aoe Chapter 42 THROMBOEMBOLIC DISEASE Russell K. Laros Jr, MD, MSc Thromboernbolic disease is the leading obstetric cause cf postpartum maternal mortality (MacKay et al, 2001), Fortunately, it is also a disease in which early recognition and proper treatment can improve the outcome dramatically. The pregnant patient is unique in that she is actually two patients; consequently, the usual diagnostic and therapeutic maneuvers rust be modified so as not to affect the fetus adversely © INCIDENCE AND PATHOPHYSIOLOGY Incidence Although thrombophlebitis is serious because of its poten= tially fatal consequences, it is, fortunately, rare in young women. Thromboembolism is reported to occur daring preg nancy with a frequency of 0.5 to 3 per thousand. Events occur with equal frequency during the antepartum and postpartum periods. Although earlier studies suggested a postpartum pre~ probably influenced by prolonged bed rest and hospitalization after both vaginal delivery and cesarean section (Barbour and Pickard, 1995), The frequent use of high-dose estrogen for lactation suppression also may have influenced postpartum events. The incidence of pulmonary embolism depends on whether or not deep venous thrombosis (DVT) is adequately treated. Untreated, as many as 24% of patients with antenatal DVT will have’ pulmonary embolism, with a mortality rate of approximately 15% (Wessles, 1976a). If patients are treated ‘with anticoagulants, embolization occurs in only 4.5%, with a mortality rate of less than 1% (Villasanta, 1965). The impor- tance of proper treatment with anticoagulation is cl dominance, these we Pathophysiology More than a century ago, Virchow described a triad of factors that play an essential role in the initiation of intra: vascular coagulation: 1. Injury to the vessel wall 2, Stasis 3. Changes in local clotting factors During pregnancy, thrombosis can occur without any Known abnormality of the endothelium. During the first trimester, however, vein distensibility increases (McCausland etal, 1961); by the third trimester, the velocity of venous flow in the lower extremities is reduced by half, in part because the gravid uterus provides a mechanical impediment to venous return (Wright et al, 1950). This tendency toward stasis is Jif the patient requires periods of prolonged bed rest, lampsia, threatened abortion, or premature labor. aid associates (1965) have shown chat fibrinogen, factor VIUL, and other vieamin K-dependent clotting factors increase during pregnancy. There is evidence of decreased fibrinolytic activity with reduced levels of available circulating plasminogen activator as well (Nilson and Kullander, 1967) Bleeding time, however, is unaffected by pregnancy (Berge ev al,, 1993). The risk of thromboembolism is enhanced by the following factors: & Thrombophilia m Lupus anticoagulant 2 Cesarean section (a ninefold inerease over vaginal delivery) = Lostcument delivery Advanced maternal age sed parity ession of lactation by estrogens Other risk factors reported (Rickles and Edwards, 1983) include the following wm Varicosities 1& Trauma or infection = Obesity © Blood type other than type O Congestive heart failure Dehydration i Shock im Disseminated cancer tm Dysproteinemia . Polycythemia vera Anemia (especially sickle cell) Additionally, a history of a prior thrombotic event in the absence of a predisposing cause or a family history of throm. boembolism suggests the possibility of a defect in the physio logic antithrombotic mechanisms ects in antithrombin III, protein C, protein S, factor V Leiden, pro- thrombin 20210, methylene reductase Jeficiency (MTHER), and plasminogen, as well as the pres- ence of lupus anticoagulant, all predispose to thromboembolic events (Much et al., 1980; Taberino et al., 1991; Florell and Rogers, 1997). Table 42-1 outlines the various inherited thrombotic disorders and their prevalence in patients with thromboembolism. ongenital dh tetrahydeofolate 845846 42Thromboembolic Disease Mu TABLE 42.1, A CLASSIFICATION OF INHERITED THROMBOTIC DISORDERS Prevalence (Patients Deficiency Inheritance with Thromboses) Clinical Features Plasma Factors ati AD 12% vie Protein AD 1-5% vie Protein S aD 1-5% VIE Factor V Leiden AD 20-30% VIE Prothrombin mutation AD 510% VTE and arterial T High factor Vil levals, ? 