During pregnancy, most venous thromboses are confined to the deep veins of the lower extremity. Approximately 70 percent of cases are located in the iliofemoral veins without involvement of the calf veins. Isolated iliac vein and calf vein thromboses occur in approximately 17 and 6 percent of cases, respectively (Chan, 2010). In contrast, in the general population, more than 80 percent of deep-vein thromboses involve calf veins, and iliofemoral or isolated iliac vein thromboses are uncommon (Huisman, 2015).
The signs and symptoms vary greatly and depend on the degree of occlusion and the intensity of the inflammatory response. Ginsberg and coworkers (1992) reported that 58 of 60 antepartum women—97 percent—had left leg thromboses. Blanco-Molina and coworkers (2007) reported left-leg involvement in 78 percent. Greer (2003) hypothesizes that this results from compression of the left iliac vein by the right iliac and ovarian artery, both of which cross the vein only on the left side. Yet, as described in Chapter 53 (Urinary Tract Infections), the ureter is compressed more on the right side.
Classically, thrombosis involving the lower extremity is abrupt in onset, and there is pain and edema of the leg and thigh. The thrombus typically involves much of the deep-venous system to the iliofemoral region. Occasionally, reflex arterial spasm causes a pale, cool extremity with diminished pulsations. Alternatively, there may be appreciable clot, yet little pain, heat, or swelling. Importantly, calf pain, either spontaneous or in response to squeezing or to Achilles tendon stretching—Homans sign—may be caused by a strained muscle or contusion. Between 30 and 60 percent of women with a confirmed lower-extremity acute deep-vein thrombosis have an asymptomatic pulmonary embolism (Superficial Venous Thrombophlebitis).
Clinical diagnosis of deep-vein thrombosis is difficult, and in an earlier study of pregnant women, the clinical diagnosis was confirmed in only 10 percent (Hull, 1990). Another challenge is that many of the common diagnostic tests that have been investigated extensively in nonpregnant patients have not been validated appropriately in pregnancy (Huisman, 2015). Shown in Figure 52-2 is one diagnostic algorithm recommended by the American College of Chest Physicians that can be used for evaluation of pregnant women (Guyatt, 2012). With a few modifications, we follow a similar evaluation at Parkland Hospital.
Algorithm for evaluation of suspected deep-vein thrombosis in pregnancy. CT = computed tomography; MR = magnetic resonance. aSigns and symptoms include swelling of the entire leg, with or without flank, buttock, or back pain. (Data from Guyatt GH, Akl EA, Crowther M, et al: Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest. 2012 Feb;141(2 Suppl):7S-47S.)
In pregnant women with suspected deep-vein thrombosis, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend compression ultrasonography of the proximal veins as the initial diagnostic test. According to the American College of Chest Physicians, this noninvasive technique is currently the most-used first-line test to detect deep-vein thrombosis (Guyatt, 2012). The diagnosis is based on the noncompressibility and typical echoarchitecture of a thrombosed vein.
For nonpregnant patients with suspected thrombosis, the safety of withholding anticoagulation for 1 week has been established for those who have a compression ultrasound examination that is initially normal (Birdwell, 1998; Heijboer, 1993). Serial compression examinations are then performed because isolated undetected calf thromboses that ultimately extend into the proximal veins will do so within 1 to 2 weeks of presentation in approximately a fourth of patients.
In pregnant women, the important caveat is that normal findings with venous ultrasonography do not always exclude a pulmonary embolism. This is because the thrombosis may have already embolized or because it arose from iliac or other deep-pelvic veins, which are less accessible to ultrasound evaluation (Goldhaber, 2004). As discussed, thrombosis associated with pulmonary embolism during pregnancy commonly originates in the iliac veins.
The results of two studies are helpful for evaluating the need for serial examinations in pregnant women suspected of having a deep-vein thrombosis but who have a negative initial compression ultrasound examination. The combined results are depicted in Figure 52-3. Chan and coworkers (2013) studied 221 pregnant and postpartum women presenting with a suspected deep-vein thrombosis. The 205 women with a negative initial study result underwent serial testing, which was negative in all cases. Of these, one woman with normal serial testing had a pulmonary embolism 7 weeks later. Le Gal and colleagues (2012) studied 210 pregnant and postpartum women with a suspected deep-vein thrombosis. Of these, 177 women without a deep-vein thrombosis were not anticoagulated and did not undergo serial testing. Two had an objectively confirmed thrombosis diagnosed within 3 months. In sum, these preliminary data suggest that a negative single complete compression ultrasonography study may safely exclude the diagnosis of deep-vein thrombosis in most pregnant women.
