Thromboembolism in Pregnancy
Practice Essentials
Pregnancy increases the risk of venous thromboembolism (VTE) 4- to 5-fold over that in the nonpregnant state. [1, 2] The two manifestations of VTE are deep venous thrombosis (DVT) and pulmonary embolus (PE). Although most reports suggest that VTE can occur at any trimester in pregnancy, studies suggest that VTE is more common during the first half of pregnancy (see the image below). Sequelae of DVT and PE include complications such as pulmonary hypertension, post-thrombotic syndrome, and venous insufficiency.
Estimated gestational age at time of diagnosis of antepartum deep venous thrombosis (n=94).
Signs and symptoms
The signs and symptoms of VTE are nonspecific and common in pregnancy. Diagnosis of VTE by physical examination is frequently inaccurate, even though one study found that 80% of pregnant women with DVT experience pain and swelling of the lower extremity.
Clinical signs and symptoms of PE are rarely encountered together; the classic symptoms are as follows [3] :
Dyspnea - 82%
Abrupt onset of chest pain - 49%
Cough - 20%
The most common presenting signs of PE are as follows:
Tachypnea
Crackles
Tachycardia
Patients with massive PE may present with the following:
Syncope
Hypotension
Pulseless cardiac electrical activity
Death
Diagnosis
Laboratory studies
D-dimer testing is often used in the diagnosis of DVT in nonpregnant patients due to its high negative predictive value. Pregnancy decreases the specificity of d-dimer testing, however d-dimer retains good negative predictive value in the setting of suspected DVT. Limited data suggests that D-dimer may have lower sensitivity in the setting of suspected PE.
Imaging studies
Imaging for DVT and/or PE is the best means of screening and evaluation for these conditions. The current initial test of choice in the evaluation of VTE is compression ultrasonography (CUS) of the lower extremity veins.
CUS has been shown to be more than 95% sensitive and specific for proximal lower extremity DVT. [4] CUS is less accurate for the diagnosis of pelvic DVT. [5] In pregnancy, CUS should be performed with the patient in the left lateral decubitus position and with Doppler analysis of flow variation during respiration to maximize the study’s ability to diagnose pelvic DVT. [6]
However, if the CUS study is equivocal, if Doppler testing is abnormal, or if suspicion of pelvic DVT is high, further evaluation with serial CUS or magnetic resonance imaging (MRI) is recommended. [7, 8, 9] MRI has been shown to have 97% sensitivity and 95% specificity for pelvic DVT in nonpregnant patients. [10]
Imaging studies used in the diagnosis of PE include the following:
Chest radiography: Recommended prior to the evaluation for PE to determine whether other etiologies may explain the patient’s symptoms (eg, pneumonia, atelectasis, pulmonary edema) and to identify the next appropriate imaging test
Ventilation/perfusion (V/Q) scanning: In a pregnant patient with no known pulmonary disease and a normal chest radiograph, V/Q scanning is the recommended study to evaluate for PE
Spiral computed tomography pulmonary angiography (CT-PA): If the patient has an abnormal chest radiograph, known pulmonary disease, or a non-diagnostic V/Q scan, then spiral CT-PA is recommended [11]
Management
Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated in the absence of contraindications. The common classes of anticoagulation drugs are as follows:
Indirect thrombin inhibitors: Include unfractionated heparin and low ̶-molecular-weight heparin (LMWH), as well as synthetic heparin pentasaccharides and orally administered Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
Direct thrombin inhibitors: Include argatroban, lepirudin, bivalirudin, dabigatran
Vitamin K antagonist: Warfarin is included in this class
Heparin (unfractionated and low molecular weight) is the preferred drug for managing VTE in pregnancy. [12]
Background
Venous thromboembolism (VTE) may occur at any time during gestation. Studies report conflicting data as to the timing in pregnancy. Although most reports suggest that VTE can occur at any trimester in pregnancy, some studies suggest that VTE is more common during the first half of pregnancy. One study of 165 episodes of VTE in pregnancy documented a higher incidence in the first trimester (see the image below). [13] Other studies have not confirmed an association between gestational age and frequency of VTE. [14, 15]
Estimated gestational age at time of diagnosis of antepartum deep venous thrombosis (n=94).
Note that most evidence suggests that VTE is more common in the postpartum period. [1, 16, 17] In a 30-year population-based study, Heit et al documented that the risk of VTE and pulmonary embolism (PE) was 5-fold and 15-fold, respectively, in the postpartum period compared to during pregnancy. [2]
Special considerations in pregnancy - Location of DVT
In pregnancy, deep venous thrombosis (DVT) is much more likely to occur in the left leg compared with the right leg. One study examined 60 cases of DVT in pregnancy: 58 occurred in the left leg, 2 were bilateral, and none occurred in the right leg. [18] The predilection for left lower extremity DVT is postulated to be the consequence of May-Thurner syndrome, in which the left iliac vein is compressed by the right iliac artery (see the image below).
