Blood Clotting Disorders in Pregnancy and Postpartum Nursing CE Course for APRNs

al., 2022; Norris, 2020). The defining components of each process are as follows:

1. Primary hemostasis:
   1. vascular spasm or vasoconstriction of the blood vessel,
   2. platelet adhesion,
   3. platelets activation (or secretion),
   4. platelet aggregation
2. Secondary hemostasis:
   1. activation of clotting factors,
   2. conversion of prothrombin to thrombin,
   3. conversion of fibrinogen to fibrin (Garmo et al., 2022)

Virchow's Triad

Rudolf Virchow, often referred to as the "father of modern pathology," is a 19th Century physician credited with identifying three significant predisposing abnormalities that can lead to the development of thrombosis. Branded "Virchow's triad," the three pathologic mechanisms influencing blood clot formation, including damage to the blood vessel wall, blood flow abnormalities, and blood hypercoagulability. Pregnancy and the postpartum period are associated with physiologic changes characteristic of Virchow's triad (Hinkle et al., 2021; McCance & Heuther, 2019).

 

Venous Stasis

Venous stasis refers to the loss of blood flow within the vessel. Blood pooling is a significant risk factor for thrombus formation, as, during venous stasis, platelets remain in contact with the endothelium for a prolonged period. During this time, clotting factors usually diluted with flowing blood become concentrated and potentially activated. Blood tends to flow slower during pregnancy in response to the pressure induced on the mother's blood vessels from the demands of the growing fetus. This causes changes in the vascular capacitance, or the blood vessel's ability to increase the blood volume without increasing the blood pressure. Around 25 weeks gestation, a reduction of venous flow velocity by approximately 50% occurs in the legs. The sluggish blood return predisposes the pregnant woman to injury of the lower extremity veins and the subsequent development of VTE. As the fetus grows, the uterus increases in size, causing increased pressure and compression of the iliac veins (large veins within the pelvis) and the major veins returning blood from the legs. Among pregnant and postpartum women, the left lower extremity and the iliofemoral region is the most common site for DVT, responsible for up to 82% of cases. The rationale for this is the anatomic location of the enlarging uterus that favors compression of the left common iliac vein. Figure 2 is a graphic depiction of the anatomy of the veins in the lower extremity (Bauer & Lip, 2023; Devis & Knuttinen, 2017; Malhotra & Weinberger, 2023c).

Figure 2

Veins of the Lower Extremity

Endothelial Injury

Vascular endothelial injury leads to platelet activation and blood clot formation to prevent blood loss and restore the integrity of the vascular wall. However, when these mechanisms are impaired or there is an underlying defect, pathologic consequences can ensue. Endothelial injury can be precipitated by numerous insults that extend beyond external tissue trauma, such as smoking, surgery, atherosclerotic disease, inflammation, or chronic elevations in blood pressure. Regardless of the precipitating event, normal blood flow is altered when the endothelium is injured, inducing "turbulence" within the vessel. Turbulence is the increased blood flow rate over the injured surface, generating disordered currents and increased friction within the vessel. Childbirth is associated with vascular injury and changes at the uteroplacental surface, which are considered major contributors to the increased risk of VTE in the immediate postpartum period. In addition, forceps, vacuum extraction, or C-section delivery can further exacerbate vascular injury (Bauer & Lip, 2023; Malhotra & Weinberger, 2023c; McCance & Heuther, 2019).

Hypercoagulability 

Abnormalities within the coagulation cascade, fibrinolytic pathways, or platelet function contribute to hypercoagulability and subsequent thrombus formation. Hypercoagulability may result from genetic or acquired etiologies and is usually multifactorial, with lifestyle and environmental factors playing key roles. Hypercoagulability resulting from inherited defects includes Factor V Leiden (FVL), prothrombin mutation (G20210A), or deficiencies of the natural proteins that prevent clotting. Some individuals may present with increased levels of certain clotting factors without any identifiable genetic mutation. The most common causes of acquired hypercoagulability include cancer, inflammation, immobility from paralysis or prolonged bed rest, surgery (especially the immediate postoperative period), pregnancy, and the postpartum period (Bauer & Lip, 2023; Hinkle et al., 2021; McCance & Heuther, 2019).

Pregnancy naturally induces a state of increased hypercoagulability in which the blood clots more easily through a set of physiologic changes. The hypercoagulable state is considered an evolutionary protective mechanism to prepare for childbirth and protect against hemorrhaging during delivery. When a woman reaches the full term of the pregnancy, approximately 500 mL of blood flows through the placenta every minute. Therefore, postpartum hemorrhage would ensue without rapid and effective hemostasis, and the mother could die from blood loss. Unfortunately, these changes also predispose women to VTE events. The physiologic mechanisms of hemostasis ensure appropriate clot formation via complex interactions between clotting factors within the coagulation cascade, platelets, and vascular endothelium. The fibrinolytic system prevents excessive coagulation by removing fibrin and unnecessary blood clots (Abe et al., 2019; Bauer, 2022).

Most coagulation factors increase during pregnancy, generating a prothrombotic state and heightening the tendency to develop abnormal blood clots. In addition to the rise in clotting factors, there is also an increase in von Willebrand factors (vWF), which is the primary mediating factor for platelet adhesion, acting like a 'glue' and binding the platelets with enough strength to withstand stress and prevent detachment during normal hemostasis. Platelets circulating in the blood travel to the site of injury and adhere to the wall of the vessel, sticking together to form a temporary platelet plug. Platelets mainly bind to collagen in tissues at the site of vessel wall injury, as exposed vWF at the damaged vessel site ignites platelet aggregation. Therefore, the increased vWF circulating within the blood during pregnancy leads to increased platelet activity and clotting. Table 1 reviews the 12 clotting factors, their primary roles, and interactions under physiologic conditions to understand better the changes in clotting factors associated with pregnancy. As a reminder, there is no clotting FVI, and clotting factors primarily depend on vitamin K and calcium ions (Ca2+), which are vital for accelerating blood clotting. D-dimer is a protein fragment produced when the body forms or breaks down blood clots. Under physiologic conditions, the D-dimer level is usually undetectable or very low. The levels increase when there is significant formation and breakdown of fibrin clots in the body. The test measures the amount of the substance released into the bloodstream when fibrin proteins in a blood clot dissolve. Due to the hypercoagulable state of pregnancy, the D-dimer is routinely elevated during pregnancy (Gross et al., 2018; Lim et al., 2018).

Table 1

Clotting Factors

Factor	Common Name	Function
FI	Fibrinogen	assists with fibrin clot formation
FII	Prothrombin*	assists FVIIIa, FIXa, and FVa in forming thrombin
FIII	Tissue Factor (TF)	assists FVII and FIV in activating FIX and FX
FIV	Ca2+	activates multiple clotting factors
FV	Proaccelerin (Labile Factor)	assists FVIIIa, FIxa, FXa, and FII in the formation of thrombin
FVII	Proconvertin (Stable Factor)*	assists TF and FIV in activating FIX and FX
FVIII	Antihemophilic Factor (AHF)	amplifies additional thrombin formation
FIX	Plasma Thromboplastin* Component (PTC) or Christmas Factor	assists FVa, FVIIIa, FXa, and II in forming thrombin
FX	Stuart-Prower Factor* (thrombokinase)	assists FVIIIa, FIxa, FVa, and II to form thrombin
FXI	Plasma Thromboplastin Antecedent (PTA) or antihemophilic factor C	increases thrombin production inside fibrin clots through the intrinsic pathway; slows fibrinolysis
FXII	Hageman Factor (contact factor)	contact activator of the kinin system
FXIII	Fibrin Stabilizing Factor (FSF)	forms bonds between fibrin strands during secondary hemostasis

*Vitamin K required (Gross et al., 2018; Norris, 2020)

During pregnancy and postpartum, the hypercoagulable state is attributed to increased clotting factors, decreased levels of certain natural blood thinning proteins, and venous stasis. Specifically, the following major physiologic changes in hemostasis occur:

• clotting factors I, II, VII, VIII, IX, X, and XII increase by 20% to 200%
• plasma fibrinogen (Factor I) concentration increases by 50%
• increase in vWF and platelet reactivity
• decline in anticoagulant activity
  • gradual and significant decrease in protein S, up to 50% by pregnancy term, and persisting for at least two months postpartum
  • progressive increase in resistance to activated protein C
• steady decline in fibrinolytic capacity, which can lead to a hypo-fibrinolytic state (impaired ability to breakdown old blood clots) by the third trimester (Bates et al., 2018; Bauer, 2022; Tlamcani et al., 2018)

 

Risk Factors 

In addition to the pathophysiological changes associated with pregnancy, several additional factors can further heighten the risk of VTEs during pregnancy. Often, there are multiple risk factors present in a single individual simultaneously. The most well-established risk factors are listed in Table 2 (Longo, 2019).

