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Dildy. © 2010 Blackwell Publishing Ltd. 21 Thromboembolic Disease Donna Dizon - Townson Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT and Intermountain Healthcare, Department of Maternal - Fetal Medicine, Provo, UT, USA Pulmonary embolism (PE), albeit a rare event, remains the leading cause of maternal mortality in the United States [1,2] . Furthermore, deep venous thrombosis (DVT) can cause signifi - cant morbidity [3] . Pregnancy - related venous thromboembolism (VTE) has been reported to occur in approximately 0.5 – 3.0 per 1000 pregnancies based on studies using radiographic documen- tation [4 – 6] . Clinical symptomatology should be confi rmed with objective testing. Almost 75% of patients who present with sus- pected thromboembolic disease, and are then subjected to testing such as Doppler ultrasound or venography, are found not to have the condition [7] . When DVT is diagnosed and heparin treat- ment instituted, the incidence of PE and maternal mortality can be decreased by threefold and 18 - fold, respectively. The goal of this review is to facilitate the recognition of the clinical signs and symptoms of VTE disorders, describe a rational approach to the work - up of a suspected hypercoagulable state, and review the use of various diagnostic and treatment modalities. Incidence and r isk f actors Although many studies about maternal mortality cite PE as the leading cause, they do not distinguish VTE from amniotic fl uid or air embolism [8 – 10] . At least half of these deaths are due to thrombotic embolism [9,11 – 15] . During 1991 – 1999, a total of 4200 deaths were determined to be pregnancy related. The overall pregnancy - related mortality ratio was 11.8 deaths per 100,000 live births and ranged from 10.3 in 1991 to 13.2 in 1999. The leading causes of pregnancy - related death were embolism (20%), hemor- rhage (17%), and pregnancy - induced hypertension (16%). The leading causes of death among women who died after a live birth (60% of all pregnancy - related deaths) were embolism (21%), pregnancy - induced hypertension (19%), and other medical con- ditions (17%) 2 (Table 21.1 ). As illustrated in Figure 21.1 , from 1970 to 1985, maternal mortality rates from PE declined by 50% [9] . The traditionally held view is that the maternal risk for VTE is greater in the imme- diate puerperium, especially following cesarean delivery. Postpartum DVT has been reported to occur 3 – 5 times more often than antepartum DVT, and 3 – 16 times more frequently after cesarean as opposed to vaginal delivery [16,17] . In contrast, Rutherford and associates found that the highest incidence of pregnancy - related VTE was not in the puerperium but in the fi rst trimester of pregnancy [18,19] (Figure 21.2 ). These authors also found that the risk of DVT did not increase with advancing ges- tational age but stayed relatively constant (see Figure 21.2 ). In contrast, PE (Figure 21.3 ) was almost twice as likely to occur in the postpartum patient and appeared to be related to the route of delivery. More recently, Gerhardt and colleagues reported on 119 women with a pregnancy - related VTE [20] . Approximately half (62 women) experienced a DVT during pregnancy: 14 (23%) in the fi rst trimester, 13 (21%) in the second trimester, and 35 (56%) in the third trimester. The other half (57 women) experi- enced a DVT in the immediate puerperium: 38 (68%) following vaginal delivery and 19 (32%) following cesarean section. In summary, pregnancy - related VTE may occur at any time during pregnancy or the immediate puerperium. A recent 30 - year pop- ulation - based study of trends in the incidence of VTE during pregnancy and post partum confi rmed the signifi cant riks of VTE during the puerperium [21] . Although the incidence of PE has decreased over time, the incidence of DVT is unchanged. Therefore, regardless of gestational age, the clinician should have a heightened awareness for the diagnosis when a gravid or post- partum woman presents with clinical symptomatology suspicious for VTE. Important risk factors for VTE during pregnancy are immobil- ity and bed rest. “ Bed rest ” is often recommended for a variety of obstetric disease such as threatened preterm labor or pre - eclampsia. The clinician should keep in mind the increased risk for VTE when making