May-Thurner syndrome
Another special consideration relevant to accurate diagnosis in pregnancy is that 12% of DVTs in pregnancy are in pelvic veins, whereas only 1% of DVTs in the general population are in pelvic veins. [5] This predilection for pelvic site DVTs in pregnancy warrants special consideration when Doppler ultrasound studies of the lower extremities do not demonstrate noncompressible regions of lower extremity veins, yet suspicion for VTE is high or Doppler flow analysis of venous flow is abnormal.
Pathophysiology
Pregnancy is a state characterized by Virchow’s triad (1: hypercoagulability, 2: venous stasis and turbulence, 3: endothelial injury and dysfunction). Pregnancy is a state of hypercoagulability due to alterations of coagulation proteins. Factors I, II, VII, VIII, IX, and X increase in pregnancy. Pregnancy increases resistance to the anti-thrombotic factors such as protein C and protein S. [19] Thrombophilias can exacerbate these changes in coagulation proteins, further increasing the patient’s risk for VTE (see the image below).
Factors affecting thrombosis in Pregnancy
Venous stasis also increases as dilation of lower extremity veins occurs followed by venous compression by the gravid uterus and enlarging iliac arteries. Situations of decreased mobility (eg, surgery, cesarean delivery, bed rest, prolonged travel or air travel) may exacerbate these factors. Endothelial injury may transpire at time of delivery. [20] These factors work together to increase risk of VTE in the pregnant and postpartum patient.
Sequelae of VTE
Sequelae of DVT and PE include complications such as pulmonary hypertension, post-thrombotic syndrome, and venous insufficiency. Post-thrombotic syndrome is not well defined; however, most definitions consist of a constellation of symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (edema, skin induration, hyperpigmentation, venous ectasia, redness, pain during calf compression, and in more severe forms, venous stasis ulcer) in the extremity affected by DVT. Mild post-thrombotic syndrome occurs in 20-40% of patients after VTE, and severe post-thrombotic syndrome occurs in 5% of patients after VTE. [21]
Epidemiology
According to the Center for Disease Control’s National Pregnancy Registry Surveillance System, between 1991 and 1999, pulmonary embolism (PE) was the leading cause of maternal mortality. Of the 4,200 pregnancy related deaths reported in the United States during those years, 20% of maternal death was attributed to PE, surpassing pregnancy-related hypertensive disorders, postpartum hemorrhage, and infection. [22] The CDC Pregnancy Mortality Surveillance System data from 2011-2012 also reported that 9.0% of maternal death within a year of pregnancy termination that was determined to be pregnancy related was attributable to thromboembolism. [23]
According to the United Kingdom Centre for Maternal and Child Inquiries 8th Report on Confidential Inquiries into Maternal Deaths in the UK, VTE was the leading cause of direct maternal death in the UK for all but the final of the two year eras reported from 1985 to 2008, more common than death from sepsis, preeclampsia, amniotic fluid embolism, or hemorrhage. [24] Interestingly, the statistically significant decrease in maternal death due to VTE in 2006-2008 era was noted after the first publication of the Royal College of Obstetricians and Gynecologist Green Top Guideline “Thromboprophylaxis during Pregnancy, Labour and after Vaginal Delivery” in 2004.
Pregnancy increases the risk of VTE 4-fold to 5-fold over the nonpregnant state. [2, 1] Overall, the prevalence of VTE in pregnancy is 0.5-2.0 per 1,000 pregnancies and accounts for 1.1 deaths per 100,000 pregnancies. [25, 13, 26, 27, 16, 28, 29] Approximately 75-80% of embolic events in pregnancy are venous. [29]
The two manifestations of VTE are deep venous thrombosis (DVT) and pulmonary embolus (PE). DVT is approximately 3 times more common that PE in pregnancy. [2]
Presentation
History and Physical Examination (DVT)
Signs and symptoms of VTE are nonspecific and common in pregnancy. Most pregnant women experience mild tachycardia, tachypnea, dyspnea, and lower extremity edema. Diagnosis of VTE by physical examination is frequently inaccurate.
The 2 most common symptoms of DVT are pain and swelling of the lower extremity. 80% of pregnant women with DVT experience these symptoms, [30] although few of them are diagnosed with DVT. Up to 70% of women experience dyspnea in pregnancy, [31] although only a few have PE.
In a cohort of 53 women diagnosed with a DVT either antepartum (n=34) or postpartum (n=19), the 2 most common symptoms were edema (80-88%) and discomfort in the extremity (80-95%). [30]
A cross-sectional study of 194 pregnant women with no prior history of VTE evaluated the reliability of 3 variables in assessing risk of DVT by physical examination. Chan et al used the mnemonic LEFt [32] :
L- Symptoms in the left lower extremity
E-Edema: Mid-calf circumference difference of ≥ 2cm
Ft- First trimester presentation
DVT was not diagnosed in women in the absence of any of these factors. Of the women with one finding, 16% had DVTs; 58% of the women with 2 or 3 findings were diagnosed with DVT. [32]
Although no commonly used scoring system for prediction of DVT has been studied prospectively in pregnancy, the above studies highlight that DVT is common in pregnant women presenting with symptoms of pain and or swelling in the lower extremity. Since the risk of VTE is increased in pregnancy and postpartum, and the morbidity and mortality is appreciable, a low threshold for initiation of evaluation is recommended. Women presenting with these findings warrant further evaluation. If DVT or PE is suspected, the patient should begin anticoagulation treatment until further investigation excludes VTE.
