Venous Thromboemboli Research Articles

Unsuspected Pulmonary Emboli Identified on Routine Cancer Staging MDCT Scans: Impact on Cancer Survival

Background: While symptomatic venous thromboemboli (VTE) clearly have an adverse impact on survival among cancer patients, the outcome of cancer patients with unsuspected pulmonary emboli (PE) found on routine cancer staging multi-row detector CT (MDCT) scans is unknown. In order to evaluate survival among cancer patients with unsuspected PE, we expanded on a previous study (O'Connell, JCO 2006; 24:4928) of such patients.Methods: We performed a retrospective chart review of cancer patients with unsuspected PE found on routine cancer staging MDCT scans between May, 2003 and August, 2006. Two patients matched for age, cancer type and stage (“controls”) were identified for each patient with unsuspected PE (“cases”). Patients with known VTE, patients already receiving anticoagulation for any reason and patients with multiple active cancers were excluded. We recorded cancer characteristics, signs and symptoms typical of PE, risk factors, presence of PE on subsequent staging scans, time to death, and cause of death. We used conditional logistic regression analysis to compare the baseline characteristics. To evaluate the impact of unsuspected PE and other covariates on survival, we used stratified Cox proportional hazard analysis and the logrank test.Results: Seventy patients with unsuspected PE and 137 matched controls were evaluated. There were no significant differences between the groups in terms of matching factors, gender, or sites of metastases. Cases were more likely to have had prior VTE and to have had surgery within the previous 2 months than were controls (p=0.008, p=0.0002, respectively). There were no differences in the time from cancer diagnosis to the index MDCT scan, use of erythropoietin, exposure to chemotherapy, presence of central lines, hormonal therapy or use of antiplatelet medication between cases and controls. As previously reported in the smaller series, cases were more likely to actually have complained to someone on the medical team of shortness of breath and fatigue than were control patients (p =0.0009, p=0.001, respectively); case patients were also more likely than control patients to complain of cough (p=0.019). There were no statistically significant differences in other signs or symptoms such as hypoxia, fever, limb pain or swelling, chest pain or tachycardia. Of the 70 patients with unsuspected PE, 17 (24.3%) had isolated subsegmental clots and 53 (75.7%) had more proximal clots. Fifty-nine of the 70 patients (84.3%) with PE received some form of anticoagulation as treatment. Using a stratified analysis adjusting for the presence of brain, liver and lung metastases and for use of erythropoietin we found that proximal unsuspected PE conferred a hazard ratio for death of 1.79 (95% CI 1.10–2.90, p =0.018) (Kaplan-Meier curves, Figure 1). Symptomatic patients with unsuspected proximal PE, in particular, had poorer overall survival than matched controls (5 months vs. 14 months, p=0.009, logrank test). Use of erythropoietin, metastases to lung, liver or lymph nodes, gender, and active treatment with chemotherapy had no significant impact on survival; brain metastases, however, conferred poorer overall survival (20.5 vs. 61 months, p=0.003) independent of PE.Conclusion: These data support our previous findings in the smaller series that patients with unsuspected PE detected on routine staging MDCT scans are more likely to be symptomatic than are matched control patients, particularly with shortness of breath, fatigue and cough. Unsuspected PE have a significant adverse impact on overall survival among cancer patients; this impact is more pronounced among those patients reporting PE-related symptoms. [Display omitted]

