بسم الله الرحمن الرحيم ،
سؤالي هذا موجه للدكتور نبيل المحترم وانا اشكره لأنه ساعد الكثيرين من أعضاء المنتدى وأرجو أن يعذرني أن كنت ساطيل قليلاً في الشرح.......
أنا متزوجة من سبع سنوات ونصف ولدي بنت عمرها ست سنوات ونصف وولد عمره أربع سنوات ووزني 65 كغم وطولي 167 ، المهم قبل سنة تورمت قدمي من عند الركبة لحد الأصابع ( اليسرى) وراجعت الطبيب العام المعتمد للتأمين الصحي الذي قام بتحويلي لأخصائي جراحة والطبيب قال انه عندي دوالي لكن غير ظاهرة وللعلم لا توجد لدي عروق الدوالي التي أراها عند السيدات وطلب مني ان اتجه للمستشفى لعمل صورة تلفزيونية لأنه اعتقد أن عندي جلطة في رجلي المهم عملت الصورة وما طلع عندي جلطة والحمدلله وكتب لي على دواء مثل الأسبرين كل يوم حبة ودهون ومضاد حيوي ، النتيجة أن الورم خف قليلاً في الشتاء ولم يذهب تماماً ، بعد ذلك عاد الورم من جديد وبقوة أكبر ولكن للكاحل ولما كنت قد تعرضت سابقاً ( أثناء فترة الدراسة ) للإصابة بالروماتيزم فقد لجأت لطبيبة روماتيزم وبعد إجراء الفحوصات المخبرية والصورة الطبقية لكاحلي الأيسر المتورم بشدة تبين اني غير مصابة بالروماتيزم ولا النقرس وأن وظائف الكبد والكلى سليمة وان هناك تورم غير معروف السبب في الكاحل .
قامت الطبيبة بتحويلي إلى طبيب آخر متخصص في جراحة الأوعية الدموية ، وبعد أن قام الطبيب بقراءة التحاليل والنظر للتقارير وفحصني وجد ان عندي دوالي داخلية وتوسع في الوريد الرئيسي مقداره 7.5 الأمر الذي يؤدي إلى ان الدم النازل للقدم لا يرجع منها وبالتالي تتورم وكتب لي دوائين الأول دانزن والثاني دوفلان ومشد خاص للرجل لمدة شهرين التزمت بالدواء ولكن المشد لم اتمكن من لبسه باستمرار لأنه حشر السائل في أصابع رجلي التي تورمت واحمرت وعند تحريكها تميل للون الأصفر مع العلم بانني قد اخترت القياس المناسب من الجراب الطبي
بعد انتهاء العلاج راجعت الدكتور وقد خف الورم قليلاً لكن الألم زاد وظهرت بعض الدوائر الزهرية تحت الجلد في رجلي وقرر ان يجري لي عملية جراحية بعد شهر رمضان المبارك
الطبيب قال اني لم استفد من العلاج ولا حل سوى الجراحة لكن بعد الجراحة يجب أن البس المشد شهرين متصلين وأن لا أحمل إلا بعد مضي سنة من تاريخ العملية لخطورة ذلك الأمر علي أما ان ابقيت الوضع كما هو وحملت ( بناء على رغبة زوجي الذي يرى ان ابني الصغير اصبح كبيراً ) فستورم رجلي أكثر وسأكون معرضة بشكل كبير جداً لخطر الجلطة نتيجة زيادة الوزن
الحقيقة أني لا أعلم هل اراجع طبيب آخر مع العلم بان هذا الطبيب من أمهر الموجودين هنا وقد احتار ان كان له راي آخر أم التزم براي الطبيب وهل فعلا المراة الحامل التي تكون مصابة بهذا التوسع تكون معرضة لخطر الجلطة . أرجو ان لا اكون قد أطلت عليك يا دكتور وادعو لك بالمزيد من النجاح والتوفيق

اختي الفاضله
خطر حدوث جلطات في مثل حالتك يزيد مع الحمل و مع كونك ولدتي قبل ذلك و اذا كان عمرك اكثر من 34 سنه . و لكن اذا حملتي لابد لكي من اخذ مانع جلطات طوال فترة الحمل مثل الهيبارين حقن مع الاسبرين و لكن لماذا تعرضي نفسك لخطر مادام عندك اولاد الحمد لله . اري ان تؤجلي الحمل و تعملي العملية اولا لاي ايضا العلاج بالهبارين غالي و عذاب حيث لابد من اخذ حقنه كل يوم و ممكن لا قدر الله يكون جلطات تذهب الي المخ و الرئة و تفقدي حياتك . اختي لعل زوجك يقرأ و يعرف الخطر الذي يتهدد حياتك . اما رأي الشخصي لو ان زوجتي مكانك و ليس عندي اطفال سوف اعالجها اولا . الاصل في ديننا لا ضرر و لا ضرار . توكلي علي الله و اعملي العملية و عام كثير لتعودي الي حياتك . زوري طبيب اخر لتأخذي رأية وتوكلي علي الله و ان اردتي اضع لكي موضوع يخص مرضك بالانجليزية قولي لي انزله حالا
بالشفاء
د.نبيل

شكرا لك دكتور نبيل على ردك ، بالنسبة لي عمري 30 سنة ولكن الدكتور قال ان التوسع 7.5 كتير على وزني يعني لو كنت انصح من هيك كان الضرر أقل وبالنسبة لزوجي فهو قال سنة مش مشكلة وما زعل بس عندما كنا نسمع ان أحدهم سيرزق بمولود يتضايق داخليا فهو يحب الأولاد ويريد أخ لابنه وبالنسبة للموضوع بالغة الانجليزية فاكون شاكرة لو أضفته ، الدكتور قال نجري العملية بشهر 10 وبترتبي امورك أن الحمل تاتي آخر 4 شهور منه بالشتاء أي احمل بعد العميلة ب 8 شهور حتى تكون الولادة بشهر 4 إن شاء الله تعالى!!!

ان شاء الله تسير امورك علي خير و عندك وقت تجيبي لة 10 اولاد ان اراد الله
هذا هو الموضوع
Overview of prevention of venous thrombosis in pregnant and postpartum women

Robert D Auerbach, MD
Charles J Lockwood, MD


UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on May 15, 2006. The next version of UpToDate (14.3) will be released in October 2006.

INTRODUCTION — Virchow's classic triad of stasis, hypercoagulability, and vascular trauma is present during pregnancy. Stasis results from compression via the gravid uterus and via estradiol-mediated increase in deep venous capacitance [1]. Hypercoagulability is a result of an increase in coagulation factors (I, II, VII, VIII, IX, X), a decrease in protein S, an increase in resistance to activated protein C, and an increase in fibrinolytic inhibitors (plasminogen activator inhibitor type-1 and type-2) [2-4]. Vascular trauma may occur during childbirth, particularly following operative vaginal or cesarean delivery. Because of these changes, pregnancy is associated with a risk of thrombosis three- to ten-fold higher than the risk in nonpregnant women (incidence of pregnancy-related venous thromboembolism 0.71 to 1.72 per 1000 pregnancies, mortality 1.1 per 100,000 deliveries) [5-8]. Manifestations of maternal thrombotic events include superficial and deep vein thrombosis, pulmonary embolus, septic pelvic thrombophlebitis, and ovarian vein thrombosis.