recommendations for limited maternal physical activity or long distance travel. Traveling long distances by air may also increase a pregnant woman ’ s risk of a PE. Chapter 21 284 Additional risk factors in the gravid woman include surgery, trauma or a prior history of superfi cial vein thrombosis [22] . Ethnic background and maternal age are important risk factors for PE. The overall mortality rate for black women was 3.2 times higher than for white women. In addition, women 40 years or older were at a 10 times greater risk of mortality than women under 25 for both ethnic groups [9] (Figure 21.4 ). Recent preg- nancy surveillance has confi rmed that pregnancy - related mortal- ity ratios continued to be 3 – 4 times higher for black women than 7 6 5 4 3 2 1 0 1970–73 1974–77 1978–81 1982–85 Date Embolism deaths Figure 21.1 Maternal deaths due to pulmonary embolism per 100,000 births from 1970 to 1985. (Reproduced by permission from Franks AL, Atrash AK, Lawson, et al. Obstetrical pulmonary embolism mortality. United States 1970 – 1985. Am J Publ Health 1990; 80: 720 – 722.) 70 60 50 40 30 20 10 0 First Second Third Postpartum Trimester Frequency (%) Figure 21.2 Distribution of deep venous thrombosis and pulmonary embolism during each trimester of pregnancy: an 11 - year review. (Reproduced by permission from 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.) Table 21.1 Causes of pregnancy - related death, by outcome of pregnancy and pregnancy - related mortality ratios ( PRMR * ). United States, 1991 – 1999. Cause of death Outcome of pregnancy (% distribution) All outcomes Live birth Stillbirth Ectopic Abortion † Molar Undelivered Unknown % PRMR (n = 2519) (n = 275) (n = 237) (n = 165) (n = 14) (n = 438) (n = 552) (n = 4200) Embolism 21.0 18.6 2.1 13.9 28.6 25.1 18.3 19.6 2.3 Hemorrhage 2.7 21.1 93.3 21.8 7.1 8.7 8.7 17.2 2.0 PIH § 19.3 20.0 0 0.6 0 12.3 11.8 15.7 1.8 Infection 11.7 18.9 2.5 33.9 14.3 11.0 12.9 12.6 1.5 Cardiomyopathy 10.1 5.1 0.4 1.8 0 3.4 11.2 8.3 1.0 CVA ¶ 5.7 0.7 0 1.2 0 3.9 8.5 5.0 0.6 Anesthesia 1.8 0.7 1.3 9.7 0 0 0.4 1.6 0.2 Other * * 17.1 14.9 0.4 16.4 50.0 33.6 27.9 19.2 2.3 Unknown 0.6 0 0 0.6 0 2.1 0.4 0.7 0.1 Total † † 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 11.8 * Pregnancy - related deaths per 100 000 live births. † Includes spontaneous and induced abortions. § Pregnancy - induced hypertension. ¶ Cerebrovascular accident. * * The majority of the other medical conditions were cardiovascular, pulmonary, and neurologic problems. † † Percentages might not add to 100.0 because of rounding. Reproduced by permission from Chang J, Elam - Evans LD, Berg CJ, et al. Pregnancy - related mortality surveillance – United States 1991 – 1999. MMWR 2003; 52(SSO2): 1 – 8. Thromboembolic Disease 285 (unprovoked) had an antepartum recurrence rate of 5.9% (95% CI 1.2 – 16%). It is assumed that the risk of recurrence diminishes as the time from initial event increases. The mean time from initial event to enrollment in the study was 4 years. In another study, on a cohort of 1104 women with previous VTE, 88 of them became pregnant and did not receive thromboprophylaxis. There were nine recurrences during pregnancy and 10 during the puer- perium, with a rate of 5.8% (95% CI 3.0 – 10.6). In pregnancy, the recurrence rate was 7.5% (95% CI 4.0 – 13.7) if the fi rst VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the fi rst VTE related to other transient risk factors [25] . Inherited and acquired thrombophilias are additional risk factors for VTE. The inherited thrombophilias include defi cien- cies of protein C, protein S, and antithrombin III, factor V Leiden, prothrombin G20210A, and the 5,10 - methylenetetrahydrofolate reductase mutations. The most commonly investigated acquired thrombophilia is the antiphospholipid syndrome. In summary, the risk of VTE varies among pregnant women, therefore individualization of management must be emphasized. This risk will depend not only on the pregnancy, but also on additional clinical factors such as a prior history of thromboem- bolism, mode of delivery, prolonged immobilization, age, and ethnicity (Table 21.2 ). In the presence of a personal or familial history of VTE, testing for thrombophilia should be accom- plished to better defi ne the specifi c risk. A comprehensive throm- bophilia work - up should include testing for