History and Physical Examination (PE)
Clinical signs and symptoms of PE are nonspecific. The classic symptoms of PE are dyspnea (82%), abrupt onset chest pain (49%), and cough (20%). [3] The most common presenting signs are tachypnea, crackles, and tachycardia. No commonly used scoring system for the prediction of PE has been studied systematically in pregnancy.
All of these signs and symptoms of PE are only rarely encountered together. These symptoms and signs are also commonly found in the pregnant patient, confounding the clinician’s ability to make the diagnosis of this life-threatening process. Therefore, if the clinician suspects PE, anticoagulation therapy and appropriate immediate diagnostic testing should be performed until the diagnosis is made or eliminated as a possibility.
Patients with massive PE may present with syncope, hypotension, pulseless cardiac electrical activity, or death.
Electrocardiogram
An electrocardiogram may exhibit findings, such as right ventricular strain and the S1Q3T3 pattern suggestive of pulmonary embolism, but these findings are infrequent and generally nonspecific. Seventy percent of patients with PE have nonspecific EKG abnormalities, findings such as tachycardia, nonspecific ST segment, and T-wave abnormalities.
Risk Factors
Risk factors for development of VTE in pregnancy include normal physiologic alterations pregnancy (see Pathophysiology), personal or family history of VTE, and the presence of a thrombophilic disorder.
The most important risk factor for a women experiencing pregnancy-related VTE is prior personal history of VTE, which increases the risk of VTE 3-fold to 5-fold. [5] The next most common risk factor is thrombophilia, which is present in 20-50% of women with VTE in pregnancy. [30, 33, 34] Other common risk factors include cesarean delivery, which conveys twice the risk of VTE as vaginal delivery, [35] obesity, maternal cardiac disease, premature delivery, and smoking. [26, 27, 16, 36, 37, 38]
Thrombophilia
Thrombophilia is a common risk factor for VTE in pregnancy and can be found in 20-50% of pregnant women presenting with VTE. [30, 33, 34] Screening for thrombophilias should be done if the results are likely to alter management. Screening is unnecessary when treatment is indicated for other reasons. The results of screening may be affected if the patient is currently pregnant, currently has an acute VTE, or is currently receiving anticoagulation therapy. For further discussion on thrombophilias in pregnancy, please see Anticoagulants and Thrombolytics in Pregnancy.
Thromboembolism in Pregnancy Workup
Laboratory Evaluation for DVT
D-dimer is often used in non-pregnant patients due to its high negative predictive value. D-dimer increases progressively throughout gestation, [39] adding to the difficulty in selecting an appropriate cut off value for reasonable specificity in pregnancy. The high negative predictive value of d-dimer for DVT in pregnancy has also been demonstrated prospectively [40, 41, 42] ; Note, however, data to support its use in the setting of suspected PE is sparse, and D-dimer may have lower sensitivity in pregnancy.
A study by Chan et al suggests that DVT may be safely excluded if the d-dimer is negative and the compression duplex ultrasonography (CUS) is normal. One hundred forty nine consecutive pregnant women were evaluated for possible DVT. Twelve were diagnosed with DVT and 1 with PE. D-dimer testing (SimpliRED assay) was positive for all 13 patients (100% sensitivity), and the specificity was 60% (identifying correctly as negative for VTE 81 of 135 patients). This study demonstrated a 100% negative predictive value in pregnancy. [41] Use of a sensitive d-dimer test coupled with compression duplex ultrasonography may be a useful algorithm for evaluation of DVT in pregnancy, although more research is needed in this area.
One suggested algorithm integrating d-dimer testing is listed below [20] :
Diagnostic algorithm for suspected Deep-Vein Thrombosis and Pulmonary Embolism during pregnancy.
Laboratory Evaluation for PE
As discussed, d-dimer can be used outside of pregnancy for its negative predictive value in settings in which PE is suspected but unlikely [41] ; however, it is less specific in pregnancy. [43] D-dimer has not been prospectively validated in the setting of suspected PE in pregnancy as it has been for DVT. Furthermore, a small retrospective study by Damodaram, et al reported poor sensitivity of only 73% for PE. [44]
Arterial blood gas has been used to evaluate the alveolar-arterial oxygen gradient. An identified increase in Alveolar-arterial (A-a) gradient may be due to a mismatch in ventilation/perfusion as seen with pulmonary embolism. The A-a oxygen gradient is not sensitive for PE in pregnancy, limiting its use. In a study of A-a gradient in 17 pregnant women with PE, [28] 58% had documented normal A-a oxygen gradients. [45] See the A-a Gradient calculator.