The Future of Medical Therapy for Venous Thromboemboli

The field of medicine has a >30-year experience of prophylactic anticoagulation treatment in surgical patients, especially those with joint replacement and hip fracture. Extensive research to find anticoagulation alternatives beyond the use of unfractionated heparin has resulted in the development of low-molecular-weight heparin and vitamin K antagonist for prophylaxis of venous thromboembolism (VTE). In this article, drug administration regimens, pharmacologic activity, major adverse events, and costs for anticoagulation treatment are reported through a literature review. Clinical trial results are reported to provide the relative risk reduction and clinical benefit considerations in the administration of these drugs. The results show that in the absence of prophylactic treatment, hospital-acquired VTE occurs in approximately 10% to 40% of medical or general surgical patients and 40% to 60% of major orthopedic surgical patients. Patients treated in a major clinical study with the pentasaccharide fondaparinux demonstrated a 12.5% incidence of VTE compared with 27.8% of patients treated with enoxaparin ( P <0.001). Major bleeding occurred in 3.1% of fondaparinux patients versus 0.3% 2 groups in the incidence of bleeding leading to death, reoperation or occurrence in a critical organ. The most recent anticoagulant class of drugs, oral direct thrombin inhibitors dabigatran and rivaroxaban, demonstrate great promise owing to fixed dosages, rapid onset and offset of action, and a predictable anticoagulation effect without coagulation monitoring. Multiple clinical trials are demonstrating efficacy and safety in VTE prevention and treatment. VTE is the leading cause of death in hospitalized patients. Successful prevention of VTE and fatal pulmonary embolism remain a challenge in patients undergoing surgery for hip fracture or joint replacement. The value of appropriate prophylaxis must be emphasized in these patients. Effective anticoagulation with intermittent pneumatic compression remains an underutilized regimen despite studies showing a significant reduction in mortality and morbidity. The newer oral direct thrombin inhibitors show significant promise.

Resolution of venous thrombo-emboli (VTE) with a factor Xa inhibitor: Initial safety and efficacy results of a randomized, phase III trial of anticoagulation plus inferior vena cava (IVC) filter versus anticoagulation alone in patients with cancer and VTE

20544 Background: Cancer-associated thrombosis is a major cause of death in patients (pts) with cancer. The 1-year survival in pts with cancer with VTE is 12% (vs. 36% without VTE). More than 20% of pts have VTE propagation and re-thrombosis on standard therapeutic anticoagulation (AC) (Prandoni 2007). The role of IVC filters in terms of efficacy, safety, prevention of pulmonary embolism (PE), and impact on survival remains controversial. Resolution of DVT takes an average of 6 months in non-cancer pts (Asbeutah 2004) and thrombi remain detectable in half of pts after a year (Kearon 2004). Methods: Pts with malignancy were eligible if they had an acute VTE (DVT and/or PE), and were randomized to standard fondaparinux sodium (FS) alone [5mg SC for pts <50 kg, 7.5mg SC for pts 50–100 kg and 10mg SC for pts >100 kg] vs FS+IVC filter. A total of 106 pts are planned. The primary endpoint is survival without recurrent VTE. Secondary endpoints include safety and clot resolution, given in this report. Due to safety review in pts ≥ 65 yrs, the dose of FS was reduced to 5mg during the conduct of the study. Pts were evaluated q 2 weeks for 4 weeks then q 4 weeks. Results: To date 33 pts were randomized and treated. All have stage IV extent, 94% are on chemotherapy; median age 67 (range 38–89%). Diagnoses include: lung (25%), GI (22%), and breast (19%); 9% have brain metastases. Of pts re-evaluated with DVTs: 15/20, 75% [95% CI: 44–90%] had complete clot resolution at an average of 45 days. Of those with PE: 8/9, 89% [95% CI: 52–100%] had complete clot resolution. Toxicities were more prominent in pts ≥ 65, 1 with marked ecchymosis and 1 with fatal hemorrhage into a brain metastasis. Conclusions: This study is ongoing and remains blinded as to treatment arm; however, current observations are important: 1) complete clot resolution has been observed in many, despite past studies using low molecular weight heparins not reporting such resolution in cancer patients; 2) the factor Xa inhibition may be responsible for this clot resolution effect; 3) the FS was well tolerated and appears safe in those over age 65 at a lower dose. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline

Echocardiography in Cryptogenic Cerebrospinal Abscess

Cerebral abscesses are uncommon in clinical practice but are potentially life-threatening, with an overall mortality rate of 4% despite the introduction of antibiotics and surgery.1 Abscesses are usually associated with a contiguous source of infection (e.g., sinusitis or otitis media), cranial trauma, or hematogenous spread from a distant infectious focus. Cryptogenic cerebral abscesses, however, occur in 15% to 30% of reported cases despite an exhaustive search for infectious sources.2,3 It is recognized that a patent foramen ovale (PFO) can serve as a gateway to the arterial circulation for venous thromboemboli, as a consequence of transient right-to-left shunting from coughing, the Valsalva, and other maneuvers that increase right atrial pressure.

