Disseminated Intravascular Coagulation in Pregnancy
Melissa C. Sisson
Marcy M. Mann
For the past 50 years, disseminated intravascular coagulation (DIC) has been described in the obstetric literature because of its tendency to accompany certain obstetrical conditions. The clinical presentation and prognostic course of DIC are diverse and make the diagnosis and management of the disease a significant clinical challenge.
The subcommittee on DIC of the International Society on Thrombosis and Hemostasis defined DIC as:
an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature which if sufficiently severe can produce organ dysfunction.1
DIC is not a separate clinical entity; rather it is an effect of other disease processes. Therefore, the treatment of DIC is focused on identification and removal of the causative agent or insult while supporting the cardiopulmonary status of the mother. DIC represents a derangement of the balance between the procoagulant and fibrinolytic systems that occurs when normal hematologic regulatory mechanisms fail.
The incidence of DIC in pregnancy varies and is dependent on the underlying obstetric complication. For example, in cases of complete placental abruption accompanied by intrauterine fetal demise (IUFD) and hemorrhage, DIC is common.2 In contrast, DIC associated with IUFD without placental abruption is quite rare except when products of conception are retained beyond 5 weeks.3 The incidence of DIC associated with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) has been reported to be 15 percent, but in preeclampsia without HELLP syndrome or placental abruption, frank DIC is almost never seen.3,4 A consumptive coagulopathy is more common in the obstetric patient than acute, fulminant DIC.1 All pregnant women may be at greater risk for DIC because of the complications unique to pregnancy that are associated with this syndrome.3 Conditions associated with DIC in pregnancy are listed in Box 16-1.
Although acute coagulopathy during pregnancy is a rare event, it is associated with profound consequences that increase morbidity and mortality for both the mother and fetus. It is therefore important for health care providers of pregnant women to be knowledgeable about DIC, to facilitate early detection, and to optimize outcome.
Normal Coagulation
Hemostasis is the process by which blood is maintained in a liquid state within vessels and bleeding from a damaged vessel is arrested. The primary components of hemostasis include the vascular endothelium, circulating platelets, and circulating blood proteins.
Disruption of the endothelium as a result of vascular damage sets into motion the three phases of hemostasis: formation of a temporary platelet plug, activation of the coagulation cascade to produce a fibrin clot, and activation of the fibrinolytic system to break down the clot. The endothelium provides a physical barrier to keep blood inside the vessels and prevents clotting by secreting nitric oxide (NO) and prostacyclin, which inhibit platelet activity.5 Exposure of subendothelial collagen stops the secretion of NO and prostacyclin and initially produces localized vasoconstriction that assists in reduction of blood flow and loss. Release of histamine and serotonin further promote vasoconstriction.
Platelets, formed in the bone marrow from megakaryocytes, circulate in the blood and play the vital role of first responders when blood loss is detected. When platelets come into contact with the collagen underlying the damaged endothelium, they swell and assume irregular shapes. Their contractile proteins contract forcefully and release granules that contain multiple active factors that cause them to adhere to each other and to collagen.6 von Willebrand factor (vWF) is found in one type of these granules and in circulating blood
and contributes to platelet activation. In addition, vWF mediates adhesion of platelets to subendothelial surfaces.7
and contributes to platelet activation. In addition, vWF mediates adhesion of platelets to subendothelial surfaces.7
Box 16-1. Obstetric Conditions Associated with Dic
Placental abruption
HELLP syndrome
Massive blood transfusions
Septic or saline abortion
Amniotic fluid embolus
Acute fatty liver of pregnancy
Retained IUFD
Demise of second twin
Platelets secrete adenosine diphosphate (ADP), and their enzymes form thromboxane A2, which causes further platelet aggregation.7
Glycoproteins on the platelet surface repulse adherence to normal endothelium but cause adherence to injured areas of the vessel wall.8 The platelet membrane contains large amounts of phospholipids that activate many stages of blood coagulation.6 Platelets have prothrombin receptors that attract prothrombin, which eventually is converted to thrombin, to the site of injury. They also play a role in clot retraction. The role of platelets in hemostasis is summarized in Table 16-1.
The second phase of hemostasis involves local activation of the coagulation cascade, which results in thrombin production and eventual formation of a fibrin clot. Circulating blood proteins, the third component of hemostasis, include those of the coagulation system, the fibrinolytic system, the kinin system, and the complement system. These systems work collectively to provide a complex system of checks and balances that regulate clot formation.