Indications for and use of anticoagulation to prevent thrombotic complications in pregnant and postpartum women will be discussed here. Anticoagulation of women with prosthetic heart values, acute venous thrombosis, pulmonary embolism, previous thromboembolism, and recurrent pregnancy loss are reviewed separately. (See "Anticoagulation during pregnancy", see "Management of pregnant women with prosthetic heart valves", see "Deep vein thrombosis and pulmonary embolism in pregnancy" and see "Evaluation and management of couples with recurrent pregnancy loss").

RISK FACTORS FOR THROMBOEMBOLISM — Risk factors associated with venous thromboembolism (VTE) are shown in Table 1 (show table 1) [5,9-14]. The magnitude of risk attributable to these factors is difficult to quantify and often not consistent across studies. The risk of thrombosis in pregnant patients with thrombophilias depends upon the thrombophilia (show table 2). The most important determinant of VTE risk in thrombophilic pregnant patients is a personal or family history of VTE [15]. For women with a previous VTE, the best estimate for risk of recurrence during pregnancy in untreated women is 2.4 percent (95% CI 0.2-6.9 percent) versus about 0.1 percent in the general obstetrical population [6,16]. The best estimate of the overall incidence of post-cesarean delivery thrombosis is 0.9 percent [11].

INDICATIONS FOR VTE PROPHYLAXIS — VTE has become the leading cause of maternal mortality in developed countries [17,18] and serious long-term maternal morbidity from chronic venous insufficiency may occur in survivors [19]. Nevertheless, there are few data from randomized trials on which to base recommendations for VTE prophylaxis. Guidelines based mainly on expert opinion have been produced by the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom [20], the American College of Chest Physicians [21], and the British Society for Haematology [22].

Antepartum VTE prophylaxis — Thromboprophylaxis is recommended throughout pregnancy for women at high risk of VTE, unless the risk factor can be removed. It should begin as early in pregnancy as is practical since the frequency of VTE is similar in each trimester [23]. Candidates for antepartum prophylaxis include:

Selected women with highly thrombogenic acquired or inherited thrombophilias or those with lesser thrombogenic thrombophilias and a personal or strong family history of VTE (show table 3) (See "Inherited thrombophilias in pregnancy" section on Indications for treatment).
Women with idiopathic VTE during a previous pregnancy or in the nonpregnant state. (See "Anticoagulation during pregnancy" section on Venous thromboembolism).
By comparison, women with a single prior VTE outside of pregnancy and related to a nonrecurring (temporary) risk factor, such as an recent major surgery, trauma, or immobilization, are at low risk of recurrence during pregnancy in the absence of an underlying thrombophilia, family history of VTE in a first degree relative, or VTE in an unusual location (eg, axillary vein) [16]. Therefore, routine antepartum anticoagulation is not necessary in these women. However, prophylaxis should be administered postpartum when the risk of thrombosis is higher than the antepartum risk (see "Postpartum management" below) [21,23].

There is no consensus as to whether VTE related to use of oral contraceptive pills should be categorized as a nonrecurring risk factor with low risk of recurrence during pregnancy [16] or hormonally mediated with high risk of recurrence during pregnancy.

Women who have risk factors (show table 1), alone or in combination, that in the jument of the clinician significantly increases their risk of antepartum VTE. (See "Prevention of venous thromboembolic disease").
Postpartum VTE prophylaxis

All women who received antepartum prophylaxis (except if the only indication is previous adverse pregnancy outcome)
All women with a prior VTE
Women with inherited lower risk thrombophilias (heterozygotes for factor V Leiden, prothrombin G20210A mutation, protein C or S deficiency; hyperhomocysteinemia unresponsive to folate therapy) but no personal history of VTE who undergo cesarean delivery [24] and, possibly, if they have a first degree relative with VTE or additional risk factors for thrombosis (show table 1). These women do not typically require antepartum prophylaxis because their risk of thromboembolism antepartum is likely less than 1 percent [25]. (See "Inherited thrombophilias in pregnancy").
Women who are at high risk of VTE because of one or more risk factors from Table 1 (show table 1)
Postpartum management of these women is discussed below (see "Postpartum management" below).

Cesarean delivery — Cesarean delivery is associated with a three- to five-fold increase in risk of thromboembolism compared to vaginal birth [11,26]. In three large series, 30, 67, and 76 percent of postpartum deaths due to pulmonary embolus occurred in women who delivered by cesarean section [5,14,27]. For this reason, thromboprophylaxis has been advocated for women undergoing transabdominal delivery.

However, selection of appropriate candidates for thromboprophylaxis is controversial. The benefit of prevention of VTE related morbidity and mortality needs to be balanced against the morbidity and cost of pharmacologic therapy and compared against alternative therapies (compression stockings or boots) or no therapy (see "Nonpharmacologic alternatives" below).

In 1995, the RCOG recommended heparin prophylaxis based on risk status (show table 4). However, 20 percent of women who developed VTE postpartum had no recognizable risk factors and only 30 percent of at-risk women received thromboprophylaxis [22]. As a result, in 2001 the RCOG recommended heparin prophylaxis for all women undergoing cesarean delivery.

By comparison, a 2001 Cochrane review on use of prophylaxis for prevention of VTE in pregnancy concluded there was insufficient evidence on which to base a recommendation [28]. Only two small randomized studies comparing use of heparin (unfractionated or LMWH) to placebo in women undergoing cesarean delivery were available [29,30].

Since the benefit of routine thromboprophylaxis has not been proven and since minor bleeding (impaired surgical hemostasis, wound hematoma) is more common in patients receiving these drugs [31], most clinicians do not recommend routine use of heparin thromboprophylaxis in all women undergoing cesarean delivery. In pregnancy, one cohort study suggested that use of graduated elastic compression stockings reduced the prevalence of postpartum VTE from 4.3 percent to 0.9 percent [32].

Pneumatic boots do not increase the risk of bleeding complications and may be more efficacious than compression stockings [33]; however, their efficacy in this patient population has also not been proven, nor has the cost-benefit been evaluated.

Given their safety and potential efficacy, we suggest that clinicians use these devices in all patients undergoing a cesarean delivery who have additional risk factors for VTE. (See "Prevention of venous thromboembolic disease" sections on Intermittent leg compression and graduated compression stockings).