Cryptogenic stroke in patients with patent foramen ovale

Paradoxical embolism through a patent foramen ovale (PFO) is a commonly identified potential mechanism of ischemic stroke, especially in young patients. The recurrent stroke rate among young cryptogenic stroke patients with a PFO is modest, but higher than normal for their age. Co-existing atrial septal aneurysm is a substantial, and the only definite, potentiator of stroke risk in patients with PFO, but PFO size, degree of functional shunting, and co-existing hypercoagulable state likely are additional risk factors. Pelvic CT and magnetic resonance venography have improved our ability to detect source venous thromboemboli and underlie new management strategies. Treatment strategies for PFOs in ischemic stroke patients include antiplatelet agents, anticoagulants, surgical closure, or percutaneous closure devices. The completion of ongoing, randomized clinical trials comparing percutaneous closure devices with medical management is likely to be hastened by the recent withdrawal of humanitarian device exemption approvals, and is urgently needed to clarify if the risks of invasive endovascular device placement are outweighed by a long-term reduction in recurrent vascular events.

Incidence of venous thromboembolic events and effect on survival in patients with lung cancer

18017 Background: Venous thromboemboli (VTE) is a known complication in patients with cancer, however the true incidence and effect on survival in patients with lung cancer is not clear. Methods: We retrospectively reviewed a cohort of 388 patients with lung cancer from 1997 to 2006 seen at the University of Alabama in Birmingham. Results: Median age was 62 and the male (n=227) to female (n=160) ratio was 1.41:1. Small cell lung cancer (SCLC) was the histology in 50 patients (13%) and non small cell lung cancer (NSCLC) in 331 patients (87%). Among NSCLC, the distribution of various subtypes was: 144 (37%) adenocarcinoma, 93 (24%) squamous cell, 7 (2%) large cells and 93 (24%) non-small cell, not otherwise specified(NOS). Metastatic disease was present in 29% (96/337) of NSCLC and extensive disease in 54% (27/50) of SCLC patients. 73% had a performance status of 0/1 and 29% had weight loss ( &gt; 5% body weight). The overall incidence of VTE was 17 % (n=64); 9 patients prior to the diagnosis and 55 patients (86%) during the course of their disease. The incidence of VTE in SCLC was 10% (n=5) and in NSCLC 19% (n=59). VTE events in patients with non-small cell histologies were: 18% in adenocarcinoma, 25% in NSCLC-NOS, and 8% in squamous cell carcinoma. In patients with SCLC the incidence of VTE in limited stage disease (3/23) was similar to extensive stage disease (2/27). In NSCLC, patients with stage 1–3 disease had an incidence rate of 16% (39/241) compared to 21% (20/96) with metastatic disease. The median survival (MS) in SCLC patients with VTE was 21 months and without DVT was 17 months (P = 0.28). The MS in patients with NSCLC with VTE was 15 months and without VTE was 18 months (P = 0.12). Conclusions: There is a high incidence of VTE in patients with both NSCLC and SCLC with a trend to increased incidence in specific histologic subtypes and increased disease burden. Despite the potential anti-neoplastic benefit of anticoagulants there was a minimal difference in overall survival between cohorts, although this study was not designed to evaluate differences in survival. This data supports trials evaluating the role of prophylactic use of anticoagulants as a means to reduce the morbidity/mortality associated with VTE in this high risk population. No significant financial relationships to disclose.

Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): Association with venous thromboembolism

Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHT-affected individuals. In the pilot study, factor VIII (FVIII) and von Willebrand factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p<0.0013, Mann-Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent ill-health, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (AVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), and VTE:VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36-71) years. Four VTE occurred in factorV Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10-132 months from VTE (odds ratio 2.41, 95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. In conclusion, HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in HHT management.

Fixed-dose, weight-adjusted, unfractionated heparin was as effective and safe as low-molecular-weight heparin for venous thromboembolism

Source Citation Kearon C, Ginsberg JS, Julian JA, et al. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboemboli...

2006 Stroke Council Award and Lecture—Patent Foramen Ovale and Stroke: What We Have Learned and What We Still Need to Know

Management of patients with cryptogenic stroke and a patent foramen ovale (PFO) is a common clinical dilemma for cardiologists, neurologists, and primary care physicians and is a rapidly growing public health challenge for society. Between 50 000 and 100 000 Americans each year present with a PFO and an ischemic stroke of otherwise undetermined etiology. Collaborative studies by cardiovascular and cerebrovascular physician-scientists over the past 2 decades have advanced our understanding of the epidemiology, pathophysiology, and management of patients with patent foramen ovale and ischemic brain disease. The recurrent stroke rate among young cryptogenic stroke patients with a PFO is modest but higher than normal for age. Coexisting atrial septal aneurysm is a substantial—and the only definite—potentiator of stroke risk in patients with PFO, but PFO size, degree of functional shunting, and coexisting hyper-coagulable state likely are additional risk factors. Pelvic computed tomographic and magnetic resonance venography has improved our ability to detect source venous thromboemboli and underlies new management strategies. Close analysis of randomized clinical trial results suggests that brain imaging demonstration of a superficial convexity stroke location indicative of a highly probable embolic stroke top may usefully guide the selection of anticoagulation versus antiplatelet therapy in medically managed patients. The completion of ongoing randomized clinical trials comparing percutaneous closure devices with medical management is likely to be hastened by the recent withdrawal of humanitarian device exemption approvals and is urgently needed to provide definitive data to guide management of these patients with a linked disorder of heart and brain.

99mTc-NC100668, a new tracer for imaging venous thromboemboli: pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro

(99m)Tc-NC100668 is a new radiotracer being developed to aid the diagnosis of thromboembolism. The structure of NC100668 is similar to a region of human alpha(2)-antiplasmin, which is a substrate for factor XIIIa (FXIIIa). The purpose of this study was to confirm the uptake of (99m)Tc-NC100668 into forming plasma clot and to establish the biodistribution of (99m)Tc-NC100668 in Wistar rats. The in vitro plasma clot uptake of (99m)Tc-NC100668 and other compounds with known affinities to FXIIIa was measured using a plasma clot assay. The biodistribution and blood clot uptake of radioactivity of (99m)Tc-NC100668 in normal Wistar rats and those bearing experimentally induced deep vein thrombi were investigated. The in vitro uptake of (99m)Tc-NC100668 was greater than that for [(14)C]dansyl cadaverine, a known substrate of FXIIIa in the plasma clot assay. The biodistribution of (99m)Tc-NC100668 in male and female Wistar rats up to 24 h p.i. showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention. In vivo the uptake and retention of (99m)Tc-NC100668 into the blood clot was greater than could be accounted for by non-specific accumulation of the radiotracer within the blood clot. (99m)Tc-NC100668 was retained by plasma clots in vitro and blood clots in vivo. No significant tissue retention which could interfere with the ability to image thrombi in vivo was observed. This evidence suggests that (99m)Tc-NC100668 might be useful in the detection of thromboembolism.