functional defi ciencies of protein C, protein S, and antithrombin III. These tests should be performed preferably when the patient is not pregnant and prior to anticoagulation. In addition, molecular tests for factor V Leiden and the prothrombin G20210A mutation, which are unaf- fected by pregnancy or anticoagulation, should also be performed. To complete the evaluation, screening for antiphospholipid syn- drome with testing for IgG and IgM anticardiolipin antibodies and lupus anticoagulant should be included. A positive test for antiphospholipid syndrome appears to carry the greatest impact on maternal and fetal outcome in subsequent pregnancies. Normal h emostasis Few systems are more complex than hemostasis. Interactions among the vessel wall, platelets, and soluble molecules in the for white women [2] . In addition, the pregnancy - related mortal- ity ratios for black women aged > 39 years were particularly high in comparison with white women in the same age group [2] . Blood groups A and AB may be associated with an increased risk for VTE during pregnancy [23] . A prior history of a VTE confers a greater risk for recurrence especially if the initial event was idiopathic or associated with a hereditary or acquired thrombophilia [24] . In a prospective cohort study investigating the risk of recurrence of pregnancy - related VTE in 125 women who had a history of VTE, heparin was withheld antepartum but administered 6 weeks postpartum in all women. The antepartum recurrence rate was 2.4% (95% CI 0.2 – 6.9%). There were no recurrences in the 44 patients (0%: 95% CI 0.0 – 8.0%) who did not have thrombophilia and had a previous episode of thrombosis that was associated with a tem- porary risk factor. Patients with a positive result for thrombo- philia and/or a previous episode of thrombosis that was idiopathic Deep venous thrombosis Pulmonary embolism 0 10 20 30 40 50 60 70 80 90 100 Frequency (%) Cesarean section Vaginal delivery Figure 21.3 The frequency of postpartum deep venous thrombosis and pulmonary embolism according to route of delivery. (Reproduced by permission from Rutherford SE, Montoro M, McGehee W, et al. Thromboembolic disease associated with pregnancy: an 11 - year review. Am J Obstet Gynecol 1991;164:286.) 20–24 White Black * Deaths per 100,000 live births 0 20 40 60 80 100 120 140 160 180 £19 ≥4025–29 Age group (yrs) Ratio 30–34 35–39 Figure 21.4 Pregnancy - related mortality ration, by age and race – United States, 1991 – 1999. (Reproduced by permission from Chang J, Elam - Evans LD, Berg CJ, et al. Pregnancy - related mortality surveillance – United States 1991 – 1999. MMWR 2003; 52(SSO2): 1 – 8.) Table 21.2 Factors associated with a higher risk of pulmonary embolism. Maternal age Ethnic background Operative delivery Prior thromboembolism Prolonged immobilization Inherited/acquired coagulation disorders Trauma Chapter 21 286 The intrinsic and extrinsic pathways lead to the fi nal common clotting pathway. Both pathways are activated by components of the vessel wall and lead to activation of progressive exponential increase in subsequent factors. In the intrinsic pathway, high molecular weight kininogen and kallikrein are cofactors for the initial step of the process, the activation of factor XII (XIIa). By catalyzing the formation of kallikrein from prekallikreins, factor XIIa also helps to initiate fi brinolysis, activate the complement system, and produce kinins [26] . Factor XI is activated by XIIa and then cleaves factor IX to form IXa. In comparison, the extrin- sic pathway is so named because this pathway relies on tissue thromboplastin as a cofactor. Tissue thromboplastin is released into the circulation following membrane damage or proteolysis [26] . Factor VII is then activated to VIIa which, with tissue thromboplastin, can activate factors IX or X. The common pathway begins with activation of factor X by either VIIa or IXa, in combination with the protein cofactor VIII:C (the antihemo- philic factor) and the calcium ion, on the platelet surface (to form PF 3 ). Factor Xa, assisted by cofactor Va, enzymatically divides prothrombin into thrombin and a peptide activation fragment, F 1 + 2 . Separation from this fragment liberates thrombin into the fl uid phase. Thrombin catalyzes the formation of fi brin mono- mers from fi brinogen and, thus, releases fi brinopeptides A