9 Disseminated intravascular coagulation Elizabeth A. Letsky MB BS FRCPath FRCOG FRCPCH

Best Practice & Research Clinical Obstetrics and Gynaecology
Vol. 15, No. 4, pp. 623±644, 2001
doi:10.1053/beog.2001.0204, available online at http://www.idealibrary.com on
Disseminated intravascular coagulation
Elizabeth A. Letsky
Consultant Perinatal Haematologist/Hon Senior Lecturer
Imperial College School of Medicine, Queen Charlotte's Hospital, Hammersmith Hospitals Trust,
Hammersmith House, 2nd Floor, Du Cane Road, London, W12 0HS, UK
Healthy pregnancy is accompanied by changes in the haemostatic system which convert it into a
hypercoagulable state vulnerable to a spectrum of disorders ranging from venous thromboembolism to disseminated intravascular coagulation (DIC). This latter is always a secondary
phenomenon triggered by speci®c disorders such as abruptio placentae and amniotic ¯uid
embolism due to release of thromboplastin intravascularly or endothelial damage resulting from
pre-eclampsia and sepsis. In modern obstetric practice the most common cause is haemorrhagic
shock with delay in resuscitation leading to endothelial damage. The initial management of
massive obstetric haemorrhage is the same whether associated with coagulopathy initially or
not. Low-grade DIC, associated with pre-eclampsia, is monitored haematologically by serial
platelet counts and serum ®brin degradation products (FDPs). Supportive measures and removal
of the triggering mechanism are the key to successful management. Outcome depends primarily
on our ability to deal with the trigger and not on direct attempts to correct the coagulation
Key words: haemostatis; coagulopathy; ®brinolysis; massive haemorrhage; transfusion; abruptio placentae; amniotic ¯uid embolism; low-grade DIC; pre-eclampsia; sepsis.
Healthy haemostasis depends on normal vasculature, platelets, procoagulant factors
with their inhibitors and ®brinolysis. These act together to con®ne the circulating blood
to the vascular bed and arrest bleeding after trauma. Normal pregnancy is accompanied
by dramatic changes in the coagulation and ®brinolytic systems1,2 where there is a
marked increase in some of the procoagulant factors, particularly ®brinogen and a suppression of ®brinolysis. These changes, together with the increased blood volume, help
to combat the hazard of haemorrhage at placental separation, but play only a secondary
role to the unique process of myometrial contraction which reduces the blood ¯ow to
the placental site. They also produce a vulnerable state for intravascular clotting, which is
expressed as a whole spectrum of disorders in pregnancy ranging from thromboembolism to bleeding resulting from disseminated intravascular coagulation (DIC).1,3
Summary of changes in haemostasis in pregnancy and delivery
The changes in the haemostatic system in normal healthy pregnancy are consistent
with a continuing low-grade process of coagulant activity. Suppression of ®brinolysis
1521±6934/01/040623‡22 $35.00/00
c 2001 Harcourt Publishers Ltd.
624 E. A. Letsky
leads to ®brin deposition in the intervillous space of the placenta and in the walls of
the spiral arteries supplying the placenta.4 As pregnancy advances, the elastic lamina
and smooth muscle of these spiral arteries are replaced by a matrix containing ®brin.
This allows expansion of the lumen to accommodate an increasing blood ¯ow and
reduces the vascular resistance of the placenta. At placental separation during normal
childbirth, a blood ¯ow of 500±800 ml/minute has to be staunched within seconds, or
serious haemorrhage will occur. Myometrial contraction plays a vital role in securing
haemostasis by reducing the blood ¯ow to the placental site. Rapid closure of the
terminal part of the spiral artery will be further facilitated by removal of the elastic
lamina. The placental site is rapidly covered by a ®brin mesh following delivery. The
increased levels of ®brinogen and other coagulation factors will be advantageous to
meet the sudden demand for haemostatic components.
The changes also produce a vulnerable state for intravascular clotting and a whole
spectrum of disorders involving coagulation which occur in pregnancy.
The ®rst problem with DIC is in its de®nition. It is never primary, but always secondary
to some general stimulation of coagulation activity by release of procoagulant substances
into the blood (Figure 1). Triggers of this process in pregnancy include endothelial
damage, the release of placental tissue, amniotic ¯uid, incompatible red cells or bacterial
products into the maternal circulation. There is a great spectrum of manifestations of
the process of DIC (Table 1). ranging from a compensated state with no clinical
manifestation but evidence of increased production and breakdown of coagulation
factors, to the condition of massive uncontrollable haemorrhage with very low
concentrations of plasma ®brinogen, pathological raised levels of ®brin degradaption
products (FDPs) and variable degrees of thrombocytopenia. Further cause for confusion
is that there appears to be a transient state of intravascular coagulation during the whole
of normal labour, maximal at the time of birth.2,5,6
Fibrinolysis is stimulated by DIC, and the FDPs resulting from the process interfere
with the formation of ®rm ®brin clots causing a vicious circle which results in further
disastrous bleeding (Figure 1).