Vaginal delivery — There are no data on which to base recommendations for postpartum prophylaxis after vaginal delivery in women with no history of VTE or thrombophilia. The RCOG has opined that clinical jument should be used in deciding whether an individual patient receives postpartum thromboprophylaxis [23]. They suggested that women with combinations of risk factors (show table 1) should be considered for a three- to five-day course of LMWH postpartum, and possibly antepartum therapy as well. We suggest a short-term intervention for prophylaxis of VTE in nonambulatory women with risk factors for thrombosis (see "Postpartum management" below).

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CHOICE OF ANTITHROMBOTIC AGENT — There are three options for anticoagulation of peripartum women: unfractionated heparin, low molecular weight heparin, and warfarin. Use of each drug depends upon several factors, including gestational age, estimated date of delivery, and whether the woman is pre- or postpartum. Although aspirin is used to diminish platelet thromboxane synthesis and platelet aggregation in the uteroplacental vasculature, its ability to prevent thromboembolism in pregnant women has not been evaluated in a controlled trial.

Unfractionated heparin — Heparin is a complex glycosaminoglycan that exerts its anticoagulant effects by potentiating antithrombin activity, increasing levels of factor Xa inhibitor [34], and inhibiting platelet aggregation [35]. Unfractionated heparin is a heterogeneous mixture of high molecular weight (range 3000 to 30,000 Daltons, average 15,000 Daltons) negatively charged molecules, which precludes transfer of any significant quantity of drug across the placenta or into breast milk [36,37]. The half-life is 30 to 60 minutes for intravenous heparin and three hours for subcutaneous heparin.

Dose — The usual dose for antepartum prophylaxis is 5000 units subcutaneously every 12 hours adjusted to produce a heparin level of 0.1 to 0.2 U/ml or anti-factor Xa level of 0.1 to 0.2 U/ml six hours after injection (show table 5) [38]. An alternative method, which avoids monitoring, is to administer 5000 units subcutaneously every 12 hours in the first trimester, and then raise the dose to 7500 units in the second trimester, and 10,000 units in the third trimester. These doses have no or minimal effects on the activated partial thromboplastin time (aPTT). Some authors recommend following anti-factor Xa levels to guide VTE prophylaxis during pregnancy. One study observed that this standard heparin regimen was inadequate to achieve the desired anti-factor Xa therapeutic range in five of nine second-trimester pregnancies and in 6 of 13 third-trimester pregnancies [38].

However, women at very high risk of thrombosis, such as those with antithrombin deficiency or homozygous for the prothrombin or factor V Leiden mutation, should receive higher therapeutic heparin doses and require frequent monitoring of the aPTT. (See "Inherited thrombophilias in pregnancy").

Management of side effects — Potential side effects of heparin therapy include hemorrhage, osteoporosis, and thrombocytopenia.

Hemorrhage — The highest risk of hemorrhage is during labor and delivery, in the presence of a bleeding diathesis (abruption, pregnancy-related liver disease, concomitant aspirin therapy), and with obstetrical conditions associated with bleeding (eg, placenta previa, abruption) [39]. An increased risk of major hemorrhage is mostly confined to women receiving therapeutic doses of heparin. Lower dose prophylaxis as described above, is associated with minor bleeding, such as wound hematoma and oozing during surgery; postpartum uterine bleeding is not increased unless there is atony.
The management of bleeding during heparin therapy depends upon the location and severity of bleeding, the risk of associated with stopping the anticoagulant, and the duration of the aPTT. In most peripartum obstetrical patients, the heparin can be stopped and restarted, if indicated, after bleeding has been controlled. However, patients with a recent VTE may be candidates for insertion of an inferior vena cava filter. Although we would be reluctant to continue low dose prophylaxis in the face of clinical bleeding from a placenta previa or abruption, there are no data that addresses the volume of bleeding in these patients compared to those not on prophylaxis.

If urgent reversal of heparin effect is required, protamine sulfate can be administered by slow intravenous infusion (not greater than 20 mg/min and no more than 50 mg over any 10 minute period). The appropriate dose of protamine sulfate is dependent upon the dose of heparin given and the time of that dose. Full neutralization of heparin effect is achieved with a dose of 1 mg protamine sulfate/100 units heparin. However, because of the relatively short half life of intravenously administered heparin, the protamine sulfate dose must be calculated by estimating the amount of heparin remaining in the plasma at the time that reversal is required. Bolus doses of more than 25 to 50 mg of protamine sulfate are seldom required, and excessive dosing can have an anticoagulant effect. If heparin is given by subcutaneous injection, repeated small doses of protamine may be needed because of prolonged heparin systemic absorption from the subcutaneous depot. Patients who have previously received protamine (including diabetic patients under treatment with NPH insulin) have an approximately 1 percent risk of anaphylaxis when protamine sulfate is administered [40].

Osteoporosis — Osteoporosis is most common with doses of heparin exceeding 15,000 U/day for more than six months [9,41-46]. Demineralization can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible [45-47].
Patients receiving such doses of heparin should receive 1500 mg of calcium and at least 400 IU vitamin D daily as prophylaxis against osteoporosis. They should also have bone densitometry studies performed after receiving six months of unfractionated heparin therapy exceeding 15,000 U/day. Evidence of osteoporosis should prompt referral to an endocrinologist familiar with treating osteoporosis in premenopausal patients. (See "Clinical use of heparin and low molecular weight heparin" and see "Drugs that affect bone metabolism", section on Heparin).

Thrombocytopenia — There are two types of heparin-related thrombocytopenia (HIT). Type I is common (10 to 20 percent of patients) and characterized by a small fall in platelet count that occurs within the first two days after heparin initiation, often returns to normal with continued heparin administration, and is of no clinical consequence [48]. The mechanism of the thrombocytopenia is nonimmune and appears to be due to a direct effect of heparin on platelet activation. Type 2 develops in fewer than 3 percent of patients, usually occurs 4 to 10 days after initiation of therapy, and is immune mediated; cessation of therapy is required to prevent serious thrombotic complications, such as white clot syndrome [9]. (See "Heparin-induced thrombocytopenia"). The diagnosis of HIT-2 can be confirmed by serotonin release assays, heparin-induced platelet aggregation assays, flow cytometry or solid phase immunoassays [49].
Because of the risk of thrombocytopenia in patients begun on heparin therapy, platelet counts should be checked within three days of initiation of treatment and followed weekly for three weeks.

Low molecular weight heparin — Low molecular weight heparins (LMWHs) are derivatives of unfractionated heparin that have a mean molecular weight of 4000 to 5000 daltons. Like unfractionated heparin, LMWH inactivates factor Xa, but has a lesser effect on thrombin. As a result, LMWHs do not prolong the aPTT. They are as effective as unfractionated heparin, with fewer side effects. A systematic review of the safety and efficacy of LMWH for thromboprophylaxis and treatment of VTE in pregnancy concluded these drugs were both safe and effective [50]. However, there is almost no information from randomized trials on efficacy in pregnant women [51]. (See "Low molecular weight heparin for venous thromboembolic disease").

