intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery. Int Angiol. 2008;27(6):500-506. 79. Czechanowski B, Heinrich F. [Prevention of venous thrombosis in recent ischaemic cerebrovascular accident: double-blind study with heparin-dihydroergotamine (author’s transl)]. Dtsch Med Wochenschr. 1981;106(39):1254-1260. 80. McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low-dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet. 1977;2(8042):800-801. 81. Warlow C, Ogston D, Douglas AS. Venous thrombosis following strokes. Lancet. 1972;1(7764):1305-1306. 82. Moser KM, LeMoine JR, Nachtwey FJ, Spragg RG. Deep venous thrombosis and pulmonary embolism. Frequency in a respiratory intensive care unit. JAMA. 1981;246(13):1422-1424. 83. Emerson PA, Marks P. Preventing thromboembolism after myocardial infarction: effect of low-dose heparin or smoking. Br Med J. 1977;1(6052):18-20. 84. Handley AJ. Low-dose heparin after myocardial infarction. Lancet. 1972;2(7778):623-624. 85. Nicolaides AN, Kakkar VV, Renney JT, Kidner PH, Hutchison DC, Clarke MB. Myocardial infarction and deep-vein thrombosis. Br Med J. 1971;1(746):432-434. 86. Warlow C, Terry G, Kenmure AC, Beattie AG, Ogston D, Douglas AS. A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet. 1973;2(7835):934-936. 87. Prescott SM, Richards KL, Tikoff G, Armstrong JD, Jr, Shigeoka JW. Venous thromboembolism in decompensated chronic obstructive pulmonary disease. A prospective study. Am Rev Respir Dis. 1981;123(1):32-36. 88. Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acute exacerbation of chronic obstructive pulmonary disease. Respiration. 1998;65(3):173-177. 89. Oger E, Bressollette L, Nonent M, et al. High prevalence of asymptomatic deep vein thrombosis on admission in a medical unit among elderly patients. Thromb Haemost. 2002;88(4):592-597.

Despite contemporary developments in pharmacology and biomedical engineering, venous thromboembolism (VTE) is not fully preventable and thus still remains a serious complication of trauma, surgery, and medical conditions. Current and previous guidelines recommend risk stratification to tailor implementation of prophylactic methods so that combined modalities are recommended based on supportive evidence in high-risk patients, although cost and potential adverse events make them less effective for low-risk groups. The reason for the increased efficacy of combined modalities is based on the multifactorial etiology of VTE as first described by Rudolph Virchow in the 19th century. Physical methods reduce venous stasis while pharmacological methods affect hypercoagulopathy. The fact that combined modalities are more effective than single modalities was first shown by Borow in 1983 followed by several studies supporting this concept. Although elastic stockings are effective in reducing further VTE rates achieved by perioperative antithrombotic prophylactic pharmacotherapy, as indicated in several places in this document, most modern studies have evaluated the role of the combination of intermittent pneumatic compression (IPC) with pharmacological methods, and this will be the focus of this section. A recent Cochrane review evaluated the efficacy of combined modalities (IPC) and pharmacological prophylaxis: treatment group) against single modalities alone (control group) to prevent pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients at high risk of VTE. A total of 11 studies that included 7431 patients were identified, of which 6 were randomized-controlled trials (RCTs). The studies evaluated orthopedic patients (n 1⁄4 6), urology patients (n 1⁄4 2), and general surgery, cardiothoracic, and gynecology patients (n 1⁄4 3). Compared to compression alone, combined modalities significantly reduced the incidence of both symptomatic PE (from about 3% to 1%; odds ratio [OR] 0.39; 95% confidence interval [CI] 0.25-0.63) and DVT (from about 4% to 1%; OR 0.43; 95% CI 0.24-0.76). Compared to pharmacological prophylaxis alone, combined modalities significantly reduced the incidence of DVT (from 4.21% to 0.65%; OR 0.16; 95% CI 0.07-0.34). The studies were underpowered with regard to PE. The comparison of compression plus pharmacological prophylaxis versus compression plus aspirin showed a nonsignificant reduction in PE and DVT in favor of the former group. Repeat analysis restricted to the RCT confirmed the above findings. The additive role of mechanical and pharmacological modalities suggests that venous stasis and hypercoagulopathy are independent pathogenetic risk factors. The IPC reduces venous stasis by producing active flow enhancement and also increases tissue factor pathway inhibitor plasma levels. The results of the above meta-analyses endorse a recommendation that high-risk patients should receive multimodal prophylaxis. Although most patients who used combined modalities in the studies reviewed were considered to be at high risk of developing VTE, future studies on this topic should use the most recent and validated criteria to define the high-risk patient.