FDPs also interfere with myometrial function and possibly cardiac function and
therefore in themselves aggravate both haemorrhage and shock (Figure 2).
Obstetric conditions associated with DIC include abruptio placentae, amniotic ¯uid
embolism, septic abortion and intrauterine infection, retained dead fetus, hydatidiform
mole, placenta accreta, pre-eclampsia and prolonged shock from any cause (see
Figure 3).
Despite the advances in obstetric care and highly developed blood trasfusion
services, haemorrhage still constitutes a major factor in maternal mortality and
There have been many reports concerning small series of patients or individual
patients with coagulation failure during pregnancy. However, no signi®cant controlled
trials of the value of the many possible therapeutic measures have been carried out.
This is mainly because no one person or unit is likely to see enough cases to randomize
patients into groups in which the numbers would achieve statistical signi®cance. Also,
the complex and variable nature of the conditions associated with DIC, which are
often self-correcting and treated with a variety of measures, make it dicult to draw
helpful conclusions from the published reports.
Disseminated intravascular coagulation 625
Local activation of coagulation
Intravascular coagulation
Fibrin deposition
Consumption of clotting
factors and platelets
Thrombosis of
small vessels
Figure 1. Disseminated intravascular coagulation: stimulation of coagulation activity and its possible
Table 1. Spectrum of severity of DIC: its relationship to speci®c complications in obstetrics.
Severity of DICa
In vitro ®ndings
Stage 1 Low-grade compensated
FDPs "
Platelets #
Stage 2 Uncompensated but no
haemostatic failure
As above, plus ®brinogen #
Platelets # #
Factors V and VIII #
Small abruptio
Severe pre-eclampsia
Stage 3 Rampant with haemostatic
Platelets # #
Gross depletion of coagulation
factors, particularly ®brinogen
FDPs " "
Abruptio placentae
Amniotic ¯uid embolism
Obstetric conditions
commonly associated
Pre-eclampsia and related
Rapid progression from stage 1 to stage 3 is possible unless appropriate action is taken.
Haematological management of the bleeding obstetric patient
The management of the bleeding obstetric patient is an acute and frightening problem.
Because of the urgency of the situation there should be a routine planned practice
agreed by haematologist, physician, anaesthetist, obstetrician and nursing sta€ in all
maternity units, to deal with this situation whenever it arises. Good, reliable,
continuing communication between the various clinicians, nursing paramedical and
laboratory sta€ is essential. There should be frequent `rehearsals'7 or `®re-drills' to
ensure that this relatively rare emergency is dealt with eciently.
It is imperative that the source of bleeding, often an unsuspected uterine or genital
laceration, be located and dealt with. Prolonged hypovolaemic shock, or indeed shock
from any cause, may also trigger DIC and this may lead to haemostatic failure and
further prolonged haemorrhage.
626 E. A. Letsky
Interfere with platelet function
Interfere with polymerization of
fibrin monomer
Figure 2. Properties of FDPs.
Trigger mechanisms of DIC
during pregnancy
Abruptio placentae
Amniotic fluid embolism
Retained dead fetus
Abortion induced with
hypertonic fluids
Intrauterine sepsis
Hydatidiform mole
Placenta accreta
Intravascular haemolysis
Incompatible blood
Large feto-maternal bleed
Figure 3. Interactions occur in many of these obstetric complications.
The management of haemorrhage is virtually the same whether the bleeding is
initiated or augmented by coagulation failure. The clinical condition usually demands
urgent treatment and there is no time to wait for results of coagulation factor assays or
sophisticated tests of the ®brinolytic system activity for precise de®nition of the extent
of haemostatic failure. (Blood may be taken for this purpose and analysed later once
the emergency is over.)
Disseminated intravascular coagulation 627
Emergency laboratory assessment of haemostatic status
In order to avoid testing artefacts it is essential that the blood be obtained by a quick,
ecient, non-traumatic technique remote from indwelling lines. Thromboplastin
release from damaged tissues may contaminate the specimen and alter the results. This
is likely to occur if diculty is encountered in ®nding the vein, if the vein is only partly
canalized and the ¯ow is slow, or if there is excessive squeezing of tissues and repeated
attempts to obtain a specimen with the same needle. In such circumstances the specimen may clot in the tube in spite of the presence of anticoagulant, or the coagulation
times of the various tests will be altered and will not re¯ect the true situation in vivo.
The platelets may aggregate in clumps and give a falsely low count.
Heparin characteristically prolongs the partial thromboplastin time and thrombin
time out of proportion to the prothrombin time. As little as 0.05 units of heparin per
millilitre will prolong the coagulation test times. It is customary, though not desirable,
to take blood for coagulation tests from lines which have been washed through with
¯uids containing heparin to keep them patent. It is almost impossible to overcome the
e€ect of such ¯uids on the blood passing through such a line however much blood is
taken and discarded before obtaining a sample for investigation. This necessitates taking
blood from another site remote from heparin infusions.