and B and facilitates activation of V, VIII:C, and XIII. A fi brin gel is created by the hydrophobic and electrostatic interactions of the fi brin α and γ chains. Subsequently, factor XIIIa forms covalent bonds linking nearby α and γ chains to form a stable polymerized fi brin clot into which water is also incorporated. Trapped within the clot are proteins that contribute to the enzymatic digestion of the fi brin matrix: plasminogen and plas- minogen activators. A variety of substances can activate plas- minogen. Plasma plasminogen activator is activated by factor XIIa. Release of tissue activators (tissue plasminogen activator) from blood vessel epithelium (especially venous) is stimulated by exercise, emotional stress, trauma, surgery, hypotensive shock, pharmacologic agents, and activated protein C [17,26,31] . The fi brinolytic enzymes streptokinase and urokinase also activate plasminogen [32] . Having been activated from plasminogen, plasmin cleaves arginyl - lysine bonds in many substrates, includ- ing fi brogen, fi brin, factor VIII, and complement [32,33] . The result of plasmin action on fi brin and fi brinogen is release of protein fragments, referred to as fi brinogen degradation products (or fi brin split products). The larger fragments, which may have slow clotting activity, are further divided by plasmin. These frag- ments have anticoagulant activity, in that they inhibit the forma- tion and cross - linking of fi brin [26] . Measurement of fi brin degradation products provides an indirect measurement of fi bri- nolysis. α 2 antiplasmin, a specifi c plasmin inhibitor that binds to fi brin and fi brinogen, is found in serum, platelets, and within the clot, along with other inhibitors of plasmin or plasminogen activity [32] . As a potent inhibitor of thrombin, antithrombin III (AT III) is important in the regulation of hemostasis. In decreasing affi n- ity, AT III binds and inactivates factors IXa, Xa, XIa, and XIIa. vicinity of an injury work to repair the vessel defect without sacrifi cing nearby vessel patency. The key processes are: (i) vasoconstriction; (ii) formation of a platelet plug; (iii) formation of a stable “ seal ” by coagulation factors; (iv) prevention of spread of the clot along the vessel wall; (v) prevention of occlusion of the vessel by clots when possible; and (vi) remodel- ing and gradual degradation of the clot after it is no longer needed. The maintenance of normal blood fl ow requires intact, patent blood vessels. After an injury, the hemostatic and fi brinolytic systems work together to protect vascular integrity and assist in repair. Vessel wall integrity, platelet aggregation, normal function of the coagulation cascade, and fi brinolysis are all vital to this process. The initial response to injury is vasoconstriction, which reduces local blood fl ow and limits the size of the defect that the thrombus is required to seal [26] . After platelets begin to adhere to the exposed vessel wall, they change shape and secrete the contents of their granules. This action leads to further platelet accumulation or aggregation, and results in the formation of a platelet plug. The numerous substances released by platelets include throm- boxane A 2 (TxA 2 ), a potent vasoconstrictor and preaggregatory agent [27,28] ; serotonin, a vasoconstrictor [28] ; and adenosine diphosphate (ADP), which enhances platelet aggregation. Platelets also produce vascular permeability factor and platelet growth factor, which stimulate fi broblasts and vascular smooth muscles [17,26] . Released platelet factor 4 (PF 4 ) and β - thromboglobulin are used as markers of platelet activity [29,30] . The platelet contractile protein, thrombasthenin, enables secre- tion of these substances and also enhances clot retraction [17] . A platelet surface phospholipoprotein, platelet factor 3 (PF 3 ), becomes available to bind factor V to catalyze the formation of thrombin. Thrombin, in turn, potentiates platelet aggregation [30] . Whereas TxA 2 is the result of platelet arachidonic acid metabo- lism, arachidonic acid in endothelial cells is metabolized to pros- tacyclin (PGI 2 ). Prostacyclin inhibits aggregation and stimulates vasodilation, and thus counteracts TxA 2 by increasing cyclic ade- nosine monophosphate (AMP) [26] . Because PGI 2 is concen- trated within the vessel wall, the greater the distance