CONSUMPTIVE COAGULOPATHY

Obstetrical syndromes commonly termed consumptive coagulopathy or disseminated

intravascular coagulation (DIC) were described in the 1901 report by DeLee in which
temporary hemophilia developed with placental abruption or with a long-dead macerated
fetus. In ensuing decades, similar but frequently less intensecoagulopathic syndromes
have been described for almost all areas of medicine (Levi, 2010b; Montagnana, 2010).
Disseminated Intravascular Coagulation in Pregnancy
Because of many definitions used and its variable severity, citing an accurate incidence for
consumptive coagulopathy is not possible in pregnant women. For example, as will be
discussed, some degree of significant coagulopathy is found with most cases of placental
abruption and amnionic-fluid embolism. Other instances in which frequently occurring but
insignificant degrees of coagulation activation can be found include sepsis, thrombotic
microangiopathies, acute kidney injury, and preeclampsia and HELLP ( hemolysis, elevated
liver enzyme levels, low platelet count) syndromes (Rattray, 2012; Su, 2012). Although
profound consumptive coagulopathy can be associated with fatty liver disease of pregnancy,
diminished hepatic synthesis of procoagulants makes a significant contribution (Nelson,
2013). When consumptive coagulopathy is severe, the likelihood of maternal and perinatal
morbidity and mortality is increased. Rattray and colleagues (2012) described 49 cases from
Nova Scotia during a 30-year period. Antecedent causes included placental abruption,
obstetrical hemorrhage, preeclampsia and HELLP syndromes, acute fatty liver, sepsis, and
amnionic-fluid embolism. Of these, 59 percent received blood transfusions, 18 percent
underwent hysterectomy, 6 percent were dialyzed, and there were three maternal deaths. The
perinatal mortality rate was 30 percent.
Pregnancy-Induced Coagulation Changes
Several changes in coagulation and fibrinolysis can be documented during normal pregnancy.
Some of these include appreciable increases in the plasma concentrations of factors I
(fibrinogen), VII, VIII, IX, and X. A partial list of these normal values can be found in the
Appendix ( p. 1288) and in Chapter 4 (p. 57). At the same time, plasminogen levels are
increased considerably, but levels of plasminogen activator inhibitor-1 and -2 (PAI-1 and
PAI-2) also increase. Thus, plasmin activity usually decreases until after delivery (Hale, 2012;
Hui, 2012). The mean platelet count decreases by 10 percent during pregnancy, and there is
increased platelet activation (Kenny, 2014). The net results of these changes include
increased levels of fibrinopeptide A, -thromboglobulin, platelet factor 4, and fibrinogenfibrin degradation products, which includes d-dimers. Along with decreased concentrations of
anticoagulant protein S, hypercoagulability, and decreased fibrinolysis, there is augmented
yet compensatedintravascular coagulation that may function to maintain the uteroplacental
interface.
Pathological Activation of Coagulation
Normal coagulation and fibrinolysis can be pathologically activated via two pathways. The
extrinsic pathway is active by thromboplastin from tissue destruction, whereas the intrinsic
pathway is initiated by collagen and other tissue components that become exposed with loss
of endothelial integrity (Fig. 41-30). Tissue factor III is an integral membrane protein. It is
released by endothelial cells to complex with factor VII, which in turn activates tenase (factor
IX) and prothrombinase (factor X) complexes. Uncontrolled thrombin generation converts
fibrinogen to fibrin, which polymerizes to deposit in small vessels of virtually every organ
system. This seldom causes organ failure, because these vessels are protected by enhanced

fibrinolysis stimulated by fibrin monomers released by coagulation. These monomers

