34: Venous thromboembolic disease

CHAPTER 34
Venous thromboembolic disease


B. Ryan Ball and Michael J. Paidas


Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Section of Maternal‐Fetal Medicine, New Haven, CN, USA


Introduction


Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) as well as pulmonary embolism (PE) and is regularly encountered in obstetrics. PE is one of the leading causes of maternal mortality in the United States. According to the CDC, in 2011–2012 it was the sixth most common cause of maternal mortality, accounting for 9.0% of maternal deaths [1]. Studies demonstrate an incidence of VTE varying between 0.6 and 2 per 1000 pregnancies. Most VTE events occur in the antepartum period [25], but in light of the shorter duration of the puerperium relative to the antepartum period, the incidence is actually higher in the puerperium [6]. Jacobsen, et al. found the incidence of VTE to be similar between the antepartum and postpartum periods, but DVT was more common in the antepartum period whereas PE was more common postpartum [7]. Virkus and colleagues [8] found the risk of VTE increases throughout the pregnancy with a marked rise at term, when pregnancy VTE risk was compared to non‐contracepting women. The absolute risk per 10 000 pregnant woman years increased from 4.1 in weeks 1–11 to 59.3 in the 40th week. The risk decreased following birth to 21.5 in the first week to 3.8 in weeks 4–6 and returned to the baseline seven weeks after delivery.


The clinical diagnosis of VTE in pregnancy is frequently difficult due to the overlapping symptoms of normal pregnancy and VTE [9].


Clinical questions



  1. What factors increase risk of VTE during pregnancy?
  2. What is the best method of diagnosing VTE in pregnancy?
  3. How should VTE in pregnancy be treated?
  4. What can be done to effectively prevent VTE in pregnancy?

Risk factors



  1. What factors increase risk of VTE during pregnancy?

Virchow’s triad of hemostasis, endothelial injury, and hypercoagulability has long been recognized as risk factors for VTE. All of these elements are present in pregnancy.


Venous stasis begins as early as the first trimester and progressively increases throughout the pregnancy. Causes of the increased stasis include progesterone‐induced venodilation, venous compression by the gravid uterus, and pulsatile compression of the left iliac vein by the right iliac artery [10]. Vascular injury occurs during the birth process and may be exacerbated by operative vaginal delivery.


Pregnancy is a time of significant physiologic changes in the maternal coagulation status. Activated protein C resistance increases and protein S activity is decreased. These changes and the elevated concentrations of fibrinogen and factors V, VIII, IX, and X all lead to increased thrombin production [11]. Concurrently, fibrinolysis is decreased by increased activity of plasminogen activator inhibitors type 1 and type 2 as well as decreased activity of tissue plasminogen activator [12].


Many factors have been shown to increase the risk of VTE in pregnancy (Table 34.1) [13]. The greatest risk for VTE in pregnancy is a personal history of prior VTE. In fact, 15–25% of VTEs in pregnancy are recurrences [14]. Thrombophilias are the next largest risk group accounting for 20–50% of VTEs occurring in pregnancy [1517]. Other risk factors include increased parity, infection, operative vaginal delivery, cesarean delivery, smoking, obesity, cancer, and surgery [7, 16, 1822].


Table 34.1 American College of Chest Physicians risk factors for venous thromboembolism





















































Major risk factors
Immobility (strict bed rest for ≥1 wk in the antepartum period)
Post‐partum hemorrhage ≥1000 ml with surgery
Previous VTE
Pre‐eclampsia with fetal growth restriction
Thrombophilia
Antithrombin
Factor V Leiden (homozygous or heterozygous)
Prothrombin G20210A (homozygous or heterozygous
Medical conditions
Systemic lupus erythematosus
Heart disease
Sickle cell disease
Blood transfusion
Post‐partum infection
Minor risk factors
BMI > 30 kg m−2
Multiple gestation
Post‐partum hemorrhage >1 l
Smoking >10 cigarettes d−1
Fetal growth restriction
Thrombophilia
Protein C deficiency
Protein S deficiency
Pre‐eclampsia

A number of inherited thrombophilias increase the risk of developing VTE during pregnancy (Table 34.2) [23]. The American College of Chest Physicians (ACCP) considers Factor V Leiden (FVL), Prothrombin G20210A, and antithrombin deficiency (ATD) major risk factors while Protein C and S deficiencies are minor risk factors for VTE in pregnancy.