Other laboratory testing (eg, cardiac enzymes, arterial blood gas, brain natriuretic peptide) is not typically helpful other than to evaluate for a possible alternative diagnosis to PE.
Imaging for DVT
The current initial test of choice in the evaluation of VTE is compression ultrasound (CUS) of the lower extremity veins. CUS has been shown to be more than 95% sensitive and specific for proximal lower extremity DVT. [4]
As mentioned above, CUS is not as accurate for diagnosis of pelvic DVT as for extremity DVT. [5] In pregnancy, CUS should be performed with the patient in the left lateral decubitus position and with Doppler analysis of flow variation during respiration to maximize the studies ability to diagnose pelvic DVT. [6]
If pelvic DVT is not suspected and the results of CUS with Doppler analysis are negative, the patient may return to routine observation. However, if the study is equivocal, if Doppler testing is abnormal, or if one’s suspicion of pelvic DVT is high, further evaluation with MRI is recommended. [7, 8, 9] MRI has been shown to have 97% sensitivity and 95% specificity for pelvic DVT in nonpregnant patients. [10] The American College of Obstetricians and Gynecologist Practice No 132 states that presumptive anticoagulation therapy may be appropriate in certain circumstances when one suspects pelvic DVT. [7] If index of suspicion for DVT is low and the results of CUS are negative, one may defer anticoagulation therapy, and the patient may be monitored. Examination of d-dimer levels may negate the need for further imaging or anti-coagulation in the setting of suspected DVT due to d-dimer’s high negative predictive value.
Imaging for PE
Imaging for either DVT and/or PE are the best methods to screen and evaluate for these issues. Note that the evaluation for suspected PE in pregnancy is similar to the nonpregnant individual. Although both spiral CT pulmonary angiogram (CTPA) and ventilation-perfusion scanning (V/Q) expose the fetus (or embryo) and mother to ionizing radiation, these potential risks must be compared to the up to 30% mortality in patients with PE left undiagnosed and untreated.
If at initial presentation a patient has concomitant symptoms or signs consistent with DVT and PE, compression ultrasonography may be considered first. If diagnostic for DVT, anticoagulation therapy is recommended, which is appropriate for both DVT and PE, avoiding further unnecessary testing for PE. A negative compression ultrasonography of lower extremity veins however does not exclude PE. If clinical suspicion still exists, further chest imaging is necessary.
A chest radiograph is recommended prior to the evaluation for PE to define other etiologies that may explain the symptoms (eg, pneumonia, atelectasis, pulmonary edema) and define the appropriate next imaging test.
Two alternative radiologic modalities exist for diagnosis of PE are spiral CT pulmonary angiography (CT-PA) and ventilation-perfusion (V/Q) scan. In the pregnant patient with no known pulmonary disease and a normal chest radiograph, ventilation-perfusion scan is the recommended study to evaluate for PE. If the patient has an abnormal chest radiograph or known pulmonary disease, spiral CT pulmonary angiography is recommended. [11]
The CT-PA uses IV contrast followed by CT scan. Filling defects may be seen on CT that are diagnostic of PE. The CT-PA is less accurate in detection of small or emboli at the peripheries of the lung. In the nonpregnant population, CTPA is preferred.
V/Q scanning is a 2-phase test. In the ventilation phase, a medical radionuclide gas is inhaled by the patient to demonstrate where air is entering the lungs. Next, the perfusion phase uses intravenous radioactive contrast to determine where blood flow is passing through the lungs. Images of both phases of the study are compared.
Areas where gas enters the lungs but blood does not may indicate embolus. The study is reported as normal, low, intermediate, or high probability for PE. These results then must be considered with pretest clinical probability of PE. Only low pretest probability combined with negative or low probability scan and high pretest probability combined with high probability scan results are diagnostic. Some patients may require CTPA after nondiagnostic V/Q scanning for definitive diagnosis, or vice versa.
V/Q scanning maybe less diagnostic in the setting of pre-existing pulmonary disease in the general population; however, in a young pregnant population these disease states are less likely. Several studies have demonstrated V/Q scanning to be either comparable or superior to CTPA for diagnosis of PE in pregnancy when chest radiographs are normal. [46, 47] The clinician’s choice of imaging test may depend on clinician preference, availability, and experience of the radiologist at the institution.
Treatment & Management
Long-Term Monitoring
Therapeutic and prophylactic management for VTE postpartum is as mentioned previously.
Estrogen-containing contraception has been shown to increase the risk of VTE 35-99 times above baseline. [48, 49] Therefore, estrogen-based contraception is contraindicated in a patient with a VTE associated with estrogen (eg, oral estrogen containing contraceptive) or thrombophilia. Nonetheless, screening all women prior to initiating estrogen-containing contraception is not recommended by ACOG. [49, 50] Other contraceptive methods that do not include estrogen, including progestin-containing contraceptives, may be considered in women with a prior VTE or known thrombophilia. [49, 50]
Medication
Medication Summary
When a high level of suspicion exists for an acute PE, empiric anticoagulation is recommended (unless contraindicated for other reasons) prior to the diagnostic evaluation. In patients with low or intermediate suspicion for PE or DVT, anticoagulation may await conclusive expeditious diagnostic testing.
Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated in the absence of contraindications. The common classes of anticoagulation drugs are as follows:
Indirect thrombin inhibitors: These include unfractionated heparin and low molecular weight heparins (eg, enoxaparin), as well as synthetic heparin pentasaccharides (eg, fondaparinux) and the new orally administered Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban).
Direct thrombin inhibitors: These include argatroban, lepirudin, and bivalirudin. This class also includes the oral medication dabigatran.
Vitamin K antagonist: This includes warfarin, however this is NOT recommended as initial anticoagulation therapy for VTE.
Heparins (unfractionated and low molecular weight) are the preferred drugs for management of VTE in pregnancy. UFH is listed as a category C drug in pregnancy and LMWH is category B. Both are large molecular weight molecules and neither crosses the placenta.
Low molecular weight heparin: Enoxaparin
Subcutaneous low molecular weight heparin (LMWH) is the preferred treatment for most patients with acute VTE. [12, 34] A large meta-analyses comparing LMWH to unfractionated heparin (UFH) showed that LMWH decreased the risk of mortality, recurrent VTE, and hemorrhage compared with heparin. [51, 52] Other advantages of LMWH may include more predictable therapeutic response, ease of administration and monitoring, and less heparin-induced thrombocytopenia. Disadvantages of LMWH include cost and longer half-life compared with heparin.
The most commonly used LMWH is enoxaparin (Lovenox). The recommended dosing of enoxaparin for acute VTE in pregnancy is 1 mg/kg every 12 hours. Some authors have suggested that LMWH dosing should be evaluated by monitoring anti-Xa level in pregnancy because of the effects of increased plasma volume and glomerular filtration rate on pharmacokinetics. [53, 54]
In a study of 13 pregnancies requiring therapeutic anti-coagulation, Barbour et al monitored the patients’ peak (2-4 hours after dosing) and trough (pre-dose) levels of anti-Xa while on weight based dosing of LMWH. They found that 85% of patients required dosing adjustments to maintain peak anti-Xa levels in therapeutic range, and noted that trough values were therapeutic only 9% of the time. [55]
Nevertheless, monitoring anti-Xa levels is not required according to American College of Chest Physician guidelines. Bates et al cite “the absence of large studies using clinical end points that demonstrate an optimal therapeutic anti-Xa range or that dose adjustments increase the safety or efficacy of therapy, the lack of accuracy and reliability of the measurement, the lack of correlation with risk of bleeding or recurrence, and the cost of the assay” as reasons making routine monitoring of anti-Xa levels difficult to justify. [34]
LMWH is excreted by the kidneys and should not be used if the patient’s creatinine clearance is less than 30 mL/min. Weight-based dosing with LMWH is only feasible in patients that weight less than 150kg. For patients, greater than 150 kg, UFH maybe preferred or else closer monitoring of anti-Xa levels should be performed to ensure therapeutic effect. [56]
Unfractionated heparin
Unfractionated heparin (UFH) may be preferred if the patient is likely to have immediate surgery because of its shorter half-life and reversibility with protamine compared with LMWH. As noted above, UFH may be preferred if creatinine clearance is less than 30 mL/min or if the patient weights >150kg. [56]
In the setting of acute VTE, UFH is administered by IV bolus, followed by IV infusion, with titration of the dose to an aPTT. The target aPTT is laboratory dependent. Many institutions have a normogram available to assist in the initial dose and titration of heparin infusions to therapeutic aPTT. The heparin infusion is typically increased or decreased by 10-30% to titrate to goal aPTT. [34]
After achieving a therapeutic and stable aPTT, the heparin can be converted to either subcutaneous UFH or LMWH. Subcutaneous UFH is less predictable for anticoagulation as significant dosing variability exists to maintain therapeutic response compared to LMWH. [34] However, due to cost, some patients may have limited access to LMWH.
If subcutaneous heparin is used, one may start at 17,500 every 12 hours, then check aPTT 6 hours after the second dose. The dose may be increased or decreased by 10-30% to titrate to therapeutic range. After aPTT is stable, it may be checked again in 3-4 days, then at least weekly thereafter. [34]
Warfarin and direct thrombin inhibitors
Warfarin freely crosses the placenta and is classified as category X by the FDA. Teratogenic effects including chondromalacia punctate, mid-face hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs, and short fingers have been described when warfarin is given in the first trimester. [57] Other possible effects are CNS abnormalities or fetal/neonatal hemorrhage and death if given at any gestational age.
Warfarin is rarely used in pregnancy. One exception is the use of warfarin after the first trimester in women with prosthetic heart valves.
There is insufficient experience to evaluate the risks and benefits of direct thrombin inhibitors in pregnancy.