LMWH has several clinical advantages over unfractionated heparin: higher bioavailability allows administration of a fixed dose without frequent laboratory monitoring, immune-mediated thrombocytopenia is rare, and bone loss may be lower. This was illustrated in the systematic review (64 studies including 2777 pregnancies) mentioned above which found no cases of HIT-2 and only a single case of an osteoporotic fracture [50]. Significant bleeding occurred in approximately 2 percent of pregnancies treated with LMWH and was usually due to obstetric causes. Bleeding occurred antepartum in 12 of the 55 cases, in association with delivery in 26, and in association with wound hematoma in 17.

The drug is more costly than unfractionated heparin, but overall cost of therapy is lower in some settings because home administration may avoid hospitalization. LMWH can be administered ante- or postpartum, but not intrapartum because their use may increase the risk of bleeding from needles or catheters employed for neuraxial anesthesia (see "Anesthesia" below). Use of LMWH does not pose a contraindication to breastfeeding.

Dose — A LMWH (dalteparin 2500 anti-factor Xa units subcutaneously daily, enoxaparin 30 mg subcutaneously twice daily, or tinzaparin 50 to 100 anti-factor Xa units/kg daily) is initiated. The data regarding the need for monitoring anti-factor Xa in pregnant patients receiving lower dose LMWH for prophylaxis are conflicting [38,52,53]. Although anti-factor Xa levels are not routinely measured in nonpregnant individuals, we recommend monitoring during pregnancy because of increased renal clearance in pregnancy, ongoing changes in maternal weight, and inadequate data establishing the optimum therapeutic dose in this population [54,55]. It is our practice to titrate the dose of LMWH to maintain prophylactic anti-factor Xa levels of 0.1 to 0.2 U/mL or therapeutic anti-factor Xa levels of 0.6 to 1.0 U/mL when assessed four hours after drug administration (show table 5).

and Factor X inhibitors

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Management of side effects — For patients who experience bleeding while receiving LMWH, protamine sulfate (1 mg/100 anti-Xa units of LMWH) can reduce clinical bleeding, presumably by neutralizing the higher molecular weight fractions of heparin within the product, which are thought to be most responsible for this complication.

Although the frequency of thrombocytopenia is very low, it is not eliminated so we would still recommend following platelet counts in a similar fashion as described above for patients taking unfractionated heparin [39]. Significant uncertainty remains as to whether use of LMWH has a less deleterious effect on maternal bone loss than unfractionated heparin [56,57]. More large studies are needed to clarify this issue. Until these data are available, we administer 1500 mg of calcium and at least 400 IU vitamin D daily as prophylaxis against osteoporosis and order bone densitometry studies after six months of therapy.

Use of LMWH may increase the risk of epidural hematoma formation upon placement of a neuraxial anesthetic (see "Anesthesia" below). For this reason, we recommend stopping therapy at 36 weeks, or earlier if preterm delivery is anticipated. Unfractionated heparin is employed until delivery.

Warfarin — Warfarin gains its anticoagulant effect from its ability to inhibit the action of vitamin K, which is a cofactor in the synthesis of the final molecular forms of factors VII, IX, X, and prothrombin. It readily crosses the placenta [58], but clinically important amounts are not passed into breast milk. There is convincing evidence that warfarin administration between the sixth and ninth weeks of gestation is potentially teratogenic [59-62]. The teratogenic effect appears to be dose related, with doses less than 5 mg/day providing the highest margin of safety [63]. Fetal hemorrhage any time in gestation is another risk, although this is rare. Therefore, warfarin is typically not used during pregnancy and definitely should be avoided in the first few weeks of pregnancy and near term. Pregnant patients with mechanical heart valves are one of the few clinical presentations in which the benefit of warfarin use in the midtrimester may outweigh the risk. (See "Management of pregnant women with prosthetic heart valves" and see "Anticoagulation during pregnancy" section on Warfarin). Warfarin can be used postpartum when long-term anticoagulation is planned.

Newer anticoagulants — Several new anticoagulants have been approved for clinical use. Although little information exists defining their role in pregnant women, direct thrombin inhibitors (DTI) and Specific Factor Xa Inhibitors are listed as pregnancy risk factor B (show table 6). These medications have shown no risk in animal studies; however, controlled human first trimester studies are not available. No evidence of second or third trimester fetal harm exists and the safety in nursing mothers is unknown. These medications are considered investigational in pregnant or breast feeding patients. (See "New anticoagulants" sections on Direct thrombin inhibitors and Factor X inhibitors).

INTRAPARTUM MANAGEMENT — Immobilization and dehydration should be avoided in all pregnant women and they should try to maintain a lateral position when recumbent to minimize stasis in the extremities.

Unfractionated heparin — Anticoagulation is discontinued for labor and delivery, except in women with prosthetic heart valves or who had an iliofemoral thrombosis or pulmonary embolism within the 30 days. The risk of heparin-related bleeding at delivery is minimal after a single prophylactic dose of unfractionated heparin or more than four hours after administration of multiple dose therapy.

In patients who have been on therapeutic doses of unfractionated heparin, an aPTT should be checked and monitored during labor if elevated. Protamine sulfate may be given to reverse a markedly prolonged aPTT at the time of vaginal or cesarean delivery (see above).

Low molecular weight heparin — There are no significant risks of treatment-related bleeding if delivery occurs more than 12 hours after a single prophylactic dose of LMWH or more than 18 to 24 hours after multiple therapeutic doses. If less time has transpired between the last LMWH dose and labor/delivery, then it should be assumed that the patient has a bleeding diathesis; monitoring factor Xa levels is not recommended as the level is not predictive of the risk of bleeding [5]. Protamine can be given if hemorrhage occurs (see above).

Anesthesia — Thromboprophylaxis regimens using low-dose unfractionated heparin are not associated with increased risk of spinal/epidural hematoma. Although these drugs are typically discontinued for labor and delivery, they do not have to be halted prior to spinal or epidural analgesia. If low-dose therapy is continued during labor and delivery, ideally the injection is delayed until after the neuraxial anesthesia has been placed.

In contrast, there are concerns about epidural hematoma formation when neuraxial anesthesia is administered to patients receiving LMWH. The American Society of Regional Anesthesia and Pain Medicine recommends that spinal/epidural anesthesia should not be given until 10 to 12 hours after administration of a prophylactic dose of LMWH to assure normal hemostasis at the time of needle insertion [5]. It is necessary to wait until 24 hours after the last LMWH dose when higher, therapeutic LMWH doses are used (eg, enoxaparin 1 mg/kg every 12 hours, enoxaparin 1.5 mg/kg daily, dalteparin 120 units/kg every 12 hours, dalteparin 200 units/kg daily, tinzaparin 175 units/kg daily). Monitoring factor Xa levels is not recommended as the level is not predictive of the risk of bleeding [5]. For this reason, as noted, we recommend stopping therapy at 36 weeks of gestation, or earlier if preterm delivery is anticipated. Unfractionated heparin is employed until delivery. (See "Prevention and treatment of adverse effects of neuraxial anesthesia" section on Spinal/epidural hematoma).