Table 2

Risk Factors for Pregnancy-associated VTE 

Inherited thrombophilia disorders (to be discussed in Part II)

Personal or family history of blood clots or a blood clotting disorder

Surgical delivery by C-section

Complications of pregnancy and childbirth (i.e., transfusion, postpartum infection, stillbirth, eclampsia, or preeclampsia)

Prolonged immobility or remaining sedentary for extended periods, including long-distance travel or bed rest during pregnancy or following delivery Travel greater than four hours more than doubles the risk for VTE

Pregnancy with multiple babies

Hormonal risk factors, which include hormonal contraception or the use of fertility treatments involving hormones

Smoking cigarettes or frequent exposure to second-hand smoke

Obesity

Pregnancy at age 35 or older

Youn gestational age (preterm delivery less than 36 weeks)

Chronic conditions such as cardiovascular disease (CVD), pulmonary disease, hypertension, varicose veins, inflammatory bowel disease, or diabetes

(CDC, 2023d; Devis & Knuttinen, 2017; Malhotra & Weinberger, 2023c; NBCA, n.d.-a)

 

Signs and Symptoms

The APRN must remain vigilant to potential signs and symptoms of VTE, as early identification and intervention are essential to mitigate complications and reduce mortality. The symptoms of VTE can overlap with the symptoms of pregnancy, which can impede early diagnosis. SVT is characterized by vein inflammation due to a thrombus directly below the skin's surface, and the most common symptoms include pain, tenderness, irritation, and erythema along the superficial vein. SVT is usually associated with varicose veins, which are enlarged, swollen, and damaged veins that appear as bulging, palpable, and bluish cords, as demonstrated in Figure 3 (Devis & Knuttinen, 2017; NBCA, n.d.-a).

Figure 3

Varicose Veins

The most common symptoms of DVT include swelling and extremity discomfort, although these vary depending on the location and the body part affected. The incidence of an isolated DVT in the iliac veins is higher during pregnancy, which can present with abdominal pain, back pain, or swelling of the entire leg. The clinical features of the three types of VTE are outlined in Table 3 (Devis & Knuttinen, 2017; Malhotra & Weinberger, 2023c).

Table 3

Common Clinical Features of VTE in Pregnancy and Postpartum

VTE	Clinical Features
SVT	Symptoms tenderness and pain in the area of the clot that worsens with pressure hardening of the vein swelling of the extremity Signs "cord-like" structure upon palpation discoloration or redness of the skin over the vein inflammation of the skin along a vein warmth of the skin around the vein
DVT	Symptoms pain or soreness at the affected site not caused by injury tightness, aching, or tingling, especially with walking localized swelling (usually unilateral) Signs skin that is warm to touch redness/erythema or bluish discoloration of the skin positive Homans' sign (pain in the calf associated with dorsiflexion of the foot)
PE	Symptoms shortness of breath, difficulty breathing, air hunger dizziness or fainting pleuritic chest pain, sharp chest pains palpitations cough, with or without bloody sputum (hemoptysis) Signs tachypnea tachycardia or irregular heart rate pulmonary rales pleural friction rub presenting manifestation can be sudden death

(CDC, 2023d; Longo, 2019; McCance & Heuther, 2019)   

 

Complications of VTE

A large/severe PE can obstruct blood flow and induce sudden death. They can also cause hypoxia or low oxygen levels in the blood, leading to permanent damage to the lungs or other organs in the body due to insufficient oxygen. PE-associated mortality during pregnancy and postpartum are often attributed to delayed diagnosis, delayed or inadequate treatment, and insufficient thromboprophylaxis (Devis & Knuttinen, 2017; McCance & Heuther, 2019).

Additional complications associated with pregnancy-related VTE include increased risk for a recurrent VTE event, post-thrombotic syndrome (PTS), and chronic thromboembolic pulmonary hypertension (CTEPH). VTEs can also obstruct blood flow to the fetus and result in fetal demise or neurological and developmental complications from hypoxia following birth. PTS is the most common, long-term, and potentially debilitating complication of a DVT. PTS is characterized by pain and swelling in the affected extremity, which can be mild to severe and occurs in 20% to 50% of patients with a DVT. PTS typically presents within three to six months of DVT diagnosis but has been reported up to two years later, even when appropriate treatment is implemented. The clinical manifestations are similar to primary venous insufficiency, but the degree and severity can vary. Symptoms are generally limited to the affected leg and include swelling, pain, heaviness, and fatigue, and can be constant or intermittent. They are usually aggravated by standing or walking and improve with elevation and rest. Patients often exhibit leg redness, dusky cyanosis when the leg is in the dependent position, varicose veins, edema, and hyperpigmentation. In its most severe form, PTS can lead to venous ulcers and permanent disability. PTS is primarily diagnosed based on clinical manifestations; no gold standard biomarker or test establishes the diagnosis. Approximately 60% of patients with PTS recover fully without residual symptoms, whereas 10% develop chronic symptoms (Devis & Knuttinen, 2017; Kahn & Mathes, 2022; NBCA, 2022).

CTEPH is a rare complication of a PE, reported in up to 4% of patients within the two years following the initial PE diagnosis. CTEPH is a condition in which abnormally high blood pressure in the arteries of the lungs causes the right side of the heart to work harder than normal, leading to heart failure. This rare and progressive condition is caused by undissolved blood clots that develop into scar tissue and impede flow in the lungs' small blood vessels. Since the most common symptom of CTEPH is shortness of breath, a symptom of PE and numerous other conditions, early diagnosis is difficult. CTEPH can be cured with a surgical intervention called pulmonary thromboendarterectomy (PTE), during which the clots are removed from the arteries in the lungs. A newer treatment, called balloon pulmonary angioplasty (BPA), involves a tiny balloon inflated inside the pulmonary artery to widen it. If the condition is left untreated, most patients with CTEPH will die within five years (Abe et al., 2019; Sahay et al., 2020).

Diagnostic Workup

All pregnant women presenting with signs or symptoms suspicious of DVT should undergo objective diagnostic testing as soon as possible since sudden death from PE is possible. Unless contraindicated, the ASH recommends initiating anticoagulation treatment when the clinical suspicion is high until the diagnosis of DVT is ruled out. Compression duplex ultrasound (CDUS) with Doppler evaluation of the iliofemoral region is the recommended first-line diagnostic tool for suspected DVT. In patients with an initial negative ultrasound with imaging of the iliac veins, the ASH suggests additional investigation with serial CDUS or magnetic resonance venography (MRV). A single CDUS may not be sufficient to rule out DVT, as up to 24% of DVTs in pregnancy are found on serial testing (Bates et al., 2018; Devis & Knuttinen, 2017; Malhotra & Weinberger, 2023c).

Ultrasound is a safe, noninvasive imaging modality that uses sound waves to generate images of internal body structures. CDUS involves a two-part process. First, ultrasound images are obtained by placing a small probe (transducer) and ultrasound gel against the skin. The transducer produces sound waves at very high frequencies, which exceed the threshold of human hearing. These high-frequency sound waves travel from the probe through the gel and into the body and are used to generate images on a computer. While imaging the deep veins of the leg, the sonographer tries to collapse or compress the veins. If a vein cannot be compressed, it is likely due to a clot being present, preventing it from collapsing. The ability to flatten a vein completely with compression is the most useful way to ensure a clot is not present. The second part of the CDUS utilizes Doppler ultrasound, a specialized technique that evaluates blood flow through the arteries and veins. Images are captured in real-time, evaluating the structures and movement of the internal organs, including blood flow through the vessels. The Doppler technique focuses on detecting abnormalities in blood flow, with the absence of blood flow confirming the diagnosis of a DVT. For patients with negative compression, poor Doppler flow in the iliac vein has reasonable accuracy for diagnosing a suspected pelvic DVT (Malhotra & Weinberger, 2023c; NBCA, n.d.-b; Needleman et al., 2018).