Thromboembolism during Hormone Therapy in Japanese Women

Japanese women are unaccustomed to taking hormone therapies such as oral contraceptives (OCs) and hormone replacement therapy (HRT); therefore, there are few studies associated with hormone treatment in Japan. This study focused on evaluating thromboembolism during hormone therapy in Japanese women. In February 2002, we mailed questionnaires regarding the monthly average number of patients who had received prescriptions for OCs and HRT, and the incidence of arterial and venous thromboemboli during hormone therapy for the last 10 years. The mailings were sent to hospitals and clinics that are registered as monitoring institutions with the Japan Association of Obstetricians and Gynecologists. Of 1083 institutes, 771 responded (71% response rate). In July 2002, to obtain additional information on hormone therapy, patient history, and outcomes, we sent follow-up questionnaires to 39 institutions that responded as having experienced cases of thromboembolism. Thirty-nine institutions (5.1% of institutions responding to survey) experienced 53 cases of thromboembolism during hormone therapy. The 53 patients included 29 who received OCs (OC patients), 13 who received HRT (HRT patients), and 11 who received other hormone treatment. Among the 29 OC patients, eight had been diagnosed as having arterial thromboembolism (ATE), including two patients with myocardial infarction (MI) and six with ischemic stroke, whereas 20 had venous thromboembolism (VTE), including two with pulmonary embolism (PE) The remaining patient had an unknown thromboembolic event. Of the OC patients, 75.9% had a thromboembolism within the first year, and 58.6% patients were in their 40s. In 13 HRT patients, seven had ATE, including two MI patients and three with ischemic brain stroke, whereas six had VTE, including one PE patient. The duration of HRT varied widely from less than 1 year to more than 3 years; moreover, the HRT type did not affect thromboembolism occurrence. More than 70% of ATE patients and less than one third of VTE patients had to be hospitalized for the treatment of thromboembolism, and more than 75% of VTE patients recovered completely. However, one third of the ATE patients recovered with mild sequelae, one OC patient had severe sequelae due to stroke, and another OC patient died due to an ischemic event. The estimated incidence of thromboembolism in OC patients and HRT patients was 3.6 to 14.4 and 1.7 to 3.4 per 100,000 woman-years, respectively. The risk factors of thromboembolism, which were found consistently in this study, included obesity, smoking, lifestyle, and aging. Approximately 95% of institutions had not experienced thromboembolism in their hormone therapy patients, suggesting the incidence of thromboembolism during hormone therapy might be low. However, according to an analysis of risk factors, screening users of hormone supplements may be essential for providing safe hormone therapy. Moreover, because of the early occurrence of thromboembolism during hormone therapy, especially with OCs, it is important to monitor and instruct patients with caution from immediately after therapy initiation.

Diffuse venous thromboemboli associated with IVIg therapy in the treatment of streptococcal toxic shock syndrome: case report and review

Streptococcal toxic shock syndrome (STSS) is a severe invasive disease with a 40-80% mortality rate. Inflammatory cytokines induced by streptococcal pyrogenic exotoxins (SPEs) produce the clinical manifestations of a flu-like syndrome, followed by high fevers and multiorgan failure. Previously published reports have described the use of intravenous immunoglobulin (IVIg) as adjunctive treatment for STSS. However, concerns have been raised about the thromboembolic complications of this therapy. We report a severe case of STSS treated with two adjunctive courses of IVIg complicated by severe bilateral pulmonary thromboemboli. To our knowledge, this is the only reported case of thromboemboli associated with IVIg for STSS. The results of this case support the cautious use of IVIg for STSS and demonstrate the need for controlled trials to determine the appropriate timing, dosage, and course of treatment.

Efficacy of mechanical prophylaxis for venous thromboembolism in patients with brain tumors

Patients with brain tumors are at considerable risk for the formation of venous thromboemboli. One method of preventing these complications is mechanical prophylaxis in which an external pneumatic compression device and graduated elastic compression stockings are used. Evidence indicates that these devices prevent deep venous thrombosis (DVT) and pulmonary embolism (PE) by limiting venous stasis and increasing fibrinolytic activity at both the local and systemic levels. The authors present evidence for the occurrence of both mechanisms and discuss the use of mechanical compression in the setting of surgery for brain tumors. They also present data proving the efficacy of these devices in patients who undergo craniotomy with motor mapping for resection of glioma and in whom the contralateral leg receives no prophylaxis. Finally, they comment on the use of anticoagulation therapy both in addition to and in place of mechanical prophylaxis.