combine with tissue plasminogen activator and plasminogen to release plasmin, which lyses
fibrinogen and fibrin monomers and polymers. The products form a series of fibrinogenfibrin derivatives that are measured by immunoassay. These are the fibrin degradation
products or fibrin-split products, which include d-dimers (see Fig. 41-30). There may also be
evidence for microangiopathic hemolysis from mechanical trauma to the red cell membrane
by fibrin strands in small vessels. This is likely a contributing cause of hemolysis in women
with preeclampsia and HELLP syndromes (Pritchard, 1976a). The pathologically activated
cycle of coagulation and fibrinolysis becomes clinically important when coagulation factors
and platelets are sufficiently depleted to cause bleedinghence, consumptive coagulopathy.
Several obstetrical conditions are accompanied by release of potent inciting factors for
clinically significant consumptive coagulation. The best known and most common, and
therefore most serious, results from thromboplastin release with placental abruption. Also,
unique to obstetrics is the immediate and profound coagulation factor depletion that can
follow entry of amnionic fluid into the maternal circulation. This causes activation of factor X
by abundant mucin in fetal squames. Other causes include activation by release of endotoxins
from gram-negative bacteria and exotoxins from gram-positive bacteria.
Diagnosis
The International Society on Thrombosis and Haemostasis has promulgated a DIC score to
aid identification and prognosis prediction (Taylor, 2001). This algorithm, shown in Table
41-6, has not been applied in obstetrical conditions but can serve as a rough guideline to
identify a pregnant woman with consumptive coagulopathy. Again, although not including
obstetrical patients, the Prowess Trial evaluated 840 subjects with severe sepsis. The
mortality rate increased from approximately 25 percent with a DIC score of 3 to 70 percent
with a score of 7 (Dhainaut, 2004).
Evaluation and Management
Obstetrical causes of consumptive coagulopathy are almost always due to an identifiable,
underlying pathological process that must be eliminated to halt ongoing defibrination. Thus,
prompt identification and removal of the source of the coagulopathy is given priority. With
surgical incisions or extensive lacerations accompanied by severe hemorrhage, rapid
replacement of procoagulants is usually indicated. Vigorous restoration and maintenance of
the circulation to treat hypovolemia cannot be overemphasized. With adequate perfusion,
activated coagulation factors, fibrin, and fibrin degradation products are promptly removed
by the reticuloendothelial system, along with restoration of hepatic and endothelial synthesis
of procoagulants. Some treatments for intravascular coagulation have been conceived by
armchair theorists and are mentioned here only to be condemned. For example, in years past,
some recommended heparin administration to block consumption of procoagulants. Others
recommended epsilon-aminocaproic acid to inhibit fibrinolysis by blocking plasminogen
conversion to plasmin. The dangers of giving heparin to an actively bleeding woman are
obvious. Fibrinolysis inhibition is probably not quite as dangerous, but any putative benefits
remain unproven.
Identification of Defective Hemostasis. Bioassay is an excellent method to detect or suspect
clinically significant coagulopathy. Excessive bleeding at sites of modest trauma
characterizes defective hemostasis. Examples include persistent bleeding from venipuncture
sites, nicks from shaving the perineum or abdomen, trauma from bladder catheterization, and
spontaneous bleeding from the gums, nose, or gastrointestinal tract. Purpuric areas at pressure
sites such as sphygmomanometer cuffs or tourniquets suggest significant thrombocytopenia.

As discussed, any surgical procedure provides the ultimate bioassay and elicits generalized
oozing from the skin, subcutaneous and fascial tissues, the retroperitoneal space, the
episiotomy, or incisions and dissections for cesarean delivery or hysterectomy.
Fibrinogen and Degradation Products. In late pregnancy, plasma fibrinogen levels
typically have increased to 300 to 600 mg/dL. Even with severe consumptive coagulopathy,
levels may sometimes be high enough to protect against clinically significant
hypofibrinogenemia. For example, defibrination caused by a placental abruption might lower
an initial fibrinogen level of 600 mg/dL to 250 mg/dL. Although this would indicate massive
fibrinogen consumption, there are still adequate levels to promote clinical coagulation
usually about 150 mg/dL. If serious hypofibrinogenemia less than 50 mg/dLis present,
the clot formed from whole blood in a glass tube may initially be soft but not necessarily
remarkably reduced in volume. Then, over the next half hour or so, as plateletinduced clot
retraction develops, the clot becomes quite small. When many of the erythrocytes are
extruded, the volume of liquid in the tube clearly exceeds that of clot. Fibrinolysis cleaves
fibrin and fibrinogen into various fibrin degradation products that are detected by several
sensitive test systems. There are many fragment types, and monoclonal antibodies in assay
kits usually measure d-dimers specific for that assay. These values are always abnormally
high with clinically significant consumptive coagulopathy. At least in obstetrical disorders,
quantification has not been correlated with outcomes, although moderate to strong
increases constitute part of the diagnostic algorithm shown in Table 41-6.
Thrombocytopenia
Seriously low platelet concentrations are likely if petechiae are abundant or if clotted blood
fails to retract within an hour or so. Confirmation is provided by a platelet count. If there is
associated severe preeclampsia syndrome, there may also be qualitative platelet dysfunction
(Chap. 40, p. 738).
Prothrombin and Partial Thromboplastin Times
Prolongation of these standard coagulation tests may result from appreciable reductions in
procoagulants essential for generating thrombin, from very low fibrinogen concentrations, or
from appreciable amounts of circulating fibrinogen-fibrin degradation products. Prolongation
of the prothrombin time and partial thromboplastin time need not be the consequence of
consumptive coagulopathy.
Placental Abruption
This is the most common cause of severe consumptive coagulopathy in obstetrics and is
discussed on page 793.
Preeclampsia Syndrome
Endothelial activation or injury is a hallmark of preeclampsia, eclampsia, and HELLP
syndrome. In general, the clinical severity of preeclampsia is directly correlated with
thrombocytopenia and fibrinogen-fibrin degradation products (Levi, 2010b; Kenny, 2014).
That said, intravascular coagulation is seldom clinically worrisome. Delivery reverses these
changes, and treatment until then is supportive. These syndromes are discussed in detail in
Chapter 40.