Serial CDUS involves repeating the test within seven days and is associated with a low rate of missed DVT; only 5 in 1,000 women with negative results are projected to present with symptomatic VTE during follow-up. CDUS has a sensitivity of 97% and a specificity of 94% for the diagnosis of femoropopliteal DVTs among the general population. However, it is less sensitive to pelvic vein and calf vein thromboses. In patients with a negative or inconclusive CDUS with increased clinical suspicion for a VTE, consideration should be given toward MRV, as it can be useful in determining the true extent of a DVT in the abdomen or pelvis. MRV is considered the second-line or alternative option for additional investigation when the initial CDUS is negative. MRV is a type of MRI scan that specifically examines the veins; however, there is limited evidence suggesting MRV of the pelvic veins might detect pelvic thrombosis not identified with ultrasonography (Bates et al., 2018; Devis & Knuttinen, 2017; Malhotra & Weinberger, 2023c).

In patients with suspected PE, ventilation-perfusion (V/Q) lung scanning is preferred over computed tomography pulmonary angiography (CTPA), as radiation exposure for the fetus should be limited. The fetal radiation dose is lower with a V/Q scan, and it is considered safer for women regarding breast-absorbed radiation dose, as it minimizes the potential impact on breast cancer risk. However, V/Q scans may not be readily accessible in all healthcare settings. In settings without access to V/Q scanners, the ASH cites a CTPA as an acceptable alternative. CTPA may also be indicated in women with abnormal chest radiographs or preexisting lung disease. Since the D-dimer assay test is typically positive (elevated) during uncomplicated and healthy pregnancies, it is not considered a reliable component of the diagnostic workup for VTE during pregnancy. The ASH guidelines warn against a high rate of false-positive results with D-dimer testing in pregnant patients. In addition, routine laboratory testing (i.e., complete blood count [CBC], comprehensive metabolic profile [CMP], liver function tests, and coagulation studies) are not useful diagnostically but may be useful for determining the underlying cause and influence treatment decisions if DVT is confirmed (Bates et al., 2018; Devis & Knuttinen, 2017; Lim et al., 2018; Malhotra & Weinberger, 2023c).

 

Risk Assessment and Prevention

As in the non-pregnant population, thrombosis can be provoked or unprovoked during pregnancy. This is key information to acquire during the risk assessment, as it significantly impacts management. Unprovoked VTE implies that no identifiable risk factor or underlying cause is evident or identifiable. In contrast, a provoked thrombus is caused by a known event, such as surgery, trauma, or prolonged immobility. Unprovoked events are considered more serious in pregnant and non-pregnant patients and often require a specialized diagnostic workup and treatment, usually under the care of a hematologist. Despite the increased risk of VTE during pregnancy, the pregnancy period is not considered a provoked event, and most pregnant women do not require thromboprophylaxis (Lip & Hull, 2023a; Malhotra & Weinberger, 2023b). In most patients, blood clots can be prevented. As part of a collaborative effort called the "Stop the Clot, Spread the Word" campaign, the CDC (2023a) joined forces with the NBCA (n.d.-c) to create a checklist for women to assess their risk for blood clots during pregnancy and postpartum. The campaign strives to enhance awareness of the signs and symptoms of blood clots and educate women on their risk factors so that they can take appropriate preventative action to mitigate their risk. The campaign encourages women to complete the checklist, identify any potential risks that may apply to them, and discuss the information with their healthcare provider. A copy of the checklist is shown in Figure 4 (CDC, 2023a; NBCA, n.d.-c).

Figure 4

Checklist for Blood Clot Risks in Pregnancy 

 

(CDC, 2023a)

The CDC (2023c) provides general recommendations for all women who are pregnant or postpartum to diminish their risk of developing a VTE, which are summarized below:

• Remain active up to delivery and after delivering the baby, as movement is the key to preventing blood clots. If sitting for long periods, exercise the legs every one to two hours.
• Get out of bed and walk as soon as possible after delivery, even after a C-section.
• Stay well hydrated; drink ten glasses of liquid daily during the pregnancy and 12 to 13 glasses daily while breastfeeding.
• For patients on bed rest, adequate hydration and compression devices are essential.

Anticoagulation Therapy

Anticoagulation is the standard treatment for acute VTE events during pregnancy and postpartum and may also be used for prophylaxis in certain high-risk patients. Anticoagulants, or "blood thinners," reduce the risk of morbidity and mortality associated with thrombotic events by helping prevent and/or dissolve existing blood clots and slowing down the body's process of generating new blood clots. In pregnancy, the choice of anticoagulation is primarily based on safety, efficacy, and adherence to therapy. There are fewer options for anticoagulation in pregnancy than in non-pregnant adults, as consideration must be given to the health and well-being of the fetus and the mother, as well as the risk for excretion to the newborn via breast milk. Clinicians should assess the risk of bleeding for all patients who develop a VTE during pregnancy or postpartum. General bleeding risk can be categorized as low risk (i.e., three-month bleeding risk of less than 2%), moderate risk (i.e., three-month bleeding risk of 2% to 13%), or high risk (i.e., three-month bleeding risk of greater than 12%). This risk is based on age, previous bleeding, cancer, thrombocytopenia, diabetes, anemia, alcohol misuse, frequent falls, recent surgery, and liver or kidney failure). Decisions to start anticoagulation therapy should be based on individual risk-to-benefit assessment. Table 4 highlights the key recommendations for anticoagulation therapy during pregnancy and postpartum, supported by the highest level of clinical evidence (Bates et al., 2018; Malhotra & Weinberger, 2023a; Witt et al., 2018).

Table 4

Strong Recommendations for Anticoagulation during Pregnancy and Postpartum

During Pregnancy	Low molecular weight heparin (LMWH) is recommended over unfractionated heparin (UFH), but both classes are acceptable for use during pregnancy.
	Fondaparinux (Arixtra) is not preferred due to limited clinical experience and its ability to cross the placenta in small amounts.
	Vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC) are contraindicated.
Postpartum	The safest options for AC include: UFH LMWH warfarin (Coumadin) acenocoumarol (Orencia) fondaparinux (Arixtra) danaparoid (Orgaran)
	DOACs should be avoided.

(Bates et al., 2018; Malhotra & Weinberger, 2023a)

Unfractionated Heparin (UFH)

UFH is a rapidly acting anticoagulation agent that works with antithrombin to block clot formation. UFH binds to antithrombin and enhances its ability to inhibit FXa and FIIa quickly. While UFH does not break down clots, it functions to prevent new ones from forming, allowing the body to dissolve any existing thrombi gradually. UFH is administered via subcutaneous injection or as a continuous IV infusion. Dosing is determined by body weight, and patients require frequent monitoring while on treatment with UFH to ensure appropriate dosing and safety. Since UFH does not rely heavily on the kidneys for its excretion, it is considered the treatment of choice for patients with underlying renal dysfunction and those with poor subcutaneous absorption (i.e., severely obese, severely underweight, or edema). The primary advantages of UFH include its rapid onset and relatively rapid termination following discontinuation of the medication. It is the preferred treatment for patients at heightened risk for bleeding due to its short half-life and reversibility. While the definitive half-life of UFH depends on the dose, the average half-life is about 30 to 90 minutes in most healthy adults. Protamine sulfate (Prosulf) is commonly used to reverse the anticoagulation effect of UFH. In non-pregnant patients taking UFH who develop life-threatening bleeding, the ASH recommends stopping the anticoagulant and administering protamine sulfate (Prosulf). One milligram (mg) of protamine sulfate will neutralize approximately 100 units of UFH. However, since the half-life of heparin is relatively short, the timing of protamine (Prosulf) administration depends on the timing of the most recent UFH exposure. As more time passes from the most recent UFH exposure, less protamine (Prosulf) is required to reverse its anticoagulant effects. However, according to the Prescribers' Digital Reference (PDR, n.d.), the use of protamine sulfate (Prosulf) was previously classified as pregnancy risk category C by the US Food & Drug Administration (FDA), indicating that it is not known if the drug can cause fetal harm when administered to pregnant women. In addition, it is unknown whether protamine sulfate (Prosulf) is excreted into human breast milk. Therefore, it should only be used cautiously during pregnancy and postpartum (Lip & Hull, 2023b; Longo, 2019; NBCA, n.d.-d; Witt et al., 2018).