The blood proteins in the coagulation system, traditionally referred to as clotting factors, are manufactured in the liver and can be functionally divided into enzymes and cofactors.5 Enzymes are activated clotting factors, whereas cofactors are substances that accelerate the rate of substrate activation by enzymes. The coagulation system is a series of self-amplifying substrate-to-enzyme interactions, activated by three types of injuries: trauma to tissue, trauma to vascular endothelium, and trauma to red blood cells (RBCs) or platelets.7
When one or more of these injuries occurs, thrombin is generated via the intrinsic pathway (contact system) or extrinsic pathway (tissue factor). The intrinsic pathway is activated when factor XII (Hageman factor) is altered due to trauma to the blood vessel or exposure to vascular wall collagen.6 The extrinsic pathway is activated by tissue thromboplastin (tissue factor), which alters factor VII.6 The final stages of clot formation begin with the activation of factor X, the first step in a converging pathway that brings the intrinsic and extrinsic pathways together. This process is represented in Figure 17-1, in Chapter 17. An important difference between the pathways is that the extrinsic pathway is activated very rapidly, most often within seconds, whereas the intrinsic pathway is more slowly activated, with clot formation complete within 1 to 6 minutes.6
Table 16.1 Role of Platelets in Hemostasis | ||||||
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The activation of factor X begins the final common pathway and leads to the conversion of circulating prothrombin to thrombin. Thrombin acts as a proteolytic enzyme and cleaves fibrinopeptides A and B from fibrinogen, a large circulating plasma protein. Fibrin monomers are formed as a result of this cleavage and are
then joined by activating factor XIII, and a stable clot is produced.6
then joined by activating factor XIII, and a stable clot is produced.6
Three major regulatory mechanisms control coagulation: the fibrinolytic system, antihrombin III (AT III), and protein C. These systems, aided by rapid blood flow and removal of activated clotting factor by the reticuloendothelial system, localize clot formation and maintain the liquid state of blood.
In the final phase of hemostasis, the fibrinolytic system begins the breakdown of fibrin when the clot is formed. This is illustrated in Figure 17-2 in Chapter 17. Plasminogen is incorporated into the fibrin clot and when activated is converted to plasmin, which systematically lyses fibrin. Four major fragments called fibrin degradation products (FDPs), also referred to as fibrin split products (FSPs), are liberated: X, Y, D, and E. The FDPs have anticoagulant properties which include disruption of fibrin polymerization, coating of platelets, and formation of soluble fibrin monomer complexes (SFMCs).6 FDPs exert their anticoagulant effect when they cannot be adequately cleared because of excess fibrin formation. The pathophysiological effect of FDPs in obstetrics is especially significant because they decrease myometrial contractility and can worsen uterine atony.3
Antihrombin III (AT III) is the central physiologic antagonist to coagulation. It is a glycoprotein that binds to activated factors XII, XI, IX, and X and slowly inactivates thrombin. AT III inactivates thrombin by forming a 1:1 molecular complex with it, and the presence of these thrombin-antithrombin (TAT) complexes confirms the presence of thrombin.9 When AT III combines with heparin, thrombin inactivation is accelerated.3
Protein C is a vitamin K–dependent proenzyme that is found in plasma. When activated by thrombin, protein C degrades activated cofactors V and VIII. Protein C then exerts an anticoagulant effect by inhibiting a portion of the coagulation cascade. Thrombomodulin and protein S serve as cofactors for protein C.3
Coagulation in Pregnancy
Pregnancy has been referred to as a hypercoagulable state. Normal changes in the hemostatic system during pregnancy are presented in Box 16-2.10 All coagulation factors are elevated with the exception of factors XI and XIII, which are believed to decrease.3 In addition, fibrinolytic activity appears to be decreased during pregnancy, probably due to an increase in plasminogen activator inhibitor.11 Levels of AT III remain unchanged, as do levels of protein C. Protein S, which potentiates the action of protein C, is also decreased.10 Alterations in the hemostatic mechanism are believed to occur in order to maintain the pregnancy and to protect from blood loss at delivery.
Box 16-2. Hemostatic Alterations in Pregnancy
Increase in factors V, VII, VIII, IX, X, XII, prothrombin
Increased fibrinogen 200–400 mg/dL to 400–600 mg/dL
Decrease in factors IX and XIII
No effect on protein C, antithrombin III
Decrease in protein S
Decreased fibrinolysis
Pathophysiology of DIC
In DIC, there is a loss of localization of coagulation due to the initial generation of thrombin by exposure to tissue factor (extrinsic pathway), the amplification of thrombin formation through the intrinsic pathway, the parallel activation of the inflammatory pathway, and the loss of adequate hemostatic and endothelial responses.12 This results in the following pathological consequences:10,12
disseminated fibrin thrombi, which results in obstruction of blood flow that produces end-organ ischemia and necrosis
activation of the kinin system, which causes vascular permeability, hypotension, and shock
activation of the complement system, which results in red cell and platelet lysis, increased vascular permeability, and shock
release of cytokines, including interleukins (IL) 1 and 6, and tumor necrosis factor (TNF)
plasmin-induced lysis of fibrin, liberation of FDPs, and further deletion of coagulation factors, which results in hemorrhage and shock.