from the lumen, the lower the concentration of PGI 2 and the higher the concentration of proaggregatory substances. As platelets begin to seal a vascular defect, the coagulation cascade produces fi brin, which is polymerized as clot and incorporated into the platelet plug. Proteolytic cleavage or conformational changes activate the circulating clotting factors at the site of injury. Factors II, VII, IX, and X require a vitamin K - dependent reaction in the liver in which γ - carboxyglutamic acid residues are attached to the protein structure. This action provides a location to form a complex with calcium ion and phospholipid receptors on the platelet or endo- thelial cell membranes. Subsequent steps in the clotting cascade occur at those sites and include the formation of thrombin. Once formed, this is released into the fl uid phase. Thromboembolic Disease 287 suggest ongoing increased fi brinolytic activity [40] . Within an hour of delivery, this fi brinolytic potential decreases, as a result of placental inhibitors [41] , and returns to normal. These changes are believed to contribute to the hypercoagulability of the puer- perium [18,19] . Levels of factors XI and XIII decrease. When the placenta separates, tissue thromboplastin is released into the cir- culation, increasing the chance for thrombosis [42] . Additional factors balancing the increased tendency toward coagulation may be a pregnancy - specifi c protein (PAPP - A) which, like heparin, facilitates neutralization of thrombin by AT III [34] . Platelet counts appear to remain in the normal range during pregnancy, but have been documented to be signifi cantly higher than prede- livery on days 8 and 12 after vaginal delivery, and continued to rise 16 days after a cesarean delivery [43] . The platelet count remained signifi cantly higher than predelivery values for 24 days after cesarean delivery [43] . Thrombophilias Approximately half of the women who have a pregnancy - related VTE possess an underlying congenital or acquired thrombophilia [44] . In almost 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an addi- tional risk factor such as pregnancy, oral contraceptive use, orthopedic trauma, immobilization or surgery [45,46] . Antithrombin III defi ciency, although the most rare of the congenital thrombophilias, is the most thrombogenic conferring a 50% lifetime and pregnancy - related risk for thrombosis [47] . AT III defi ciency occurs in approximately 0.02 – 0.17% of the general population and 1.1% of individuals with a history of VTE. Defi ciencies of protein C and protein S, although less thrombo- genic than AT III defi ciency, are more common [47] . Carrier rates for defi ciencies of protein C and S are 0.14 – 0.5% in the general population. In individuals who have had a history of VTE, 3.2% will have either protein C or protein S defi ciency. As a result of the Human Genome Project and major advances in gene identifi cation, common genetic predispositions to thrombophilia, including factor V Leiden and the prothrombin G20210A mutation, have been described. Resistance to APC is now known to be the most common genetic predisposition to AT III acts as a substrate for these serine proteases but forms stable intermediate bonds with the active portion and, thus, neu- tralizes the respective enzyme [34] . Heparin binds to AT III and induces a conformational change that increases the affi nity of AT III for thrombin. The otherwise slow inactivation of thrombin by AT III is accelerated greatly by even small amounts of heparin. After a stable thrombin – AT III complex is formed, heparin is released and available for repetitive catalysis. Excess amounts of AT III are normally present in the circulation, and some are bound to endothelial cell membranes via heparan, a sulfated mucopolysaccharide with a function similar to heparin. The pres- ence of heparan on intact endothelial cell surfaces and its binding to AT III, which neutralizes thrombin, help to prevent local extension of the thrombus beyond the sites of vessel injury [35] . Defi ciency of AT III leads to a substantially higher incidence of thrombotic events [36] . Proteins C and S are normally part of the protein C anticoagu- lant system. Like certain clotting factors, their synthesis depends on vitamin K and involves addition of γ - carboxyglutamic acid residues that enable