Aside from uncontrolled bleeding events, additional potential side effects of UFH include redness and irritation at the injection site, elevations in liver enzymes, reduced bone mineral density measures within four to seven years following treatment, and increased risk for osteoporotic fractures. The most clinically relevant and devastating adverse effect of UFH is heparin-induced thrombocytopenia (HIT). HIT is a potentially fatal acquired disorder that occurs in response to the administration of UFH. Affected patients form antibodies against heparin and the platelet factor-4 (PF4) complex. Immune complexes of HIT antibodies and PF4/heparin bind to the surface of platelets and activate them. Activated platelets adhere to the blood vessel lining, promote clotting activity, and clump together, causing overuse of platelets, thereby inducing thrombocytopenia. Damage to the blood vessel wall and platelet clumping associated with HIT can lead to blood clot formation despite the presence of UFH. UFH administration is the most common cause of the condition, but LMWH agents and fondaparinux (Arixtra) also carry a potential risk, albeit less than UFH. The prevalence of HIT is up to 5% of patients receiving some form of heparin therapy, and if left untreated, 50% to 89% of affected patients will develop a thrombosis. In most cases, UFH is administered for seven to ten days before the onset of HIT symptoms, and the clinical presentation can be variable. The most common clinical signs include bleeding, bruising, ecchymosis, new thrombosis formation, or an increase in the size of a current thrombosis despite being on anticoagulation therapy. The risk for HIT in pregnancy appears rare; however, most data is limited to case reports. Further, the safety and efficacy of therapeutic agents used for HIT are not well established in pregnancy (Crowther, 2023; Indiana Hemophilia & Thrombosis Center [IHTC], n.d.; Kuter, 2022). While it remains unclear why some patients develop HIT while others do not, some of the strongest risk factors include the following:

• longer duration of heparin therapy (greater than five days)
• higher doses of heparin
• indication for treatment, with surgical (orthopedic) and trauma patients at the highest risk, followed by patients with cardiovascular disease and cardiovascular interventions
• gender, with females affected more commonly than males (Crowther, 2023; IHTC, n.d.; Kuter, 2022)

Since UFH does not cross the placenta, it is considered an acceptable form of anticoagulation in pregnancy. While it is less expensive than LMWH, HIT is 10-fold more common with UFH than LMWH. Although the overall risk for HIT during pregnancy appears low, the risk has been premised on limited clinical data. Since the preponderance of available data in non-pregnant patients demonstrates a higher risk of HIT with UFH prophylaxis over LMWH, the ASH only recommends UFH in circumstances where LMWH is not an option, such as due to limited accessibility, high cost, or other contraindications. UFH may be preferred over LMWH in pregnant women with severe renal insufficiency, as its metabolism is renal and hepatic. UFH does not pass into breast milk due to its large molecular size and negative charge and is therefore considered an acceptable option in women who are lactating (Bates et al., 2018; Bauer, 2022; NBCA, n.d.-d).

Low Molecular Weight Heparin (LMWH)

LMWHs are subcutaneous injections that work by inhibiting thrombin and factor Xa. Some of the most common LMWH agents include dalteparin (Fragmin), enoxaparin (Lovenox), nadroparin (Fraxiparin), and tinzaparin (Innohep). LMWH metabolism is exclusively renal and is dosed based on the patient's body weight. ASH guidelines recommend using the patient's actual body weight when calculating the dose, including those with obesity and a body mass index (BMI) above 30. The dose of LMWH should be adjusted in patients with creatinine clearance (CrCl) under 30mL/min, or an alternative agent such as UFH should be considered. LMWHs are preferred over UFH due to an enhanced maternal safety profile. They carry a lower risk of HIT and are less likely to be associated with reduced bone mineral density. LMWHs do not cross the placenta and are safe for the developing fetus. LMWH has clinical data demonstrating that it is excreted into breast milk in small amounts but with limited bioavailability. Therefore, LMWH is unlikely to be absorbed by a breastfeeding infant and is considered acceptable for use during lactation (Bates et al., n.d., 2018; Malhotra & Weinberger, 2023a; Witt et al., 2018).

Contraindications to LMWH include major acute bleeding or a history of HIT within the prior 100 days. The ASH advises against the routine monitoring of anti-Xa levels to guide dosing as monitoring demonstrates no difference in recurrent VTE or bleeding risk. Currently, anti-Xa tests are unreliable, and there is no established therapeutic range for LMWH in pregnancy. Further, monitoring is not routinely available in all centers and is associated with a higher cost of care as well as more frequent blood tests and clinic visits without corresponding benefits (Bates et al., n.d., 2018; Malhorta & Weinberger, 2023a).

Fondaparinux (Arixtra)

Fondaparinux (Arixtra) is a factor Xa inhibitor chemically related to LMWH. While it is more effective than LMWH in most studies, it carries an increased risk of bleeding. It works as a synthetic selective factor Xa inhibitor and is most commonly used to manage superficial thrombophlebitis, which can progress to a VTE if left untreated. Despite these benefits, fondaparinux (Arixtra) crosses the placenta, and therefore, LMWHs are preferred during pregnancy. However, no data demonstrate that fondaparinux (Arixtra) is excreted in breast milk and is considered a safe option in women who are breastfeeding (Bates et al., n.d., 2018; Nisio et al., 2018).

Direct Oral Anticoagulants (DOAC)

DOACs are a relatively novel group of anticoagulants that directly inhibit specific proteins within the clotting cascade. DOACs are classified into two basic categories: direct thrombin inhibitors and factor Xa inhibitors. Dabigatran (Pradaxa) is a direct thrombin inhibitor that exerts its anticoagulant effects by binding directly to thrombin, thereby inhibiting soluble and fibrin-bound thrombin. Since thrombin enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents thrombus development. Rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) are oral direct factor Xa inhibitors, which work by selectively and reversibly blocking the activity of FXa, thereby preventing clot formation. They affect FXa presence within the bloodstream and a preexisting clot but do not affect platelet aggregation. The 2016 American College of Chest Physicians (ACCP), the executive summary update of the ACCP 2016 guidelines (2021), and the 2019 European Society of Cardiology (ESC) guidelines recommend using DOACs over other medications as they are non-inferior in terms of efficacy with an improved safety profile based on a reduced risk of major bleeding compared to warfarin (Coumadin). They also carry the added advantage of a rapid onset of action and a predictable pharmacokinetic profile, which negates the need for monitoring and dose adjustments (Kearon et al., 2016; Konstantinides & Meyer, 2019; Stevens et al., 2021; Tritschler et al., 2018).

Since DOACs are relatively new, there remains limited clinical data regarding their safety, tolerability, and efficacy during pregnancy and postpartum. Dabigatran (Pradaxa) and other factor Xa inhibitors have demonstrated their ability to cross the placenta and are not recommended during pregnancy. Further, reproductive effects in humans remain definitively unknown at this time. Case reports suggest there is low excretion of rivaroxaban (Xarelto) into breast milk. Due to the limited clinical experience and the potential for adverse bleeding outcomes in infants, the ASH strongly advises against the use of DOACs in breastfeeding women (Bates et al., n.d., 2018; Malhorta & Weinberger, 2023a).

Vitamin K Antagonists (VKA)

VKAs are the oldest class of oral anticoagulants and prevent coagulation by suppressing the synthesis of vitamin K-dependent factors. They act as antagonists to vitamin K, impairing the liver's ability to process it into clotting factors, thereby curbing blood clotting. The goal of VKA therapy is to decrease the clotting tendency of blood but not to prevent clotting entirely. There are several types of VKAs, which include warfarin (Coumadin), acenocoumarol (Ascumar), phenprocoumon (Marcoumar), and coumatetralyl (Racumin); however, warfarin (Coumadin) is the most widely used and well-studied oral anticoagulant in the US. As a class, VKAs are not acceptable options for anticoagulation during pregnancy. They cross the placenta and carry a potential risk for teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits. Exposure during early pregnancy can cause embryopathy, whereas exposure later in pregnancy can cause intracranial hemorrhage (Bates et al., n.d., 2018; Hull et al., 2023; Tritschler et al., 2018).