Useful rapid screening tests for haemostatic failure include the platelet count, partial
thromboplastin time, or accelerated whole-blood clotting time (which tests intrinsic
coagulation), prothrombin time (which tests extrinsic coagulation), the thrombin time
and estimation of ®brinogen (Figure 4).
The measurement of FDPs provides an indirect test for ®brinolysis. In obstetric
practice the measurement of FDPs is usually part of the investigation of suspected acute
or chronic DIC. In the acute situation raised FDPs only con®rm the presence of DIC, but
are not diagnostic, and once the specimen is taken the laboratory measurement should
be delayed until after the emergency is over. Although frequently measured, the level of
soluble ®brin has not been shown in a large controlled trial to be of diagnostic or
prognostic value in obstetric patients with haemorrhage.9 Skilled laboratory workers
can be performing a much more valuable service in providing results of coagulation
screening tests and in providing blood and blood products suitable for transfusion. Of the
tests of coagulation, probably the thrombin time, an estimation of the thrombin
clottable ®brinogen in a citrated sample of plasma, is the most valuable overall rapid
screen of haemostatic competence of coagulation factors in a previously haemostatically
normal bleeding patient. The thrombin time of normal plasma is adjusted in the
laboratory to 10±15 seconds, and the ®brin clot formed is ®rm and stable. In the most
severe forms of DIC there is no clottable ®brinogen in the sample, and no ®brin clot
appears even after 2±3 minutes. Indication of severe DIC is obtained usually by a
prolonged thrombin time which is observed not only with depleted ®brinogen but in
conditions where FDPs are increased.
There is no point whatsoever in the obstetrician, anaesthetist or nursing sta€
wasting time trying to perform bedside whole-blood clotting tests which furnish little
information of practical value and only create more panic. The valuable hands at the
bedside are of more use doing the things they are trained to do in this emergency
situation rather than wasting time performing a test which is time-consuming, of little
value or signi®cance unless performed under strictly controlled conditions, and will
not contribute much, if anything, to management. The alerted laboratory worker will
be able to provide helpful results on which the obstetrician can act within 30 minutes
628 E. A. Letsky
time (TT)
Figure 4. In vitro screening tests of coagulation and their relationship to the systems involved.
of receiving the specimen in the laboratory. The tests referred to above are
straightforward and should be available from any routine haematology laboratory.
Management of severe haemorrhage
Management of severe haemorrhage must include prompt and adequate ¯uid
replacement in order to avoid renal shutdown.10 If e€ective circulation is restored
without too much delay FDPs will be cleared from the blood mainly by the liver,
which will further aid restoration of normal haemostasis.
Plasma substitutes. There is much controversy around which plasma substitute to give to
any bleeding patient. The remarks which follow relate to the supportive management of
acute haemorrhage from the placental site and/or birth canal and should not be taken to
apply to those situations in which hypovolaemia may be associated with severe
hypoproteinaemia such as occurs in septic peritonitis, burns and bowel infarction. The
choice lies between simple crystalloids, such as Hartmann's solution or Ringer lactate,
and arti®cial colloids, such as dextrans, hydroxyethyl starch and gelatin solution or the
very expensive preparations of human albumin (albuminoids). If crystalloids are used,
two to three times the volume of estimated blood loss should be administered because
Disseminated intravascular coagulation 629
the crystalloid remains in the vascular compartment for a shorter time than colloids
when renal function is maintained.
The infusion of plasma substitutes, i.e. plasma protein, dextran, gelatin and starch
solutions may result in adverse reactions. Although the incidence of severe reactions is
rare, they are diverse in nature, varying from allergic urticarial manifestations and mild
fever to life-threatening anaphylactic reactions due to spasm of smooth muscle, with
cardiac and respiratory arrest.11
Dextrans adversely a€ect platelet function, may cause pseudo-agglutination and interfere with interpretation of subsequent blood grouping and cross-matching tests. They
are, therefore, contraindicated in the woman who is bleeding due to a complication associated with pregnancy where there is a high chance of there being a serious haemostatic
defect already. The anaphylactoid reactions accompanying infusion of dextrans are probably related to IgG and IgM antidextran antibodies which are found in high concentrations in all patients with severe reactions. Of greater signi®cance in modern obstetric
practice, acute fetal distress has been reported in mothers given Dextran 70 who
su€ered anaphylactoid reactions.12 These Dextran-induced anaphylactoid reactions have
resulted in uterine hypertonia with subsequent severe fetal bradycardia even though
immunoprophylaxis with Dextran Hapten has been administered.13 There are many
suitable superior alternatives for plasma expansion, and the Royal College of
Obstetricians recommends that Dextran should be avoided in obstetric practice.14
Many studies suggested that the best way to deal with hypovolaemic shock initially is
by transfusing simple balanced salt solutions (crystalloid) followed by red cells and fresh
frozen plasma (FFP).15±17 Some advocate the use of a derivative of bovine gelatin ±
polygeline (Haemaccel) ± as a ®rst-line ¯uid in resuscitation. It has a shelf-life of 8 years