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The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

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Deep vein thrombosis (DVT) and pulmonary embolism (PE) are major health problems with potential serious outcomes. Acute PE may be fatal. Pulmonary hypertension can develop in the long term from recurrent PE. Often overlooked is postthrombotic chronic venous disease occurring as a result of DVT causing deep venous reflux or obstruction, with skin changes and ulceration causing an adverse impact on quality of life and escalation of health care costs. In North America and Europe, the annual incidence is approximately 160 per 1 00 000 for DVT, 20 per 1 00 000 for symptomatic nonfatal PE, and 5 per 1 00 000 for fatal autopsy-detected PE. The prevalence of venous ulceration is at least 300 per 1 00 000 and approximately 25% are due to DVT. Estimates of the overall annual costs of cumulative volume index vary from 600 to 900 million € (US$720 million-1 billion) in Western European countries, representing 1% to 2% of the total health care budget, to 2.5 billion € (US$3 billion) in the United States. Virchow triad of factors that predispose to venous thromboembolism (VTE) are venous stasis, alterations in blood constituents, and changes in the endothelium; these are as true today as when postulated in the 19th century. Principal clinical predisposing factors are immobilization, trauma, surgery, malignancy, and previous history of venous thrombosis. Other predisposing factors are age, obesity, infection, the postpartum period, varicose veins, dehydration, and hormone therapy. In the background for all of these is predisposition due to thrombophilia. Patients admitted to hospital, surgical or medical, are particularly at risk of VTE and the problem continues after discharge. 28 Without prophylaxis, the incidence of DVT is high and depends, among others, on age, number of risk factors, and type and duration of surgery. The annual number of VTE-related deaths in 6 European countries has been estimated as 3 70 000 and three-fourth of these was from hospital-acquired VTE. Although VTE is an appealing target for maximally effective prevention, there is still a low rate of appropriate prophylaxis worldwide, particularly for acute medically ill patients. Continuing efforts to educate combined with hospital-wide protocols, local audits for VTE prevention, electronic alerts, and use of clinical nurse specialists have been shown to result in a marked increase in appropriate application of guidelines. The use of electronic medical alerts is particularly effective.

factors associated with retrobulbar/peribulbar block: a prospective study in 1383 patients. Br J Anaesth. 2000;85(5):708-711. 19. Hirschman DR, Morby LJ, Hirschman DR, Morby LJ. A study of the safety of continued anticoagulation for cataract surgery patients. Nursing Forum. 2006;41(1):30-37. 20. Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001;135(6):393-400. 21. O’Donnell MJ, Kearon C, Johnson J, et al. Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin. Ann Intern Med. 2007; 146(3):184-187. 22. Woods KDJ, Kathirgamanathan K, Yi Q, Crowther MA. Lowdose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin. 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Costs and clinical outcomes associated with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging in patients receiving long-term oral anticoagulant therapy. Chest. 2004; 125(5):1642-1650. 28. Spyropoulos AC, Turpie AG, Dunn AS, et al. Perioperative bridging therapy with unfractionated heparin or low-molecularweight heparin in patients with mechanical prosthetic heart valves on long-term oral anticoagulants (from the REGIMEN Registry). Am J Cardiol. 2008;102(7):883-889. 29. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004;164(12):1319-1326. 30. Jaffer AK, Brotman DJ, Bash LD, Mahmood SK, Lott B, White RH. Variations in perioperative warfarin management: outcomes and practice patterns at nine hospitals. Am J Med. 123(2):141-150. 31. Hammerstingl C, Tripp C, Schmidt H, et al. 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Review of 6,000 patient records from our laboratory showed 609 individuals who received continuous intravenous infusion heparin therapy for thromboembolic disease. 40/609 (6.5%) of these patients were found to have a platelet count of less than 150,000 cell/mm . Of this group, 34/40 (85%) exhibited thrombocytopenia prior to heparin therapy that was attributable to consumptive coagulopathy in 21/40 (52.5%), sepsis or malignancy in 11/40 (27.5%), and cimetidine or sulfisoxazole in 2/40 (5%). Heparin therapy had no adverse effect on the platelet count in these individuals, and the count returned to normal in surviving individuals if the underlying cause was successfully treated or the offending drug removed. Only 6/40 (15%) of the patients developed low platelet counts during the course of heparin therapy; this represents 6/609 (0.98%) of the population receiving heparin. The etiology of thrombocytopenia in 5/6 (83%) of the cases was traced to metastatic cancer (3), burn wound sepsis (1), and septic shock (1). Only 1/609 (0.16%) of these patients developed low platelet count that could be attributed to heparin. Thus, the incidence of heparin-induced thrombocytopenia is extremely rare in our hospital population.