Warfarin (Coumadin) and acenocoumarol (Ascumar) are the only two VKAs considered acceptable for use in women who are breastfeeding, as they are unlikely to be secreted in breast milk. Small clinical studies demonstrate no detectable levels of these two agents in breast milk. However, both medications should be avoided within 48 hours of vaginal deliveries and 72 hours of C-section deliveries due to the heightened risk of bleeding. While warfarin (Coumadin) and acenocoumarol (Ascumar) are considered acceptable when breastfeeding, they are usually reserved for patients who are not candidates for the other anticoagulation options. VKAs require more frequent monitoring and special consideration due to their side effect profile and high risk for drug and food interactions. Whereas patients on LWMHs do not require any routine monitoring of therapeutic levels, patients on warfarin (Coumadin) therapy require ongoing surveillance of blood to ensure therapeutic levels of the drug are maintained. Vitamin K is found in many foods, such as green leafy vegetables and certain oils. If the consumption of vitamin K-rich foods increases, the patient will require higher warfarin (Coumadin) doses to maintain therapeutic levels. Whereas a reduced intake of foods rich in vitamin K, the warfarin (Coumadin) dose may need to be reduced to prevent bleeding. Therefore, patients should be advised to maintain a consistent diet regarding vitamin K intake weekly. If patients skip a dose (or take an extra dose) of warfarin (Coumadin), the warfarin (Coumadin) level may be altered for several days, as both vitamin K and warfarin (Coumadin) levels rise gradually. In addition, there are several other special considerations regarding dietary and medication interactions while on warfarin (Coumadin) therapy. Various medications, nutritional supplements, and herbal preparations can interfere with the metabolism of warfarin (Coumadin), leading to an increased risk for bleeding or reduced efficacy of the medication, thereby increasing the risk for blood clot formation. Therefore, patients must be counseled on the importance of reporting new medications or dietary preparations before starting to avoid potential interactions. Some of the most common interactions are listed in Table 5 (Bates et al., n.d., 2018; Hull et al., 2023).

 

Table 5

Common Warfarin (Coumadin) Drug, Herbal, and Dietary Interactions

(Bates et al., n.d., 2018; Hull et al., 2023)

 

Thromboprophylaxis

While the physiologic changes of pregnancy increase the risk of thrombosis, they are insufficient to warrant pharmacological intervention in the general population. While most women do not require thromboprophylaxis during pregnancy, all women should be subjected to vigilant clinical surveillance throughout pregnancy. Thromboprophylaxis is typically reserved for those considered to be at greater risk. VTE thromboprophylaxis can be mechanical (i.e., intermittent pneumatic compression (IPC) devices or graduated compression stockings) or pharmacological. IPC devices are cuffs placed around the legs, filled with air, that squeeze the legs. This mechanism facilitates increased blood flow through the veins of the legs to help prevent blood clots. There are many IPC devices, and most are used in the hospital setting. Graduated compression stockings are specialized stockings, usually prescribed by a clinician, that are available in various compression strengths measured in mmHg, as listed below. The stockings are tightest around the foot and gradually loosen around the calf (Bauer, 2022; Malhotra & Weinberger, 2023b). The stockings compress the lower extremity to help increase blood flow to the heart from the lower extremities:

• 15-20 mmHg (mild) – treats mild spider veins, slight varicose veins, and achy legs
• 20-30 mmHg (moderate) – treats leg fatigue and heaviness, moderate spider veins, pronounced varicose veins
• 30-40 mmHg (firm) – treats severe varicose veins, post sclerotherapy, and prevention of post-thrombotic syndrome (Blood Clot Recovery Network, n.d.).

The ASH guidelines do not recommend using compression devices as a prevention strategy, as recommendations primarily focus on anticoagulation therapy. The perspective on using compression stockings in pregnancy varies across the literature. Many sources cite the safe and effective use of IPC devices or graduated compression stockings following cesarean section in hospitalized women during pregnancy. However, the efficacy of mechanical thromboprophylaxis in the outpatient setting during pregnancy or the postpartum period is not well-described due to a lack of clinical evidence. In women without underlying thrombophilia who have a history of a VTE but are not currently taking anticoagulants, the ASH makes specific recommendations regarding the need for pharmacological thromboprophylaxis. For an enhanced understanding of the clinical decision-making tool demonstrated in Figure 5, the ASH specifically cites hormonal risk factors as pregnancy, postpartum, and hormonal contraception, and nonhormonal provoking risk factors, including surgery, trauma, and prolonged immobilization (Bates et al., 2018; Malhotra & Weinberger, 2023b).

Figure 5

Thromboprophylaxis during Pregnancy

In summary, the ASH recommendations demonstrated in Figure 5 include the following:

• women with unprovoked VTE should receive both antepartum (during pregnancy) prophylaxis and postpartum prophylaxis
• women with provoked VTE and hormonal risk factor(s) should receive both antepartum prophylaxis and postpartum prophylaxis
• women with provoked VTE and temporary nonhormonal risk factors do not require antepartum prophylaxis but should receive postpartum prophylaxis (Bates et al., 2018)

For pregnant women who require anticoagulation thromboprophylaxis, the ASH recommends standard-dose LMWH during the antepartum period and either standard or intermediate-dose during the postpartum period.

• Standard-dose regimens:
  • Enoxaparin (Lovenox) 40 mg subcutaneously (SC) once daily
  • Dalteparin (Fragmin) 5,000 units SC once daily
  • Tinzaparin (Innohep) 4,500 units SC daily or 75 units/kg/day for patients at extremes of weight (i.e., severely underweight or severely obese)
• Intermediate-dose regimens:
  • Enoxaparin (Lovenox) 40 mg SC every 12 hours or 80 mg once daily
  • Dalteparin (Fragmin) 5,000 units SC every 12 hours or 10,000 units once daily
  • Tinzaparin (Innohep) 10,000 units SC daily (Bates et al., n.d., 2018).

The American College of Obstetricians and Gynecologists (ACOG, 2018) recommends the following for thromboprophylaxis using UFH:

• 5,000 to 7,500 units SC every 12 hours in the first trimester
• 7,500 to 10,000 units SC every 12 hours in the second trimester
• 10,000 units SC every 12 hours in the third trimester (unless the activated partial thromboplastin time [aPTT] is elevated (Malhotra & Weinberger, 2023b)

Treatment of Acute VTE in Pregnancy

Most patients can be safely managed on an outpatient basis and do not need to be hospitalized. However, outpatient management may not be appropriate for high-risk patients who meet any of the following criteria:

• abnormal vital signs or hemodynamic instability
• severe analgesic requirements
• massive DVT that is potentially limb-threatening
• advanced gestational age
• maternal comorbidities
• contraindications to LMWH
• lack of home support, illiteracy, or evidence of complex difficulty with understanding the essential aspects of anticoagulation, patient education, and management (Bates et al., 2018)

Treatment with therapeutic anticoagulation markedly reduces mortality in patients with acute VTE, as well as reduces the risk of recurrent VTE and PTS in patients with DVTs. Therapeutic anticoagulation is essentially a higher dose than thromboprophylaxis to ensure adequate anticoagulation. Before prescribing therapeutic anticoagulation and to ensure safety, it is recommended that the patient undergo baseline laboratory testing inclusive of the following:

• CBC
• renal and hepatic function panel
• coagulation profile to measure the blood's clotting capacity, including prothrombin time (PT), international normalized ratio (INR), and aPTT (Bates et al., 2018; Lim et al., 2018; Malhotra & Weinberger, 2023c)

It is not recommended to routinely check a platelet count because the risk of HIT is very low in pregnancy. However, checking a CBC after 3 to 4 weeks of therapy is reasonable. No further monitoring is needed if the platelet count is stable (Bauer, 2023).

PT is measured in seconds and refers to the amount of time it takes for the plasma portion of the blood to clot. The INR is a standardized number that is calculated from the PT result. Usually, the INR is reported and monitored in patients treated with anticoagulation therapy. One of the most common reasons for performing PT/INR testing is to monitor warfarin (Coumadin) levels. Higher than normal PT/INR levels indicate a higher risk for bleeding due to the body's impaired ability to clot blood. While on warfarin (Coumadin), the PT/INR must not exceed therapeutic thresholds. The target INR for patients with VTE is usually between 2 and 3. The aPTT test is commonly performed alongside the PT/INR when evaluating patients with suspected bleeding or blood clotting disorders. While the PT test assesses how well all the coagulation factors in the extrinsic and common pathways of the coagulation cascade are functioning collectively, the aPTT evaluates the clotting factors within the intrinsic and common pathways (American Association of Clinical Chemistry [AACC], 2021; Hull et al., 2023; Lip & Hull, 2023a).