Findings from two studies of serial and nonserial compression ultrasound examinations in pregnant and postpartum women. CUS = compression ultrasonography. DVT = deep vein thrombosis. VTE = venous thromboembolism. (Data from Chan, 2013; Le Gal, 2012.)
Magnetic Resonance Imaging
This imaging technique allows excellent delineation of anatomical detail above the inguinal ligament. Thus, in many cases, magnetic resonance (MR) imaging is immensely useful for diagnosis of iliofemoral and pelvic vein thrombosis. The venous system can also be reconstructed using MR venography (Chap. 46, Imaging During Pregnancy). Erdman and associates (1990) reported that MR imaging was 100-percent sensitive and 90-percent specific for detection of venographically proven deep-vein thrombosis in nonpregnant patients. Importantly, almost half of those without deep-vein thrombosis were found to have nonthrombotic conditions that included cellulitis, myositis, edema, hematomas, and superficial phlebitis.
Khalil and coworkers (2012) used MR venography to study the natural history of pelvic vein thrombosis after vaginal delivery. Among the 30 asymptomatic patients who were all within four days of delivery, 30 percent had a definitive thrombosis in either the iliac or ovarian veins, and another 37 percent had a suspected thrombosis. Our experiences with hundreds of postpartum MR scans do not support these findings. Thus, although the clinical significance of their findings is uncertain, it seems clear that some degree of pelvic vein intraluminal filling defect may be a normal finding.
These specific fibrin degradation products are generated when fibrinolysin degrades fibrin, as occurs in thromboembolism (Chap. 41, Pregnancy-Induced Coagulation Changes). Their measurement is frequently incorporated into diagnostic algorithms for VTE in nonpregnant patients (Wells, 2003). Screening with the d-dimer test in pregnancy, however, is problematic for several reasons. As shown in the Appendix (Serum and Blood Constituents), depending on assay sensitivity, d-dimer serum levels rise with gestational age along with substantively elevated plasma fibrinogen concentrations (Murphy, 2015). Levels are also affected by multifetal gestation and cesarean delivery (Morikawa, 2011). d-Dimer concentrations can also be elevated in certain pregnancy complications such as placental abruption, preeclampsia, and sepsis syndrome. Moreover, higher levels have been observed in sickle-cell carriers and in women of African and South Asian racial origin (Grossman, 2016). For all these reasons, their use during pregnancy remains uncertain, but a negative d-dimer test should be considered reassuring (Lockwood, 2012; Marik, 2008).
Optimal management of VTE during pregnancy has not undergone major clinical study to provide evidence-based practices. There is, however, consensus for treatment with anticoagulation and limited activity. If thrombophilia testing is performed, it is done before anticoagulation. Heparin induces a decline in antithrombin levels, and warfarin lowers protein C and S concentrations. The results of these tests do not change treatment (Connors, 2017).
Anticoagulation is initiated with either unfractionated heparin (UFH) or LMWH. Although either type is acceptable, most recommend one of the LMWHs (Bates, 2016; Kearon, 2016). For example, the American College of Chest Physicians suggests preferential use of LMWH during pregnancy because of better bioavailability, longer plasma half-life, more predictable dose response, reduced risks of osteoporosis and thrombocytopenia, and less frequent dosing (Bates, 2012). Dosages are shown in Table 52-5.
