A detailed discussion of the clotting system, the anticoagulant system, and the fibrinolytic system is beyond the scope of this manual and can be found elsewhere in more comprehensive textbooks. A practical and user-friendly version of the complex regulatory pathways of hemostasis and fibrinolysis is presented in Fig. 7-1.
Hemostatic and fibrinolytic pathways. The primary initiator of coagulation is tissue factor (TF) which is not normally expressed by cells in contact with the circulation (ie, endothelial cells). Following vascular disruption, perivascular, cell membrane–bound TF complexes with plasma-derived factor VII or its more active form (VIIa) to directly convert factor X to Xa. TF/VIIa can also indirectly generate Xa by converting factor IX to IXa, which, in turn, complexes with factor VIIIa to convert X to Xa. Factor Xa, once generated, complexes with its cofactor, Va, to convert prothrombin (factor II) to thrombin (IIa). Thrombin activates platelets and cleaves fibrinogen to generate fibrin monomers, which spontaneously polymerize and are cross-linked by thrombin-activated factor XIIIa to form a stable clot. Clotting is restrained by a series of anticoagulant proteins. The initial anticoagulant response is by TF pathway inhibitor (TFPI) that binds to the TF/VIIa/Xa complex to rapidly stop TF-mediated clotting. However, thrombin-activated factor XIa maintains clotting by serving as an alternative activator of factor IX on the surface of platelets. Thus, effective inhibition of the clotting cascade requires prevention of factor IXa- and Xa-mediated clotting. Activated protein C and protein S (APC/S) complex serve this function by inactivating factors VIIIa and Va, respectively. However, the most crucial endogenous anticoagulant system involves antithrombin (AT) inactivation of thrombin and Xa directly. Finally, fibrinolysis breaks down the fibrin clot. Fibrinolysis is mediated by tissue-type plasminogen activator (tPA) that binds to fibrin where it activates plasmin. Plasmin, in turn, degrades fibrin but can be inactivated by α2-antiplasmin embedded in the fibrin clot. Fibrinolysis is primarily inhibited by type-1 plasminogen activator inhibitor (PAI-1), the fast inactivator of tPA. Thrombin activatable fibrinolytic inhibitor (TAFI) is an alternative antifibrinolytic protein.
As a result of physiologic changes in pregnancy, VTE occurs at a rate that is 4-fold higher compared to the nonpregnant state.4 The postpartum period is even more thrombogenic, with VTE twice as likely as a given 6-week period during pregnancy. That VTE does not occur more often is remarkable, given the paradoxical challenges presented to the hemostatic system during pregnancy.
During early placentation, syncytiotrophoblasts penetrate maternal uterine vessels to establish the primordial uteroplacental circulation. Subsequently, endovascular extravillous cytotrophoblasts invade decidual and superficial myometrial spiral arteries, orchestrating a morphologic conversion of these vessels to achieve high-volume, low-resistance blood flow into the intervillous space. Fetal survival requires that these processes occur in the absence of either significant decidual hemorrhage (ie, abruption) or intervillous thrombosis. To ensure maternal survival, decidual hemorrhage must be avoided throughout pregnancy.
The most profound hemostatic challenge is faced by mothers during the third stage of labor. Following separation of the placenta from the uterine wall after delivery of the infant, hemostasis must be rapidly achieved in 140 remodeled spiral arteries to avoid potentially catastrophic hemorrhage. While local factors such as high decidual tissue factor (aka thromboplastin) expression contribute to this placental site hemostasis, dramatic changes in the mother’s expression of clotting and anticlotting factors are also required to meet this hemostatic challenge.
In addition to an innate hypercoagulability, venous stasis and vascular trauma complete Virchow classic triad5 (Fig. 7-2). Venous stasis is present as a result of mechanical impedance of the lower extremity vasculature by the gravid uterus, and estrogen-mediated vascular dilation.6 Endothelial damage is often present during the puerperium, especially with operative delivery, hypertensive disease, tobacco use, and infections.