Table 34.2 The risk of venous thromboembolism in pregnant patient with selected thrombophilias


Source: Adapted from: Han CS, Paidas MJ, Lockwood CJ. Clotting disorders. In: High Risk Pregnancy: Management Options, 4th edition. Edited by David K. James, Philip J. Steer, Carl P. Weiner, Bernard Gonik, Caroline A. Crowther, and Stephen Robson, 2010. Elsevier, Philadelphia, PA.





























































Condition Prevalence in European populations Prevalence in patients with VTE in pregnancy Risk of VTE without prior history Risk of VTE with prior history
Factor V Leiden (FVL)
Heterozygous 5.3% 44 0.26% >10%
Homozygous 0.07% <1 1.50% >10%
Prothrombin mutation (PGM)
Heterozygous 2.90% 17 0.37–0.5% >10%
Homozygous 0.02% <1 2.8 >10%
Compound FVL/PGM 0.17% <1
4.70%
Protein C deficiency 0.2–0.3% <14 0.8–1.7%
Protein S deficiency 0.03–0.13% 12 <1–6.6%
Antithrombin deficiency 0.02–1.1% 1 3–7.2% 11–40%

FVL is the thrombophilia most commonly encountered by obstetricians. Its prevalence is highest in Caucasians of European decent with carrier frequencies estimated at 5–9% and is less common among those of Asian and African descent [24]. Only about 1% of women with FVL mutations are homozygous and they tend have to have a higher incidence of VTE [25, 26]. Retrospective data demonstrates heterozygous carriers of FVL have a 5–10‐fold relative risk for VTE during pregnancy, and it is present in 43% of pregnant women with their first thrombotic event [27, 28, 29, 30]. Among heterozygotes without a family or personal history of thrombosis, the risk of VTE is only 0.25%. For patients with a family or personal history of VTE, the risk may be as high as 10% [28]. One large multicenter prospective National Institute of Child Health and Human Development (NICHD) study looked at 4885 gravid patients without a personal history of thrombotic event. Of the 134 FVL carriers, there was no increased risk of VTE [31].


The second most prevalent inherited thrombophilia is Prothrombin G20210A (PGM), which leads to elevated prothrombin levels. Among European Caucasians the carrier prevalence is 2–4%. Similar to FVL, PGM is less common in those of Asian and African descent [24, 25]. Studies have shown a wide range in the carrier frequency among women having their first VTE during pregnancy with rates ranging from 3.8% to 31% [27, 30]. Women who are carriers of PGM without a personal or family history of VTE appear to have a low risk (0.37%) of VTE during pregnancy; however, that risk increases to over 10% for those with prior VTE or for family history of VTE. The probability appears to be higher for those who are homozygous for PGM mutation, but the available data is limited [30]. Even without a prior history of VTE FVL and PGM compound heterozygotes have a much higher risk (4.6%) of a VTE during pregnancy and puerperium even without a prior history [27].


Less common but more thrombogenic than FVL or PGM is ATD. Many mutations have been identified at the antithrombin gene loci, which lead to a wide spectrum of phenotypes. Type I disease is a quantitative disorder while type II is a qualitative dysfunction. Type I is less common, comprising only 12% of the cases of ATD, but it is much more thrombogenic, accounting for 80% of symptomatic cases. In contrast to FVL and PGM the prevalence of ATD in highest in Asian populations with some groups having a prevalence of up to 2–5%, while among Caucasian Europeans it is estimated at 0.02–1.15% [24, 32]. The risk of VTE in pregnancy can be high with ATD, but there is large variability among phenotypes. Robertson reported an OR 4.69 for VTE in pregnancy [26]. Retrospective studies have estimated the odds ratio for the more thrombogenic type 1 disease to be 282 compared to a much smaller risk with type II disease (OR 28) [33, 13]. It is estimated that the lifetime risk of VTE in those with type I disease is 50% [34]. One case series of 63 untreated women with type 1 ATD who went through pregnancy without anticoagulation found 18% had a thrombotic complication during pregnancy and additional 33% had a VTE postpartum [35].


