3: A 65-year-old woman with metastatic ovarian cancer presented with swelling of the face and both arms, headache, …

Genetic prothrombotic factors in children with otogenic lateral sinus thrombosis

Lateral sinus thrombosis (LST) is an uncommon, but life-threatening complication of both acute and chronic otitis media. There is some evidence that acquired or hereditary prothrombotic disorders are risk factors for LST. The aim of this work was to evaluate the role of thrombotic screening, anticoagulant therapy or prophylaxis in patients with either acute or chronic otitis media and LST. The medical records of five children hospitalized at Pediatric Hospital Bambino Gesù of Rome because of acute or chronic otitis media complicated by mastoiditis and LST were reviewed. All children underwent laboratory workup for hypercoagulability. All the five children were found to be heterozygote for the C677T MTHFR mutation and a child presented also heterozygosity for factor V Leiden mutation. They have been successfully treated with anticoagulant therapy without sequels. Children with acute or chronic otitis media may have a prothrombotic tendency that becomes clinically evident because of the inflammatory state. Patients with a family and/or personal history of thrombosis and/or thrombophilic conditions need anticoagulant prophylaxis also in the absence of clear signs of LST. Treatment with low molecular weight is successful in patients with LST.

Hormonal Contraception and Thrombotic Risk: A Multidisciplinary Approach

Heightened publicity about hormonal contraception and thrombosis risk and the publication of new guidelines by the World Health Organization in 2009 and the Centers for Disease Control and Prevention in 2010 addressing this complex issue have led to multidisciplinary discussions on the special issues of adolescents cared for at our pediatric hospital. In this review of the literature and new guidelines, we have outlined our approach to the complex patients referred to our center. The relative risk of thrombosis on combined oral contraception is three- to fivefold, whereas the absolute risk for a healthy adolescent on this therapy is only 0.05% per year. This thrombotic risk is affected by estrogen dose, type of progestin, mechanism of delivery, and length of therapy. Oral progestin-only contraceptives and transdermal estradiol used for hormone replacement carry minimal or no thrombotic risk. Transdermal, vaginal, or intrauterine contraceptives and injectable progestins need further study. A personal history of thrombosis, persistent or inherited thrombophilia, and numerous lifestyle choices also influence thrombotic risk. In this summary of one hospital's approach to hormone therapies and thrombosis risk, we review relative-risk data and discuss the application of absolute risk to individual patient counseling. We outline our approach to challenging patients with a history of thrombosis, known thrombophilia, current anticoagulation, or family history of thrombosis or thrombophilia. Our multidisciplinary group has found that knowledge of the guidelines and individualized management plans have been particularly useful for informing discussions about hormonal and nonhormonal options across varied indications.

Thrombophilia and the risk of thromboembolic events in women on oral contraceptives and hormone replacement therapy

Thrombophilia contributes to the risk of thrombosis in women using female hormones. The objective of the present study was to evaluate the prevalence of thrombophilia in women with thromboembolic events (TEEs) using oral contraceptives or hormone replacement therapy (HRT) and assess the contribution of a family history and the duration of hormone use in predicting thrombosis. A retrospective analysis was performed of the case records of women who developed a TEE while on oral contraceptives or HRT and were referred for thrombophilia evaluation over a 4-year period. Among 85 women who developed a TEE while on oral contraceptives or HRT, 65 had at least one additional thrombophilia risk factor. Of the 85 cases, 23 tested positive for more than two thrombophilias, 16 had factor V Leiden, five had the prothrombin gene G20210A polymorphism, 26 had antiphospholipid antibodies, 10 had elevated homocysteine, four had protein C deficiency, and seven had protein S deficiency. There were 64 TEE: 16 pulmonary emboli, 17 cerebrovascular events, 11 intra-abdominal thromboses, 13 deep venous thromboses, five cases of superficial thrombophlebitis, and two retinal vein thromboses. Of the 65 women, 37% had a positive family history of thrombosis. Approximately half of the women had been taking oral contraceptives or HRT for more than 1 year. There is a high prevalence of thrombophilia in women who developed a TEE while using oral contraceptives or HRT for more than 1 year. Family and personal history of thrombosis should be carefully evaluated in all women before initiating or continuing oral contraceptives or HRT, and a positive history may warrant a thrombophilia screening.

Hemostasis and Thrombosis Centers Pilot Sites Registry: Thrombophilia Evaluation in Children.

A family history (FH) of thrombophilia may prompt a referral to a pediatric thrombophilia clinic. The International Society of Thrombosis and Haemostasis recommends a step-wise thrombophilia evaluation for children with venous thrombosis, but there are no screening recommendations for asymptomatic children with a FH of thrombophilia. There is limited data on how many children are evaluated by a pediatric hematologist for a FH of thrombophilia or how these children are managed. We utilized the Centers for Disease Control and Prevention (CDC) Thrombosis and Hemostasis Centers Pilot Sites Registry to characterize children without a personal history of thrombosis who are referred to Thrombosis Centers (TCs). The CDC initiated the registry between eight TCs, including four pediatric sites. We queried the database for pediatric subjects, who enrolled in the registry between August 2003-March 2006. Data collection included referral patterns, laboratory and radiological tests ordered, diagnosis, and treatments. Three hundred thirty-two subjects were identified, ages 0–17 years (average 9 years). Fifty-five (16.6%) have no personal history of thrombosis. Among the 55 asymptomatic children 4 (7.3%) were referred exclusively for a FH of thrombosis without thrombophilia, 12 (21.8%) were referred exclusively for a FH of thrombophilia without a FH of thrombosis, 11 (20.0%) were referred for a FH of both thrombosis and thrombophilia, and 28 (50.9%) did not have a FH of thrombosis or thrombophilia. The latter subjects may have been referred to the TCs for anticoagulation management or for evaluation of a condition associated with thrombophilia such as migraine. No asymptomatic subjects were referred from the in-patient setting, 48 (87.3%) were referred from the out-patient setting, and 7 (12.7%) were self-referred. Of the 55 asymptomatic children, 19 (34.5%) were referred with a prior diagnosis of thrombophilia. Table 1 compares testing at the TCs of symptomatic and asymptomatic subjects. Three asymptomatic subjects with a FH of thrombosis and thrombophilia received anticoagulation prophylaxis, and 3 subjects received a recommendation for prophylaxis for future high risk situations. In summary, 16.6% of children enrolled in the CDC registry have no personal history of thrombosis. A significant proportion of these asymptomatic children have testing for prothrombotic risk factors prior to referral and at the TCs. We are conducting research to determine who and when to screen for thrombophilia, potential complications of such testing, when to provide genetic counseling, and optimal clinical application of the results.Thrombophilia Testing at Pediatric Thrombosis Centers% subjects tested forGenetic testsAnticoagulants/Antiphospholipid antibodiesClotting factorsScreening testsLipids/HomocysteineAll (n=332)42.554.843.756.636.5Symptomatic (n=277)38.652.744.057.832.1Asymptomatic (n=55)61.865.541.850.958.2Among asymptomatics with:FH of thrombosis (n=4)10010025100100FH of thrombophilia (n=12)757541.741.758.3FH of thrombosis and thrombophilia (n=11)72.763.627.336.481.8No FH (n=28)46.457.15053.642.9