We agree with Buimeret al. [1Buimer M. Lok C.A.R. Nieuwland R. Ris C. Van Der Post J.A.M. Placental corticotrophin‐releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal.J Thromb Haemost. 2008; 6: 1837Abstract Full Text Full Text PDF Google Scholar] that the total number of microparticles in maternal plasma is not a measure of placental shedding of debris. We made our view clear in the discussion of our article [2Freeman D.J. Tham K. Brown E.A. Rumley A. Lowe G.D. Greer I.A. Fetal corticotrophin‐releasing hormone mRNA, but not phosphatidylserine‐exposing microparticles, in maternal plasma are associated with factor VII activity in pre‐eclampsia.J Thromb Haemost. 2008; 6: 421-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] that ‘the total microparticle population (in maternal plasma) comprises a mixture of fetal and maternal‐derived microparticles and is not a specific marker of placental debris.’ We did not claim that the overall procoagulant activity of total microparticles was specific for placenta‐derived microparticles and stated ‘our prothrombinase assay would detect total PS‐exposing microparticles and would be unable to distinguish between fetal and maternal‐derived material.’ While the letter of Buimeret al. [1Buimer M. Lok C.A.R. Nieuwland R. Ris C. Van Der Post J.A.M. Placental corticotrophin‐releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal.J Thromb Haemost. 2008; 6: 1837Abstract Full Text Full Text PDF Google Scholar] refers to our study as measuring the number or concentration of microparticles, this is not the case. Our interest in microparticle prothrombinase activity, and fetal CRH mRNA, in maternal plasma was in their interaction with the maternal coagulation system. We did not suggest that either measure would be a useful marker for placental dysfunction. Proteins are not the only molecules of interest with biological activity on the microparticle membrane. In the process of apoptosis, phosphatidyl serine molecules, which normally reside in the inner leaflet of the cell membrane, flip over to the outer leaflet. This alerted us to the possibility that the exposed PS could act as a platform for assembly for coagulation factors. Rather than using FACS to identify the number of microparticles, we used the prothrombinase assay, which is dependent on the expression of PS molecules on the surface of the microparticles; hence our reference in the article to ‘phosphatidylserine‐exposing microparticles’ and our unit of measurement of nm PS equivalents [2Freeman D.J. Tham K. Brown E.A. Rumley A. Lowe G.D. Greer I.A. Fetal corticotrophin‐releasing hormone mRNA, but not phosphatidylserine‐exposing microparticles, in maternal plasma are associated with factor VII activity in pre‐eclampsia.J Thromb Haemost. 2008; 6: 421-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Because we are not measuring actual numbers of microparticles but relating their biological activity to measures of coagulation activation in the same sample, hemoconcentration is not a concern. These phosphatidylserine‐exposing microparticles may represent yet another subset of the total microparticle population but one that can be identified by its biological activity. We do state that we consider fetal CRH mRNA levels in maternal blood to be one measure of placental debris. CRH is made by cytotrophoblasts. Placental CRH mRNA is subject to upregulation in situations of fetal stress and placental dysfunction. There appears to be little doubt that fetal CRH mRNA expression is upregulated in pre‐eclampsia, as indicated by a number of cDNA array experiments; see, for example, Nishizawaet al. [3Nishizawa H. Pryor‐Koishi K. Kato T. Kowa H. Kurahashi H. Udagawa Y. Microarray analysis of differentially expressed fetal genes in placental tissue derived from early and late onset severe pre‐eclampsia.Placenta. 2007; 28: 487-97Crossref PubMed Scopus (0) Google Scholar]. Therefore, as Buimeret al. point out, we cannot discount the possibility that our observation of increased fetal CRH mRNA levels may result from no change in shedding of placental debris but that each ‘package’ of debris contains more copies of CRH transcript. This could potentially confound our observed relationship between fetal CRH mRNA and factor VIIa activity. However, if fetal CRH mRNA was merely a non‐specific marker for the presence of a pre‐eclamptic placenta, we might have expected to observe a relationship between fetal CRH mRNA and other circulating markers that are well known to be associated with pregnancies complicated by pre‐eclampsia, such as markers of endothelial activation. We did not observe this. The authors state that they have no conflict of interest.

Objective The preterm birth rate in Scotland has been increasing in recent years. Although preterm birth rates show a social gradient, it is unclear how this gradient has been affected by the overall increase. We examined time trends in singleton live preterm birth rates in relation to area-based socio-economic indicators.Design Population-based retrospective cohort study.Setting Scotland.Participants All singleton live births delivered in Scottish hospitals between 1980 and 2003 (n = 1 423 993).Main outcome measures Singleton live preterm birth rates in each deprivation quintile were derived. Subgroup analyses of those born moderately preterm (32-36 weeks), very preterm (28-31 weeks) and extremely preterm (24-27 weeks) were performed.Results The rate of singleton live preterm births increased from 49.7 per 1000 live births in the 5-year period 1980-84 to 56.1 per 1000 in the 4-year period 2000-03, a relative increase of 12.9%. A marked social gradient was apparent at all time periods: relative indices of inequality were 1.63 (95% CI 1.38-1.92) in 1980-84 and 1.55 (1.44-1.66) in 2000-03. Similar social gradients existed for all gestational age subgroups. Smoking status at first antenatal contact and increased obstetric intervention, possibly reflecting improvements in fetal monitoring and neonatal care, appeared to explain some but not all the social gradient.Conclusions Social inequalities in preterm birth were apparent in Scotland between 1980 and 2003. In addition to helping pregnant women to stop smoking, other means to reduce social inequalities are required.