TABLE 52-5Anticoagulation Regimen Definitions ||Download (.pdf) TABLE 52-5 Anticoagulation Regimen Definitions
|Anticoagulation Regimen ||Definition |
|Prophylactic LMWHa ||Enoxaparin, 40 mg SC once daily |
Dalteparin, 5,000 units SC once daily
Tinzaparin, 4,500 units SC once daily
|Therapeutic LMWHb ||Enoxaparin, 1 mg/kg every 12 hours |
Dalteparin, 200 units/kg once daily
Tinzaparin, 175 units/kg once daily
Dalteparin, 100 units/kg every 12 hours
May target an anti-Xa level in the therapeutic range of 0.6–1.0 units/mL for twice daily regimen; slightly higher doses may be needed for a once-daily regimen.
|Minidose prophylactic UFH ||UFH, 5,000 units SC every 12 hours |
|Prophylactic UFH ||UFH, 5,000–10,000 units SC every 12 hours |
UFH, 5,000–7,500 units SC every 12 hours in first trimester
UFH 7,500–10,000 units SC every 12 hours in the second trimester
UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated
|Therapeutic UFHb ||UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5–2.5) 6 hours after injection |
|Postpartum anticoagulation ||Prophylactic LMWH/UFH for 4–6 weeks or vitamin K antagonists for 4–6 weeks with a target INR of 2.0–3.0, with initial UFH or LMWH therapy overlap until the INR is 2.0 or more for 2 days |
|Surveillance ||Clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep-vein thrombosis or pulmonary embolism |
TABLE 52-6Some Recommendations for Thromboprophylaxis during Pregnancy ||Download (.pdf) TABLE 52-6 Some Recommendations for Thromboprophylaxis during Pregnancy
| ||Pregnancy ||Postpartum |
|Clinical Scenario ||ACOGa ||ACCPb ||ACOGa ||ACCPb |
|Prior single VTE |
|Risk factor no longer present ||Surveillance only ||Surveillance only ||Postpartum anticoagulationc “Surveillance only acknowledged by some experts.” ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Pregnancy- or estrogen-related or no known association (idiopathic) and not receiving long-term therapy ||Prophylactic UFH or LMWH or “Surveillance only acknowledged by some experts” ||Prophylactic or intermediate-dose LMWH ||Postpartum anticoagulationc ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Receiving long-term warfarin ||NSS ||Adjusted-dose LMWH or 75% of a therapeutic dose of LMWH ||NSS ||Resume long-term anticoagulation |
|Associated with a high-risk thrombophiliad and not receiving long-term anticoagulation or an affected first-degree relative ||Prophylactic, intermediate-, or adjusted-dose LMWH or UFH ||NSS ||Postpartum anticoagulationc or intermediate- or adjusted-dose LMWH or UFH × 6 weeksc ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Associated with a low-risk thrombophiliae and not receiving treatment ||Prophylactic or intermediate-dose LMWH or UFH or surveillance only ||NSS ||Postpartum anticoagulationc or intermediate-dose LMWH or UFH ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Two or more prior VTEs with or without thrombophilia |
|Not receiving long-term therapy ||Prophylactic or therapeutic-dose UFH or LMWH ||NSS ||Postpartum anticoagulationc or therapeutic-dose LMWH or UFH × 6 weeks ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Receiving long-term anticoagulation ||Therapeutic-dose LMWH or UFH ||Adjusted-dose LMWH or 75% of a therapeutic dose of LMWH ||Resumption of long- term anticoagulation ||Resumption of long-term anticoagulation |
|No prior VTE |
|High-risk thrombophiliad ||Surveillance only or prophylactic or intermediate-dose LMWH or UFH ||Prophylactic or intermediate-dose LMWH ||Postpartum anticoagulationc ||Intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Positive family history VTE and homozygous factor V Leiden or prothrombin 20210A mutation ||NSS ||Prophylactic or intermediate-dose LMWH ||NSS ||Prophylactic or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Negative family history VTE and homozygous factor V Leiden or prothrombin 20210A mutation ||Surveillance only or prophylactic LMWH or UFH ||Surveillance only ||Postpartum anticoagulationc ||Prophylactic- or intermediate-dose LMWH or warfarin target INR 2.0–3.0 × 6 weeks |
|Positive family history VTE and low-risk thrombophiliase ||Surveillance only ||Surveillance only ||Postpartum anticoagulationc or intermediate-dose LMWH or UFH ||Prophylactic or intermediate-dose LMWH or in women not protein C or S deficient, warfarin target INR 2.0–3.0 |
|Low-risk thrombophiliae ||Surveillance only ||Surveillance only if no family history ||Surveillance only; postpartum anticoagulation with additional risk factorsf ||Surveillance only if no family history |
|Antiphospholipid antibodies || || || |
|History of VTE ||Prophylactic anticoagulation with UFH or LMWH (?plus low-dose aspirin) ||NSS ||Prophylactic anticoagulationc; referral to specialistg ||NSS |
|No prior VTE ||Surveillance only or prophylactic |
LMWH or UFH or prophylactic
LMWH or UFH plus low-dose aspirin if prior recurrent pregnancy loss or stillbirth
|Prophylactic- or intermediate-dose UFH or prophylactic-dose LMWH, both given with 75–100 mg/day aspirinh ||Prophylactic heparin plus low-dose aspirin × 6 weeks if prior recurrent pregnancy loss or stillbirthg ||NSS |
During pregnancy, heparin therapy is continued, and for postpartum women, anticoagulation is begun simultaneously with warfarin. Recall that pulmonary embolism develops in as many as 60 percent of patients with untreated venous thrombosis, and anticoagulation decreases this risk to less than 5 percent. In nonpregnant patients, the mortality rate with a pulmonary embolism approximates 1 percent (Douketis, 1998; Pollack, 2011).