The process is a self-perpetuating cycle of excessive clot formation and hemorrhage. Activation of the systemic inflammatory response can amplify coagulation through proinflammatory mediators, and likewise, DIC can amplify the inflammatory response and worsen the cycle.12 DIC secondary to obstetric complications linked to endothelial dysfunction may give rise to systemic inflammatory response syndrome (SIRS), which may result in multiple organ dysfunction syndrome (MODS).
Predisposing Obstetric Conditions
In normal pregnancy, the coagulation and fibrinolytic systems appear to be in a hyperdynamic state with both increased production and turnover of several procoagulants.3,13 It has therefore been suggested that pregnancy may represent a state in which there is an increased susceptibility to DIC. The intrapartum activation of
coagulation—as evidenced by increases in FPA, activated Hageman factor (XIIa), SFMCs, and activation of fibinolysis, indicated by increased FDPs—implies that normal parturition may actually represent a low-grade DIC.13 Hypothetically, a pregnant woman exposed to a specific stimulus, such as release of tissue thromboplastin during placental abruption, may be at far greater risk for overt coagulopathy than her nonpregnant counterpart. There is to date no scientific evidence to support this theory. The obstetric conditions more commonly associated with DIC and related coagulation abnormalities are described in Box 16-1. Changes that occur in the hemostatic system during normal pregnancy are presented in Box 16-2.
coagulation—as evidenced by increases in FPA, activated Hageman factor (XIIa), SFMCs, and activation of fibinolysis, indicated by increased FDPs—implies that normal parturition may actually represent a low-grade DIC.13 Hypothetically, a pregnant woman exposed to a specific stimulus, such as release of tissue thromboplastin during placental abruption, may be at far greater risk for overt coagulopathy than her nonpregnant counterpart. There is to date no scientific evidence to support this theory. The obstetric conditions more commonly associated with DIC and related coagulation abnormalities are described in Box 16-1. Changes that occur in the hemostatic system during normal pregnancy are presented in Box 16-2.
Placental abruption, which complicates approximately 1 percent of deliveries, is considered a common obstetric cause of DIC.2 Up to 10 percent of patients with a clinically significant abruption may have a coagulopathy, with postpartum hemorrhage the most frequent cause of death.13 Severe coagulation defects occur most often when the abruption results in IUFD.14 When the abruption is severe, the coagulopathy is related to systemic consumption of clotting factors and activation of fibrinolysis, rather than local consumption of clotting factors as occurs with retroplacental clot formation.14 The trophoblast contains the highest concentration of tissue thromboplastin, and the continued release of thromboplastin from the site of the abruption into the systemic circulation results in disseminated consumption of clotting factors and secondary fibrinolysis.3 Thromboplastins activate the coagulation system through the extrinsic pathway by binding factor VII.3 The degree of thrombocytopenia, AT III consumption, hypofibrinogenemia, and D-dimer elevation correlates with the clinical severity of the abruption, and with the time interval between placental separation and delivery.3 Postpartum hemorrhage is the most common cause of maternal morbidity secondary to placental abruption. It is likely that this is related to an increase in FDPs that lead to uterine atony.3
Preeclampsia or eclampsia may initially produce thrombocytopenia due to platelet consumption but rarely causes overt coagulopathy. It is the endothelial damage related to preeclampsia or eclampsia that causes a low-grade compensated DIC. A number of coagulation abnormalities have been observed in preeclampsia. AT III, which is unaltered in normal pregnancy, is reduced. Levels of D-dimer are elevated. Factor VIII consumption and FPA concentration are increased, reflecting the conversion of fibrinogen to fibrin.
Frank DIC in preeclampsia or eclampsia is rarely seen in the absence of placental abruption or HELLP syndrome.15,16 An international multicenter study found the frequency of DIC in HELLP syndrome to be 6 percent and in severe preeclampsia to be 1 percent.17 When eclampsia occurs, the incidence of DIC rises to 7 to 10 percent.18 Although many women with preeclampsia demonstrate a subclinical coagulopathy, those who experience another complication such as placental abruption or HELLP syndrome are at significantly greater risk for mortality.
Amniotic fluid embolus (AFE), also referred to as anaphylactoid syndrome of pregnancy, is a rare obstetric complication characterized by profound hypotension, hypoxia, cardiovascular collapse, and coagulopathy. Maternal mortality associated with this condition is reported to be 60 to 80 percent.19 Of those who survive, only 15 percent are neurologically intact. Should the initial cardiopulmonary insults be survived, the patient may die from the ensuing coagulopathy.20 A thorough discussion of this condition is presented in Chapter 19 of this text.
The etiology of the coagulopathy in AFE is controversial. Although amniotic fluid is known to have a procoagulant effect, its role in the syndrome remains inconclusive.20 Laboratory abnormalities include marked hypofibrinogenemia. Clark and colleagues postulated that the coagulopathy in both placental abruption and AFE is due to activation of the clotting cascade after exposure of the maternal circulation to fetal antigens with thromboplastin-like effects.19
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