Thromboembolic Disease 299 Postpartum m anagement Conversion from heparin to warfarin anticoagulation should be initiated post partum in the hospital to minimize the maternal risk of complications. Once the patient has delivered and is suf- fi ciently stable, full heparin anticoagulation should be resumed. Then, oral warfarin therapy should be started with 10 – 15 mg orally per day for 2 – 4 days, followed by 2 – 15 mg/day as indicated by the INR or PT [109] . Heparin and warfarin therapy should be overlapped for the fi rst 5 – 7 days post partum until an INR of approximately 2. 0 – 3.0 has been achieved. One approach is to give the warfarin sodium at 6 p.m., then draw an INR or PT at 6 a.m. the following day, adjusting the dose for the subsequent day ’ s warfarin according to that morning ’ s results. Once the patient is therapeutically anticoagulated, heparin is discontinued. Postpartum suppression of lactation with estrogen is associated with a much higher incidence of thromboembolic complications and is contraindicated [175,176] . Prophylaxis of t hromboembolism The dosage of heparin needed during pregnancy appears to increase because of increases in heparin - binding proteins, plasma volume, renal clearance, and heparin degradation by the placenta. All contribute to a decreased bioavailability of heparin. Due to a lack of adequate prospective trials, a number of different prophy- lactic regimens have been proposed. Low - dose prophylaxis with UFH may be administered via 5000 – 7500 units every 12 hours during the fi rst trimester, 7500 – 10,000 units every 12 hours during the second trimester, followed by 10,000 units every 12 hours during the third trimester unless the aPTT is elevated. Alternatively, LMWH may be used. For low - dose prophylaxis, dalteparin 5000 units once or twice daily or enoxaparin 40 mg once or twice daily may be used. Adjusted - dose prophylaxis may be accomplished with either dalteparin 5000 – 10,000 units every 12 hours or enoxaparin, 30 – 80 mg every 12 hours [165] . An increase from 5000 units to 7500 – 10,000 units in the third tri- mester [42] is often recommended [177] . Except for doses exceeding 8000 units, laboratory monitoring is not usually required [42] . Caution should be used in the patient with dimin- ished renal function, such as seen during pre - eclampsia, which may elevate heparin levels. Employing perioperative (cesarean) prophylaxis may be con- sidered for certain patients, such as individuals who are obese, have diffi culty ambulating or have been at prolonged bed rest. Conservative mechanical methods, such as intermittent pneu- matic compression boots or graduated elastic compression stock- ings, may be used. A recent decision analysis investigated the use of thromboprophylaxis after cesarean delivery. The authors compared four methods: universal subcutaneous heparin prophylaxis, heparin prophylaxis only for patients with a genetic thrombophilia, use of pneumatic compression stockings, and no thromboprophylaxis. Use of pneumatic compression stockings after cesarean delivery was the strategy with the lowest numbers of adverse events. Universal prophylaxis with heparin was associ- ated with an excess risk of heparin - induced thrombocytopenia clotting profi le and hematocrit should be drawn. There are three basic choices in the approach to anticoagulant management in such patients. 1 Continue therapeutic anticoagulation. This approach is recom- mended for particularly high - risk patients, such as those with recent PE, iliofemoral thrombosis or mechanical heart valve pros- theses. Because a more uniform therapeutic heparin level is desir- able, the patient may be changed from subcutaneous injection to continuous IV infusion. A heparin level of 0.4 units/mL or a low therapeutic aPTT (close to 1.5 times normal) may be desirable in these surgical patients. 2 Reduce the subcutaneous heparin dose. In patients at lower risk of thromboembolism, the heparin dose can be reduced to a pro- phylactic level (5000 units every 12 hours); this dose is not associ- ated with increased surgical bleeding. 3 Stop or withhold heparin administration. For patients at increased risk for operative bleeding (i.e. suspected placenta accreta) and at relatively low risk of clot propagation, heparin may be temporarily withheld or its effects reversed with prot- amine sulfate. Non - pharmacologic prophylaxis (e.g. pneumatic compression stockings) may be substituted during the intraop- erative period. With patients who are anticoagulated and in whom rapid reversal is deemed essential, protamine sulfate can be used to reverse either UFH or LMWH. One milligram of protamine sulfate neu- tralizes 100 units of heparin. To determine the proper dose of protamine, several approaches are available. One is to calculate the amount of circulating heparin by estimating the plasma volume at 50 mL/kg of body weight and multiplying the plasma volume by the heparin concentration [17] . In most institutions, however, this procedure may not be technically feasible. If heparin level is not available, the amount of protamine sulfate to give should be underestimated or slowly titrated to the whole - blood clotting time because of the short half - life (rapid metabolism) of heparin and the irreversible anticoagulant effect of excess prot- amine. No single dose should exceed 50 mg. A 50 mg dose is almost never needed because it would neutralize 5000 units of circulating heparin, an amount highly unlikely to be present. Protamine sulfate should be administered IV over 20 – 30 minutes to prevent hypotension. In patients receiving adjusted - dose subcutaneous heparin, a dose of 5 – 10 mg of protamine sulfate is often suffi cient; further doses may be given, depending on the aPTT value. It should be emphasized that for vaginal delivery, even signifi cantly prolonged aPTT values rarely result in clinical hemorrhage, and thus do not require protamine sulfate therapy. Patients who present for delivery on warfarin anticoagulant are at heightened risk for bleeding with either vaginal or operative delivery. Parental vitamin K can help to regenerate the clotting factors within 12 hours. If there is little time or reversal is not adequate, fresh frozen plasma can be given to supply clotting factors. Regardless, the pregnant woman should be sta- bilized and be suffi ciently able to clot before operative delivery is initiated. Chapter 21 300 study to prevent postoperative DVT in non - pregnant patients, a dose of 1 IU/kg/h reduced the incidence of DVT from 22% to 4%. Thrombolytic t herapy Defi brinating agents may be indicated in cases of life - threatening thromboembolism [191 – 194] . Streptokinase, urokinase, and tissue plasminogen activator activate plasminogen, which sets in motion the body ’ s natural fi brinolytic system. Although helpful in early management of massive PE, thrombolysis plus heparin may not yield improved mortality over heparin alone [191] . Because of the potential risk of bleeding, thrombolytic therapy has not been recommended within 10 days of surgery or parturi- tion [193] . Recommended treatment schedules vary, but all consist of an IV loading dose followed by continuous infusion for 12 – 72 hours, depending on the clinical situation [192] . Thrombolytic therapy is followed by anticoagulant therapy to prevent recurrence. A review of 172 patients by Turrentine et al. demonstrated that thrombolytic therapy could be used relatively safely during pregnancy in selected clinical situations (Table 21.13 ) and that these agents were partially or completely success- ful in 86 – 90% of recipients [194] . Nonetheless, the authors sug- gested that traditional therapies should be used fi rst and, if unsuccessful, thrombolytic agents should be reserved for life - or limb - threatening VTE with the understanding of the increased risk of bleeding complications. Ancrod, derived from Malayan pit viper venom, is contraindi- cated in pregnancy. Animal studies have shown a high incidence of fetal death. Postpartum hemorrhage from the placental site also occurs at a greater frequency. Inferior v ena c ava fi lter p lacement The safe placement of inferior vena cava fi lters to prevent PE has been reported during pregnancy. Eleven patients with DVT and who were presumed to have an increased risk of PE underwent placement of a temporary inferior vena cava fi lter between 1998 and 2004. All the fi lters were placed at the suprarenal inferior vena cava prior to delivery. During fi lter placement, anticoagu- lant therapy was continued and then stopped intrapartum. No induced thrombosis and bleeding per VTE [178] . Another group performed a decision analysis comparing no thromboprophylaxis to intermittent pneumatic compression and confi rmed that mechanical thromboprophylaxis is estimated to a cost - effective strategy [179] . Early postoperative ambulation is also important in preventing thromboembolism. Low - dose heparin is accepted as prophylaxis for a variety of surgical procedures [180] . Although in some general surgical or orthopedic patients dihydroergota- mine in combination with heparin is felt to be more effective than heparin alone [181,182] , its use in pregnant or parturient women has not been studied. Thus, its use cannot be recommended. The combination of mechanical methods, especially pneumatic com- pression, and low - dose heparin may be the optimal approach for high - risk patients [183,184] . LMWH has been found useful in abdominal surgery; one dose is given preoperatively, followed by additional doses once every 24 hours [185,186] . According to the ACCP recommendations, patients with a history of a single episode of VTE, associated with a transient risk factor that is no longer present, should undergo antepartum clini- cal surveillance and postpartum anticoagulation [55] . In patients with a history of a single episode of VTE and thrombophilia or a strong family history and not currently on lifelong anticoagula- tion, antepartum prophylactic or intermediate - dose LMWH or minidose or moderate - dose UFH, plus postpartum anticoagula- tion is recommended. Intermediate - dose LMWH is defi ned as dalteparin 5000 U SC q12 h or enoxaparin 40 mg SC q12 h. Minidose heparin is UFH 5000 U SC q12 h and moderate - dose UFH is UFH SC q12 h in doses adjusted to target an anti - Xa level of 0.1 – 0.3 U/mL [55] . Therapeutic anticoagulation is necessary during pregnancy for those patients with mechanical heart valves [187] or inherited defi ciency of a natural anticoagulant such as AT III [188] . In women with AT III defi ciency, successful out- comes have been achieved with the use of subcutaneous and IV heparinization, accompanied by infusion of AT III concentrate at the time of abortion or delivery [188] . AT III defi ciency should be considered when heparin requirements increase beyond typical dosages. Without such therapy, maternal morbidity or mortality and fetal loss are extremely high. Defi ciencies of pro- teins C and S are also associated with thrombotic tendency [189] . In patients with medical histories remarkable for VTE, a system- atic comprehensive approach to thrombophilic screening should be pursued. Knowledge of an individual ’ s thrombophilic status can be used to better predict VTE recurrence risk [24] . Antiplatelet agents such as aspirin and dipyridamole may be helpful in preventing thrombosis in the arterial circulation and with some prosthetic heart valves. There is no known role for these agents in the prevention of pregnancy - associated VTE disease. Perioperative prophylaxis with dextran appears benefi cial in some surgical patients, but the risk of bleeding is higher than with heparin, and dextran ’ s usefulness in pregnant patients has not been established [187] . A potential but currently unproven approach in pregnancy for intrapartum prophylaxis in patients without an active thrombotic process is ultra - low - dose IV heparin [190] . In a randomized Table 21.13 Maternal and perinatal outcome in 172 patients who received thrombolytic therapy during pregnancy. n % Hemorrhage 14 8 Preterm birth 10 6 Perinatal deaths 10 6 Maternal deaths 2 1 Reproduced by permission from Turrentine MA, Braeems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol 1995; 50: 534 – 541. Thromboembolic Disease 301 of opinion regarding heparin prophylaxis during pregnancy, there is uniform agreement that anticoagulant therapy is war- ranted in the puerperium [35,37,38,205 – 211] . For patients with recurrent thromboembolism or a family history of these defi ciencies, prenatal screening for AT III, protein C, and protein S appears reasonable. Antiphospholipid s yndrome ( APS ) Individuals presenting with clinical signs of thrombosis or embo- lism which is objectively confi rmed should receive heparin, either unfractionated or low molecular weight, according to accepted therapeutic regimens. Since minimal doses of heparin may prolong the aPTT without a therapeutic level being achieved, it is best to follow these patients with anti - factor Xa levels to ensure adequacy of therapy. Patients with APS and a prior thrombosis appear to have a risk of recurrent thrombosis that is substantially higher than the recurrent risk with most other thrombophilias. Retrospective studies have shown that up to 70% of APS patients have recurrent thrombotic events during the 5 – 6 years following their initial thrombosis [212,213] . Prospective studies have con- fi rmed a high risk of recurrent thrombosis among APS patients [214] . As such, most experts recommend long - term thrombopro- phylaxis in patients with APS who have experienced a thrombotic event. References 1 Berg CJ , Atrash HK , Koonin LM , Tucker M . Pregnancy - related mor- tality in the United States, 1997 – 1990 . Obstet Gynecol 1996 ; 88 : 161 – 167 . 2 Chang J , Elam - Evans LD , Berg CJ , et al. Pregnancy - Related Mortality Surveillance – United States 1991 – 1999 . MMWR 2003 ; 52 ( SSO2 ): 1 – 8 . 3 Bonnar J . Can more be done in obstetric and gynecologic practice to reduce morbidity and mortality associated with venous thrombo- emblism? Am J Obstet Gynecol 1999 ; 180 ( 4 ): 784 – 791 . 4 Toglia MR , Weg JG . Venous thromboembolism during pregnancy . N Engl J Med 1996 ; 335 : 108 – 114 . 5 Gherman RB , Goodwin TM , Leung B , Byrne JD , Hethumumi R , Montoro M . Incidence, clinical characteristics, and timing of objec- tively diagnosed venous thromboembolism during pregnancy . Obstet Gynecol 1999 ; 94 : 730 – 734 . 6 Lindqvist P , Dahlback B , Marsal K . Thrombotic risk during preg- nancy: a population study . Obstet Gynecol 1999 ; 94 : 595 – 599 . 7 Ginsberg JS . Management of venous thromboembolism . N Engl J Med 1996 ; 334 : 1816 – 1828 . 8 Rochat RW , Koonin LM , Atrash HK , et al. Maternal mortality in the United States: report from the Maternal Mortality Collaborative . Obstet Gynecol 1988 ; 72 : 91 – 97 . 9 Franks AL , Atrash HK , Lawson HW , et al. Obstetrical pulmonary embolism mortality, United States, 1970 – 85 . Am J Pub Health 1990 ; 80 : 720 – 722 . 10 Lawson HW , Atrash HK , Franks AL . Fatal pulmonary embolism during legal induced abortion in the United States from 1972 to 1985 . Am J Obstet Gynecol 1990 ; 162 : 986 – 990 . complications occurred at time of fi lter placement. No symptom- atic PE occurred during or after delivery. Subsequently, all the fi lters were removed [195] . Placement of a vena cava fi lter has also been successfully performed during early labor followed by vaginal delivery without incident [196] . Surgical i ntervention With pregnancy, surgical intervention may be indicated in some clinical situations, such as replacement of a thrombosed cardiac valve prosthesis, thrombectomy for acute iliofemoral thrombosis, embolectomy of a life - threatening massive PE, vena cava inter- ruption for recurrent venous emboli despite adequate anticoagu- lation, or when anticoagulation is absolutely contraindicated. Embolectomy is a heroic measure, which may occasionally be life saving. Transvenous catheter embolectomy has been performed successfully for expeditious management of massive PE with car- diovascular collapse [197] . There are a variety of methods for interruption of the vena cava. These include complete ligation, Te fl on clips, and devices inserted transvenously, such as the umbrella fi lter or the Greenfi eld fi lter [198] . Special c onsiderations Antithrombin III d efi ciency The fi rst evidence of an inherited AT III defect is frequently a thromboembolic event. Pregnant patients with inherited AT III defi ciency often require therapeutic anticoagulation through the pregnancy and the puerperium [188,189,199 – 204] . In addition to heparin therapy throughout pregnancy [199,201,202,204] , IV administration of AT III concentrate may be necessary to mini- mize the patient ’ s risk of a thromboembolism [188,189] . This can be accomplished with fresh frozen plasma, but AT III concentrate is preferable [199,201,202] . The loading dose of AT III is 50 – 70 units/kg. This is followed by 20 – 30 units/kg/day to maintain an AT III level of 80% of normal [200] . The higher the AT III level, the less heparin will be required for therapeutic anticoagula- tion. If these patients remain untreated during pregnancy, 68% will develop thromboembolism [188,200,203,204] . In patients who require high doses of heparin to achieve anticoagulation, prophylactic biweekly doses of AT III concentrate may be neces- sary [203] . Many patients require lifelong anticoagulation, which is best achieved by oral anticoagulants when not pregnant and heparin throughout pregnancy. Protein C or S d efi ciencies In contrast to patients with AT III defi ciency, patients with protein C or S defi ciency carry a lower risk of antepartum throm- bosis [35,37,38,204 – 211] . The incidences of antepartum throm- bosis in the untreated patient with protein C and protein S defi ciency in one series were 17% and 0% respectively. The post- partum risks, however, were similar [204] . While there is a split Chapter 21 302 31 Comp PC , Esman CT . Generation of fi brinolytic activity by infusion of activated protein C in dogs . J Clin Invest 1981 ; 68 : 1221 – 1228 . 32 Robbins KC . The plasminogen - plasmin enzyme system . In: Colman RW , Hirsh J , Marder VJ , et al., eds. Hemostasis and Thrombosis . Philadelphia : JB Lippincott , 1982 . 33 Bonnar J , McNichol GP , Douglas AS . Coagulation mechanisms during and after normal childbirth . BMJ 1970 ; 2 : 200 – 203 . 34 Brandt JT . Current concepts of coagulation . Clin Obstet Gynecol 1985 ; 28 : 3 – 14 . 35 Comp PC , Clouse L . Plasma proteins C and S: the function and assay of two natural anticoagulants . Lab Management 1985 ; 23 : 29 – 32 . 36 Megha A , Finzi G , Poli T , et al. Pregnancy, antithrombin III defi - ciency and venous thrombosis: report of another case . Acta Heamatol 1990 ; 83 : 111 – 114 . 37 Broekmans AW , Bertina RM , Reinalda - Poot J , et al. Hereditary protein - S defi ciency and venous thromboembolism . Thromb Haemost 1985 ; 53 : 273 – 277 . 38 Marciniak E , Wilson HD , Marlar RA . Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood . Blood 1985 ; 65 : 15 – 20 . 39 Woodhams BJ , Candotti G , Shaw R , et al. Changes in coagulation and fi brinolysis during pregnancy: evidence of activation of coagula- tion preceding spontaneous abortion . Thromb Res 1989 ; 88 : 26 – 30 . 40 Hathaway WE , Bonnar J . Perinatal Coagulation . New York : Grune and Stratton , 1978 . 41 Bonnar J , McNichol GP , Douglas AS . Fibrinolytic enzyme system and pregnancy . BMJ 1969 ; 3 : 387 – 389 . 42 Bonnar J . Venous thromboembolism and pregnancy . Clin Obstet Gynecol 1981 ; 8 : 445 – 473 . 43 Atalla RK , Thompson JR , Oppenheimer CA , Bell SC , Taylor DJ . Reactive thrombocytosis after caesarean section and vaginal deliv- ery: implications for maternal thromboembolism and its preven- tion . Br J Obstet Gynaecol 2000 ; 107 ( 3 ): 411 – 414 . 44 Grandone E , Margaglione M , Colaizzo D , et al. Genetic susceptibility to pregnancy - related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations . Am J Obstet Gynecol 1998 ; 179 : 1324 – 1328 . 45 De Stefano V , Leone G , Mastrangelo S , et al. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow - up after diagnosis of 238 patients with congenital defi - ciency of antithrombin III, protein C, protein S . Thromb Haemost 1994 ; 72 : 352 – 358 . 46 Middeldorp S , Henkens CM , Koopman MM , et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis . Ann Intern Med 1998 ; 128 : 15 – 20 . 47 Eldor A . Thrombophilia, thrombosis and pregnancy . Thromb Haemost 2001 ; 86 : 104 – 111 . 48 Bertina RM , Koeleman BPC , Koster T , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C . Nature 1994 ; 396 : 64 – 67 . 49 Dahlback B . Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene . Haemostasis 1994 ; 24 : 139 – 151 . 50 Zoller B , Dahlback BD . Linkage between inherited resistance to acti- vated protein c and factor v gene mutation in venous thrombosis . Lancet 1994 ; 343 : 1536 – 1538 . 11 McLean R , Mattison ET , Cochrane NE . Maternal mortality study annual report 1970 – 1976 . NY State J Med 1979 ; 79 : 39 – 43 . 12 Kaunitz AM , Hughes JM , Grimes DA , et al. Causes of maternal mortality in the United States . Obstet Gynecol 1985 ; 65 : 605 – 612 . 13 Gabel HD . Maternal mortality in South Carolina from 1970 to 1984: an analysis . Obstet Gynecol 1987 ; 69 : 307 – 311 . 14 Sachs BP , Yeh J , Acher D , et al. Cesarean section related maternal mortality in Massachusetts, 1954 – 1985 . Obstet Gynecol 1988 ; 71 : 385 – 388 . 15 Barbour LA , Pickard J . Controversies in thromboembolic disease during pregnancy: a critical review . Obstet Gynecol 1995 ; 86 : 621 – 633 . 16 Bergqvist A , Bergqvist D , Hallbook T . Acute deep vein thrombosis (DVT) after cesarean section . Acta Obstet Gynecol Scand 1983 ; 62 : 473 – 477 . 17 Letsky EA . Coagulation problems during pregnancy . In: Lind T , ed. Current Review in Obstetrics and Gynecology . Edinburgh : Churchill Livingstone , 1985 . 18 Rutherford SE , Phelan JP . Deep venous thrombosis and pulmonary embolism in pregnancy . Obstet Gynecol Clin North Am 1991 ; 18 : 345 – 370 . 19 Rutherford SE , Montoro M , McGehee W , et al. Thromboembolic disease associated with pregnancy: an 11 - year review, SPO Abstract 139 . Am J Obstet Gynecol 1991 ; 164 : 286 . 20 Gerhardt A , Scharf RE , Beckmann MW , et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium . N Engl J Med 2000 ; 342 : 374 – 380 . 21 Heit JA , Kobbervig CE , James AH , Petterson TM , Bailey KR , Melton LJ . Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30 - year population - based study . Ann Intern Med 2005 ; 143 ( 10 ): 697 – 706 . 22 Danilenko - Dixon DR , Heit JA , Silverstein MD , et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population - based, case control study . Am J Obstet Gynecol 2001 ; 184 ( 2 ): 104 – 110 . 23 Larsen TB , Johnsen SP , Gislum M , Moller CA , Larsen H , Sorensen HT . ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population - based, nested case - control study . J Thromb Haemost 2005 ; 3 ( 2 ): 300 – 304 . 24 Brill - Edwards P , Ginsberg J , Gent M , et al. For the recurrence of clot in this pregnancy study group . N Engl J Med 2000 ; 343 : 1439 – 1444 . 25 De Stefano V , Martinelli I , Rossi E , et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without anti- thrombotic prophylaxis . Br J Haematol 2006 ; 135 ( 3 ): 386 – 391 . 26 Stead RB . Regulation of hemostasis . In: Goldhaber SZ , ed. Pulmonary Embolism and Deep Venous Thrombosis . Philadelphia : WB Saunders , 1985 : 27 – 40 . 27 Needleman P , Minkes M , Raz A . Thromboxanes: selected biosynthesis and distinct biological properties . Science 1976 ; 193 : 163 – 165 . 28 Thompson AR , Harker CA . Manual of Thrombosis and Hemostasis . Philadelphia : FA Davis , 1983 . 29 Files JC , Malpass TW , Yee EK , et al. Studies of human platelet alpha - granule release in vivo . Blood 1981 ; 58 : 607 – 618 . 30 Kaplan KL , Owen J . Plasma levels of B - thromboglobulin and platelet factor 4 and indices of platelet activation in vivo . Blood 1981 ; 57 : 199 – 202 . Thromboembolic Disease 303 68 Markisz JA . Radiologic and nuclear medicine diagnosis . In: Goldhaber SZ , ed. Pulmonary Embolism and Deep Venous Thrombosis . Philadelphia : WB Saunders , 1985 : 41 – 72 . 69 Moser KM , LeMoine JR . Is embolic risk continued by location of deep venous thrombosis? Ann Intern Med 1981 ; 94 : 439 – 444 . 70 Huisman MV , Buller HR , ten Case JW , Vreeken JR . Seriel imped- ance plethysmography for suspected deep venous thrombosis in outpatients: the Amsterdam General Partitions Study . N Engl J Med 1986 ; 314 : 823 – 882 . 71 Kohn H , Konig B , Mostbeck A . Incidence and clinical feature of pulmonary embolism in patients with deep vein thrombosis: a pro- spective study . Eur J Nucl Med 1987 ; 13 : S11 – S13 . 72 Mohr DN , Ryu JH , Litin SC , Rosenow EC III . Recent advances in the management of venous thromboembolism . Mayo Clin Proc 1988 ; 63 : 281 – 290 . 73 Monreal M , Salvador R , Ruiz J . Below - knee deep venous thrombosis and pulmonary embolism (letter) . AJR 1987 ; 149 : 860 . 74 Nicholas GG , Lorenz RP , Botti JJ , et al. The frequent occurrence of false - positive results in phleborrheography during pregnancy . Surg Gynecol Obstet 1985 ; 161 : 133 – 136 . 75 Kakkar V . The diagnosis of deep vein thrombosis using the 125I fi brinogen test . Arch Surg 1972 ; 104 : 152 – 159 . 76 Bentley PG , Kakkar VV . Radionuclide venography for the demon- strations of the proximal deep venous system . Br J Surg 1979 ; 66 : 687 – 690 . 77 Wells PS , Anderson DR , Roger M , et al. Evaluation of D - dimer in the diagnosis of suspected deep vein thrombosis . N Engl J Med 349 ( 13 ): 1227 – 1235 . 78 Bockenstedt P . D - Dimer in venous thromboembolism . N Engl J Med 349 ; 13 : 1203 – 1204 . 79 Epiney M , Boehlen F , Boulvain M , et al. D - dimer levels during delivery and the postpartum . J Thromb Haemost 2005 ; 3 ( 2 ): 268 – 271 . 80 Kline JA , Williams GW , Hernandez - Nino J . D - dimer concentrations in normal pregnancy: new diagnostic thresholds are needed . Clin Chem 2005 ; 51 ( 5 ): 825 – 829 . 81 Hron G , Kollars M , Binder BR , Eichinger S , Kyrle PA . Identifi cation of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation . JAMA 2006 ; 296 : 397 – 402 . 82 Rosenow EC III , Osmundson PJ , Brown ML . Pulmonary embolism . Mayo Clin Proc 1981 ; 56 : 161 – 178 . 83 Leclerc JR . Pulmonary embolism . In: Rakel RE , ed. Conn ’ s Current Therapy – 1994 . Philadelphia : WB Saunders , 1994 : 199 – 205 . 84 Bell WR , Simon TL , DeMets DL . The clinical features of submassive pulmonary emboli . Am J Med 1977 ; 62 : 355 – 360 . 85 Dorfman GS , Cronan JJ , Tupper TB , et al. Occult pulmonary embo- lism: a common occurrence in deep venous thrombosis . AJR 1987 ; 148 : 263 – 267 . 86 Schiff MJ , Feinberg AW , Naidich JB . Noninvasive venous examina- tions as a screening test for pulmonary embolism . Arch Intern Med 1987 ; 147 : 505 – 507 . 87 Robin ED . Overdiagnosis and overtreatment of pulmonary embo- lism: the emperor may have no clothes . Ann Intern Med 1977 ; 87 : 775 – 776 . 88 Moses DC , Silver TM , Bookstein JJ . The complementary roles of chest radiography, lung scanning and selective pulmonary angiog- raphy in the diagnosis of pulmonary embolism . Circulation 1974 ; 44 : 179 – 185 . 51 Dizon - Townson DS , Nelson LM , Jang H , Varner MW , Ward K . The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis . Am J Obstet Gynecol 1997 ; 176 : 883 – 886 . 52 Ridker PM , Miletich JP , Hennekens CH , Buring JE . Ethnic distribu- tion of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening . JAMA 1997 ; 277 ( 16 ): 1305 – 1307 . 53 Dizon - Townson D , Miller C , Sibai BM , et al. The relationship of factor V Leiden mutation and pregnancy outcomes for mother and fetus . Obstet Gynecol 2005 ; 106 : 517 – 524 . 54 Dahlman TC , Hellgren M , Blomback M . Thrombosis prophylaxis in pregnancy with use of subcutaneous heparin adjusted by monitoring heparin concentration in plasma . Am J Obstet Gynecol 1989 ; 161 : 420 – 425 . 55 Bates SM , Greer IA , Hirsh J , Ginsberg JS . Use of antithrombotic agents during pregnancy. The Seventh ACCP Conference on antithrombotic and thrombolytic therapy . Chest 2004 ; 126 : 627S – 644S . 56 Barnes RW , Wu KK , Hoak JC . Fallibility of the clinical diagnosis of venous thrombosis . JAMA 1975 ; 234 : 605 – 608 . 57 Bergqvist A , Bergqvist D , Lindhagen A , et al. Late symptoms after pregnancy - related deep vein thrombosis . Br J Obstet Gynaecol 1990 ; 97 : 338 – 344 . 58 Hull RD , Hirsh J , Carter CJ , et al. Pulmonary angiography, ventila- tion lung scanning, and venography for clinically suspected pulmo- nary embolism with abnormal perfusion lung scan . Ann Intern Med 1983 ; 98 : 891 – 899 . 59 Raghavendra BN , Rosen RJ , Lam S , et al. Deep venous thrombosis: detection by high - resolution real - time ultrasonography . Radiology 1984 ; 152 : 789 – 792 . 60 Douketis JD , Ginsberg JS . Diagnostic problems with venous thromboembolic disease in pregnancy . Haemostasis 1995 ; 25 : 58 – 71 . 61 PIOPED Investigators . Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED) . JAMA 1990 ; 263 : 2753 – 2759 . 62 Gottlieb RH , Widjaja J , Tian L , Rubens DJ , Voci SL . Calf sonography for detecting deep vein thrombosis in symptomatic patients: experi- ence and review of the literature . J Clin Ultrasound 1999 ; 27 ( 8 ): 415 – 420 . 63 Spritzer CE , Evans AC , Kay HH . Magnetic resonance imaging of deep venous thrombosis in pregnant women with lower extremity edema . Obstet Gynecol 1995 ; 85 : 603 – 607 . 64 Bettman MA , Paulin S . Leg phlebography: the incidence, nature and modifi cations of undesireable side effects . Radiology 1977 ; 122 : 101 – 108 . 65 Ginsberg JSA , Hirsh J , Rainbow AJ , et al. Risks to the fetus of radio - logic procedures used in the diagnosis of maternal venous thromboembolic disease . Thromb Haemost 1989 ; 61 : 189 – 196 . 66 American College of Obstetricians and Gynecologists . Education Bulletin Number 233. Teratology . Washington, DC : American College of Obstetricians and Gynecologists , 1997 . 67 American College of Obstetricians and Gynecologists . Committee Opinion Number 299. Guidelines for Diagnostic Imaging During Pregnancy . Washington, DC : American College of Obstetricians and Gynecologists , 2004 . Chapter 21 304 111 Samama M . [The new heparins.] Presse Med 1986 ; 15 : 1631 – 1635 . 112 Gillis S , Shushan A , Eldor A . Use of low molecular weight heparin for prophylaxis and treatment of thromboembolism in pregnancy . Int J Gynecol Obstet 1992 ; 39 : 297 – 301 . 113 Fejgin MD , Lourwood DL . Low molecular weight heparins and their use in the obstetrics and gynecology . Obstet Gynecol Surv 1994 ; 49 : 424 – 431 . 114 Rasmussen C , Wadt J , Jacobsen B . Thromboembolic prophylaxis with low molecular weight heparin during pregnancy . Int J Obstet Gynecol 1994 ; 47 : 121 – 125 . 115 Sturridge F , Letsky E . The use of low molecular weight heparin for thrombophylaxis in pregnancy . Br J Obstet Gynaecol 1994 ; 101 : 69 – 71 . 116 Ginsberg JS , Hirsh J . Use of antithrombotic agents during preg- nancy . Chest 1995 ; 108 : 3055 – 3115 . 117 Lensing AW , Prins MH , Davidson BE , et al. Treatment of deep - venous thrombosis with low molecular weight heparins: a meta - ananlysis . Arch Intern Med 1995 ; 155 : 601 – 607 . 118 Koopman MMW , Prandoni P , Piovella F . Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low - molecular weight heparin administered at home . N Engl J Med 1996 ; 334 : 682 – 687 . 119 Levine M , Gent M , Hirsh J , et al. A comparison of low - molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep - vein throm- bosis . N Engl J Med 1996 ; 334 : 677 – 681 . 120 White TM , Bernene JL , Marino AM . Continuous heparin infusion requirements: diagnostic and therapeutic implications . JAMA 1979 ; 241 : 2717 – 2720 . 121 DeSwart CAM , Nijmeter B , Roelofs JMM , et al. Kinetics of intrave- nously administered heparin in normal humans . Blood 1982 ; 60 : 1251 – 1258 . 122 Perry PJ , Herron GR , King JC . Heparin half - life in normal and impaired renal function . Clin Pharmacol Res 1974 ; 16 : 514 – 519 . 123 Basu D , Gallus A , Hirsh J , et al. A prospective study of the value of monitoring heparin treatment with the activated partial thrombo- plastin time . N Engl J Med 1972 ; 287 : 324 – 327 . 124 Hyers TM , Hull RD , Weg JG . Antithrombotic therapy for venous thromboembolic disease . Chest 1986 ; 89 : 265 – 355 . 125 Holm HA , Abildgaard U , Kalvenes S . Heparin assays and bleeding complications in treatment of deep venous thrombosis with particu- lar reference to retroperitoneal bleeding . Thromb Haemost 1985 ; 53 : 278 – 281 . 126 Lepercq J , Conard J , Borel - Derlon A , et al. Venous thromboembo- lism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies . Br J Obstet Gynaecol 2001 ; 108 ( 11 ): 1134 – 1140 . 127 Kearon C , Ginsberg J , Julian JA . Comparison of fi xed - dose weight - adjuested unfractionated heparin and low - molecular - weight heparin for acute treatment of venous thromboembolism . JAMA 2006 ; 296 : 935 – 942 . 128 Clagett GP , Anderson FA , Heit J , et al. Prevention of venous throm- boembolism . Chest 1995 ; 108 ( suppl 4 ): S312 – 334 . 129 Bergqvist D , Benoni G , Bjorgell O , et al. Low molecular - weight heparin (enoxaparin) as prophylaxis against venous thromboembo- lism after total hip replacement . N Engl J Med 1996 ; 335 : 696 – 700 . 130 Geerts WH , Jay RM , Code K , et al. A comparison of low - dose heparin with low - molecular - weight heparin as prophylaxis against 89 McFarlane MJ , Imperiale TF . Use of the alveolar - arterial oxygen gradient in the diagnosis of pulmonary embolism . Am J Med 1994 ; 96 : 57 – 62 . 90 Powrie R , Star JA , Rosene - Montella K . Deep venous thrombosis and pulmonary embolism in pregnancy . Med Health RI 1998 ; 81 ( 4 ): 141 – 143 . 91 Gold WM , McCormack KR . Pulmonary function response to radio- sotope scanning of the lungs . JAMA 1966 ; 197 : 146 – 148 . 92 Vincent WR , Goldberg SJ , Desilets D . Fatality immediately following rapid infusion of macroaggregates of 99mTc albumin (MAA) for lung scan . Radiology 1968 ; 91 : 1181 – 1184 . 93 Mills SR , Jackson DC , Older RA , et al. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series . Radiology 1980 ; 136 : 295 – 299 . 94 Kipper MS , Moser KM , Kortman KE , et al. Long - term follow - up of patients with suspected pulmonary embolism and a normal lung scan. Perfusion scans in embolic subjects . Chest 1982 ; 82 : 411 – 415 . 95 Urokinase Pulmonary Embolism Trial . A national cooperative study . Circulation 1973 ; 43 ( suppl II ): 47 . 96 Henkin RE . Radionuclide detection of thromboembolic disease . In: Kwaan HC , Bowie EJQ , eds. Thrombosis . Philadelphia : WB Saunders , 1982 : 236 – 252 . 97 Alderson PO . Scintigraphic evaluation of pulmonary embolism . Eur J Nucl Med 1987 ; 13 : S6 – S10 . 98 National Council on Radiation Protection and Measurements . Medical Radiation Exposure of Pregnant and Potentially Pregnant Women . Bethesda, MD : National Council on Radiation Protection and Measurements , 1977 . 99 Nichols AB , Beller BA , Cochari S , et al. Detection of pulmonary embolism by positron imaging of inhaled 15O - labeled carbon dioxide . Semin Nucl Med 1980 ; 10 : 252 – 258 . 100 Cross JJ , Kemp PM , Walsh CG , Flower CD , Dixon AK . A random- ized trial of spiral CT and ventilation perfusion scintigraphy for the diagnosis of pulmonary embolism . Clin Radiol 1998 ; 53 : 177 – 182 . 101 Lipchik RJ , Goodman LR . Spiral computed tomography in the eval- ution of pulmonary embolism . Clin Chest Med 1999 ; 20 : 731 – 738 . 102 Kim KL , Muller NL , Mayo JR . Clinically suspected pulmonary embolism: utility of spiral CT . Radiology 1999 ; 210 : 693 – 697 . 103 Traeger SM . Failure to wedge pulmonary hypertension during pul- monary artery catheterization: a sign of totally occlusive pulmonary embolism . Crit Care Med 1985 ; 13 : 544 – 547 . 104 Fairfax WR , Thomas F , Orme JF . Pulmonary artery catheter occlu- sion as an indication of pulmonary embolism . Chest 1984 ; 86 : 270 – 272 . 105 Lewis JF , Anderson TW , Fennel WH , et al. A clue to pulmonary embolism obtained during Swan - Ganz catheterization . Chest 1982 ; 81 : 257 – 529 . 106 Dalen JE , Banas JS , Brooks HC , et al. Resolution rate of acute pul- monary embolism in man . N Engl J Med 1969 ; 280 : 1194 – 1199 . 107 Dalen JE , Brooks HL , Johnson LW , et al. Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients . Am Heart J 1971 ; 81 : 175 – 185 . 108 Ezekowitz MD , Pope CF , Smith EO . Indium - 111 platelet imaging . In: Goldhaber SE , ed. Pulmonary Embolism and Deep Vein Thrombosis . Philadelphia : WB Saunders , 1985 : 261 – 267 . 109 Hirsch J . Heparin . N Engl J Med 1991 ; 324 : 1565 . 110 Bratt G , Tornebohm E , Lockner D , et al. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment . Thromb Haemost 1985 ; 53 : 208 – 211 . Thromboembolic Disease 305 conference on neuraxial anesthesia and anticoagulation) . Reg Anesth Pain Med 2003 ; 28 ( 3 ): 172 – 197 . 151 Ginsberg JS , Kowalchuck G , Brill - Edwards P , et al. Heparin therapy in pregnancy: effects on the fetus . Clin Res 1988 ; 36 : A410 . 152 Ginsberg JS , Hirsh J , Tuner C , et al. Risks to the fetus of anticoagu- lant therapy during pregnancy . Thromb Haemost 1989 ; 61 : 197 – 203 . 153 Ginsberg JS , Hirsh J . Use of antithrombotic agents during preg- nancy . Chest 1992 ; 315 : 1109 – 1114 . 154 Colvin BT , Machin SJ , Barrowcliffe TW , et al. Audit of oral antico- agulant treatment. The BCHS British Haemostasis and Thrombosis Task Force of the British Society for Haematology . J Clin Pathol 1993 ; 46 ( 12 ): 1069 – 1070 . 155 Stevenson RE , Burton OM , Ferlauto GJ , Taylor HA . Hazards of oral anticoagulants during pregnancy . JAMA 1980 ; 243 : 1549 – 1551 . 156 Chang MKB , Harvey D , de Swiet M . Follow - up study of children whose mothers were treated with warfarin during pregnancy . Br J Obstet Gynaecol 1984 ; 91 : 70 – 73 . 157 Hull R , Delmore T , Carter C , et al. Adjusted subcutaneous heparin versus warfarin sodium in the long - term treatment of venous thrombosis . N Engl J Med 1982 ; 306 : 189 – 194 . 158 Standing Advisory Committee for Haematology of the Royal College of Pathologists . Drug interaction with coumarin derivative antico- agulants . BMJ 1982 ; 185 : 274 – 275 . 159 Horn JR , Danzinger LH , Davis RJ . Warfarin - induced skin necrosis: report of four cases . Am J Hosp Pharm 1981 ; 38 : 1763 – 1768 . 160 Lebsack CS , Weibert RT . “ Purple toes ” syndrome . Postgrad Med 1982 ; 71 : 81 – 84 . 161 Park S , Schroeter AL , Park YS , Fortson J . Purple toes and livido reticularis in a patient with cardiovascular disease taking coumadin . Arch Dermatol 1993 ; 129 : 775 – 780 . 162 Hirsch J . The treatment of venous thromboembolism . Nouv Rev Fr Hematol 1988 ; 30 : 149 – 153 . 163 Gallus A , Jackaman J , Tillet J , et al. Safety and effi cacy of warfarin started early after submassive venous thrombosis or pulmonary embolism . Lancet 1986 ; 2 : 1293 – 1296 . 164 Turpis AG , Eriksson BI , Lassen MR , Bauer KA . Fondaparinux, the fi rst selective factor Xa inhibitor . Curr Opin Haematol 2003 ; 10 ( 5 ): 327 – 332 . 165 American College of Obstetricians and Gynecologists . Education Bulletin Number 19. Thromboembolism in Pregnancy . Washington, DC : American College of Obstetricians and Gynecologists , 2000 . 166 Moser KM , Fedullo PE . Venous thromboembolism: threes simple decisions (part 2) . Chest 1983 ; 83 : 256 – 260 . 167 Ellison MJ , Sawyer WT , Mills TC . Calculation of heparin dosage in a morbidly obese woman . Clin Pharm 1989 ; 8 : 65 – 68 . 168 Tenero DM , Bell HE , Deitz PA , Bertino JS Jr . Comparative dosage and toxicity of heparin sodium in the treatment of patients with pulmonary embolism versus deep - vein thrombosis . Clin Pharm 1989 ; 8 : 40 – 43 . 169 Anderson G , Fagrell B , Holmgren K , et al. Subcutaneous administra- tion of heparin: a randomized comparison with intravenous admin- istration of heparin to patients with deep - vein thrombosis . Thromb Res 1982 ; 27 : 631 – 639 . 170 Schulman S , Rhedin A , Lindmarker P , et al. A comparison of six weeks with six months of oral anticoagulant therapy after a fi rst episode of venous thromboembolism . N Engl J Med 1995 ; 332 : 1661 – 1665 . venous thromboembolism after major trauma . N Engl J Med 1996 ; 355 : 701 – 707 . 131 Hall JG , Pauli RM , Wilson KM . Maternal and fetal sequelae of anticoagulation during pregnancy . Am J Med 1980 ; 68 ( 1 ): 122 – 140 . 132 Walker AM , Jick H . Predictors of bleeding during heparin therapy . JAMA 1980 ; 244 : 1209 – 1212 . 133 Lee RH , Goodwin TM . Massive subchorionic hematoma associated with enoxaparin . Obstet Gynecol 2006 ep; 108 ( 3 Pt 2): 787 – 789 . 134 Chong BH , Pitney WR , Castaldi PA . Heparin - induced thrombocy- topenia: association of thrombotic complications with heparin - dependent IgG antibody that induces thromboxane synthesis and platelet aggregation . Lancet 1982 ; 2 : 1246 – 1249 . 135 Fausett MB , Vogtlander M , Lee RM , et al. Heparin - induced throm- bocytopenia is rare in pregnancy . Am J Obstet Gynecol 2001 ; 185 ( 1 ): 148 – 152 . 136 Magnani HN . Heparin induced thrombocytopenia (HIT): an over- view of 230 patients treated with orgaran (Org 10172) . Thromb Haemost 1993 ; 70 : 554 – 561 . 137 Galle PC , Muss HB , McGrath KM , et al. Thrombocytopenia in two patients treated with low - dose heparin . Obstet Gynecol 1978 ; 52 (suppl): 95 – 115 . 138 Phillips YY , Copley JB , Stor RA . Thrombocytopenia and low dose heparin . South Med J 1983 ; 76 : 526 – 528 . 139 Hirsch J , Daeln JE , Deykin D , Poller L . Heparin: mechanisms of action, dosing considerations, monitoring, effi cacy, and safety . Chest 1992 ; 102 : 337 – 350 . 140 Rao AK , White GC , Sherman L , et al. Low incidence of thrombocy- topenia with porcine mucosal heparin. A prospective multicenter study . Arch Intern Med 1989 ; 149 : 1285 – 1288 . 141 Harenberg J . Letter to the Editors - in - Chief. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy . Thromb Res 2007 ; 119 : 385 – 388 . 142 Mazzolai L , Hohlfeld P , Spertini f, Hayoz D, Schapira M, Duchosal MA. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy . Blood 2006 ; 108 ( 5 ): 1569 – 1570 . 143 Griffi th GC . Heparin osteoporosis . JAMA 1965 ; 143 : 85 – 88 . 144 De Swiet M , Ward PD , Fidler J , et al. Prolonged heparin therapy in pregnancy causes bone demineralization . Br J Obstet Gynaecol 1983 ; 90 : 1129 – 1134 . 145 Zimran A , Shilo S , Fisher D , et al. Histomorphometric evaluation of reversible heparin - induced osteoporosis in pregnancy . Arch Intern Med 1986 ; 146 : 386 – 388 . 146 Dahlman T , Lindvall N , Hellgren M . Osteopenia in pregnancy during long - term heparin treatment: a radiologic study postpartum . Br J Obstet Gynaecol 1990 ; 97 : 221 – 224 . 147 Dahlman TC . Osteoporotic fractures and the recurrence of throm- boembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin . Am J Obstet Gynecol 1993 ; 168 : 1265 – 1270 . 148 Dahlman TC , Sjoberg HE , Ringertz H . Bone mineral density during long - term prophylaxis with heparin in pregnancy . Am J Obstet Gynecol 1994 ; 170 : 1315 – 1320 . 149 American Society of Regional Anesthesia . Recommendations for Neuraxial Anesthesia and Anticoagulation . Park Ridge, IL : American Society of Regional Anesthesia , 1998 . 150 Horlocker TT , Wedel DJ , Benzon H , et al. Regional anesthesia in the anticoagulated patient: defi ning risk (the second ASRA consensus Chapter 21 306 191 Urokinase - Streptokinase Pulmonary Embolism Trial . Phase 2 results. A cooperative study . JAMA 1974 ; 229 : 1606 – 1613 . 192 Sharma GVRK , Cella , G , Parisi AF , et al. Thrombolytic therapy . N Engl J Med 1985 ; 306 : 1268 – 1276 . 193 Moran KT , Jewell ER , Persson AV . The role of thrombolytic therapy in surgical practice . Br J Surg 1989 ; 76 : 298 – 304 . 194 Turrentine MA , Braems G , Ramirez MM . Use of thrombolytics for the treatment of thromboembolic disease during pregnancy . Obstet Gynecol Surv 1995 ; 50 : 534 – 541 . 195 Kawamata K , Chiba Y , Tanaka R , Higashi M , Nishigami K . Experience of temporary inferior vena cava fi lters inserted in the perinatal period to prevent pulmonary embolism in pregnant women with deep vein thrombosis . J Vasc Surg 2005 ; 41 ( 4 ): 652 – 656 . 196 Clark SL , Blatter DD , Jackson GM . Placement of a temporary vena cava fi lter during labor . Am J Obstet Gynecol 2005 ; 193 ( 5 ): 1746 – 1747 . 197 Kramer FL , Teitelbaum G , Merli GJ . Panvenography and pulmonary angiography in the diagnosis of deep venous thrombosis and pulmonary thromboembolism . Radiol Clin North Am 1986 ; 24 : 397 – 418 . 198 Hux CH , Wagner R , Rattan P , et al. Surgical treatment of thrombo- embolic disease in pregnancy . Proceedings of the Society of Perinatal Obstetricians, January 30 – February 1, 1986 : 62 . 199 Brandt P . Observations during the treatment of antithrombin III defi cient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion . Thromb Res 1981 ; 22 : 15 – 24 . 200 Hellgren M , Tengborn L , Abildgaard U . Pregnancy in women with congenital antithrombin III defi ciency: experience of treatment with heparin and antithrombin . Obstet Gynecol Invest 1982 ; 14 : 127 – 130 . 201 Samson D , Stirling Y , Woolf L , et al. Management of planned preg- nancy in a patient with congenital antithrombin III defi ciency . Br J Haematol 1984 ; 56 : 243 – 249 . 202 Leclerc JR , Geerts W , Panju A , et al. Management of antithrombin III defi ciency during pregnancy without administration of anti- thrombin III . Thromb Res 1986 ; 41 : 567 – 573 . 203 Schwartz RS , Bauer KA , Rosenberg RD , et al. Clinical experience with antithrombin III concentrate in treatment of congenital and acquired defi ciency of antithrombin . Am J Med 1989 ; 87 ( suppl 3B ): 535 – 605 . 204 Conrad J , Horellou MH , van Dredan P , et al. Thrombosis and preg- nancy in congenital defi ciencies in antithrombin III, protein C or protein S: study of 78 women . Thromb Haemost 1990 ; 63 : 319 – 320 . 205 Rose PG , de Moerloose PA , Bounameaux H . Protein S defi ciency in pregnancy . Am J Obstet Gynecol 1986 ; 155 : 140 – 141 . 206 Malm J , Laurell M , Dahlbeck B . Changes in the plasma levels of vitamin K dependent protein C and S and of C4b - binding protein during pregnancy and oral contraception . Br J Haematol 1988 ; 68 : 437 – 443 . 207 Lao TT , Yuen PMP , Yin JA . Protein S and protein C levels in Chinese women during pregnancy, delivery, and puerperium . Br J Obstet Gynaecol 1989 ; 96 : 167 – 170 . 208 Lao TT , Yin JA , Ng WK , Yuen PMP . Relationship between maternal antithrombin III and protein C/protein S levels before, during, and after delivery . Gynecol Obstet Invest 1990 ; 30 : 87 – 90 . 209 Tharakan T , Baxi LV , Dinguid D . Protein S defi ciency in pregnancy. A case report . Am J Obstet Gynecol 1993 ; 168 : 141 – 142 . 171 Hirsch J . The optimal duration of anticoagulant therapy for venous thrombosis . N Engl J Med 1995 ; 332 : 1710 – 1711 . 172 Barbour LA , Smith JM , Marar RA . Heparin levels to guide throm- boembolism prophylaxis during pregnancy . Am J Obstet Gynecol 1995 ; 173 : 1869 – 1873 . 173 Nelson DM , Stempel LE , Fabri PJ , et al. Hickman catheter use in a pregnant patient requiring therapeutic heparin antiocoagulation . Am J Obstet Gynecol 1984 ; 149 : 461 – 462 . 174 Barss VA , Schwartz PA , Greene MF , et al. Use of the subcutaneous heparin pump during pregnancy . J Reprod Med 1985 ; 30 : 899 – 901 . 175 Daniel DG , Campbell H , Turnbull AC . Puerperal thromboembolism and suppression of lactation . Lancet 1967 ; 2 : 287 – 289 . 176 Jeffcoate TNA , Miller J , Roos RF , Tindall VR . Puerperal thrombo- embolism in relation to the inhibition of lactation by oestrogen therapy . BMJ 1968 ; 4 : 19 – 22 . 177 Howell R , Fidler J , Letsky E , de Swiet M . The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial . Br J Obstet Gynaecol 1983 ; 90 : 1124 – 1128 . 178 Quinones JN , James DN , Stamilio DM , Cleary KL , Macones GA . Thromboprophylaxis after cesarean delivery: a decision analysis . Obstet Gynecol 2005 ; 106 ( 4 ): 733 – 740 . 179 Casele H , Grobman WA . Cost - effectiveness of thromboprophylaxis with intermittent pneumatic compression at cesarean delivery . Obstet Gynecol 2006 ; 108 ( 3 Pt 1 ): 535 – 540 . 180 Collins R , Scrimgeour A , Peto R . Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin . N Engl J Med 1988 ; 318 : 1162 – 1173 . 181 Kakkar VV , Stamatatkis JD , Bentley PG , et al. Prophylaxis for post- operative deep - vein thrombosis: synergistic effect of heparin and dihydroergotamine . JAMA 1979 ; 241 : 39 – 42 . 182 Salzman EW , Hirsh J . Prevention of venous thromboembolism . In: Colman RW , Hirsh J , Marder VJ , Slazman EW , eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice , 2nd edn . Philadelphia : JB Lippincott , 1987 : 1252 – 1264 . 183 Stringer MD , Kakkar VV . Prevention of venous thromboembolism . Herz 1989 ; 14 : 135 – 147 . 184 Clark - Peterson DL , Synan IS , Dodge R , et al. A randomized trial of low - dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis after gynecologic oncol- ogy surgery . Am J Obstet Gynecol 1993 ; 168 : 1146 – 1154 . 