Virchow classic triad of hypercoagulability.
In a review of International Classification of Disease-9 (ICD-9) codes from over 9 million pregnancy admissions and over 73,000 postpartum admissions in the United States National Inpatient Sample (NIS), a list of medical and obstetric risk factors for VTE was identified. See Tables 7-1 and 7-2 for a listing of common risk factors in the development of VTE.
TABLE 7-1.Medical Conditions and the Risk of VTE4 ||Download (.pdf) TABLE 7-1. Medical Conditions and the Risk of VTE4
|Complication ||Odds ratio (OR) ||95% CI |
|Thrombophilia ||51.8 ||38.7-69.2 |
|History of thrombosis ||24.8 ||17.1-36.0 |
|Antiphospholipid antibody syndrome ||15.8 ||10.9-22.8 |
|Lupus ||8.7 ||5.8-13.0 |
|Heart disease ||7.1 ||6.2-8.3 |
|Sickle cell disease ||6.7 ||4.4-10.1 |
|Obesity ||4.4 ||3.4-5.7 |
|Diabetes ||2.0 ||1.4-2.7 |
|Hypertension ||1.8 ||1.4-2.3 |
|Smoking ||1.7 ||1.4-2.1 |
|Substance abuse ||1.1 ||0.7-1.9 |
TABLE 7-2.Obstetric Conditions and the Risk of VTE4 ||Download (.pdf) TABLE 7-2. Obstetric Conditions and the Risk of VTE4
|Complication ||OR ||95% CI |
|Transfusion ||7.6 ||6.2-9.4 |
|Disorders of fluid, electrolyte, and acid-base balance ||4.9 ||4.1-5.9 |
|Postpartum infection ||4.1 ||2.9-5.7 |
|Anemia ||2.6 ||2.2-2.9 |
|Hyperemesis ||2.5 ||2.0-3.2 |
|Antepartum hemorrhage ||2.3 ||1.8-2.8 |
|Cesarean versus vaginal delivery ||2.1 ||1.8-2.4 |
|Multiple gestation ||1.6 ||1.2-2.1 |
|Postpartum hemorrhage ||1.3 ||1.1-1.6 |
|Preeclampsia and gestational hypertension ||0.9 ||0.7-1.0 |
|Preterm labor ||0.9 ||0.7-9.5 |
|Thrombocytopenia ||0.6 ||0.8-4.1 |
Patients with underlying hypercoagulable states are at even higher risk for VTE and other obstetric adverse outcomes. These thrombophilic states can be divided into inheritable mutations and acquired disorders.
The most common significant inherited thrombophilias include heterozygosity for the factor V Leiden (FVL) mutation heterozygosity, and prothrombin G20210A (PGM) gene mutations. Rarer causes of inherited thrombophilias include antithrombin (AT) deficiency, protein S deficiency, and protein C deficiency. See Table 7-3 for a summary of these thrombophilias, their respective inheritance patterns, and risks of thromboses.
TABLE 7-3.The Risk of VTE in Pregnant Patients With a Thrombophilia7 ||Download (.pdf) TABLE 7-3. The Risk of VTE in Pregnant Patients With a Thrombophilia7
|Condition ||Inheritance ||Prevalence in European populations ||Risk of thrombosis without prior history ||Risk of thrombosis with prior history |
|Antithrombin deficiency ||AD ||0.02%-1.1% ||3.0%-7.2% ||11%-40% |
|Prothrombin mutation (PGM) ||AD || || || |
| Homozygous || ||0.02% ||2.8% ||>10% |
| Heterozygous || ||2.9% ||0.37%-0.5% ||>10% |
|Factor V Leiden (FVL) ||AD || || || |
| Homozygous || ||0.07% ||1.5% ||>10% |
| Heterozygous || ||5.3% ||0.26% ||>10% |
| Compound heterozygous FVL/PGM || ||0.17% ||4.7% || |
|Protein C deficiency ||AD ||0.2%-0.3% || 0.8%-1.7% || |
|Protein S deficiency ||AD ||0.03%-0.13% || <1%-6.6% || |
|Hyperhomocysteinemia ||AR ||<5% || OR 6.1 || |
|Elevated factor VII ||AD || || ~0.1% || |
|Elevated factor VIII ||AD || || ~0.1% || |
|Elevated factor XI ||AD || || ~0.1% || |
The most common acquired thrombophilia is antiphospholipid antibody syndrome (APAS). Approximately 2% of APAS patients will experience a VTE in pregnancy, accounting for approximately 14% of VTE events in pregnancy. Diagnosis of APAS requires one clinical criterion and one laboratory criterion, as defined at the international consensus conference in 2006.8 (See Table 7-4).