and can be stored at room temperature. It is iso-oncotic and does not interfere with
platelet function or subsequent blood grouping or crossmatching. Renal function is
improved when it is administered in hypovolaemic shock. Haemaccel is generally
considered to be non-immunogenic and therefore does not trigger the production of
antibodies in humans, even on repeated challenge. The reactions which occur related to
Haemaccel infusion are thought to be due to histamine release18, the incidence and
severity of reactions being proportional to the extent of histamine release. There have
been a few reports of severe reactions with bronchospasm and circulatory collapse,
although rarely, but there has been only one report of a fatality.19 Nevertheless,
whatever substitute is used, it is only a stop gap until suitable blood component therapy can be
The use of blood and component therapy
Whole blood may be the treatment of choice in coagulation failure associated with
obstetric disorders, but whole fresh blood is not available from regional centres in the
UK. To release blood components earlier than the usual 18±24 hours would increase
the risk of serologically incompatible transfusions, viral hepatitis and human
immunode®ciency virus (HIV). Syphilis, cytomegalovirus and Epstein±Barr virus are
examples of other infections which may be transmitted in fresh blood. Their viability
diminishes rapidly on storage at 48C. These infections, particularly in immunosuppressed or pregnant patients, can be particularly hazardous. All red cell concentrates
from units in the UK are now ®ltered, removing virtually all white cells ± which
further reduces the hazard of transfusion-transmitted infection.20
630 E. A. Letsky
Fresh frozen plasma (FFP). FFP contains all the coagulation factors present in plasma
obtained from the whole blood within 6 hours of donation. Frozen rapidly and stored
at ÿ308C, the factors are well preserved for at least 1 year.
Cryoprecipitate. Although cryoprecipitate is richer in ®brinogen than FFP it lacks
antithrombin (AT) which is rapidly consumed in obstetric bleeding associated with
DIC.21 The use of cryoprecipitate also exposes the recipient to more donors and the
potential associated hazards.
Platelets. Platelets, an essential haemostatic component, are not present in FFP and their
functional activity rapidly deteriorates in stored blood. The platelet count re¯ects both
the degree of intravascular coagulation and the amount of bank blood transfused. A
patient with persistent bleeding and a very low platelet count (520 109 l) may be
given concentrated platelets, although they are seldom required in addition to FFP to
achieve haemostasis in obstetric haemorrhage. A spontaneous recovery from the
coagulation defect is to be expected once the uterus is empty and well contracted,
provided that blood volume is maintained by adequate replacement monitored by
central venous pressure and urinary output.
Quite frequently the platelet count continues to fall in the ®rst 12±24 hours after
massive haemorrhage even though haemostasis has been achieved. This is not an
indication for platelet transfusion in the non-bleeding patient with normal coagulation
screening tests.
Red cell transfusion. Cross-matched blood should be available within 40 minutes of the
maternal specimen reaching the laboratory. If the woman has had regular antenatal
care her blood group and antibody screen will be documented. There is a good case
for giving uncross-matched blood of her own group should the situation warrant it,
provided that blood has been properly processed at the transfusion centre. If the blood
group is unknown, uncross-matched group O Rh (D) negative blood may be given if
necessary. By this time laboratory screening tests of haemostatic function should be
available. If these prove to be normal, but vaginal bleeding continues, the cause is
nearly always concealed trauma or bleeding from the placental site due to failure of the
myometrium to contract. It is imperative that the source of bleeding, often an
unsuspected uterine or genital laceration, should be located and dealt with. Prolonged
hypovolaemic shock, or indeed shock from any cause, may trigger DIC and this may
lead to haemostatic failure and further prolonged haemorrhage.
If the blood loss is replaced only by stored bank blood which is de®cient in the labile
clotting factors V and VIII and platelets, then the circulation will rapidly become
depleted in these essential components of haemostasis even if there is no DIC initially
as the cause of haemorrhage. It is advisable to transfuse 2 units of FFP for every 4±6
units of bank red cells administered.
It seems sensible in any event, whatever the cause of bleeding, to change the initial
plasma substitute and transfuse FFP once it has thawed, while waiting for compatible
blood to be available.
A spontaneous recovery from the coagulation defect is to be expected once the
uterus is empty and well contracted, provided that blood volume is maintained by
adequate replacement monitored by central venous pressure and urinary output.
The single most important component of haemostasis at delivery is contraction of
the myometrium, stemming the ¯ow from the placental site. Massive transfusion of all
clotting factors and platelets will not stop haemorrhage if the uterus remains ¯abby.
Disseminated intravascular coagulation 631
Vaginal delivery will make a less severe demand on the haemostatic mechanism than
delivery by Caesarean section, which requires the same haemostatic competence as
any other major surgical procedure. Should DIC be established with the fetus in utero,
rather than embarking on heroic surgical delivery it is better to correct the DIC and
wait for spontaneous delivery if possible, or stimulate vaginal delivery, avoiding softtissue damage.