POSTPARTUM MANAGEMENT — The highest risk period for VTE or pulmonary embolism is postpartum [7,64]. A meta-analysis of nine studies found 66 percent of VTE occurred antepartum and 35 percent occurred postpartum [64]. Using these figures, the estimated relative distribution of VTE events during pregnancy and the puerperium would be 0.23 per day during pregnancy and 0.82 per day in the postpartum period. Thus, the postpartum period is a particularly important time for thromboprophylaxis.

Short term thromboprophylaxis — We feel that women with no history of VTE and no thrombophilia but who have risk factors which raise the clinician's concern about VTE, such as obesity, are candidates for nonpharmacologic or anticoagulant prophylaxis until they achieve full ambulation.

Prolonged postpartum thromboprophylaxis — Higher risk patients should receive thromboprophylaxis regardless of mode of delivery, and therapy should be continued for four to six weeks postpartum. However, the duration of therapy depends upon the reason for prophylaxis and ongoing risk of VTE. Therapy is longer, as an example, in patients who remain immobilized in a cast.

In high risk patients, subcutaneous heparin (5000 units subcutaneously BID) is administered 6 to 12 hours after cesarean delivery or four to six hours after vaginal delivery (if there is no significant bleeding) concurrently with warfarin for the initial four to five days and/or 48 hours after the woman has reached a therapeutic INR (ie, 2.0 to 3.0) on such therapy [23]. This avoids the potential early thrombotic effect of warfarin, which impairs the synthesis of naturally occurring inhibitor of coagulation (proteins C) before producing an anticoagulant effect due to the inhibition of procoagulant clotting factors (factors II, VII, IX, and X). Warfarin is used postpartum instead of heparin because transfer across the placenta is no longer relevant, it can be taken orally, has no osteopenic effects and its use is compatible with breast feeding. It is indicated for postpartum thromboprophylaxis planned for more than a few days duration. Heparin or LMWH is preferred for short-term postpartum anticoagulation. Initiation of warfarin therapy, laboratory monitoring, and management of complications are discussed in detail separately. (See "Clinical use of warfarin").

If LMWH is used postpartum, it also may be initiated 6 to 12 hours after cesarean delivery or four to six hours after vaginal delivery (if there is no significant bleeding). If an epidural catheter is in place, then removal and dosing schedules need to be coordinated to minimize the risk of epidural hematoma from trauma when the catheter is extracted. (See "Prevention and treatment of adverse effects of neuraxial anesthesia" section on Spinal/epidural hematoma).

However, LMWH is generally not indicated for long-term postpartum prophylaxis because of its expense and inconvenience. We would consider using it in a patient who is noncompliant with laboratory monitoring of coumadin therapy.

-4-
NONPHARMACOLOGIC ALTERNATIVES — Graduated elastic compression stockings and pneumatic compression boots are the primary alternatives to pharmacologic prophylaxis. Although their role in decreasing VTE in pregnancy has yet to be defined, graduated elastic compression stockings have been shown to increase femoral vein flow in late pregnancy [65]. Pneumatic compression stockings improve blood flow, decrease stasis and increase blood flow in femoral vessels by 240 percent [66]. Pneumatic compression stockings also increase fibrinolysis by increasing levels of plasminogen activator [67]. In a meta-analysis of moderate risk nonpregnant patients undergoing surgery, these devices were shown to decrease the incidence of DVT by 60 percent [68]. As they have no hemorrhagic risk and have been effective as prophylaxis in surgical gynecologic oncology patients [69], pneumatic compression stockings should be an ideal device in at risk pregnant patients who are at prolonged bed rest or undergoing cesarean delivery.
SUMMARY AND RECOMMENDATIONS

Pregnancy is associated with an increased risk of thrombosis due to pregnancy related stasis, hypercoagulability, and vascular trauma. (See "Introduction" above).
Risk factors associated with venous thromboembolism (VTE) in pregnant and postpartum women are shown in Table 1 (show table 1). (See "Risk factors for thromboembolism" above).
We recommend antepartum thromboprophylaxis throughout pregnancy for women at high risk of VTE, unless the risk factor can be removed (Grade 1B). Candidates for antepartum prophylaxis include: selected women with acquired or inherited thrombophilias and women with idiopathic VTE during a previous pregnancy or in the nonpregnant state. (See "Antepartum VTE prophylaxis" above).
We recommend postpartum thromboprophylaxis for all women who received antepartum thromboprophylaxis and all women with a prior VTE (Grade 1B). We suggest postpartum thromboprophylaxis for women who are at high risk of VTE because of one or more risk factors from Table 1 (show table 1) (Grade 2C). (See "Postpartum VTE prophylaxis" above).
We suggest that clinicians use compression stockings and pneumatic boots in all patients undergoing a cesarean delivery who have additional risk factors for VTE (Grade 2B). (See "Cesarean delivery" above).
Use of low molecular weight heparin may increase the risk of epidural hematoma formation upon placement of a neuraxial anesthetic. For this reason, we suggest stopping therapy at 36 weeks or earlier if preterm delivery is anticipated (Grade 2B). (See "Anesthesia" above).
For most patients, anticoagulation is discontinued intrapartum. (See "Intrapartum management" above).
A variety of postpartum interventions for prophylaxis against thrombosis are available and may be used short- or long-term, depending upon the individual's specific clinical circumstances. (See "Postpartum management" above).

هذا عن الوقاية مع الحمل و طرق العلاج تكون متشابهه مع او دون اما الجراحة حل جذري

و هذا الوقاية هن الجلطات عموما


Prevention of venous thromboembolic disease

Graham F Pineo, MD


UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on April 24, 2006. The next version of UpToDate (14.3) will be released in October 2006.

INTRODUCTION — Pulmonary embolism is responsible for approximately 150,000 to 200,000 deaths per year in the United States [1,2]. Despite significant advances in the prevention and treatment of venous thromboembolism (here taken to include both venous thrombosis and pulmonary embolism), pulmonary embolism remains the most common preventable cause of hospital death. Thus, it is vital that efforts continue to find means of preventing and managing venous thromboembolism that are safer and more effective [3].

Venous thromboembolism often complicates the course of sick and hospitalized patients, but it can also occur in ambulatory and otherwise healthy individuals (see "Hospitalization" below). Effective and safe prophylactic measures are now available for most high-risk patients [4-8]. Prophylaxis is more effective for preventing death and morbidity from VTE than is the treatment of established disease.