TABLE 7-4.Diagnosis of Antiphospholipid Antibody Syndrome ||Download (.pdf) TABLE 7-4. Diagnosis of Antiphospholipid Antibody Syndrome
|Clinical criteria ||Obstetric || |
History of 3 unexplained consecutive spontaneous abortions ≤10 gestational age (GA), or
History of 1 unexplained fetal death ≥10 wk GA (morphologically and karyotypically normal), or
History of preterm delivery <34 wk GA, as a sequelae of preeclampsia or uteroplacental insufficiency, including the following:
Nonreassuring fetal testing indicative of fetal hypoxemia (eg, abnormal Doppler flow velocimetry waveform)
Oligohydramnios (amniotic fluid index ≤5 cm)
Intrauterine growth restriction (IUGR) <10th percentile
| ||Nonobstetric || |
Arterial thrombosis, including cerebrovascular accidents, transient ischemic attacks, myocardial infarction, amaurosis fugax
Venous thromboembolism (VTE), including deep venous thrombosis (DVT), pulmonary emboli (PE), or small vessel thrombosis
|Laboratory criteria || |
Should be present on 2 occasions, >12 wk apart, and no more than 5 y prior to clinical manifestation
APAS is a thrombogenic disorder that arises from autoimmune targeting of proteins binding to exteriorized anionic phospholipids on endothelial cell membranes, such as cardiolipin and phosphatidylserine. In more than half of APAS patients, the responsible antibodies arise as a result of underlying disorders such as systemic lupus erythematosus (SLE). Diseases such as SLE induce endothelial compromise, which expose the anionic phospholipids that bind to specialized proteins, creating neoantigens recognized by the immune system. The antiphospholipid antibodies increase the thrombogenic potential by inhibiting anionic phospholipid-binding endogenous anticoagulants (such as β2-glycoprotein-I, annexin V, antithrombin, thrombomodulin, proteins C and S) and inducing procoagulants (such as tissue factor, plasminogen activator inhibitor-1, von Willebrand factor, and activation of complement).
The type and concentration of antiphospholipid antibody predict its pathogenicity. Low-positive anticardiolipin IgG and IgM are seldom associated with medical complications. Medium or high titers of anticardiolipin and presence of lupus anticoagulant are associated with 4-fold higher rates of thrombosis.
Screening for Thrombophilias in Pregnancy
The utility of screening for thrombophilia in pregnancy remains highly debated. The American College of Obstetricians and Gynecologists currently recommend screening in cases where results will affect management decisions such as duration and dosage of treatment.9 Screening may be considered in the following clinical settings:
A personal history of VTE that was associated with a nonrecurrent risk factor (eg, fractures, surgery, prolonged immobilization)
A first-degree relative (eg, parent or sibling) with known high-risk thrombophilia or VTE before age 50 years in the absence of other risk factors
Routine screening for inheritable thrombophilias is not recommended in other situations, such as a history of adverse pregnancy outcomes, fetal loss, preeclampsia, fetal growth restriction, and placental abruption. However, screening for acquired thrombophilias, such as antiphospholipid antibodies, may be appropriate in patients with such a history.