Arterial embolization for haemorrhage in the obstetric patient (see Chapter 5)
Transcatheter arterial embolization has been used for the control of pelvic haemorrhage
resulting from trauma, malignancy and radiation since the late 1960s. During the last
two decades there has been an increasing use of transcatheter embolization of the
internal iliac or uterine artery for control of post-partum haemorrhage.22,23 The general
concensus is that selective emergency arterial embolization is an e€ective means of
controlling severe intractable post-partum haemorrhage. High-risk surgery is avoided,
and reproductive ability is maintained.
DIC in clinical conditions
Abruptio placentae
Premature separation of the placenta, or abruptio placentae, is the most frequent
obstetric cause of coagulation failure. Many of the problems which confront the
attendant in this situation are common to other conditions associated with DIC in
pregnancy so that abruption will be used as the central focus to discuss management
Abruptio placentae can occur in apparently healthy women with no clinical warning
or in the context of established pre-eclampsia. It is possible that clinically silent placental
infarcts may pre-dispose to placental separation by causing low-grade abnormalities of
the haemostatic system such as increased Factor VIII consumption and raised FDPs.24
There is a great spectrum in the severity of the haemostatic failure in this
condition25 which appears to be related to the degree of placental separation. Only
10% of patients with abruptio placentae show signi®cant coagulation abnormalities.26 In
some small abruptions there is a minor degree of failure of haemostatic processes and
the fetus does not succumb. When the uterus is tense and tender and no fetal heart
can be heard, the separation and retroplacental bleeding are extensive. No guide to
the severity of the haemorrhage or coagulation failure will be given by the amount of
vaginal bleeding. There may be no external vaginal blood loss, even when the placenta
is completely separated, the fetus is dead, the circulating blood is incoagulable and
there is up to 5 litres of concealed blood loss resulting in hypovolaemic shock.
Haemostatic failure may be suspected if there is persistent oozing at the site of
venepuncture or bleeding from the mucous membranes of the mouth or nose. Simple
rapid screening tests, as described above and referred to below, will con®rm the
presence of DIC. There will be a low platelet count, greatly prolonged thrombin time,
low ®brinogen, together with raised FDPs, due to secondary ®brinolysis stimulated by
the intravascular deposition of ®brin.27 A recent report28, which linked elevated
thrombomodulin with abruptio placentae, showed that the combination of thrombomodulin and ultrasound as a `double-marker' detected all cases of abruption in this small
series. The authors suggest that thrombomodulin may prove useful in the diagnosis of
abruption associated with trauma or unexplained vaginal bleeding and may become a
632 E. A. Letsky
useful routine screening test. The mainstay of treatment is to restore and maintain the
circulating blood volume. This not only prevents renal shutdown and further
haemostatic failure caused by hypovolaemic shock, but helps clearance of FDPs which
in themselves act as potent anticoagulants. It has also been suggested that FDPs inhibit
myometrial activity, and serious post-partum haemorrhage in women with abruptio
placentae was found to be associated with high levels of FDPs.29,30 High levels of FDPs
may also have a cardiotoxic e€ect, resulting in low cardiac output and blood pressure
despite a normal circulating blood volume (Figure2).
If the fetus is dead, the aim should be prompt vaginal delivery avoiding soft-tissue
damage, once correction of hypovolaemia is underway. Following emptying of the
uterus, myometrial contraction will greatly reduce bleeding from the placental site,
and spontaneous correction of the haemostatic defect usually occurs shortly after
delivery, if the measures recommended above have been taken. However, post-partum
haemorrhage is a not an infrequent complication and is the commonest cause of death
in abruptio placenta.7
In cases where the abruption is small and the fetus is still alive, prompt Caesarean
section may save the baby, if vaginal delivery is not imminent. FFP, bank red cells and
platelet concentrates should be available to correct the potentially severe maternal
coagulation defect.
In rare situations where vaginal delivery cannot be stimulated and haemorrhage
continues, Caesarean section is indicated even in the presence of a dead fetus. In these
circumstances normal haemostasis should be restored as far as possible by the
administration of FFP and platelet concentrates if necessary, as well as transfusing red
cells before surgery is undertaken.
Despite extravasion of blood throughout the uterine muscle, the function of the
uterine muscle is not impaired, and good contraction will follow removal of fetus,
placenta and retroperitoneal clot. Regional anaesthesia or analgesia is contraindicated.
Expansion of the lower limb vascular bed resulting from regional block can add to the
problem of uncorrected hypovolaemia. In the presence of haemostatic failure there is
the additional hazard of bleeding into the epidural space.
In recent years, heparin has been used to treat many cases of DIC, whatever their
cause. There is, however, no objective evidence to demonstrate that its use in abruptio
placentae decreased morbidity and mortality although anecdotal reports in the older
literature continued to suggest this.31 Very good results have been achieved without
the use of heparin.32 Its use, with an intact circulation, would be sensible and logical to
break the vicious circle of DIC, but in the presence of already defective haemostasis
with a large bleeding placental site it may prolong massive local and generalized
Treatment with anti®brinolytic agents such as EACA or Trasylol (Aprotinin) can
result in blockage of small vessels of vital organs, such as the kidney or brain, with ®brin.