Direct oral anticoagulants
Because data on the maternal and fetal safety of direct oral anticoagulants (DOACs) are scant, these agents are generally avoided in pregnancy. A meta-analysis by Areia and Mota-Pinto supports the conclusion that DOACs should be avoided during pregnancy. Their analysis showed a miscarriage rate of 22.2% and an elective termination of pregnancy in 21.8% of 339 cases; fetal anomalies linked to the use of DOACs occurred in 3.6%. [58]
Complications of medical management
After initiation of anticoagulation therapy, patients should be monitored for progressive or refractory VTE (eg, extension of DVT or continued pulmonary emboli), bleeding (major bleeding occurs in 1-3% of patients anticoagulated with UFH), [59] and heparin allergies including heparin-induced thrombocytopenia (HIT).
HIT occurs in 1-3% of nonpregnant patients using UFH and even less often in patients using LMWH(estimated at 1/1,000). [60] HIT is an immune response due to development of drug-induced IgG antibodies that leads to a hypercoagulable state of the venous system and may also involve the arterial system.
Appropriate monitoring for HIT depends on the clinical circumstance. Patients on therapeutic anticoagulation with UFH should have platelets checked every other day from days 4 to 14 after initiation of therapy. If the patient is on prophylactic dose UFH, platelets should be followed every 2-3 days from days 4-14 after initiation of therapy. Platelet monitoring may stop if heparin therapy is stopped. Routine platelet count monitoring is not required with LMWH. [59]
HIT should be considered if platelet count drops 50% or more for baseline (even if above 100 x 10^9/L) or falls below 100 x 10^9/L, if new venous or arterial thrombosis occurs after initiation of heparin, if anaphylactoid reactions occurs after IV UFH infusion, or if skin necrosis occurs even in the absence of thrombocytopenia. Mild thrombocytopenia occurs in approximately 10-20% of patients treated with heparin and is generally benign if serial monitoring documents a return to pretreatment platelet levels.
HIT is a thrombocytopenic state that is paradoxically more likely to produce both arterial and venous thromboembolism. If HIT is suspected, heparin therapy should be discontinued, and consultation with a hematologist should be expeditiously obtained to determine the best of method of anti-coagulation or prevention of embolus (e.g. vena cava filter, direct thrombin inhibitors). Platelet transfusion is typically considered contra-indicated as it increases the risk of thrombosis in HIT.
Labor and delivery
Many patients may present in labor while undergoing therapeutic anticoagulation. Most patients do not have increased delivery-related bleeding. [61] Temporary discontinuation of anti-coagulation is for the purpose of availability of regional anesthesia for the patient and to decrease the risk of epidural or spinal hematoma.
The American Society of Regional Anesthesia and Pain Medicine guidelines state that neuraxial regional anesthesia should be withheld for 12 hours following the last prophylactic LMWH dose or 24 hours following the last therapeutic LMWH dose. These guidelines also assert that neuraxial anesthesia in patients using prophylactic UFH up to 5,000 units twice daily is safe, although less is known about higher doses. [61]
Several reasonable management options exist for anticoagulation prior to delivery. Patients may be converted from LMWH to subcutaneous UFH at 36 weeks or sooner if delivery is expected earlier to permit access to timely regional anesthesia in labor. If a patient is using UFH and presents in labor, aPTT can be checked before placement of neuraxial anesthesia to ensure clearance. If delivery is planned, subcutaneous LMWH or UFH may be discontinued 24-36 hours prior to anticipated delivery or induction. If prolonged periods without anticoagulation is undesirable, subcutaneous LMWH or UFH can be discontinued and the patient can be anti-coagulated with IV UFH because of its shorter half-life. IV UFH can be discontinued 4-6 hours prior to delivery. [34] Prior to neuraxial anesthesia, IV UFH could also be stopped and aPTT checked to ensure clearance.
Postpartum
Anticoagulation may be restarted with UFH or LMWH 4-6 hours following vaginal delivery or 6-12 hours following cesarean delivery. [7] If neuraxial blockade was used, prophylactic anti-coagulation should not be restarted any sooner than 2 hours following epidural removal. [62] Although the ideal time to restart therapeutic anticoagulation following epidural removal is unclear, waiting 12 hours after removal of the epidural may be a reasonable approach. [7]
The total length and intensity of anticoagulation therapy depends on the timing of the VTE, whether or not the VTE occurred in the setting of pregnancy or other transient risk settings, and the presence of and specific type of any thrombophilia.
Pregnant patients with acute VTE are typically treated with therapeutic anticoagulation for a minimum of 6 months, and for at least 6 weeks postpartum. [34] Again, note that VTE is most likely to be more common in the postpartum period.