Fetal Death and Delayed Delivery

Consumptive coagulopathy associated with prolonged retention of a dead fetus is unusual
today because fetal death can be easily confirmed and there are highly effective methods for
labor induction. Currently, the syndrome is only occasionally encountered when there is one
dead twin fetus and an ongoing pregnancy. With singleton pregnancies, if the dead fetus is
undelivered, most women enter spontaneous labor within 2 weeks. Gross disruption of
maternal coagulation rarely develops before 4 weeks (Pritchard, 1959, 1973). After 1 month,
however, almost a fourth will develop consumptive coagulopathy. The pathogenesis of
coagulopathy appears to be mediated by thromboplastin released by the dead fetus and the
placenta (Jimenez, 1968; Lerner, 1967). Typically, the fibrinogen concentration falls during 6
weeks or more to levels that are normal for nonpregnant adults, but in some cases, this
declines to < 100 mg/dL. Simultaneously, fibrin degradation product and d-dimer levels
become elevated in serum, and moderate thrombocytopenia develops (Pritchard, 1973). If
enough time elapses to seal the placental-decidual interface, these coagulation defects may
correct spontaneously before evacuation (Pritchard, 1959).
Discordant Fetal Death in Multifetal Gestation
Obvious coagulation derangement occasionally develops in a multifetal pregnancy in which
there is at least one fetal death and survival of another (Chescheir, 1988; Landy, 1989). This
situation is uncommon, and in one study of 22 such pregnancies, none developed a
coagulopathy (Petersen, 1999). Most cases are seen in monochorionic twins with shared
circulations, which are described in Chapter 45 (p. 904). The course in such a woman cared
for at Parkland Hospital is shown in Figure 41-31. In this case, the coagulopathy ceased
spontaneously, and the surviving healthy twin was delivered near term. The placenta of the
long-dead fetus was filled with fibrin.
Amnionic-Fluid Embolism
This uniquely obstetrical syndrome was described in 1941 by Steiner and Lushbaugh and
became classically characterized by the abrupt onset of hypotension, hypoxia, and severe
consumptive coagulopathy. Even so, amnionic-fluid embolism has great individual variation
in its clinical manifestation. For example, only one of these three clinical hallmarks
predominates in some affected women. Despite variations in the reported incidence of this
uncommon but extremely important complication, many reports describe a similar frequency.
A study that included 3 million births in the United States cited an estimated frequency of 7.7
cases per 100,000 births (Abenhaim, 2008). The United Kingdom Obstetric Surveillance
System reported an incidence of 2.0 per 100,000 births (Knight, 2010). And review of more
than 4 million births in Canada yielded an incidence of 2.5 per 100,000 births (Kramer,
2012). Another review of data from five high-resource countries cites frequencies from 1.9 to
6.1 per 100,000 deliveries. The case-fatality rates in all of these studies ranged from 11 to 43
percent. From another perspective, amnionic-fluid embolism was the cause of 10 to 15
percent of all pregnancy-related deaths in the United States and Canada (Berg, 2003; 2010;
Clark, 2008; Kramer, 2012). Predisposing conditions are rapid labor, meconium-stained
amnionic fluid, and tears into uterine and other large pelvic veins. Other risk factors
commonly cited include older maternal age; postterm pregnancy; labor induction or
augmentation; eclampsia; cesarean, forceps, or vacuum delivery; placental abruption or
previa; and hydramnios (Knight, 2010, 2012; Kramer, 2012). The association of uterine
hypertonus appears to be the effect rather than the cause of amnionic-fluid embolism. This is
likely because uterine blood flow ceases when intrauterine pressures exceed 35 to 40 mm Hg.
Thus, a hypertonic contraction would be the least likely circumstance for amnionic fluid and
other debris to enter uterine veins (Clark, 1995). Because of this, there is also no association