Over several days, leg pain dissipates. After symptoms have abated, graded ambulation is begun. Elastic stockings are fitted, and anticoagulation is continued. Recovery to this stage usually takes 7 to 10 days. Graduated compression stockings are continued for 2 years after the diagnosis to reduce the incidence of postthrombotic syndrome (Brandjes, 1997). This syndrome can include chronic leg paresthesias or pain, intractable edema, skin changes, and leg ulcers.
This agent should be considered for the initial treatment of thromboembolism and in situations in which delivery, surgery, or thrombolysis may be necessary (American College of Obstetricians and Gynecologists, 2017b). Unfractionated heparin can be administered by one of two alternatives: (1) initial intravenous therapy followed by adjusted-dose subcutaneous UFH given every 12 hours; or (2) twice-daily, adjusted-dose subcutaneous UFH with doses adjusted to prolong the activated partial thromboplastin time (aPTT) into the therapeutic range 6 hours postinjection (Bates, 2012). As shown in Table 52-5, the therapeutic dose for subcutaneous UFH is usually 10,000 units or more every 12 hours.
For intravenous therapy, several protocols are acceptable. In general, if UFH is used, it is initiated with a bolus intravenous dose of 70 to 100 U/kg, which is 5000 to 10,000 U. This is followed by continuous intravenous infusions beginning at 1000 U/hr or 15 to 20 U/kg/hr. This infusion rate is titrated to achieve an aPTT 1.5 to 2.5 times control values (Brown, 2010; Linnemann, 2016). Intravenous anticoagulation is maintained for at least 5 to 7 days, after which treatment is converted to subcutaneous heparin to maintain the aPTT to at least 1.5 to 2.5 times control throughout the dosing interval. For women with lupus anticoagulant, aPTT does not accurately assess heparin anticoagulation, and thus anti-factor Xa levels are preferred.
The duration of full anticoagulation varies, and no studies have defined the optimal duration for pregnancy-related thromboembolism. In nonpregnant patients with VTE, evidence supports a minimum treatment duration of 3 months (Kearon, 2012). For pregnant patients, the American College of Chest Physicians recommends anticoagulation throughout pregnancy and postpartum for a minimum total duration of 3 months (Bates, 2012). Lockwood (2012) recommends that full anticoagulation be continued for at least 20 weeks followed by prophylactic doses if the woman is still pregnant. Prophylactic doses of subcutaneous UFH can range from 5000 to 10,000 U every 12 hours titrated to maintain an anti-factor Xa level of 0.1 to 0.2 U/mL, measured 6 hours after the last injection. If the VTE occurs during the postpartum period, Lockwood (2012) recommends a minimum of 6 months of anticoagulation treatment.