 

Acute SVT

SVTs are traditionally treated with nonsteroidal anti-inflammatories (NSAIDs) such as Ibuprofen (Motrin), compression stockings, and warm compresses. NSAIDs should be avoided during pregnancy, and acetaminophen (Tylenol) should be used. While SVT is generally considered a benign condition that can be managed conservatively, it can be complicated by the extension of the superficial thrombus into the deep venous system. According to the ASH, clinicians may consider anticoagulation therapy in patients with acute SVT where there are risk factors. The ASH suggests that LMWH be prescribed for pregnant women with confirmed SVT; however, they acknowledge that there is low certainty of the evidence for a net health benefit from using anticoagulation for acute SVT (Bates et al., n.d., 2018).

Acute DVT

The ASH strongly recommends LMWH as the first-line therapy for acute DVT, using either once-daily or twice-per-day dosing regimens with LMWH; studies demonstrate no clear difference between dosing regimens. However, twice-per-day dosing is considered more burdensome for patients, and consideration should be given to patient adherence to the dosing schedule when deciding upon which regimen to prescribe. The most commonly used therapeutic anticoagulation agent is enoxaparin (Lovenox), administered at a dose level of 1 mg/kg SC injection every 12 hours or 1.5mg/kg SC injection once daily (Bates et al., n.d., 2018). Additional options for therapeutic LMWH include the following:

• dalteparin (Fragmin) 200 units/kg SC daily, or dalteparin (Fragmin) 100 units/kg SC every 12 hours
• tinzaparin (Innohep) 175 units/kg SC daily (ACOG, 2018; Bauer, 2023)

The ASH advises against routine monitoring of anti-FXa levels in patients on therapeutic anticoagulation as there is no data to support this practice, and there is no validated therapeutic range for LMWH. If UFH is used, therapeutic dosing is titrated to keep the aPTT between 1.5 and 2 times baseline (Bates et al., n.d., 2018; Bauer, 2023).

 

Acute PE

The ASH recommends following the same therapeutic anticoagulation measures for acute DVT in pregnant women with acute PE who are hemodynamically stable. The ASH advises against adding thrombolytic therapy to therapeutic anticoagulation; weak evidence supports its clinical benefit. The ASH suggests adding thrombolytic therapy to anticoagulation in pregnant women with acute PE and life-threatening hemodynamic instability, although the evidence is limited. In this setting, the addition of thrombolytic therapy is associated with a 50% reduction in mortality, despite the increased risk for bleeding events (Bates et al., n.d., 2018). Refer to the next section for information on thrombolytic therapy and clinical considerations during pregnancy.

 

Anticoagulation with Delivery

In pregnant women receiving LMWH at therapeutic doses for acute VTE, scheduled childbirth is recommended with discontinuation of the LMWH 24 hours before the induction. This recommendation reduces the risk of maternal bleeding and hemorrhage during childbirth. Patients with proximal DVT or PE diagnosed two to four weeks before delivery are considered at high risk for recurrent VTE with a prolonged interruption in anticoagulation. In these patients, anticoagulation should be converted to UFH and discontinued four to six hours before expected delivery or anticipated need for epidural insertion. The aPTT level should be drawn four hours after stopping UFH to ensure normalization (Bates et al., n.d., 2018; Bauer, 2023).

 

Postpartum Anticoagulation

The ideal time to restart anticoagulation after delivery is based on clinical judgment; however, LMWH and UFH are usually resumed four to six hours after vaginal delivery and six to twelve hours after cesarean delivery unless postpartum bleeding occurs. For patients with an acute VTE in the active phase of treatment, continuation with LMWH or UFH can be used. LMWH or UFH should be administered for at least five days and an additional one to two days after a therapeutic INR is obtained for patients transitioning to warfarin (Coumadin). Fondaparinux (Arixtra) can also be used in the postpartum period. DOACs can be used for patients who are not breastfeeding. Women with pregnancy-associated VTE typically require anticoagulation for at least six weeks postpartum. However, many clinicians opt to continue through 12 weeks until the risk for VTE normalizes to the non-pregnant state (Bates et al., n.d., 2018; Bauer, 2023).

Thrombolytic Therapy

Thrombolytic therapy is a specific type of anticoagulation that involves potent anticoagulation medication geared toward directly dissolving the thrombus. Thrombolytic therapy is generally reserved for patients with serious complications related to DVT or PE and with a low risk of serious bleeding complications. Thrombolytic therapy is most effective when initiated shortly after diagnosing a DVT or PE. Thrombolytic therapy aims to reduce the thrombus burden to alleviate symptoms and improve quality of life. The objectives for massive PE also include reducing mortality and recurrent PE and preventing CTEPH. For acute DVT, the goals include preventing PTS and, in some patients, preserving the limb (Bates et al., 2018; Lip & Hull, 2023a).

There are several thrombolytic drugs administered systemically via the intravenous route, and the most common types include streptokinase (Streptase), urokinase (Kinlytic), recombinant tissue plasminogen activator (rt-PA, alteplase), and tenecteplase (TNKase). These agents actively dissolve the thrombus by converting plasminogen into plasmin. While each agent has specific considerations, warnings, and precautions, all carry a similar risk of bleeding. Absolute contraindications to thrombolytic therapy include intracranial hemorrhage, malignant intracranial neoplasm, active bleeding, or stroke within the prior three mon. In pregnant women, thrombolytic therapy poses a higher risk for maternal hemorrhage than other types of anticoagulation, as well as an increased risk for fetal complications such as serious bleeding events, neurocognitive deficits, and fetal demise (Ho et al., 2018; Ucar, 2019). The ASH guidelines warn clinicians to carefully balance the risks and benefits of using thrombolytic therapy and make the following conditional recommendations based on only low-quality evidence available in this population (Bates et al., 2018):

• In pregnant women with acute PE and life-threatening hemodynamic instability, the ASH suggests administering systemic thrombolytic therapy in addition to anticoagulation therapy.
• In pregnant women who are hemodynamically stable, the ASH advises against systemic thrombolytic therapy.
• In pregnant women with acute lower extremity DVT, the ASH advises against adding catheter-directed thrombolysis (CDT) to anticoagulation in pregnant women with acute lower extremity DVT.

 

Catheter-directed Thrombolysis (CDT)

Catheter-directed thrombolysis (CDT) is primarily indicated for acute iliofemoral DVT or an extensive, multilevel DVT. CDT is a minimally invasive targeted therapy geared toward dissolving an obstructive thrombus. CDT involves X-ray imaging to guide the thrombolytic medication to the site of the thrombus to dissolve the blockage. However, X-rays carry radiation exposure and pose risks to the fetus premised on the gestational age, which must be considered. The actual risk depends on how far along the pregnancy is, the type of X-ray imaging, its accompanying degree of radiation exposure, and the area of the body under examination (RadiologyInfo.org, 2022).

There is no solid evidence regarding CDT's clinical considerations and use in pregnant women. The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial included 300 non-pregnant patients with DVT involving the femoral vein who were randomized to receive CDT with anticoagulation or anticoagulation only. Patients were followed for 24 months, and CDT did not appear to reduce the risk of PTS in non-pregnant patients. The ATTRACT study cites potential fetal harm associated with radiation exposure and the risk of major bleeding. Pregnancy-specific data is limited to case series with low certainty of the evidence, so it is difficult to draw substantive conclusions regarding benefit. Therefore, at this point, CDT should be reserved for patients with severe, limb-threatening DVT (Bates et al., 2018; Kearon et al., 2019; Malhorta & Weinberger, 2023a).

 

Part II: Thrombophilia Disorders and Pregnancy

An increased propensity or predisposition for VTE characterizes thrombophilia disorders. During pregnancy, the thrombogenic potential of these disorders is associated with a heightened risk for VTE due to the maternal physiologic adaptations to pregnancy (Colucci & Tsakiris, 2020). According to the ACOG (2018), it remains controversial whether there is an association between inherited thrombophilias and uteroplacental thrombosis leading to adverse pregnancy outcomes, such as fetal loss, severe pregnancy-induced high blood pressure (preeclampsia), intrauterine growth restriction (IUGR), stillbirth, and placental abruption. Despite the lack of definitive evidence, this potential association has led to increased screening for thrombophilias before and during pregnancy. Thrombophilia disorders may be inherited or acquired, and the most common conditions affecting pregnancy are listed in Table 6 (Colucci & Tsakiris, 2020; Lockwood & Bauer, 2023).