20-25% Recurrent VTE High factor 1X levels ? 10% vie High factor X levels ? > vie High factor XI levels ? 10% VIE Impaired Clot Lysis Dystibrinogenemia AR 12% Venous T > Arterial T Plasminogen deficiency AD and AR, 2% vie TPA deficiency aD vie ‘Metabolic Defects Homocysteinemia (CS) AR +1300,000 VTE and arterial T Methelene tetiahydrofolate Reductase deficiency AR 0-25% VTE and arterial T (homozygous) £0, autosomal dominant, AR, autosomal wcossive: T, thrombosis; VTE, venous thrmboomolem, ‘Acaoted tom Robsterye AS, Rodgers GM Unde on selected inbred venous thrombotic dsorcers. Am J Hematol 68:256, 2001 Whether or not patients hospitalized and placed at strict bed rest because of premature labor are at an increased risk for venous thromboembolism (VTE) is an area of debate. There is a single publication that reports an incidence of VTE in pre- mature labor patients at bed rest of 15.6 cases per 1,000, con pared with O.8 cases per 1,000 in the remainder of their Pregnant population (Kovacevich et al., 2000). Review of our own data over the past 25 years has not shown increased risk for patients hospitalized with premature labor. Overall, the risk during pregnancy and postpartum is 5.5 times greater than that for nonpregnant. controls (Hathaway and Bonnar, 1987). With the availability of effec- tive contraceptives, mote women are delaying childbearing, and a concomitant increase in the incidence of VTE can be expected because of the increase in maternal age. ® piacnosis It is as important to diagnose thromboembolism as it is difficult. Anticoagulation, although an invaluable therapeutic tool, is not without hazard. Therefore, the physician should be certain of this diagnosis before committing a patient to a lengthy course of treatment. Deep Venous Thrombosis The signs and symptoms most commonly used in the diagnosis of deep venous. thrombosis (DVT) are listed in Table 42-2. Leg swelling is a measured difference between leg circumferences of greater than 2 em. A positive Homans sign is pain in the calf when the great toe is passively dorsiflexed. Unfortunately, many of the complaints listed occur as normal physiologic changes of pregnancy. Ina study by Haeger (1969), not only were none of these symptoms or signs specific hut their presence in limbs with and without thrombosis also occurred with almost equal frequency. Of patients thought to have clinically certain DVT, 45% had an entirely normal venous system by venography. Conversely, venograms in. patients with pulmonary emboli have demonstrated clots in a totally asympromatic limb (Cranley et al., 1976). In only 10% of patients is the diagnosis of DVT made before the occurrence of fatal pulmonary embolism (Coon, 1976). It appears that the ‘more symptomatic the thrombus, the more tightly adherent it is to the vessel wall The diagnosis of septic pelvic thrombophlebitis may be even more difficult to confirm, and the only signs may be chills and a hectic febrile course (Duff and Gibbs, 1983). Pelvic examination is frequently unrevealing, and the diagnosis is usually made on the basis of failure to respond to a 48- to 72-hour regimen of adequate antibiotic therapy including coverage of anaerobes. Doppler Ultrasonography Doppler ultrasound technique has become the diagnostic study of choice in cases of suspected proximal vein occlusion Mig TABLE 422. SiGNs AND SyMPTOMS OF DEEP VENOUS THROMBOSIS Muscle pain Paipable deep linear cord Tendemoss Swelling Homans sign Dilated superficial veinsClinical Suspicion of Deep Vein Thrombosis \ xt ™“ ni WT Venopram FIGURE 42-1 Diagnostic algorithm for suspected deep voin thrombosis in pregnancy. (Cronan, 1991). A 5 MHz transducer is placed over the vein, Venous flow produces a characteristic low-pitched sound that is abolished by venous occlusion. Concomitant evaluation of venous anatomy, flow, augmentation (increased flow with mus- cular activity in the calf), and compression (elimination of residual lumen by firm pressure with the transducer probe using cone hand) yields a correct diagnosis with a high degree of sensitivity and specificity