Novel streptokinase nanodevices for enhanced thrombolysis: Preparation, in vitro and in vivo studies

PURPOSE: Venous thromboemboli constitute an increasing problem in children with complex medical problems. The treatment of thromboemboli in children is challenging because unlike in adults, the use of thrombolytics is not well studied and is often associated with bleeding. These risks can be minimized by delivering the thrombolytic agent specifically and directly to the clot. Our objective is to use novel dendritic nanodevices loaded with streptokinase (SK) to achieve enhanced clot lysis. We hypothesize that these nanodevices enhance clot lysis by improving the stability of streptokinase, decreasing its immunogenicity and allowing more effective diffusion of the nanodevice into the clot to deliver the drug.

Medical management of venous thromboembolic disease

Venous thromboembolic disease (deep vein thrombosis and pulmonary embolism) are common disorders with serious morbid and mortal complications. Given the varied modes of presentation, a high clinical index of suspicion in patients at risk must exist among physicians. Standard therapy has consisted of intravenous unfractionated heparin and overlapping administration of an oral Vitamin K antagonist, commonly Warfarin. Although an effective strategy, many practical limitations exist, including the need for prolonged hospitalization, frequent laboratory monitoring for anticoagulant effect, and erratic dose-response curves. Recently, subcutaneous low-molecular-weight heparins have emerged as safe and effective alternatives for unfractionated heparin. Appropriate patients may be treated with low-molecular-weight heparins and oral Warfarin entirely as outpatients, with similar efficacy and risk of recurrent thromboembolic events and hemorrhage. Thrombolytic therapy is a reasonable alternative in patients with iliofemoral venous thrombosis and/or pulmonary embolism resulting in hemodynamic compromise or obstructing significant pulmonary vasculature. Risks of serious hemorrhagic side effects including intracranial hemorrhage, along with the added economic burden, have limited widespread acceptance of thrombolytic therapy as primary treatment. Emerging oral direct thrombin inhibitors and other novel agents stand to move the treatment of patients with venous thromboemboli to even greater levels of safety and efficacy.

Behçet's Disease and Venous Thromboemboli in Childhood

Behçet's Disease and Venous Thromboemboli in Childhood

Magnetic resonance direct thrombus imaging: a novel technique for imaging venous thromboemboli

Invasive testing is now seldom required in patients with suspected venous thromboembolism (VTE). However, a corollary of noninvasive imaging is increased complexity as results are often yielded as probabilities rather than definitive answers and additional testing is frequently required following initial imaging. This creates a milieu in which misunderstandings and protocol violations are common, potentially leading to diagnostic errors. A highly accurate noninvasive imaging technique which allows immediate treatment decisions to be made is needed. Magnetic resonance direct thrombus imaging (MRDTI) is a novel technique which detects methaemoglobin in clot, allowing visualisation of thrombus without using intravenous contrast. It has two major advantages over conventional modalities which identify it as having the potential to fill this role. Firstly, direct visualisation of thrombus overcomes many of the pitfalls of conventional techniques, which have either identified thrombus as a filling defect or in terms of surrogates. Secondly, simultaneous imaging of the legs and chest allows a comprehensive assessment of thrombus load, minimising the importance of overlooked subsegmental pulmonary embolism (PE) and potentially facilitating more titrated treatment. Early data suggest MRDTI is highly accurate for the detection of both deep vein thrombosis (DVT) and PE, and ongoing out-come studies are evaluating the safety of withholding treatment in suspected DVT and PE on the basis of negative MRDTI alone. If favorable, a multi-centre outcome study evaluating cost-effectiveness as well as safety would be justified. Subject to further evaluation, this technique has the potential greatly to simplify and standardise the investigation of suspected VTE.