between this disorder and hypertonus from oxytocin. In obvious cases of amnionic-fluid
embolism, the clinical picture is unquestionably dramatic. The classic example is that of a
woman in the late stages of labor or immediately postpartum who begins gasping for air and
then rapidly suffers seizures or cardiorespiratory arrest complicated by massive hemorrhage
from consumptive coagulopathy. It has become apparent that there is a variation in the
clinical manifestations of this condition. For example, we and others have managed several
women in whom otherwise uncomplicated vaginal or cesarean delivery was followed by
severe acute consumptive coagulopathy without overt cardiorespiratory difficulties. In those
women, consumptive coagulopathy appears to be the forme fruste of amnionic-fluid
embolism (Kramer, 2012; Porter, 1996).
Etiopathogenesis
Some amnionic fluid commonly enters the maternal circulation at the time of normal delivery
through a minor breach in the physiological barrier between maternal and fetal
compartments. Thus, it is fortunate that infused amnionic fluid is generally innocuous, even
in large amounts (Adamsons, 1971; Stolte, 1967). At delivery, squames, other cellular
elements of fetal origin, and trophoblasts can be identified in maternal peripheral blood
(Clark, 1986; Lee, 1986). These are presumed to enter venous channels from the placental
implantation site or from small lacerations that inevitably develop in the lower uterine
segment or cervix with delivery. Although these events are usually innocuous, amnionic fluid
constituents in some women initiate a complex series of pathophysiological sequelae shown
in Table 41-7. The wide range of clinical manifestations underscores the subjective nature of
diagnosis of many of these women. ofound coagulopathy, one can reasonably conclude that
amnionic fluid and its constituents have a multitude of actions. For example, tissue factor in
amnionic fluid presumably activates factor X to incite coagulation (Ecker, 2012; Levi, 2013).
Others that have been described include endothelin-1 expressed by fetal squames,
phosphatidylserine expressed by amnion, and complement activators (Khong, 1998; Zhou,
2009). An anaphylactoid reaction with complement activation has been postulated because
serum levels of tryptase and histamine are also elevated (Benson, 2001; Clark, 1995).
Pathophysiology
Animal studies in primates and goats have provided important insights into central
hemodynamic aberrations caused by amnionic fluid infused intravenously (Adamsons, 1971;
Hankins, 1993). In general, evidence for fetal debris embolization and toxicity increases with
the volume infused and the amount of meconium contamination (Hankins, 2002). If a
response is evoked, its initial phase consists of pulmonary and systemic hypertension. A
similar response was reported in a woman in whom transesophageal echocardiography was
performed within minutes of collapse. Findings included a massively dilated akinetic right
ventricle and a small, vigorously contracting, cavity-obliterated left ventricle (Stanten, 2003).
Profound oxygen desaturation is often seen in the initial phase, and this is the cause of
neurological injury in most survivors (Harvey, 1996). All of these observations are consistent
with failure to transfer blood from the right to the left heart because of severe and unrelenting
pulmonary vasoconstriction. This initial phase is probably followed by decreased systemic
vascular resistance and diminished cardiac output (Clark, 1988). Women who survive beyond
these first two phases invariably have a consumptive coagulopathy and usually lung and brain
injury.

Postmortem Findings. Histopathological findings may be dramatic in fatal cases of