This is a family of derivatives of unfractionated heparin, and their molecular weights average 4000 to 5000 daltons compared with 12,000 to 16,000 daltons for conventional heparin. None of these heparins cross the placenta, and all exert their anticoagulant activity by activating antithrombin. The primary difference is their relative inhibitory activity against factor Xa and thrombin. Specifically, UFH has equivalent activity against factor Xa and thrombin, but LMWHs have greater activity against factor Xa than against thrombin. They also have a more predictable anticoagulant response and fewer bleeding complications than UFH because of their better bioavailability, longer half-life, dose-independent clearance, and decreased interference with platelets (Tapson, 2008). These LMWH compounds are cleared by the kidneys and must be used cautiously when there is renal dysfunction.
Several studies have shown that VTE is treated effectively with LMWH (Quinlan, 2004; Tapson, 2008). Using serial venograms, Breddin and associates (2001) observed that these compounds were more effective than UFH in reducing thrombus size without increasing mortality rates or major bleeding complications. Several different treatment regimens using adjusted-dose LMWH for treatment of acute VTE are recommended by the American College of Obstetricians and Gynecologists (2017b,c) and are listed in Table 52-5.
Pharmacokinetics in Pregnancy
LMWHs available for use in pregnancy include enoxaparin, tinzaparin, and dalteparin. Enoxaparin (Lovenox) pharmacokinetics were studied in 36 women with VTE during pregnancy or immediately postpartum (Rodie, 2002). The dose was approximately 1 mg/kg given twice daily based on early pregnancy weight. Treatment was monitored by peak anti-factor Xa activity at 3 hours postinjection, with a target therapeutic range of 0.4 to 1.0 U/mL. In 33 women, enoxaparin provided satisfactory anticoagulation. In the other three women, dose reduction was necessary. None developed recurrent thromboembolism or bleeding complications. In postcesarean women with a body mass index (BMI) ≥35, Stephenson and associates (2016) found that weight-based dosing of enoxaparin 0.5 mg/kg twice daily more effectively achieved prophylactic peak anti-Xa levels between 0.2 to 0.6 U/mL than a fixed dose of 40 mg daily. Similar findings were reported by Overcash and colleagues (2015).
For tinzaparin (Innohep), a dosage of 75 to 175 U/kg/d was necessary to achieve peak anti-factor Xa levels of 0.1 to 1.0 U/mL (Smith, 2004). In studies of dalteparin (Fragmin) pharmacokinetics, conventional starting doses of dalteparin—100 U/kg every 12 hours—were likely insufficient to maintain full anticoagulation (Barbour, 2004; Jacobsen, 2003). Thus, slightly higher doses than that shown in Table 52-5 may be required.
Standard prophylactic and therapeutic dosages recommended by the American College of Obstetricians and Gynecologists (2017b) for various LMWHs are listed in Table 52-5. Whether such dosages require adjustments during the course of pregnancy is controversial (Berresheim, 2014; Cutts, 2013). Some suggest periodic measurement of anti-factor Xa levels 4 to 6 hours after an injection with dose adjustment to maintain a therapeutic level. Large studies using clinical end points that demonstrate an optimal therapeutic range or show that dose adjustments increase therapy safety or efficacy are lacking. Accordingly, the American College of Chest Physicians and others note that routine monitoring with anti-Xa levels is difficult to justify (Bates, 2012; McDonnell, 2017).
Early reviews concluded that LMWHs were safe and effective (Lepercq, 2001; Sanson, 1999). Despite this, in 2002, the manufacturer of Lovenox warned that its use in pregnancy had been associated with congenital anomalies and a higher risk of hemorrhage. After its own extensive review, the American College of Obstetricians and Gynecologists (2017b) concluded that these risks were rare, that their incidence was not higher than expected, and that no cause-and-effect relationship had been established. It further concluded that enoxaparin and dalteparin could be given safely during pregnancy. Other reports confirm their safety (Andersen, 2010; Bates, 2012; Galambosi, 2012).
Nelson-Piercy and coworkers (2011) assessed the safety of tinzaparin through a comprehensive study of 1267 treated pregnant women. There were no maternal deaths or complications from regional analgesia. Although thrombocytopenia developed in 1.8 percent, there were no cases of heparin-induced thrombocytopenia (Newer Agents). The allergy incidence was 1.3 percent. Osteoporotic fractures in three women (0.2 percent) were judged to be related to tinzaparin (Newer Agents). A total of 43 women (3.4 percent) required medical intervention for bleeding. Of 15 stillbirths, four were judged as possibly being related to tinzaparin use. But, none of the neonatal deaths or congenital abnormalities was attributed to tinzaparin. The authors concluded that tinzaparin during pregnancy was safe for mother and fetus. LMWHs are also safe during breastfeeding (Lim, 2010).