binding, via calcium ions, to cell surfaces. Protein C is attached to endothelial cells, and protein S is attached to endothelial and platelet membranes. Endothelial cell surfaces also have a specifi c protein receptor for thrombin – thrombo- modulin. The binding of thrombin to thrombomodulin, in the presence of protein S, activates protein C (APC) and promotes anticoagulation. Complexes of APC and adjacently bound protein S cofactor proteolyze the phospholipid - bound factors VIII:Ca and Va. This action results in a second mechanism to prevent extension of the thrombus beyond the area of vessel injury [35] . Defi ciencies of either protein C or S are associated with an increase in thromboembolic events [35,37] . Homozygosity of protein C defi ciency leads to fatal neonatal purpura fulminans [38] . Changes in h emostasis in p regnancy A century ago, Virchow described the triad of blood hypercoagu- lability, venous stasis, and vascular damage conferring an increased risk for thrombosis. All these conditions occur during pregnancy, thus conferring an increased risk for pregnancy - related VTE (Table 21.3 ). Estrogen stimulation of hepatic synthe- sis of several procoagulant proteins increases with pregnancy. Levels of factors V, VII, VIII, IX, X, XII, and fi brinogen increase. Venous stasis secondary to progesterone - mediated smooth muscle vascular relaxation and mechanical compression by the gravid uterus occurs. Placental separation and operative delivery can cause endothelial vascular damage. Compensatory mechanisms such as concomitant rise in fi bri- nolytic activity help to maintain coagulation equilibrium [39] . As pregnancy progresses, a low - grade chronic intravascular coagula- tion results in fi brin deposition in the internal elastic lamina and smooth muscle cells of the spiral arteries of the placental bed [40] . Increased fi brin split products and d - dimers during this period Table 21.3 Hemostatic changes during pregnancy. Hemostatic changes promoting thrombosis Increased levels of factor V, VII, VIII, IX, X, XII, fi brinogen Placental inhibitors of fi brinolysis Tissue thromboplastin released into the circulation at placental separation Venous stasis of the lower extremities Endothelial damage associated with parturition Hemostatic changes countering thrombosis Decreased levels of factor XI, XIII Pregnancy - specifi c protein neutralizing AT III Chapter 21 288 of 104 women with a median postthrombosis interval of 11 years revealed that 4% had ulceration, and only 22% were without complaints [57] . Finally, it is important to remember that preg- nant patients commonly complain of swelling and leg discomfort and, as such, do not require objective testing in every instance. It is important to remember that the fi rst sign of DVT may be the occurrence of a PE. In a similar manner, silent DVT has been found in 70% of patients with angiographically proven PE [58] . During the initial evaluation in a pregnant patient with clinical symptomatology suspicious for a pregnancy - related VTE, risk factors as described above should be sought. Again “ bed rest ” or limited physical activity, which is frequently recommended for a variety of obstetric diseases, is a common risk factor for VTE events. Diagnostic s tudies Ultrasound Non - invasive testing is usually the fi rst step in confi rming the diagnosis of DVT. Real - time imaging with compression ultra- sound (CUS), including duplex Doppler, is the method of choice. CUS uses fi rm compression with the ultrasound transducer probe to detect an intraluminal defect. Experience is required for accu- rate interpretation, and the affected leg should be compared with the unaffected one. Maneuvers such as Valsalva (which distends the vein and slows proximal fl ow), release of pressure over a distal vein (which causes a rapid proximal fl ow of blood), and squeez- ing of the muscles all cause changes in Doppler shift. Real - time imaging in the presence of DVT may detect a mass in the vessel lumen, a failure of the lumen diameter to increase with Valsalva or a failure of the vein to compress with pressure [59] . Alternatively, imaging may identify a hematoma, popliteal cyst or other pathology to explain the patient ’ s symptoms. In a symp- tomatic non - pregnant individual, CUS has a sensitivity of 95% for proximal DVT (73% for distal DVT) and specifi