Table 6

Common Inherited Thrombophilia Disorders in Pregnancy

Inherited	FVL
	Methylenetetrahydrofolate reductase (MTHFR)
	Prothrombin G20210A (prothrombin gene mutation [PGM])
	Protein C deficiency
	Protein S deficiency
	Antithrombin deficiency (ATD)
Acquired	Antiphospholipid antibody syndrome (APS)

(Colucci & Tsakiris, 2020; Lockwood & Bauer, 2023)

 

Factor V Leiden (FVL)

A mutation in the FV gene causes FVL. FVL gene mutations cause Factor V to be inactivated more slowly than normal, allowing the clotting process to remain active longer. As a result, this increases the patient's risk for VTE. Considered the most common inherited form of thrombophilia, FVL affects approximately 3% to 8% of people with European ancestry. Although the condition increases the risk of VTE, only about 10% of affected individuals ever develop abnormal clots, with DVT and PE among the most common. FVL is inherited in an autosomal dominant manner. The chance of developing abnormal blood clots depends on whether the individual has inherited one or two copies of the FVL mutation in each cell. Those who inherit two copies of the mutation (one from each parent) are at higher risk of developing a thrombus than those who inherit just one copy. Most individuals affected by the condition have one "normal" F5 gene and one with the factor V Leiden gene mutation. In the general population, 1 in 1,000 people per year (PPY) develop an abnormal blood clot. In patients with one copy of the FVL mutation, the risk of thrombus formation is 3 to 8 in 1,000 PPY, whereas two copies of the mutation heighten the risk to 80 in 1,000 PPY (Albagoush et al., 2023; Genetic and Rare Diseases Information Center [GARD], 2023a; Middeldorp, 2023).

FVL can affect pregnancy outcomes as it can cause blood clots to form in the vessels of the placenta, leading to recurrent pregnancy loss (RPL). The American Society of Reproductive Medicine has defined RPL as two or more failed pregnancies before the 20th week of pregnancy (Albagoush et al., 2023; NIH, 2010). According to a systematic review and meta-analysis by Eslami and colleagues (2020), clinical studies have demonstrated that FVL mutation increases the risk of VTE 80 times in homozygote carriers (FVL homozygotes) and seven times in heterozygote carriers (FVL heterozygotes). FVL also increases the risk of preeclampsia (Eslami et al., 2020).

Methylenetetrahydrofolate Reductase (MTHFR) 

MTHFR is an enzyme that converts dietary folate (methylenetetrahydrofolate) to its active form (methyltetrahydrofolate). Folate is essential to generate DNA and modify proteins within the body. All healthy individuals carry two copies of MTHFR, which are involved in breaking down the amino acid homocysteine into methionine. Genetic variations in the MTHFR gene can lead to decreased function or inactivation of this enzyme, which results in increased homocysteine levels, especially in those deficient in folate. Hyperhomocysteinemia is characterized by increased homocysteine levels in the blood and is associated with a marked increase in the risk for VTE. Elevated homocysteine levels carry prothrombotic properties, causing vascular injury, platelet accumulation, and increased risk for forming occlusive thrombosis. Approximately 10% of the first episodes of VTE are due to elevated homocysteine levels. Patients who inherit the condition usually have a mutation in MTHFR, causing increased homocysteine production. Studies suggest that women with two MTHFR variants are twice as likely to have a child with a neural tube defect (NTD); however, the risk is incredibly low, around 0.14% (Dean, 2016; Mandava, 2018; National Institute of Health [NIH], 2022).

While an MTHFR mutation is cited as a potential risk factor for VTE in pregnancy, several studies have failed to demonstrate a statistical association between MTHFR mutation and VTE (GARD, 2023b). According to ACOG (2018), homozygosity for the MTHFR gene mutation is the most common cause of hyperhomocysteinemia. MTHFR mutations do not appear to convey an increased risk of VTE in pregnant women, as elevated homocysteine levels are considered a weak risk factor for VTE. Further, the incidence of VTE associated with MTHFR is significantly reduced through dietary folate intake (ObG Project, n.d.-b). Current clinical guidelines do not recommend changes in prenatal care based on MTHFR gene variant status. All women of childbearing age should take the standard dose of folic acid supplementation (400 mcg per day) for NTD risk reduction in the newborn (Dean, 2016). Many controversies surround the clinical significance of MTHFR gene mutation and its impact on RPL and adverse pregnancy outcomes. Several studies have demonstrated a correlation between MTHFR and recurrent miscarriages and adverse pregnancy outcomes, including IUGR, preeclampsia, preterm labor, preterm premature rupture membranes (PPROM), ablation placenta, and stillbirth. However, the evidence is limited, and the impact of MTHFR on pregnancy outcomes requires additional investigation (ObG Project, n.d.-b; Turgal et al., 2018).

 

Prothrombin G20210A (prothrombin gene mutation [PGM])

Prothrombin G20210A gene mutation is also referred to as prothrombin thrombophilia. Patients with this mutation produce excess amounts of prothrombin (FII), which leads to an abundance of thrombin in the circulation, thereby increasing the tendency to form VTE. A G20210A mutation is present in about 1 in 50 non-Hispanic white people and is more common in those of European ancestry. It is considered the second most common inherited form of thrombophilia. Prothrombin thrombophilia follows autosomal dominant inheritance, and the risk of developing a VTE is linked to the inheritance pattern of the condition. Heterozygous patients have a risk of 2 to 3 in 1,000 PPY, whereas homozygous patients have a risk of up to 20 in 1,000 PPY. Research suggests that PGM is associated with an increased risk of RPL and may also increase the risk of other complications during pregnancy, such as preeclampsia, slow fetal growth, and placental abruption. However, most women with PGM have normal pregnancies (GARD, 2023c; Moake, 2022).

 

Protein C and Protein S Deficiency

Proteins C and S are part of the body's innate anticoagulation system. Therefore, clots may form without regulation if the functioning of one or both of these proteins is impaired. Patients with deficiencies in either or both proteins are at increased risk for VTE events. A genetic mutation in the PROC gene causes inherited protein C deficiency. The degree of deficiency can be mild to severe. In the rare instance that a patient inherits two mutated copies of the protein C gene, the disease can be very severe, heightening the risk for intracranial thromboembolism in infants and VTE during childhood. Although rare, newborns who are homozygous for protein C deficiency are at risk for neonatal purpura fulminans, a life-threatening condition involving severe clotting throughout the body. Inherited protein S deficiency is caused by a genetic mutation in the PROC1 gene and may occur in conjunction with protein C deficiency. Patients who inherit two mutated copies are at higher risk for developing a more severe form of purpura fulminans, which can lead to hemorrhagic tissue necrosis or disseminated intravascular coagulation (DIC). Deficiencies in either or both of these proteins are associated with placental thrombosis, hypoperfusion, fetal loss, and stillbirth (AACC, 2020; NIH, 2009, 2013; ObG Project, n.d.-a).

 

Antithrombin Deficiency

Antithrombin is the body's primary thrombin inhibitor, a natural anticoagulant. Inherited antithrombin deficiency reduces levels of circulating antithrombin and predisposes patients to developing VTEs. Most patients affected by inherited antithrombin deficiency endure their first VTE before age 40, usually a DVT or SVT. About 40% of patients with antithrombin deficiency develop a PE, which makes the condition particularly dangerous (NBCA, 2013). Women with antithrombin deficiency are at particularly high risk for developing clots during pregnancy or after delivery. According to the National Organization for Rare Diseases (NORD, 2018), the incidence of VTE during pregnancy in women with antithrombin deficiency can extend up to 50%. Women are also at a marginally increased risk for fetal loss without appropriate treatment, most likely due to thrombus formation in the placenta, obstructing blood and oxygen to the fetus (NBCA, 2013).

 

Antiphospholipid Antibody Syndrome (APS)

APS is the most common acquired thrombophilia disorder during pregnancy. APS is a systemic autoimmune disorder characterized by thrombosis and heightened risk for RPL secondary to the presence of antiphospholipid antibodies (aPL). The body develops aPL that attack and damage phospholipids, which are present on the lining of blood vessels and play an important role in maintaining the integrity of cell wall membranes. When these antibodies attack phospholipids, the blood cells become damaged, degrade, and lead to thrombosis formation. Arterial and/or VTE development is the hallmark of the condition. Patients who have APS are also at higher risk for thrombocytopenia. The antibodies either destroy the platelets or the platelets are used up during the clotting process; this heightens the risk for mild to serious bleeding events (Lockwood & Lockshin, 2022; NHLBI, 2022a).