compared with venography (Lensing etal, 1989). The sensitivity and specificity in the evaluation of popliteal and femoral vein thromboses are 91% and 99%, respectively. Doppler flow studies are less effective in calf vein thrombosis, with a sensitivity and specificity of 36% and 95%, respectively (Polak and Wilkinson, 1991). When DVT below the popliteal vein is suspected, serial measurements are necessary to rule out propagation of a clot Ina comparative study of 985 outpatients, Doppler low studies were superior to impedance plethysmography in derecting DVT (Heijboer et al., 1993). The algorithm used by the authors to evaluate pregnant women thought to have a DVT is shown in Figure 42-1 Venography For years, venography has been the reference standard against which all other methods are compared. Although ‘venography is the most specific, it has limitations—it is inva- sive, expensive, and difficult to integpret unless all of the deep veins are filled adequately. It cannot be used to demonstrate the pelvic venous plexus. The procedure cannot be repeated fre- quently, and the contrast material can cause chemical phlebitis. Venography has not often been used during pregnaney because of possible hazards to the fetus, bur it is a useful tool when results of other studies are equivocal. The radiation to the fecus is only 0.0005 Gy (Ginsberg et al., 1989). Impedance Plethysmography This technique utilizes temporary occlusion of venous return by inflation of a thigh cuff. The occlusion causes an inctease in the venous volume of the calf. Release of the cuff 42/Thromboembolic Disease 847 results in a rapid decrease in volume as the blood drains prox- imally. If venous obstruction is present, the rate of outflow is diminished. These changes in blood volume can be detected by measurement of electrical resistance in the calf (Toy and Schrier, 1978). Clarke-Pearson and Jelovsek (1981) documented the relia- bility of this technique in the gynecologic patient and sug- gested that it could also be a sensitive and specific test during pregnancy; however, only a few cases of documented DVT during pregnancy have been studied with this technique, and its ultimate place in the diagnostic armamentarium remains unclear. Ginsberg and colleagues (1989) demonstrated that the combination of Doppler ultrasound and photoplethysmog: raphy are more reliable than either study alone in predicting the presence or absence of proximal DVT. Unfortunately, preg- nant patients were not included in their series. Blood Tests for Thrombosis Hirsh (1981) summarized several tests that reflect the for- mation of intravascular fibrin. Results are invariably positive when thrombosis has occurred. Unfortunately, the findings are also positive in the presence of hematomas or inflammatory ‘exudates containing fibrin. The assay for fbrinopeptide A and the fibrin degradation product, D-dimer, are the most sensitive, ‘The finding of a normal level of either of these essentially rules out DVT. Pulmonary Embolism Clinical Signs and Symptoms Although small emboli may go unrecognized by the patient, the hallmark of pulmonary embolism is dyspnea. The major sign is tachypnea, Table 42-3 shows the signs and symptoms most frequently encountered (Sasahara et al., 1983). Small emboli become lodged more peripherally and can produce infarction accompanied by pleural signs that include cough, hemoprysis, pleuritic chest pain with splinting, and a friction rub, although for many patients, emboli infarction and its asso- ciated symptoms are absent. Leg discomfort and shortness of breath can be the result of uterine enlargement in the third trimester but may also indicate multiple small emboli. Also, multiple small emboli can mimic a major embolus. Massive pulmonary embolism, defined for clinical purposes as occlusion. Mig TABLE 42.3. SIGNS AND SYMPTOMS OF PULMONARY EMBOLISM Tachypnea 89" Dyspnea Bt Pleuriic pain R Agprehension 59 Cough 54 Tachycardia 43 Hemoptysis| 34 Temperature >37°C 34 * Percentage of patents with proven aumarary emboli having thoso fnngs From Sasshara AA, Stare GVAK, Barsamian EM, el: Purmonany tomboembolem. JANIS 249-2085, 1963 Copyright 1868, American Medical esooaten