However, LMWHs should be avoided in women with renal failure. Moreover, when given within 2 hours of cesarean delivery, these agents raise the risk of wound hematoma (van Wijk, 2002).
Women receiving either therapeutic or prophylactic anticoagulation should be converted from LMWH to the shorter half-life UFH in the last month of pregnancy or sooner if delivery appears imminent. The purpose of conversion to UFH has less to do with any risk of maternal bleeding at the time of delivery, but rather with neuraxial blockade complicated by an epidural or spinal hematoma (Chap. 25, Safety). The American College of Chest Physicians recommends that women scheduled for a planned delivery who are receiving twice-daily adjusted-dose subcutaneous UFH or LMWH discontinue their heparin 24 hours before labor induction or cesarean delivery (Bates, 2012). Patients receiving once-daily LMWH should take only 50 percent of their normal dose on the morning of the day before delivery. The American College of Obstetricians and Gynecologists (2017c) advises that adjusted-dose subcutaneous LMWH or UFH can be discontinued 24 to 36 hours before an induction of labor or scheduled cesarean delivery. The American Society of Regional Anesthesia and Pain Medicine advises withholding neuraxial blockade for 10 to 12 hours after the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose (Horlocker, 2010).
If a woman begins labor while taking UFH, clearance can be verified by an aPTT. Reversal of heparin with protamine sulfate is rarely required and is not indicated with a prophylactic dose of heparin. For women in whom anticoagulation therapy has temporarily been discontinued, pneumatic compression devices are recommended.
Anticoagulation with Warfarin Compounds
Vitamin K antagonists are generally contraindicated because they readily cross the placenta and may cause fetal death and malformations from hemorrhages (Chap. 12, Warfarin). They do not accumulate in breast milk and are thus safe during breastfeeding.
Postpartum venous thrombosis is usually treated with intravenous heparin and oral warfarin initiated simultaneously. The initial dose of warfarin is usually 5 to 10 mg for the first 2 days. Subsequent doses are titrated to achieve an international normalized ratio (INR) of 2 to 3. To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C effect of warfarin, these women are maintained on therapeutic doses of UFH or LMWH for 5 days and until the INR is in a therapeutic range for 2 consecutive days (American College of Obstetricians and Gynecologists, 2017c; Stewart, 2010).
Treatment in the puerperium may require larger doses of anticoagulant. Brooks and colleagues (2002) compared anticoagulation in postpartum women with that of age-matched nonpregnant controls. The former required a significantly larger median total dose of warfarin—45 versus 24 mg—and a longer time—7 versus 4 days—to achieve the target INR.
Of newer oral anticoagulants, dabigatran (Pradaxal) inhibits thrombin. Rivaroxaban (Xarelto) and apixaban (Eliquis) inhibit factor Xa. Currently, very few reports address these newer agents during pregnancy, and thus the human reproductive risks are essentially unknown (Bates, 2012). Dabigatran crosses the human placenta (Bapat, 2014). However, it is unknown whether any of these agents are excreted in breast milk. Because of the potential for infant harm, a decision should be made to either avoid breastfeeding or use an alternative anticoagulant, such as warfarin, in postpartum women (Burnett, 2016).
Complications of Anticoagulation
Three significant complications associated with anticoagulation are hemorrhage, thrombocytopenia, and osteoporosis. The latter two are unique to heparin, and their risk may be reduced with LMWHs. The most serious complication is hemorrhage, which is more likely if there has been recent surgery or lacerations. Troublesome bleeding also is more likely if the heparin dosage is excessive. Unfortunately, management schemes using laboratory testing to identify when a heparin dosage is sufficient to inhibit further thrombosis, yet not cause serious hemorrhage, have been discouraging.