Fibrinogen bellingham: a gamma-chain R275C substitution and a beta-promoter polymorphism in a thrombotic member of an asymptomatic family.

Congenital dysfibrinogenemia is a rare cause of unexplained thrombosis. However, most individuals with dysfibrinogenemia are asymptomatic, suggesting that co-morbid factors contribute to thrombo-embolic events. The potential roles of additional genetic or acquired prothrombotic risk factors are poorly understood because detailed family studies are lacking. Herein, we describe a family whose propositus was a young Caucasian man with recurrent venous thrombo-emboli and dysfibrinogenemia due to heterozygosity for an Arg-->Cys substitution at residue 275 in the gamma-chain. The only additional thrombophilic abnormality found in the proband was heterozygosity for a G/A transition at position -455 in the fibrinogen beta-chain promoter; a genotype associated with high acute phase levels of fibrinogen. The proband's father, who died of a cerebral artery thrombosis, carried the gammaR275C substitution but not the beta-promoter -455 variant. Among 14 living relatives, eight were heterozygous for one or the other mutation and only one, a 21-year-old niece, was dually affected. None had suffered bleeding or thrombosis. In vitro studies of the proband's purified fibrinogen revealed markedly abnormal thrombin-catalyzed polymerization and delayed fibrin clot lysis by tPA-activated plasmin. We hypothesize that the gammaR275C substitution predisposes to thrombosis by generating clots that are relatively resistant to fibrinolysis. The clinical risk is low, however, in the absence of an additional thrombophilic mutation. The beta-promoter variant could, theoretically, contribute to this risk by augmenting expression of the dysfibrinogen under conditions of stress. Like the common hereditary thrombophilias, heterozygous familial dysfibrinogenemia induces thrombosis in the setting of multiple prothrombotic influences.

Optical detection of triggered atherosclerotic plaque disruption by fluorescence emission analysis.

Fluorescence emission analysis (FEA) has proven to be very sensitive for the detection of elastin, collagen and lipids, which are recognized as the major sources of autofluorescence in vascular tissues. FEA has also been reported to detect venous thromboemboli. In this paper we have tested the hypothesis that FEA can reproducibly detect in vivo and in vitro triggered plaque disruption and thrombosis in a rabbit model. Fluorescence emission (FE) spectra, recorded in vivo, detected Russell's viper venom (RVV)-induced transformation of atherosclerotic plaque. FE intensity at 410-490 nm 4 weeks after angioplasty was significantly lower (P < 0.0033 by analysis of variance) in RVV-treated rabbits when compared to control animals with stable plaque. FE spectral profile analyses also demonstrated a significant change in curve shape as demonstrated by polynomial regression analysis (R2 from 0.980 to 0.997). We have also demonstrated an excellent correlation between changes in FE intensity and the structural characteristics detected at different stages of "unstable atherosclerotic plaque" development using multiple regression analysis (R2 = 0.989). Thus, FEA applied in vivo is a sensitive and highly informative diagnostic technique for detection of triggered atherosclerotic plaque disruption and related structural changes, associated with plaque transformation, in a rabbit model.

Thrombolytic therapy for venous thromboembolism.

The role of thrombolytic therapy for venous thromboembolism remains uncertain. To date, no well-designed randomized clinical trial has shown that the benefits of thrombolysis exceed the risks for a well-defined subgroup of patients with acute pulmonary embolism. Recent reports have underscored the risks of thrombolytic therapy. The largest multinational registry of patients in whom acute pulmonary embolism had been diagnosed found that 3% of 311 patients who underwent thrombolysis for acute pulmonary embolism suffered an intracranial hemorrhage. Because of the serious risk associated with systemic thrombolysis, investigators have continued to study methods that rapidly remove venous thromboemboli while minimizing the risk. Reports of catheter fragmentation combined with thrombolysis as well as catheter-directed thrombolysis are promising, but well-designed clinical trials are needed to clarify the utility of these techniques.