Practical approaches to the prevention of venous thromboembolism (VTE) in medical and surgical patients will be reviewed here. Detailed discussions about specific pharmacologic agents are presented separately. (See "Clinical use of heparin and low molecular weight heparin" and see "Clinical use of warfarin").

RISK OF VTE — Fatal pulmonary embolism occurs with the following frequency in patients who do not receive prophylaxis:

0.1 to 0.8 percent in patients undergoing elective general surgery
2 to 3 percent in patients undergoing elective hip replacement
4 to 7 percent in patients undergoing surgery for a fractured hip
RIsk factors — Most risk factors for venous thromboembolic disease have been identified in surgical populations. In one large prospective cohort study, 21,903 consecutive surgical patients were followed for 30 days postoperatively [9]. Deep vein thrombosis and pulmonary embolism were rare, diagnosed in 0.11 and 0.14 percent of patients, respectively. Independent risk factors for thromboembolism included:

Age >50 years
History of varicose veins (OR 7.2, 95% CI 3.8-13.7)
History of myocardial infarction (OR 2.9, 95% CI 1.8-4.8)
History of cancer (OR 2.4, 95% CI 1.9-3.2)
History of atrial fibrillation (OR 2.1, 95% CI 1.2-3.4)
History of ischemic stroke (OR 1.8, 95% CI 1.3-2.7)
History of diabetes mellitus (OR 1.7, 95% CI 1.2-2.2)
Additional risk factors that increase the risk of venous thrombosis include previous venous thromboembolism, obesity, heart failure, paralysis, or the presence of an inhibitor deficiency state. Factor V Leiden is the most common cause of inherited thrombophilia, accounting for 40 to 50 percent of cases. The prothrombin gene mutation, deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases. (See "Activated protein C resistance and factor V Leiden").

The risk is enhanced in patients with more than one predisposition to thrombosis. One study, for example, noted a 10-fold increase in risk of any venous thromboembolism and a 20 fold increase in risk of idiopathic thromboembolism among men who had both the Leiden mutation and hyperhomocysteinemia when compared to men with neither abnormality [10]. The risk of VTE among individuals with both hyperhomocysteinemia and factor V Leiden was far greater than the sum of the individual risks associated with either abnormality alone. Medical patients who are immobilized (eg, with congestive heart failure, cancer, stroke, or following myocardial infarction) also present a significant risk for venous thromboembolism. (See "Overview of the causes of venous thrombosis").

Pregnancy — The risk of VTE is increased in association with pregnancy. This phenomenon may relate in part to the progressive increase in resistance to activated protein C that is normally observed in the second and third trimesters [11].

The risk during both the intrapartum and the postpartum periods appears to be accentuated in those women who have an inherited deficiency of a naturally occurring anticoagulant, such as antithrombin III, protein C, or protein S. In one study, for example, the frequency of developing venous thrombosis during pregnancy or the postpartum period was approximately 8-fold greater in deficient compared with non-deficient women [12]. (See "Deep vein thrombosis and pulmonary embolism in pregnancy" and see "Anticoagulation during pregnancy").

Hospitalization — There is a high risk of developing VTE while hospitalized for a reason other than DVT or pulmonary embolus. Based upon a review of residents of Olmsted County for the period from 1980 through 1990, the age- and sex-adjusted incidence of VTE was more than 130 times greater among hospitalized patients (960 per 10,000 person-years) than among community residents (7.1 per 10,000 person-years) [13]. For both groups, the incidence of VTE increased with advancing age, and, with the exception of women <40 years of age, was higher in hospitalized men than women.

Approximately one-half of community-based cases occurred in patients who developed VTE while residing in a nursing home or within 90 days of hospital discharge. The net result was that approximately 60 percent of all cases of VTE occurred in hospitalized, recently discharged, or nursing home patients [13,14].

Surgery — Patients undergoing surgical procedures are divided into the following risk categories (show table 1) [15]:

Low risk — Low risk patients are under the age of 40, have none of the risk factors listed above, will require general anesthesia for less than 30 minutes, and are undergoing minor elective, abdominal, or thoracic surgery. Without prophylaxis their risk of proximal vein thrombosis is less than 1.0 percent, and risk of fatal pulmonary embolism is less than 0.01 percent.

Moderate risk — Moderate risk patients are over the age of 40, will require general anesthesia for more than 30 minutes, and have one or more of the above risk factors. Without prophylaxis, their risk of proximal vein thrombosis is 2 to 10 percent, and their risk of fatal pulmonary embolism is 0.1 to 0.7 percent.

High risk — High risk patients include those over the age of 40 who are having surgery for malignancy or an orthopedic procedure of the lower extremity lasting more than 30 minutes, and those who have an inhibitor deficiency state or other risk factors. The risk of proximal vein thrombosis and fatal pulmonary embolism in this group is 10 to 20 percent and 1.0 to 5.0 percent, respectively.

The high risk associated with orthopedic surgery results from a number of factors that contribute to venous stasis, including the supine position on the operating table, the anatomic positioning of the extremity, and, in patients undergoing total knee replacement, inflation of a thigh tourniquet to obtain a bloodless field [15]. In addition, intimal injury may result from positioning of the extremity, and compression of the femoral vein may occur due to flexion and adduction of the hip during surgery on this joint.

PREVENTION OF VTE — There are two approaches to the prevention of fatal pulmonary embolism [15]:

Primary prophylaxis is carried out using either drugs or physical methods that are effective for preventing deep vein thrombosis.
Secondary prevention involves the early detection and treatment of subclinical venous thrombosis by screening postoperative patients with objective tests that are sensitive for venous thrombosis.
Primary prophylaxis is preferred in most clinical circumstances; it is more cost-effective than treatment of complications when they occur. Secondary prevention should never replace primary prophylaxis; it is reserved for patients in whom primary prophylaxis is either contraindicated or ineffective.

Primary prophylaxis — Characteristics of the ideal primary prophylactic method are described in Table 2 (show table 2). The prophylactic measures most commonly used include:

Low dose heparin
Low molecular weight heparin
Use of the substituted pentasaccharide fondaparinux
Oral anticoagulants (International Normalized Ratio [INR] of 2.0 to 3.0)
Intermittent pneumatic compression (IPC)
Prophylaxis is ideally started before or shortly after surgery and continued until the patient is fully ambulatory [15]. For a patient undergoing total hip or total knee replacement, the minimum duration of prophylaxis with LMWH or warfarin should be 7 to 10 days [15]. Seven published reports and two meta-analyses support the need for continued prophylaxis with LMWH for 28 to 42 days following total hip replacement [16-24]. There is less of a need for extended prophylaxis beyond 10 days for patients undergoing total knee replacement (see "High risk surgical patients" below) [21].

.