APS can affect up to 5% of women during pregnancy and is considered an established acquired thrombophilia risk factor leading to increased risk for RPL (Eslami et al., 2020). Aside from RPL, pregnant women with APS are at increased risk of IUGR, placental insufficiency, preeclampsia, premature birth, and stillbirth. Pregnant women with APS can still have successful pregnancies, as treatment during pregnancy reduces the frequency of thrombosis and associated adverse pregnancy outcomes (Lockwood & Lockshin, 2022). Although APS is the most common acquired thrombophilia of pregnancy, interestingly, neither the ASH nor ACOG guidelines outline thromboprophylaxis or management of the condition. Some sources cite that APS should be suspected in patients who develop one or more unprovoked venous or arterial thrombotic events, especially young patients. APS should also be considered in patients who endure specific adverse outcomes related to pregnancy, such as fetal death after ten weeks' gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses under ten weeks' gestation (Erkan & Ortel, 2023). Nevertheless, the ACOG (2018) guidelines only briefly mention testing for the presence of the acquired antibodies, but only in the setting of RPL or stillbirth; otherwise, it is not routinely included in the thrombophilia workup.

 

Risk Assessment

It is estimated that 5% to 8% of the US population has a genetic risk factor known to predispose VTE. Knowledge of the risk of a VTE and its associated complications helps guide clinical decision-making, prevention, and management during pregnancy and postpartum (Colucci & Tsakiris, 2020). Inherited thrombophilia disorders are further broken down into high-risk and low-risk, as denoted in Table 7. Studies consistently demonstrate the highest incidence of VTE in women with high-risk variants (homozygotes) of inherited thrombophilia (Malhotra & Weinberger, 2023c).

Table 7

Inherited Thrombophilia Risk Types

High-risk types	FVL homozygotes Antithrombin deficiency PGM homozygotes Compound heterozygote FVL and PGM (combination of both)
Low-risk types	FVL heterozygote PGM heterozygote Protein C deficiency Protein S deficiency MTHFR

(Lockwood & Bauer, 2023)

Cross and colleagues (2017) performed a systematic review and meta-analysis evaluating pregnancy, thrombophilia, and the risk for a first VTE. They concluded that women with a positive family history of VTE have a 3.7-fold to 8.5-fold increased risk of pregnancy-associated VTE. Inherited thrombophilia increases the risk of pregnancy-associated VTE up to 34-fold. History of a prior VTE indicates an increased risk for another VTE with subsequent pregnancy (Bates et al., 2018). In women with FVL homozygote, the ACOG (2018) cites a 2.2% to 14.0% risk of VTE per pregnancy without a prior VTE, whereas the risk increases to 17% in women with a previous VTE. While the ASH and ACOG guidelines collectively acknowledge the limited evidence available to guide the screening for and management of thrombophilias in pregnancy, both support the need for the following critical information to confer individual risk:

• personal history of a VTE (in either a pregnant or non-pregnant state)
• family history of VTE in a first-degree relative (parents, siblings, or children)
• risk level (high versus low) of the underlying thrombophilia disorder (ACOG, 2018; Bates et al., 2018).

 

Screening for Thrombophilia Disorders

ACOG cautions against the routine screening for thrombophilia disorders in pregnancy, as screening is "useful only when results will affect management decisions and it is not useful in situations in which treatment is indicated for other risk factors" (2018, p. e23). ACOG supports the targeted assessment for inherited thrombophilia in only the following clinical situations and if testing results are suspected to influence management:

• a personal history of VTE, with or without a recurrent risk factor, and no prior thrombophilia testing
• a first-degree relative with a history of high-risk inherited thrombophilia (ACOG, 2018)

For all other clinical scenarios, ACOG advises against routine thrombophilia testing. Screening is not recommended for women with a history of fetal loss or adverse pregnancy outcomes since there is insufficient evidence that prophylaxis during pregnancy would prevent recurrence in these patients (ACOG, 2018).

 

Diagnostic Workup

For women who meet the criteria to undergo screening for thrombophilia, the recommended screening panel includes the following:

• FVL mutation
• Prothrombin G20210A mutation
• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency
• Antiphospholipid antibodies (ACOG, 2018)

The optimal time for performing these tests is at least six weeks following the thrombotic event and ideally when the patient is not pregnant, as certain testing may not be reliable during pregnancy. Further, anticoagulation and hormonal therapies can also lead to unreliable findings. For instance, clinicians should be aware that warfarin (Coumadin) can increase antithrombin levels when evaluating for antithrombin deficiency. Therefore, a normal level in the setting of warfarin (Coumadin) therapy does not definitively rule out the presence of antithrombin deficiency (NBCA, n.d.-a). Table 8 designates the testing method and clinical considerations for performing the diagnostic workup. Since current evidence demonstrates a lack of association between MTHFR and negative pregnancy outcomes, including the increased risk for VTE, ACOG advises against screening for MTHFR mutation analysis (ACOG, 2018).

Table 8

Laboratory Analysis for Inherited Thrombophilias 

	FVL	Antithrombin deficiency	PGM	Protein C deficiency	Protein S deficiency
Analysis method	Activated C protein resistance assay If abnormal, perform DNA analysis	Antithrombin activity	DNA analysis	Protein C activity	Functional Assay
Reliable during pregnancy?	YES	YES	YES	YES	NO
Reliable with acute VTE? (<6 weeks)	YES	NO	YES	NO	NO
Reliable on anticoagulation?	NO	NO	YES	NO	NO

(ACOG, 2018)

 

Thromboprophylaxis in the Context of Inherited Thrombophilia

All pregnant women with an inherited thrombophilia disorder should undergo an individualized risk assessment. Women with a history of VTE should consistently receive both antepartum and postpartum thromboprophylaxis. Women currently receiving long-term anticoagulation should continue on anticoagulation throughout the antepartum and postpartum period, as long as it is acceptable. Thromboprophylaxis dosing follows the recommendations described earlier in women without underlying thrombophilia disorders (Bates et al., 2018). The management of pregnant women without a history of VTE is more complex; it relies heavily on the risk level of the specific inherited thrombophilia in conjunction with the family history of VTE. Table 9 outlines ASH recommendations for pregnant women with underlying thrombophilia disorders without a prior VTE. All of the recommendations in Table 9 are conditional recommendations due to limited and low-quality evidence, except for the following, which are considered strong recommendations (Bates et al., n.d., 2018, 2019):

• The ASH strongly recommends postpartum thromboprophylaxis in pregnant women with protein C deficiency and a positive family history of VTE.
• The ASH strongly recommends postpartum thromboprophylaxis in pregnant women with protein S deficiency and a positive family history of VTE.
• The ASH strongly recommends postpartum thromboprophylaxis in pregnant women with AT and a positive family history of VTE.

Table 9

Thromboprophylaxis in the Context of Inherited Thrombophilia Among Pregnant Women Without a Personal History of VTE

FVL Heterozygote	Antepartum and postpartum thromboprophylaxis are not necessary
FVL Homozygote	Antepartum and postpartum thromboprophylaxis recommended
PGM Heterozygote	Antepartum and postpartum thromboprophylaxis are not necessary
PGM Homozygote	Postpartum thromboprophylaxis is recommended; Antepartum is recommended only if there is a positive family history of VTE
AT Deficiency	Antepartum and postpartum thromboprophylaxis is recommended only if there is a positive family history of VTE (STRONG)
Protein C or S deficiency	Antepartum thromboprophylaxis is not necessary; Postpartum thromboprophylaxis is recommended only if there is a positive family history of VTE (STRONG)
Combined Thrombophilia	Antepartum and postpartum thromboprophylaxis recommended

(Bates et al., 2018, 2019)

 

Closing Thoughts

The guidelines regarding the appropriate management of blood clotting during pregnancy and postpartum are fluid and continually changing as new evidence and clinical data are unveiled. The exact effects of inherited thrombophilia on pregnancy outcomes remain controversial. Many women with a personal or family history of VTE or a diagnosis of an inherited thrombophilia disorder require specialized care under the direction of a high-risk obstetrician and/or a hematology specialist.

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