Postpartum therapeutic anticoagulation may consist of continued use of therapeutic heparin, or the patient may be bridged to warfarin. Discontinuation in heparin early in the transition to warfarin may cause increased short-term risk of VTE. To minimize this risk during conversion to warfarin, the patient should remain on therapeutic anticoagulation with heparin for at least 4-5 days while the warfarin is titrated to a goal INR of 2.0-3.0. Warfarin has a narrow therapeutic window and has significant variability in dosing. It requires close monitoring to ensure therapeutic range anti-coagulation. The annual incidence of major bleeding related to warfarin is 2-5%. [56]
Both heparins and warfarin are considered safe in lactation. No evidence exists that either enter the breast milk in quantities that create any anticoagulation effects in the breast-fed infant.
For further detail on the use of thrombolytics and vena cava filters in pregnancy, please refer to the
Prophylaxis for VTE
Decisions to provide prophylaxis for VTE in pregnancy must be based on the patient’s history. Pertinent to the decision is if the patient has experienced VTE previously, whether the patient has experienced more than one VTE in the past, whether or not a prior VTE occurred with a transient risk factor (eg, prolonged immobility or surgery), whether or not a prior VTE occurred in association with a pregnancy or estrogen-related state, whether or not a low or high risk thrombophilia is present, and whether or not the patient was receiving long-term anti-coagulation therapy prior to pregnancy.
Patients undergoing cesarean delivery have twice the risk of VTE as patients in the setting of vaginal delivery. Sequential compression devices may be used during cesarean delivery and continued until the patient is ambulatory. Early ambulation is a recommended strategy for thromboprophylaxis in women undergoing cesarean delivery. [34] In the absence of other risk factors, medical thromboprophylaxis with heparin or LMWH is not recommended because the overall risk of VTE is low and is comparable to other surgical procedures where prophylaxis is not recommended. [34]
Early recognition and widespread implementation of thromboprophylaxis guidelines has shown a significant decrease in VTE related deaths in the UK. According to the United Kingdom Centre for Maternal and Child Inquiries 8th Report on Confidential Inquiries into Maternal Deaths in the UK, VTE was the leading cause of direct maternal death in the UK for all but the final of the two year eras reported from 1985 to 2008, more common than death from sepsis, preeclampsia, amniotic fluid embolism, or hemorrhage. [24] Interestingly, the statistically significant decrease in maternal death due to VTE in 2006-2008 era was noted after the first publication of the Royal College of Obstetricians and Gynecologist Green Top Guideline “Thromboprophylaxis during Pregnancy, Labour and after Vaginal Delivery” in 2004.
Implementation of the American College of Obstetricians and Gynecologists (ACOG) and ACCP guidelines for the prevention of thromboembolism can help reduce the rates of VTE related morbidity and mortality in the US. The following recommendations are based on the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Ed) for venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. The following recommendations are based on the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Ed) for venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. [63]
Risk Factor | Recommendations |
Women with a single episode of VTE associated with a transient risk factor that is no longer present | Clinical surveillance and anticoagulant prophylaxis postpartum* |
Women with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) and a strong family history of thrombosis who are not receiving long-term anticoagulants | Prophylactic or intermediate-dose LMWH or unfractionated heparin (UFH), plus postpartum anticoagulation for at least 6 wk (for a total minimum duration of therapy of 6 mo) |
Women with antithrombin deficiency and no previous VTE | Antepartum and postpartum prophylaxis |
Women with thrombophilia (other than antithrombin deficiency) and no previous VTE | Clinical surveillance or prophylactic LMWH or UFH and anticoagulant prophylaxis postpartum* |
Women with multiple (≥ 2) episodes of VTE who are not receiving long-term anticoagulants | Prophylactic, intermediate-dose or adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulation postpartum |
Women with multiple (≥ 2) episodes of VTE who are receiving long-term anticoagulants | Adjusted-dose UFH or LMWH followed by resumption of long-term anticoagulation postpartum |
All women with previous DVT, antenatal and postpartum | Use of graduated elastic compression stockings |
Women with recurrent pregnancy loss (≥ 3 miscarriages) and women with severe or recurrent preeclampsia, placental abruption, or otherwise unexplained intrauterine growth retardation | Screen for thrombophilia and antiphospholipid antibodies |
Women with antiphospholipid antibody syndrome and a history of multiple (≥ 2) early pregnancy losses or ≥ 1 late pregnancy losses, preeclampsia, intrauterine growth retardation (IUGR), or abruption | Antepartum aspirin plus prophylactic or intermediate-dose UFH or LMWH |
Women with APLAs and a history of VTE who are usually receiving long-term oral anticoagulation therapy | Adjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum |
* If the previous risk factor is pregnancy or estrogen-related or additional risk factors (such as obesity) are present, antenatal anticoagulant prophylaxis is recommended. |
According to recommendations from ACOG, VTE prophylaxis during pregnancy and/or the postpartum period may be required for persons with the following risk factors [64] :
A diagnosis of VTE during a previous pregnancy
A history of VTE, including during pregnancy or with the use of hormonal contraceptives
A history of thrombophilia with or without a personal or family history of VTE
Once the diagnosis of venous thromboembolism (VTE) is made, therapeutic anticoagulation should be initiated in the absence of contraindications. The goals of pharmacotherapy are to prevent or correct thromboembolic disorders, prevent complications, and reduce morbidity.