amnionic-fluid embolism such as the one shown in Figure 41-32. The detection of such
debris, however, may require special staining, and even then, it may not be seen. In one study,
fetal elements were detected in 75 percent of autopsies and in 50 percent of specimens
prepared from concentrated buffy coat aspirates taken antemortem from a pulmonary artery
catheter (Clark, 1995). Several other studies, however, have demonstrated that fetal squamous
cells, trophoblasts, and other debris of fetal origin may commonly be found in the central
circulation of women with conditions other than amnionic-fluid embolism. Thus, the
diagnosis is generally made by identifying clinically characteristic signs and symptoms and
excluding other causes.
Management and Clinical Outcomes
Immediate resuscitative actions are necessary to interdict the high mortality rate. As
discussed, the initial period of systemic and pulmonary hypertension that frequently heralds
amnionic-fluid embolism is transient. Tracheal intubation, cardiopulmonary resuscitation, and
other supportive measures must be instituted without delay. Treatment is directed at
oxygenation and support of the failing myocardium, along with circulatory support that
includes rapid blood and component replacement. That said, there are no data indicating that
any type of intervention improves maternal or fetal prognosis. In undelivered women
undergoing cardiopulmonary resuscitation, consideration should be given to emergency
cesarean delivery to perhaps optimize these efforts and improve newborn outcome. Decision
making for perimortem cesarean delivery is more complex in a woman who is
hemodynamically unstable but who has not suffered cardiac arrest (Chap. 47, p. 956). Most
reports describe dismal outcomes with amnionic-fluid embolism. However, this is likely
influenced by underdiagnosis and reporting biases that favor the most severe cases, which are
recognized but also have the greatest mortality rates. Several reports are illustrative. From a
California database of 1.1 million deliveries, there was a 60-percent mortality rate with
amnionicfluid embolism (Gilbert, 1999). In a report from the Suzhou region of China, 90
percent of mothers died (Weiwen, 2000). This latter report emphasizes that death can be
amazingly rapid because 12 of the 34 women who died did so within 30 minutes. The
mortality rate was less dismal in the largest study from a Canadian database. Of 120 women
with an amnionic-fluid embolism, only a fourth died. In many reports, survivors commonly
have profound neurological impairment. Clark (1995) observed that only 8 percent of women
who lived despite cardiac arrest survived neurologically intact. As perhaps expected, perinatal
outcomes are also poor and are inversely related to the maternal cardiac arrest-to-delivery
interval. Even so, neonatal survival rate is 70 percent, but unfortunately, up to half of
survivors suffer residual neurological impairment. In the Canadian study, 28 percent of
infants were considered to be asphyxiated at birth (Kramer, 2012).
Sepsis Syndrome
Various infections that are accompanied by endo- or exotoxin release can result in sepsis
syndrome in pregnant women. Although a feature of this syndrome includes activation of
coagulation, seldom does sepsis alone cause massive procoagulant consumption. Escherichia
coli bacteremia is frequently seen with antepartum pyelonephritis and puerperal infections,
however, accompanying consumptive coagulopathy is usually not severe. Some notable
exceptions are septicemia associated with puerperal infection or septic abortion caused by
exotoxins released from infecting organisms such as group A Streptococcus pyogenes,
Staphylococcus aureus , or Clostridium perfringens or sordellii. Treatment of sepsis
syndrome and septic shock is discussed in Chapter 47 (p. 946).

Purpura Fulminans
This severeoften lethalform of consumptive coagulopathy is caused by microthrombi in
small blood vessels leading to skin necrosis and sometimes vasculitis. Debridement of large
areas of skin over the extremities and buttocks frequently requires treatment in a burn unit.
Purpura fulminans usually complicates sepsis in women with heterozygous protein C
deficiency and low protein C serum levels (Levi, 2010b). Recall that homozygous protein C
deficiency results in fatal neonatal purpura fulminans (Chap. 52, p. 1031).
Abortion
Septic abortionespecially associated with the organisms discussed abovecan incite
coagulation and worsen hemorrhage, especially with midtrimester abortions. Indeed, sepsis
syndrome accompanied by intravascular coagulation accounts for 25 percent of abortionrelated deaths (Saraiya, 1999). In the past, especially with illegal abortions, infections with
Clostridium perfringens were a frequent cause of intense intravascular hemolysis at Parkland
Hospital (Pritchard, 1971). More recently, however, septic abortions from infection with
Clostridium sordellii have emerged as important causes (Chap 18, p. 357). Second-trimester
induced abortions can stimulate intravascular coagulation even in the absence of sepsis. BenAmi and associates (2012) described a 1.6-percent incidence in 1249 late secondtrimester
pregnancies terminated by dilatation and evacuation. Two thirds were done for fetal demise,
which may have been contributory to coagulopathy. Another source of intense coagulation is
from instillation of hypertonic solutions to effect midtrimester abortions. These are not
commonly performed currently for pregnancy terminations (Chap. 18, p. 369). The
mechanism is thought to initiate coagulation by thromboplastin release into maternal
circulation from placenta, fetus, and the decidua by the necrobiotic effect of the hypertonic
solutions (Burkman, 1977).