Low dose heparin — Low dose subcutaneous heparin for perioperative prophylaxis of venous thrombosis is usually given in a dose of 5,000 units two hours preoperatively and then every 8 or 12 hours postoperatively. An early prospective randomized study of over 4000 patients found that low dose heparin reduced the incidence of fatal pulmonary embolism in patients undergoing major surgical procedures from 0.7 to 0.1 percent compared to controls [25]. Pooled data from meta-analyses then confirmed that low dose heparin reduces the incidence of all deep vein thrombosis, proximal deep vein thrombosis, and all pulmonary emboli, including fatal pulmonary emboli [5,6,8]. Most of the patients in these trials underwent abdominothoracic surgery (particularly for gastrointestinal disease), but patients having gynecologic and urologic surgery, as well as mastectomy or vascular procedures, were also included.

Low dose heparin is also effective in reducing the incidence of venous thrombosis in nonsurgical patients. Two studies have shown that low molecular weight heparin was superior to placebo in the prevention of VTE in hospitalized medical patients with congestive heart failure, chronic obstructive pulmonary disease, sepsis, and a variety of other conditions who were immobilized for at least three days [26,27].

The incidence of major bleeding complications is not increased by low dose heparin, but there is an increase in minor wound hematomas. The platelet count should be monitored regularly in all patients on low dose heparin to detect the rare but significant development of heparin-induced thrombocytopenia.

In addition to the relatively low side effect profile, low dose heparin has the advantage that it is relatively inexpensive and easily administered. Anticoagulant monitoring is not required.

LMW heparin — A number of low molecular weight heparin preparations are available. (See "Clinical use of heparin and low molecular weight heparin"). These drugs have the advantage that they can be given once or twice a day at a constant dose without any laboratory monitoring. In addition, there is a lower incidence of thrombocytopenia than with unfractionated heparin. As an example, one randomized double-blind study of patients after hip surgery found that thrombocytopenia occurred in 9 of 332 patients (2.7 percent) receiving unfractionated heparin compared to none of 333 receiving low molecular weight heparin [28].

Low molecular weight heparin fractions have been evaluated for prophylaxis of venous thrombosis in a number of situations, primarily surgical:

Randomized clinical trials comparing low molecular weight heparin with unfractionated heparin in general surgical patients have found that low molecular weight heparins given once or twice daily are as effective or more effective in preventing thrombosis [7,8,29]. The incidence of major bleeding was similar for both classes of drug in most of the reports, although one study found an advantage for low molecular weight heparin when all bleeding end points were taken into consideration [29].
A number of randomized trials have compared low molecular weight heparin to unfractionated heparin, warfarin, acenocoumarol, or fondaparinux for the prevention of venous thrombosis following total hip replacement [7,8,16-22,29-35]. In North America, LMWH or warfarin are most commonly used prophylaxis for high risk procedures (eg, total joint replacement). In Europe, prophylaxis has routinely started preoperatively, while in North America, prophylaxis has been started postoperatively because of a concern for perioperative bleeding.
In the meta-analysis comparing preoperative with postoperative initiation of prophylaxis of DVT following total hip replacement surgery, it was shown that total DVT rates (but not proximal DVT rates) and major bleeding occurred significantly less frequently in the preoperative group compared with those who received postoperative prophylaxis [36]. LMWH started immediately before or early after surgery in patients undergoing total hip replacement resulted in significantly lower rates of both total and proximal DVT when compared with warfarin [35]. There was no difference between the preoperative and postoperative LMWH arms with respect to efficacy, but there was more major bleeding in the preoperative LMWH group when compared with warfarin.

Comparison across trials of patients with hip surgery has been difficult, since the drugs under investigation and their dosing schedules vary from one clinical trial to another. Even within the same clinical trial there can be considerable inter-center variability [30]. Bleeding rates vary quite widely across studies and different definitions are frequently used. The commonly used traditional classification for major or minor bleeding is recommended [30,31,36].

Although the number of patients undergoing total knee replacement now equals the number undergoing total hip replacement, there have been fewer trials in patients undergoing knee replacement [21,30,37,38]. Fondaparinux was shown to be superior to enoxaparin in reduction of total venous thromboembolism following total knee replacement surgery [39].
LMWH has been compared with compression stockings for the prevention of venous thromboembolism following neurosurgery [40,41]. In one study, LMWH plus compression stockings was superior to compression stockings alone [40] and in the other study LMWH was superior to the use of compression stockings [41].
Low molecular weight heparin significantly decreases the rate of total (31 versus 44 percent) and proximal (6 versus 15 percent) deep vein thrombosis when compared with unfractionated heparin in patients suffering multiple trauma [42].
Low molecular weight heparin (enoxaparin) appears as effective as subcutaneous unfractionated heparin as prophylaxis in elderly patients who are bedridden because of acute medical illnesses [43].
Low molecular weight heparin was shown to be as effective and safe as low dose heparin given three times a day in patients following acute ischemic stroke [44].
Oral anticoagulation — Oral anticoagulation (with warfarin) can be commenced preoperatively, at the time of surgery, or in the early postoperative period for prophylaxis of deep vein thrombosis. (See "Clinical use of warfarin") However, therapy started at the time of surgery or in the early postoperative period may not prevent small venous thrombi from forming during or soon after surgery, because the anticoagulant effect is not achieved until the third or fourth postoperative day [45]. Nonetheless, warfarin appears to effectively inhibit extension of such thrombi, if present, thereby preventing clinically important venous thromboembolism. The two step warfarin protocol appears to be no more effective than warfarin started the night before surgery in patients undergoing total knee replacement [46].

Warfarin has been compared with low molecular weight heparin in patients undergoing total hip replacement surgery [30-32,45-47]. Most studies showed superior benefit with LMWH, with two of the studies having a statistically significant difference favoring LMWH [32,46].
In studies comparing the efficacy and safety of LMWH with warfarin in patients undergoing total knee replacement the incidence of total deep vein thrombosis has been less in the LMWH group but the incidence of proximal venous thrombosis has been similar [29,30,38].

In a comparison of warfarin to external pneumatic compression after total hip replacement, warfarin was significantly more effective [48].
In a study of patients with hip fractures, warfarin was superior to aspirin or placebo for the prevention of deep vein thrombosis [49]. Similar results were noted in a post-discharge retrospective analysis of patients undergoing total hip arthroplasty; the administration of warfarin was associated with a lesser incidence of symptomatic venous thrombosis requiring rehospitalization compared to patients not receiving warfarin [50].
Intermittent leg compression — Intermittent pneumatic leg compression prevents venous thrombosis by enhancing blood flow in the deep veins of the legs, thereby preventing venous stasis. Pneumatic compression also reduces plasminogen activator inhibitor-1 (PAI-1) levels via an unknown mechanism and consequently increases endogenous fibrinolytic activity [51]. Thus, intermittent leg compression has both local and systemic effects. (See "Vascular endothelial function and the mechanisms of thrombolysis").