The National Partnership for Maternal Safety reviewed current guidelines and made the following recommendations for prophylaxis which included the following [65] :
The authors recommend that all pregnant women should undergo risk assessment for VTE throughout pregnancy. In particular, clinicians should assess patients during the first prenatal visit, during any antepartum hospitalizations, immediately postpartum during a hospitalization for childbirth, and after they are discharged home after a delivery.
Clinicians should use a patient's modified Caprini or Padua score to identify those who are at high risk for VTE and who are therefore candidates for thromboprophylaxis.
For antepartum outpatient prophylaxis, treatment-dose low-molecular-weight (LMW) heparin or unfractionated heparin (UFH) is recommended for women with a clinical history of multiple VTE episodes, VTE with high-risk thrombophilia, or VTE with acquired thrombophilia.
For all antepartum patients who are hospitalized for 3 days or longer who are not at high risk for bleeding or imminent childbirth, prophylaxis with daily LMW heparin or twice-daily UFH is recommended.
Women undergoing cesarean delivery who are not receiving pharmacologic thromboprophylaxis should also receive perioperative mechanical thromboprophylaxis. Depending on their specific risk factors, these women should also receive postoperative pharmacologic thromboprophylaxis with LMW
Heparin or UFH, based on Royal College of Obstetricians and Gynaecologists (RCOG) criteria or modified Caprini scores.
Extended postpartum pharmacologic thromboprophylaxis after hospitalization for childbirth is recommended. For example, women with a clinical history of multiple VTE episodes, VTE with high-risk thrombophilia, or VTE with acquired thrombophilia should receive a 6-wk treatment dose of LMW heparin or UFH.
A systematic review by Croles et al that included 36 studies reported that women with antithrombin, protein C, or protein S deficiency or with homozygous factor V Leiden should be considered for antepartum or postpartum thrombosis prophylaxis, or both. Women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutation, or compound heterozygous factor V Leiden and prothrombin G20210A mutation should generally not be prescribed thrombosis prophylaxis on the basis of thrombophilia and family history alone. [66]
Anticoagulants, Hematologic
Class Summary
Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated in the absence of contraindications. Anticoagulants prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation. In patients with heparin-induced thrombocytopenia, LVAD implantation has been performed successfully, albeit with additional risk, by using alternative anticoagulants.
Heparin may be used if thrombocytopenia is not present. Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents the recurrence of a clot after spontaneous fibrinolysis. Heparin does not cross the placenta.
Warfarin, which is administered orally, is used if long-term anticoagulation is needed. The international normalized ratio (INR) is followed, with a target range of 2-3. Warfarin crosses the placenta and is teratogenic, causing a constellation of anomalies known as warfarin embryopathy, with greatest risk between the sixth and twelfth week of gestation. Warfarin is still often recommended in pregnant patients with mechanical heart valves.
Enoxaparin is produced by the partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa.
Enoxaparin binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). It does not actively lyse but is able to inhibit further thrombogenesis, preventing clot reaccumulation after spontaneous fibrinolysis.
The advantages of enoxaparin include intermittent dosing and a decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. The drug has a wide therapeutic window, and aPTT does not correlate with the anticoagulant effect. The maximum antifactor Xa and antithrombin activities occur 3-5 hours after administration. Enoxaparin does not appear to cross the placenta.
LMW heparin with antithrombotic properties; it enhances inhibition of factor Xa and thrombin by antithrombin, with minimal effect on aPTT.
Tinzaparin is an LMW heparin with antithrombotic properties; it enhances inhibition of factor Xa and thrombin by antithrombin, with minimal effect on aPTT. Does not cross placenta in human studies.
Argatroban is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation.
Dabigatran etexilate is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. A study by Bapat et al has concluded that dabigatran crosses the human placenta. It inhibits thrombin-induced platelet aggregation.
Bivalirudin inhibits coagulant effects by preventing thrombin-mediated cleavage of fibrinogen to fibrin.
Fondaparinux is a synthetic heparin pentasaccharide that causes an antithrombin lll mediated selective inhibition of factor Xa. This interrupts the blood coagulation cascade, which in turn inhibits thrombin formation and thrombus development.
Rivaroxaban is a selective and reversible inhibition factor of Xa (FXa) in the intrinsic and extrinsic coagulation pathways. This interrupts the blood coagulation cascade, which in turn inhibits thrombin formation and thrombus development. A study by Bapat et al concluded that rivaroxaban crosses the human placenta.
Inhibits platelet activation and fibrin clot formation via direct, selective, and reversible inhibition of free and clot-bound factor Xa. Factor Xa, as part of the prothrombinase complex, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.
Selective Xa inhibitor, inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation.
Antiplatelet Agents
Class Summary
These agents can be considered to help prevent future ischemic strokes.
Aspirin's efficacy in preventing stroke relies on the inhibitory effect of aspirin on platelet function. This presumably helps to prevent thrombus formation and propagation.
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