It has been suggested30,34 that Trasylol may be helpful in the management of
abruptio placentae, particularly in those cases with uterine inertia associated with high
levels of FDPs. There is a high incidence (1.5%) of abruptio placentae in the obstetric
admissions (18 000/annum) at the Groote Schuur Obstetric Unit in Cape Town where
the ®rst study was carried out. The selection of Trasylol depended on its alleged
anticoagulant activity in addition to its well-known anti®brinolytic properties.35 There
has been a resurgence of use of Trasylol recently, particularly in cardiac surgery.36
where signi®cant reduction in blood loss has been shown following cardiac bypass
operations. This is thought to be due predominantly to platelet sparing. It is doubtful
whether Trasylol would have any advantage in management of obstetric DIC.
Disseminated intravascular coagulation 633
Obstetricians appear unconvinced of the bene®ts of Trasylol in the treatment of DIC
and abruptio placentae. Prompt supportive measures alone, maintaining central
venous pressure and replacing blood loss together with essential coagulation factors,
will of course result in reduction in FDPs. This will improve myometrial function and
contribute to the return of healthy haemostasis.
A report on reducing the frequency of severe abruption from Dallas, Texas37 noted
that the reduction in fetal death associated with abruption by 50% over a period
covering more than 30 years (1958±90) could be accounted for by the decrease in
women of very high parity and to an increase in the proportion of Latin-American as
opposed to black women in the population served. Abruption in the latter part of the
study recurred in 12% of subsequent pregnancies and proved fatal to the fetus in 7%,
which was unchanged from earlier experience. With modern supportive measures,
maternal death due directly to abruption is now extremely rare.
Placenta accreta
The morbid adherence of the placenta to the uterus results from the invasion of
placental villi into the myometrium without underlying decidua and is described as
accreta, increta or pancreta, depending on the extent of the penetration.
It usually presents in the early post-partum period with massive haemorrhage
during dicult removal of the placenta. It is associated with placenta praevia and with
uterine scar from a previous Caesarean section38 but can occur in a normally sited
placenta without any previous scar.
The preferred management of this condition in the presence of severe haemorrhage
is hysterectomy, but arterial embolization is being used increasingly with preservation
of the uterus22,23 (see Chapter 5). A recent report of controlling haemorrhage by
subendometrial vasopressin infusion during Caesarean section in six women from one
centre, thus avoiding hysterectomy, deserves further investigation.39
As the incidence of Caesarean section rises world wide this complication of
pregnancy is likely to increase, and in many centres placenta accreta is becoming the
main cause of massive intractable haemorrhage at delivery, leading to hysterectomy.40
In one centre, a review of emergency hysterectomy in obstetric practice showed a
reduction over the decade 1985 to 1994 but a changing pattern in the primary cause. In
the ®rst 5 years it was uterine atony (42%) followed by placenta accreta (25.5%).
However in the second period, 1990±94, the predominant indication was placenta
accreta (41.7%) followed by uterine atony (29.2%).41
In spite of every precaution and prompt management, placenta accreta remains a
potent cause of the rare maternal mortality in the developed world.41,42 It is also, in
my experience, a relatively common cause of DIC resulting from shock due to massive
haemorrhage before hysterectomy is undertaken.
Amniotic ¯uid embolism7,43,44
This obstetric disaster usually occurs during or shortly after a vigorous labour with an
intact amniotic sac, but can occur during a Caesarean section. It is thought that amniotic
¯uid enters the maternal circulation via lacerations of membranes and placenta. Platelet
®brin thrombi are formed and trapped within the pulmonary blood vessels: profound
shock follows, accompanied by respiratory distress and cyanosis. There is a high
mortality at this stage from a combination of respiratory and cardiac failure.45 If the
mother survives long enough, massive intravascular coagulation with almost total
634 E. A. Letsky
consumption of coagulation factors invariably follows. There is bleeding from
venepuncture sites and severe haemorrhage from the placental site after delivery.
Con®rmation of diagnosis is usually made post-mortem by ®nding histological evidence of
amniotic ¯uid and fetal tissue within the substance of the maternal lungs; occasionally,
similar material may be aspirated from a central venous pressure (CVP) catheter line ±
see below. It is, therefore, dicult to assess the value of therapeutic measures taken, in
the few reports which have appeared, for the successful management of a clinical picture
which can usually only be suggestive of amniotic ¯uid embolism.46±50 A signi®cantly
reduced maternal mortality rate was reported in a population-based study in California
where the clinical diagnosis of amniotic ¯uid embolism in survivors was included.49
The major di€erential diagnoses of amniotic ¯uid embolism in the collapsed patient
are primary cardiovascular catastrophes such as pulmonary embolus or aspiration in
the anaesthetized patient. Apart from the bleeding and evidence of DIC associated
with amniotic ¯uid embolism, pulmonary embolus has speci®c features. Aspiration is
usually associated with bronchospasm which is very rare in amniotic ¯uid embolus.43
At any time, if there is doubt about the diagnosis, the rapid ¯uid infusion necessary for
the treatment of amniotic ¯uid embolus should be controlled by careful assessment of
the CVP. Such rapid ¯uid infusion would cause a marked rise in CVP in patients with
pulmonary embolus, and could well lead to fatal ¯uid overload. In addition, the
presence of the CVP line will allow aspiration of fetal material from the great veins,
supportive of the diagnosis of amniotic ¯uid embolus.50 Such material can also be found
in maternal sputum.51 Since fetal material has been found in pulmonary arterial blood
in some women who did not have amniotic ¯uid embolus.52 such a ®nding should not
be considered pathognomonic for amniotic ¯uid embolus.