Intermittent pneumatic compression is virtually free of clinically important side effects and offers a valuable alternative in patients who have a high risk of bleeding. It may produce discomfort in some patients, and should not be used in those with overt evidence leg ischemia caused by peripheral vascular disease. It is also contraindicated if a patient has been at bed rest or immobilized for more than 72 hours without any form of prophylaxis, since it may cause a newly formed clot to disloe.

Intermittent pneumatic leg compression reduces the incidence of venous thrombosis in moderate risk general surgical patients and in patients undergoing neurosurgery or coronary artery bypass grafting [52-54]. It is less effective in patients undergoing hip surgery or knee replacement, preventing calf vein thrombosis but not proximal vein thrombosis [48,55,56]. In a retrospective study of patients recovering from total hip arthroplasty, pneumatic compression reduced the incidence of rehospitalization for symptomatic venous thromboembolism, but only for patients who were not overweight, defined as body mass index less than 25 (show figure 1) [50]. (See "Clinical evaluation of the overweight adult", section on Body mass index).

A variety of well accepted, comfortable, and effective intermittent pneumatic devices are currently available which may be applied preoperatively, at the time of surgery, or in the early postoperative period. These devices should be used continuously until the patient is fully ambulatory, with only temporary removal for nursing care or physiotherapy. With the rapidly decreasing length of stay in patients undergoing orthopedic surgery, the use of IPC devices has decreased. Furthermore, compliance with these devices has been problematic. In a prospective review it was shown that the duration and degree of compression was suboptimal in patients undergoing total hip replacement when intermittent compression was the sole form of prophylaxis [57].

Intermittent compression devices are useful in the early postoperative period in patients who are at high risk for bleeding, such as following intracranial surgery or for patients who have epidural catheters for extended analgesia. Pharmacologic agents can be commenced when the risk of bleeding has decreased. Pneumatic compression may be used in conjunction with LMWH in patients considered at very high risk of post-operative venous thromboembolism [15].

Graduated compression stockings — Graduated compression stockings reduce venous stasis in the limb by applying a graded degree of compression to the ankle and calf, with greater pressure b**** applied distally. They reduce the incidence of postoperative venous thrombosis only in low risk general surgical patients [58] and in selected moderate risk patients (eg, neurosurgical) [40,41,53,59]. It is unclear whether the use of graduated compression stockings in combination with other forms of prophylaxis results in any further risk reduction [60].

Aspirin — Although meta-analyses indicate that aspirin decreases the frequency of venous thrombosis following general or orthopedic surgery, this reduction is significantly less than that obtained using other agents [61]. Based upon these findings, a multinational trial randomly assigned 13,356 patients undergoing surgery for hip fracture and 4088 patients undergoing elective hip or knee arthroplasty to receive placebo or 160 mg/day of aspirin for 35 days, in addition to other thromboprophylactic measures (eg, subcutaneous heparin) prescribed at the discretion of the treating physician [62]. Fatal pulmonary embolism and deep venous thrombosis were both significantly reduced by the addition of aspirin (each with an absolute risk reduction of 0.4 percent), while fatal and non-fatal arterial events (myocardial infarction or stroke) and all cause mortality which were the primary end points for the study were not decreased. Wound related and gastrointestinal bleeding and the need for transfusion were significantly more common in the aspirin treated group.

Thus, aspirin may have some activity in preventing venous thromboembolism, but its lower efficacy than other measures precludes its use as monotherapy in most cases, and its therapeutic index when used alone or in conjunction with other anticoagulants has not been well defined. Therefore, aspirin cannot be recommended at present for the prophylaxis of venous thrombosis [63].

Fondaparinux — The synthetic heparin pentasaccharide fondaparinux (Arixtra, Org31540/SR90107A) catalyzes factor Xa inactivation by AT III without inhibiting thrombin [64,65]. The efficacy of fondaparinux has been demonstrated in patients undergoing major orthopedic surgery in whom there was an overall 50 to 60 percent reduction in risk of venous thromboembolic disease, primarily distal DVT, when compared to low molecular weight heparin [39,66,67]. In a separate study, use of fondaparinux for one month, rather than one week, reduced the incidence of documented VTE from 35 to 1.4 percent [68]. (See "Clinical use of fondaparinux", section on Hip fracture surgery).

Fondaparinux was approved by the FDA for the prophylaxis of deep vein thrombosis in patients undergoing surgery for hip fracture, hip replacement, or knee replacement in December, 2001. The cost of treatment with fondaparinux has been estimated at approximately $44 per day; in comparison, the costs of unfractionated heparin and low molecular weight heparin are $2 to $3 and $24 to $35 dollars per day, respectively [69].

Investigational agents — Initial studies with the orally active synthetic antithrombin agent ximelagatran (Exanta) have shown promising results in preventing VTE in patients undergoing hip or knee replacement surgery when compared with LMWH [70-72] or warfarin [73,74]. (See "New anticoagulants", section on Ximelagatran).

A dose finding study has also been reported with the use of the nematode anticoagulant protein (rNAPc2, which inhibits the tissue factor-activated factor VII complex) in patients undergoing total knee replacement [75]. This agent also shows promise with respect to both efficacy and safety in this setting. Further published reports with these agents are awaited with interest to determine their future role in prophylaxis of venous thromboembolism in high-risk patients.

Low molecular weight heparin can be made absorbable through the gastrointestinal tract [5,76]. An international multicenter study is underway comparing the efficacy and safety of oral heparin in two dose regimens with LMWH for the prevention of venous thromboembolism following total hip replacement surgery.

A number of other investigations are underway with new antithrombotic agents. Most of the current interest is in the development of oral factor Xa inhibitors.

RECOMMENDATIONS — The primary prophylactic approach depends upon the patient's risk category and the type of surgery (show table 1). The recommendations that follow are derived from randomized trials with low false positive and false negative errors unless otherwise stated. Readers are referred to the report on the "Prevention of venous thromboembolism" for the Seventh American College of Chest Physicians Consensus Conference on Antithrombotic Therapy for complete details [63]. The following are general recommendations:

Each hospital should develop a formal strategy for the prevention of venous thromboembolism all risk categories for surgical and medical patients [6].
The use of aspirin for prophylaxis in all patients groups is not recommended, as other measures are more efficacious.
The use of routine ultrasonography screening at discharge or during outpatient follow-up is not recommended in asymptomatic patients.
Antithrombotic prophylaxis should be used with caution in patients having spinal puncture or epidural catheter placement for regional anesthesia or continued analgesia. The recommendations of the American Association for Regional Anaesthesia should be consulted [75,76].
Low risk surgical patients — Prophylaxis other than early ambulation usually is not recommended in low risk patients [63]. However, prophylaxis may be used in certain circumstances. It is the custom in some countries to use graduated compression stockings, but this practice is not based upon evidence from clinical trials.

Moderate risk surgical patients — The following are recommendations for prophylaxis in moderate risk patients: