FIGURE 31-1. Regulation and inhibition of thrombin generation. Red arrows represent normal pathways of inhibition interfered with by the underlying conditions causing DIC.

In the past, extrinsic and intrinsic coagulation pathways were described as though they were alternative modes of clotting activation. This process is now more accurately understood as beginning almost universally with the exposure of the circulation to tissue factor and activation of the traditional extrinsic pathway, with subsequent augmentation or facilitation of this process through secondary activation of the intrinsic pathway.¹ Ultimately, both mechanisms are involved in most types of clotting and involve thrombin generation as a fundamental initial step.^2–5

Intrinsic to the process of clot formation via conversion of fibrinogen to fibrin is the near-simultaneous initiation of clot lysis via conversion of plasminogen to plasmin, accompanied by repair of the damaged blood vessel.^2–4 Thrombin generation is pivotal in both clot formation, and fibrinolysis.^2–6

Generation of thrombin is regulated at three pivotal points in the coagulation cascade; by antithrombin (which inhibits both conversion of factor X to Xa and directly inhibits the action of thrombin itself), by activated protein C (which inhibits activation of factors V and VIII), and by tissue factor pathway inhibitor (TFPI) (which interferes with the tissue factor/factor VIIa complex; see Figure 31-1).⁴ This process of clot formation and dissolution is normally both localized to the site of endothelial injury and limited in effect. Such tight control and localization is vital; under normal circumstances, these two processes are finely balanced, thus limiting both bleeding and potential clot-related tissue ischemia.

DIC represents a pathologic hyperactivation of both thrombotic and thrombolytic aspects of this system which may be initiated by a number of factors, and generally involves interference with normal thrombin generation pathway at each of the three levels described above (see Figure 31-1). Subsequent uncontrolled, nonlocalized thrombin generation and uncoupled secondary fibrinolysis may result in both tissue ischemia due to microvascular thrombosis and hemorrhage due to plasmin generation with excessive fibrinolysis and ongoing consumption of clotting factors involved with the initial thrombin-induced fibrin generation. In the general clinical practice of medicine, abnormal thrombosis and tissue ischemia are generally the primary sources of morbidity and of clinical concern, as reflected in the official International Society of Thrombosis and Hemostasis definition of DIC: “An acquired syndrome characterized by 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.”⁷ In contrast, in obstetrics, the hemorrhagic phase of DIC is generally of primary clinical concern except in select cases of severe sepsis. Although excess generation of thrombin and activation of plasmin represent the primary pathophysiologic derangements in DIC, the condition is actually incredibly complex, and involves enhancement or suppression of virtually every step in the complex clotting cascade.^2–4,8,9

During pregnancy, the potential for clinical pathology related to abnormal coagulation is enhanced, both secondary to increased hepatic production of most clotting factors, and due to several unique characteristics of placental trophoblasts.¹⁰ Under normal conditions, this “supercharged” coagulation system is vital in achieving hemostasis following placental separation. However, the same factors that provide essential protection from postpartum hemorrhage also create a setting for a perfect storm should this finely balanced system become unlinked. Such imbalance has several possible origins; for example, the DIC associated with sepsis is related to cytokine release and may be viewed as a component of the systemic inflammatory response syndrome.^2,3,11 The DIC associated with acute fatty liver of pregnancy on the other hand is closely related to altered hepatic function and a deficiency in antithrombin III.¹² However, most obstetric conditions causing DIC are directly related to the procoagulant effects of trophoblast tissue. These characteristics include a strong expression of tissue factor, thrombomodulin and endothelial protein C receptor, and a relative reduction in expression of TFPI (all of which enhance coagulation), and a simultaneous increase in plasminogen activator inhibitor and thrombin-activated fibrinolysis inhibitor against a background of unchanged levels of tissue plasminogen activator (which suppress fibrinolysis).^13–17 The normal coagulation sequence is also enhanced by exposure to anionic phospholipid surfaces which can accelerate the conversion of prothrombin to thrombin by factors Xa and Va by up to 250,000-fold.¹⁸ It is, therefore, not surprising that the many common causes of DIC in pregnancy (placental abruption, amniotic fluid embolism, prolonged fetal demise) involve abnormal disruption of trophoblastic tissue and subsequent uncontrolled activation of the coagulation/fibrinolysis pathways described above. The resultant microvascular clotting, tissue ischemia, and accelerated depletion of clotting factors lead to the clinical signs and symptoms associated with obstetric DIC.