185 European Fraxiparin Study (EFS) Group . Comparison of a low molecular weight heparin and unfractionated heparin for the pre- vention of deep vein thrombosis in patients undergoing abdominal surgery . Br J Surg 1988 ; 75 : 1058 – 1063 . 186 Hirsch J , Barrowcliffe TW . Standardization and clinical use of LMW heparin . Thromb Haemost 1988 ; 59 : 333 – 337 . 187 Salazar E , Zajarias A , Gutierrez N , et al. The problem of cardiac valve prostheses, anticoagulants, and pregnancy . Circulation 1984 ; 70 ( suppl I ): 169 – 177 . 188 Nelson DM , Stempel LE , Brandt JT . Hereditary antithrombin III defi ciency and pregnancy: report of two cases and review of the literature . Obstet Gynecol 1985 ; 65 : 848 – 853 . 189 De Stefano V , Leone G , DeCarolis S , et al. Management of pregnancy in women with antithrombin III congenital defect: report of four cases . Thromb Haemost 1988 ; 59 : 193 – 196 . 190 Negus D , Friedgood A , Cox SJ , et al. Ultra - low dose intravenous heparin in the prevention of postoperative deep - vein thrombosis . Lancet 1980 ; 1 : 891 – 894 . Thromboembolic Disease 307 210 Faught W , Garner P , Jones G , Ivey B . Changes in protein C and protein S levels in normal pregnancy . Am J Obstet Gynecol 1995 ; 172 : 147 – 150 . 211 Goodwin TM , Gazit G , Gordon EM . Heterozygous protein C defi - ciency presenting as severe protein C defi ciency and peripartum thrombosis: successful treatment with protein C concentrate . Obstet Gynecol 1995 ; 86 : 662 – 664 . 212 Rosove MH , Brewer PM . Antiphospholipid thrombosis: clinical course after the fi rst thrombotic event in 70 patients . Ann Intern Med 1992 ; 117 : 303 – 308 . 213 Khamastha MA , Cuadrado MJ , Mujic F , et al. The management of thrombosis in antiphospholipid antibody syndrome . N Engl J Med 1995 ; 332 : 993 – 997 . 214 Schulman S , Svenungsson E , Granqvist S . Duration of Anticoagulation Study Group. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous throm- boembolism following anticoagulant therapy . Am J Med 1998 ; 104 : 332 – 338 . 308 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 22 Etiology and Management of Hemorrhage Irene Stafford 1 , Michael A. Belfort 2 & Gary A. Dildy III 3 1 Maternal - Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA 2 Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT and HCA Healthcare, Nashville, TN, USA 3 Maternal - Fetal Medicine, Mountain Star Division, Hospital Corporation of America, Salt Lake City, UT and Department of Obstetrics and Gynecology, LSU Health Sciences Center, School of Medicine in New Orleans, New Orleans, LA, USA In patients with major obstetric hemorrhage, three measures must be promptly taken: identify the cause, arrest the bleeding and management of hypovolemia, anemia and coagulopathy. Continued hemorrhage, particularly if concealed or underesti- mated, may result in the onset of irreversible shock. Although the percentage of death caused by hemorrhage decreased by approximately one - third between 1979 – 1986 and 1991 – 1997, it continues to be a leading cause of pregnancy - related mortality [1 – 3] . An estimated 140,000 women worldwide die every year from postpartum hemorrhage, with over 50% of these occurring within the fi rst 24 hours after delivery [4] . Postpartum hemor- rhage remains among the top three causes of maternal deaths in the United States, with life - threatening hemorrhage occurring in 1 in 1000 deliveries [5] . The major obstetric causes for ante- partum hemorrhage are placental abruption and placenta previa, while postpartum hemorrhage is most commonly caused by uterine atony, retained placenta, and genital tract lacerations. Other less common but sometimes more serious causes include uterine rupture, uterine inversion and abnormal placental inva- sion (placenta accreta, increta, and percreta). Management of these conditions along with management of hemorrhage related to inherited or acquired bleeding disorders will be discussed in this chapter. Conditions caused by pregnancy (HELLP syn- drome, acute fatty liver of pregnancy, amniotic fl uid embolism) and disseminated intravascular coagulation are discussed in other chapters. Massive hemorrhage may also result from surgical causes in pregnant or postpartum women. These include liver rupture in HELLP syndrome, and rupture of aortic, splenic, and renal artery aneurysms. Although rare, these should be considered in patients with hemorrhagic shock and concealed bleeding in whom an obstetric cause such as abruption, pelvic hematoma or uterine rupture is unlikely. Placental a bruption Placental abruption is defi ned as the premature separation of a normally situated placenta, and may be partial or complete. The underlying mechanism is unknown, but most explanations center around vascular or placental abnormalities, including increased fragility of vessels, vascular malformations or abnormal placenta- tion [6,7] . Often, in the acute setting, the etiology of abruption may be clear. For example, shearing forces are most likely respon- sible for abruption resulting from trauma. There is strong evi- dence linking abruption to abnormal fi rst - trimester changes, suggesting that abruption may be chronic in nature. Abnormal serum analytes and placental biology studies support this notion [8] . Hemorrhage occurs into the decidua basalis, forming a hema- toma which splits the decidua [9] . As the hematoma expands, further placental separation ensues. Large Epidemiol ogic studies report an incidence ranging from 5.9 to 6.5 per 1000 singleton births and 12.2 per 1000 twin births [10] . Discrepancies in rates of abruption are reported, mainly because abruption can also be discovered upon histologic examination of the placenta in other- wise normal pregnancies. Pre - eclampsia is the most common risk factor and is found in approximately 50% of women with placen- tal abruption [11] . Other risk factors include preterm premature rupture of membranes, polyhydramnios, advanced maternal age, cocaine use, smoking, multiparity, chorioamnionitis, blunt trauma and possibly thrombophilias. Black women are more at risk than other population groups [12,13] . Bleeding in the fi rst trimester has been linked with increased rates of abruption later in pregnancy [14,15] and there is approximately a 10% recur- rence rate during a subsequent pregnancy. Placental abruption is associated with multiple adverse perinatal outcomes including a ninefold increased risk of intrauterine fetal demise, a threefold rise in preterm birth and a twofold increase in growth restriction. The risk of stillbirth has been found to correlate with the extent of placental separation, with higher rates of death associated with . throm- boembolism following anticoagulant therapy . Am J Med 1998 ; 104 : 332 – 338 . 308 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan. of the value of monitoring heparin treatment with the activated partial thrombo- plastin time . N Engl J Med 1972 ; 287 : 324 – 327 . 124 Hyers TM , Hull RD , Weg JG . Antithrombotic therapy. Dallas, TX, USA 2 Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT and HCA Healthcare, Nashville, TN,