The object of the treatment is to sustain the circulation while the intravascular
thrombin in the lungs is cleared by the ®brinolytic response of the endothelium of the
pulmonary vessels. If bleeding from the placental site can be controlled by stimulation
of uterine contraction, then the logical treatment is carefully monitored transfusion of
FFP and packed red cells with heparin administration and, if necessary, ventilation.
Retention of the dead fetus
The question of intrauterine fetal death and haemostatic failure has been reviewed in
the past.53 There is a gradual depletion of maternal coagulation factors following
intrauterine fetal death, and the changes are not usually detectable in vitro until after
3±4 weeks.
Thromboplastic substances released from the dead tissues in the uterus into the
maternal circulation are thought to be the trigger of DIC in this situation, which occurs
in about one-third of patients who retain the dead fetus for more than 4±5 weeks.
Problems arising from defective haemostasis are not observed in modern obstetric
practice because labour is induced promptly following diagnosis of fetal death before
clinically signi®cant coagulation changes have developed.
Rupture of the membranes is recommended once induced labour is established in
such patients, as there is a risk of precipitate labour and amniotic ¯uid embolism has
been known to occur.
Retained dead fetus and living twin
The occurrence of single fetal death in a pre-term multiple pregnancy poses unique
therapeutic dilemmas. The incidence of this problem is unknown but is likely to be
Disseminated intravascular coagulation 635
observed more frequently with the advent of widespread use of ultrasound in
obstetrics. In addition, on occasion, selective termination of the life of the a€ected twin
is being o€ered in situations where only one fetus has been shown to be a€ected with
a genetic disorder or involved in twin/twin transfusion syndrome. Haemostatic failure
appears to be a hazard for the remaining fetus rather than for the mother.
Induced abortion
Changes in haemostatic components consistent with DIC have been demonstrated in
patients undergoing abortion induced with hypertonic solutions of saline and urea.54±57
This combination appears to be particularly hazardous58 in comparison to the use of
urea and prostaglandin or oxytocin.59 The stimulus appears to be the release of tissue
factor into the maternal circulation from the placenta, which is damaged by the
hypertonic solutions.
In later pregnancy DIC has been described with both dilatation and evacuation60 and
also with prostaglandin and oxytocin termination.61 The haemorrhage resulting may
be massive and has resulted in maternal deaths. Prompt restoration of the blood
volume and transfusions with red cells and FFP, as described above, should resolve the
situation which, once the uterus is empty, is self-limiting. A unique case of DIC
associated with chronic ectopic pregnancy has been reported.62
Intrauterine infection63
Endotoxic shock associated with septic abortion and ante-partum or post-partum
intrauterine infection can trigger DIC.64,65 Infection is usually with Gram-negative
organisms. Fibrin is deposited in the microvasculature owing to endothelial damage by
the endotoxin, and secondary red cell intravascular haemolysis with characteristic
fragmentation, so-called micro-angiopathic haemolysis, is characteristic of the condition.
The patient is usually alert and ¯ushed with a rapid pulse and low blood pressure.
Transfusion has little or no e€ect on the hypotension in comparison to its bene®t in
the obstetric emergencies complicated by DIC triggered by hypovolaemic shock.
Elimination of the uterine infection remains the most important aspect of management; this is probably best performed by a short intensive period of antibiotic therapy
followed by evacuation of the uterine contents. If the uterus is empty and contracted,
there is no undue risk of severe bleeding from the placental site. If there is evidence of
a consumptive coagulopathy, heparin may be useful as part of the management of this
hazardous emergency63,66,67 but this remains controversial.
In recent years this complication of pregnancy is rarely seen. If not recognized and
treated promptly it is associated with a very high mortality rate.