In addition to hemorrhage caused by consumption of available clotting factors, recent data have highlighted important direct pathologic effects of fibrin degradation products and plasmin themselves. These factors result in both increased synthesis and release of interleukins which aggravate existing systemic endothelial damage and result in complement activation and the release of kinins, which causes additional tissue damage and increased vascular permeability.¹⁹ Such permeability leads to loss of intravascular volume and may further aggravate the cycle of DIC-hemorrhage-shock-DIC.¹⁹ Early reversal of these abnormalities is essential for the achievement of optimal outcomes and is one important rationale for the aggressive use of clotting factor replacement in current massive transfusion protocols.^20–23

TERMINOLOGY

DIC in pregnancy is often made more confusing by imprecise vernacular usage of this term. Although the severe pre-eclampsia/HELLP syndrome sequence may be accompanied by significant thrombocytopenia, as well as qualitative platelet dysfunction, such findings are part of a microangiopathic process that principally involves physical platelet (and erythrocyte) destruction rather than their widespread consumption within fibrin clots. In the absence of concomitant placental abruption or end-stage disease resulting in widespread tissue ischemia, true DIC is not generally seen with pre-eclampsia/HELLP syndrome.⁴ In a similar manner, women experiencing severe postpartum hemorrhage without sufficient replacement of clotting factors may experience a dilutional coagulopathy due to external loss of blood rather than widespread intravascular consumption. This is not DIC, although the term is often used in this situation. Under these circumstances, the situation is often made even more complex by the eventual appearance of hemorrhage-induced tissue ischemia which may in fact result in a true consumptive coagulopathy complicating the primary dilutional coagulopathy. In this chapter, we use the term DIC to refer to a process of uncontrolled, nonlocalized intravascular thrombin formation and fibrinolysis, which may be either subclinical or clinical.

CAUSES OF DIC IN PREGNANCY

Table 31-1 lists common causes of DIC in pregnancy. Placental abruption is the most common of these conditions.^24,25 In the vast majority of cases, abruption does not lead to DIC. The severity of the abruption appears to correlate with the likelihood and degree of DIC; indeed, in one large series, DIC was only seen with abruption sufficiently severe to cause fetal death.²⁵ In the era of electronic fetal heart-rate monitoring, it is generally possible to intervene surgically in cases of abruption before fetal death; perhaps a better clinical guideline today is that DIC rarely occurs in the absence of an abruption sufficiently severe to cause fetal heart-rate abnormalities that would generally be associated with fetal death in the absence of medical intervention. The point here is twofold. First, minor degrees of clinical abruption associated with a category I fetal heart-rate tracing do not require laboratory assessment of clotting function. Second, emergent delivery for placental abruption should be routinely accompanied by stat laboratory evaluation of clotting status. This may allow early preparation and replacement of clotting factors should the patient experience clinical hemorrhage from DIC.

Along with placental abruption, amniotic fluid embolism is the only cause of acute and clinically significant DIC in pregnancy.²⁶ With amniotic fluid embolism, DIC is generally accompanied or preceded by cardiovascular collapse, making the differential diagnosis short. Patients suffering acute, unexpected hypoxia and cardiovascular collapse during labor or shortly after delivery warrant assessment of clotting status, even if clinically evident bleeding is not apparent. An uncommon variant of amniotic fluid embolism has also been described in which the only manifestation is intractable DIC occurring in the immediate postpartum period.²⁷ Distinguishing such patients from those with concealed abruption is difficult, but generally not important, as treatment would be similar for both conditions. In fact, amniotic fluid embolism and abruption-related DIC are, from a pathophysiologic standpoint, probably similar.²⁶

Although less common than placental abruption, postpartum hemorrhagic shock is the most common etiology of life-threatening coagulopathy.²⁸

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