Protein C is an anticoagulant responsible for the deactivation of factor Va and factor VIIIa thereby inhibiting clot formation [25]. Deficiencies in protein C synthesis or function are found in 0.2–0.3% of those with European ancestry and is more common in those of Asian and African descent [24]. Protein C deficiency is moderately pro‐thrombogenic during pregnancy. The risk is likely proportional to the deficiency of substrate and/or function. Zotz et al. found the relative risk of a first VTE in pregnancy to be RR 3.0 if using <73% of normal protein C activity as the cutoff and RR 13.0 if using <50% as the cutoff in a case control study [28]. A review of available retrospective case controlled studies showed a modest risk of VTE (OR 4.76) in patients with hereditary protein C deficiency [26].


Protein S accelerates activated protein C’s disruption of factors Va and VIIIa, ultimately suppressing thrombin formation. It is a less common than protein C deficiency with a prevalence of 0.03–0.13% in the Caucasian European population. Due to the infrequency of protein S deficiency there are limited studies regarding its risks during pregnancy. Robertson’s review of available case controlled studies showed an OR 3.19 of VTE and pregnancy [26]. Conard et al.’s evaluation of 44 pregnancies in 17 patients with congenital protein S deficiency showed no thrombosis during pregnancies without anticoagulation, but had five post‐partum thrombotic events (17%) [35].


Diagnosis



  1. 2. What is the best method of diagnosing VTE in pregnancy?

DVT


Clinical symptoms

The typical presentation of a patient with DVT is erythema, edema, warmth, and pain in the affected area. A palpable venous cord or Homan’s sign may be present. These findings, however, are nonspecific and studies show them present in only about 50% of patients with confirmed DVT.


D dimer

Laboratory assays for D‐dimer (a fibrin degradation product) levels are commonly used to rule out venous thrombosis in non‐pregnant patients. When D‐dimer levels are low, the chance of DVT is low. These tests are not usually helpful in pregnancy because the physiologic increases in D‐dimer levels in pregnancy exceed normal values in 78% of second trimester and 100% of third trimester patients [36]. Chan, et al. found that D‐dimer values were elevated throughout pregnancy and were further increased in pregnant women diagnosed with DVT. By increasing the threshold value they were able to improve the specificity without a significant decrease in sensitivity [37]. Prospective trials are needed to further evaluate the use of the increased threshold values in the management of DVT during pregnancy.


Imaging

The gold standard test for diagnosis of DVT is a venogram with IV contrast. However, because of the invasive nature of the test and other good alternatives, it is rarely used today.


The most common test for diagnosis is Doppler venous ultrasound. This is done by insonating the veins of the leg and serially compressing them with the ultrasound transducer. A non‐compressible vein is indicative of venous thrombosis. The sensitivity and specificity of venous ultrasound in proximal thrombosis is 90–100% but is lower for distal veins [38]. Goodacre et al. found that in non‐pregnant patients the sensitivity in proximal DVT was 96.4% and 75.2% in distal DVTs [39].


PE


Clinical symptoms

Symptoms of PE include shortness of breath, chest pain, hypoxia, tachycardia, cough, tachypnea, hemoptysis, hypotension, and syncope [40, 41]. Among 38 pregnant women diagnosed with acute PE the most common findings were tachycardia (65%), dyspnea (63%), tachypnea (57%), pleuritic chest pain (55%), cough (24%), and sweating (18%) [42].


Imaging

Diagnostic testing for PE has changed over the years. Originally, pulmonary angiography was considered the gold standard. The ventilation‐perfusion scan replaced pulmonary angiography because of the invasive nature of the test and associated complications. In more recent years, CT pulmonary angiography has become more common and outside of pregnancy is usually the diagnostic test of choice.

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Jul 19, 2020 | Posted by in GYNECOLOGY | Comments Off on 34: Venous thromboembolic disease
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