There are two types—the most common is a nonimmune, benign, reversible thrombocytopenia that develops within the first few days of therapy and resolves in approximately 5 days without therapy cessation. The second is the severe form of heparin-induced thrombocytopenia (HIT), which results from an immune reaction involving IgG antibodies directed against complexes of platelet factor 4 and heparin. The diagnosis of HIT is based on a drop in the platelet count of more than 50 percent or thrombosis beginning 5 to 10 days after the start of heparin in association with the appearance of platelet-activating HIT antibodies. The fall in platelet count in HIT occurs rapidly—over a period of 1 to 3 days—and is assessed relative to the highest platelet count after the start of heparin. The typical nadir is 40,000 to 80,000 platelets per microliter (Greinacher, 2015).
Although the incidence of HIT is approximately 3 to 5 percent in nonpregnant individuals, it is <0.1 percent in obstetrical patients (Linkins, 2012). Fausett and coworkers (2001) reported no cases among 244 heparin-treated gravidas compared with 10 among 244 nonpregnant patients. Accordingly, the American College of Chest Physicians recommends against platelet count monitoring when the risk of HIT is considered to be less than 1 percent. In others, they suggest monitoring every 2 or 3 days from day 4 until day 14 (Linkins, 2012).
When HIT is diagnosed, heparin therapy is stopped and alternative anticoagulation initiated. Platelet transfusions are avoided (Greinacher, 2015). LMWH may not be entirely safe because it has some cross reactivity with UFH. The American College of Chest Physicians recommends danaparoid (Orgaran)—a sulfated glycosaminoglycan heparinoid (Bates, 2012; Linkins, 2012). In a review of nearly 50 pregnant women with either HIT or a skin rash, Lindhoff-Last and associates (2005) concluded that danaparoid was a reasonable alternative. However, they reported two fatal maternal hemorrhages and three fetal deaths. Magnani (2010) reviewed case reports of 83 pregnant women treated with danaparoid. Although it was generally effective, two patients died related to bleeding, three patients suffered nonfatal major bleeds, and three women developed thromboembolic events unresponsive to danaparoid. The drug has been removed from the U.S. market.
Other agents are fondaparinux (Arixtra)—a pentasaccharide factor Xa inhibitor and argatroban (Novastan)—a direct thrombin inhibitor (Kelton, 2013; Linkins, 2012). Successful use in pregnancy has been reported (Elsaigh, 2015; Knol, 2010). Tanimura and coworkers (2012) successfully used argatroban, and later fondaparinux, to manage HIT in a pregnant woman with hereditary antithrombin deficiency.
Bone loss may develop with long-term heparin administration—usually 6 months or longer—and is more prevalent in cigarette smokers. UFH can cause osteopenia, and this is less likely with LMWHs (Deruelle, 2007). Women treated with any heparin should be encouraged to take an oral daily 1500-mg calcium supplement (Cunningham, 2005; Lockwood, 2012). In one study, Rodger and colleagues (2007) found that long-term use of dalteparin for a mean of 212 days was not associated with a significant decline in bone mineral density.
Anticoagulation and Abortion
The treatment of deep-vein thrombosis with heparin does not preclude pregnancy termination by careful curettage. After the products are removed without trauma to the reproductive tract, full-dose heparin can be restarted in several hours.
Anticoagulation and Delivery
The effects of heparin on blood loss at delivery depend on several variables: (1) dose, route, and timing of administration; (2) number and depth of incisions and lacerations; (3) intensity of postpartum myometrial contractions; and (4) presence of other coagulation defects. Blood loss should not be greatly increased with vaginal delivery if the episiotomy is modest in depth, there are no lacerations, and the uterus promptly contracts. Unfortunately, such ideal circumstances do not always prevail. For example, Mueller and Lebherz (1969) described 10 women with antepartum thrombophlebitis treated with heparin. Three women who continued to receive heparin during labor and delivery bled remarkably and developed large hematomas. Thus, heparin therapy generally is stopped during labor and delivery. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend restarting UFH or LMWH no sooner than 4 to 6 hours after vaginal delivery or 6 to 12 hours after cesarean delivery. We wait at least 24 hours to restart therapy after cesarean delivery or after vaginal delivery with significant lacerations.
Slow intravenous administration of protamine sulfate generally reverses the effect of heparin promptly and effectively. It should not be given in excess of the amount needed to neutralize the heparin, because it also has an anticoagulant effect.