city of 96% for detecting all DVT, with a negative predictive value of 98% and a positive predictive value for 97% in the non - pregnant symp- tomatic patient [60] . At least 50% of small calf thrombi are missed due to collateral venous channels [61,62] . Repeating the examination within 2 – 3 days may reveal a previously latent clot. During pregnancy, the iliac vessels are especially diffi cult to image. This is due to pressure from the gravid uterus on the inferior vena cava. As a result, Doppler fi ndings must be inter- preted cautiously. In the puerperal patient, imaging may visualize thrombosis [48 – 50] . Eighty to 100% of cases of resistance to APC are due to the factor V Leiden mutation. This is a missense muta- tion in the gene encoding factor V protein. Individuals with factor V Leiden have normal levels of factor V protein, but this protein is resistant to the normal degradation by APC. The abnormal factor V protein fails to undergo the normal conformation change required for the proteolytic degradation by APC. Heterozygous carriers have a sevenfold increase in the risk for venous throm- bosis, whereas homozygous carriers have an 80 - fold increased risk. Carrier rates for factor V Leiden are 6 – 8% in northern Europeans and 4 – 6% in US Caucasians [51,52] . In the largest prospective observational study, 134 heterozygous carriers for the FVL mutation were identifi ed among 4885 gravidas (2.7%) with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation car- riers (0%, 95% CI 2.7%). Three pulmonary emoboli and one deep venous thrombosis occurred (0.08%, 95% CI 0.02 – 0.21%), all in FVL non - carriers. Thus, although the FVL is a rather common mutation in the Caucasian population, the relative risk of a pregnancy - related thromboembolic event in a heterozygote carrier is low [53] . Another mutation in the 3 ′ untranslated region of the prothrombin gene, prothrombin G20210A, leads to elevated prothrombin levels ( > 155%) and a 2.1 - fold increase in the risk for thrombosis. The prevalence of the mutation in the Caucasian population is 2%. The prevalence of the mutation is 6% among unselected patients with thrombosis and about 18% in families with unexplained thrombophilia. Deep v enous t hrombosis Clinical d iagnosis In the gravid patient, DVT appears to occur more often in the deep proximal veins and has a predilection for the left leg [15,54,55] . The clinical diagnosis of DVT [56] is diffi cult and requires objective testing. Of those patients with clinically sus- pected DVT, half will not be confi rmed by objective testing. Due to the long - term implications of anticoagulant therapy and the expense of a hypercoagulable work - up, clinical symptomatology of VTE should usually be confi rmed with objective testing before a diagnosis is rendered. Symptoms and signs of DVT are illustrated in Table 21.4 . Swelling is considered whenever there is at least a 2 cm measured difference in circumference between the affected and normal limbs. Homan ’ s sign is present when passive dorsifl exion of the foot in a relaxed leg leads to pain, presumably in the calf or pop- liteal areas. The Lowenberg test is positive if pain occurs distal to a BP cuff rapidly infl ated to 180 mmHg. The presence of marked swelling, cyanosis or paleness, a cold extremity or diminished pulses signals the rare obstructive iliofemoral vein thrombosis. DVT has also signifi cant long - term implications, and a prior history of DVT may affect the patient ’ s symptomatology. Years after a severe obstructive DVT, patients may experience postphle- bitic syndrome (skin stasis dermatitis or ulcers). An investigation Table 21.4 Clinical symptoms and signs of lower extremity deep venous thrombosis. Unilateral pain, swelling, tenderness, and/or edema Limb color changes Palpable cord Positive Homan ’ s sign Positive L ö wenberg test Limb size difference > 2 cm . Donna Dizon - Townson Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT and Intermountain Healthcare, Department of Maternal - Fetal. reserve in humans after cardiac trans- plantation . Circulation 1985 ; 71 : 866 – 872 . 283 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy women with history of peripartum cardiomyopathy who did not have an abortion . N Engl J Med 2001 ; 344 : 1567 – 1571 . 130 Elkyam U . Pregnant again after peripartum cardiomyopathy: to be