Purpura fulminans
This rare complication of infection sometimes occurs in the puerperium, precipitated
by Gram-negative septicaemia. Extensive haemorrhage occurs into the skin in
association with DIC. The underlying mechanism is unknown but there appears to be
an acute activation of the clotting system resulting in the deposition of ®brin thrombi
within blood vessels of the skin and other organs.68 The extremities and face are
usually involved ®rst, the purpuric patches having a jagged and erythematous border,
which can be shown histologically to be the site of a leukocytoclastic vasculitis. Rapid
enlargement of the lesions which become necrotic and gangrenous is associated with
636 E. A. Letsky
shock, tachycardia and fever. Without treatment the mortality rate is high, and among
those who survive, digit or limb amputation may be necessary. The laboratory ®ndings
are those of DIC with leukocytosis. In this situation treatment with heparin should be
started as soon as the diagnosis is apparent. It will prevent further consumption of
platelets and coagulation factors. It should always be remembered, however, that
bleeding from any site in the presence of defective coagulation factors will be
aggravated by the use of heparin. Survival in purpura fulminans is currently much
improved because of better supportive treatment for the shocked patient and e€ective
control of the triggering infection, together with heparin therapy.
Low-grade DIC, pre-eclampsia and related syndromes
Rampant uncompensated DIC results in severe haemorrhage with the characteristic
laboratory ®ndings described above. However, low-grade DIC does not usually give
rise to any clinical manifestations, although the condition is a potentially hazardous one
for both mother and fetus (Table 1).
In vitro detection of low-grade DIC
Many in vitro tests have been claimed to detect low-grade compensated DIC, and
space does not allow an account of all of these.
FDPs. Estimation of FDPs will give some indication of low-grade DIC if these are
signi®cantly raised when ®brinogen, platelets and screening tests of haemostatic
function appear to be within the normal range.
Soluble ®brin complexes. The action of thrombin on ®brinogen is crucial in DIC.
Thrombin splits two molecules of ®brinopeptide A and two molecules of ®brinopeptide
B from ®brinogen. The remaining molecule is called a ®brin monomer and polymerizes
rapidly to ®brin (Figure 5). Free ®brinopeptides in the blood are a speci®c measure of
thrombin activity and high levels of ®brinopeptide A have been shown to be associated
with compensated DIC in pregnancy.6
Soluble ®brin complexes made up of ®brin±®brinogen dimers are increased in
conditions of low-grade DIC.69 These complexes are generated during the process of
thrombin generation and the conversion of soluble ®brinogen to insoluble ®brin
(Figure 5). Levels of soluble ®brin complexes are increased in patients with severe preeclampsia and with a retained dead fetus.9,70
Factor VIII. During normal pregnancy the levels of both von Willebrand factor (vWF)
and Factor VIII coagulation activity (VIIIC) rise in parallel.71,72 An increase in the ratio
of vWF to Factor VIIIC has been observed in conditions accompanied by low-grade
DIC, whether associated with pregnancy or not.
The stages in the spectrum of severity of DIC (see Table 1) are not strictly delineated,
and there may be rapid progression from low-grade compensated DIC, as diagnosed by
paracoagulation tests described above, to the rampant form with haemostatic failure.
Many investigators now believe that gestational hypertension with or without
proteinuria, intrauterine growth retardation (IUGR), haemolysis, elevated liver
enzymes and low platelets (HELLP) syndrome, acute fatty liver of pregnancy (AFLP)
and eclampsia are part of the same disease process73 which presents with the related
Disseminated intravascular coagulation 637
Prothrombin (II)
(IIa) Thrombin
Fibrin monomers + fibrinopeptides
XIIIa Fibrin polymers
Figure 5. The ®nal common pathway of the coagulation cascade: conversion of ®brinogen to ®brin induced
by thrombin.
signs and symptoms depending on the organ targeted by small-vessel coagulopathy and
varying degrees of DIC.
Haemostatic changes in pre-eclampsia (Table 2)
There have been many reports and reviews showing that the circulating platelet count is
reduced in pre-eclampsia.74,75 The platelet count can be used to monitor severity of the
disease process as well as an initial screening if there is concern about signi®cant
coagulation abnormalities.76 A fall in the platelet count may precede any detectable rise
in serum FDPs in women subsequently developing pre-eclampsia. The combination of a
reduced platelet life span and a fall in the platelet count without platelet-associated
antibodies (see below) indicates a low-grade coagulopathy. Platelets may either be
consumed in thrombus formation or may su€er membrane damage from contact with
abnormal surfaces and be prematurely removed from the circulation. Rarely, in very
severe pre-eclampsia, the patient develops micro-angiopathic haemolytic anaemia.
These patients have profound thrombocytopenia and this leads to confusion in the
di€erential diagnosis between pre-eclampsia, haemolysis, elevated liver enzymes, low
platelet count syndrome (HELLP)77 and thrombotic thrombocytopenic purpura (TTP)
(see below).
Activation of the haemostatic mechanisms in normal pregnancy has led to the view
that the haematologic manifestations of pre-eclampsia merely represent augmentation
of the hypercoagulable state which accompanies normal pregnancy. In this respect
many studies have been carried out on levels of individual coagulation factors. No clear
Table 2. Haemostatic changes in pre-eclampsia.
Increased ratio von Willebrand factor (VWF)/factor VIIIC
Decreased prostacyclin generation
Decreased plasma antithrombin (AT) concentration
Increased soluble ®brinogen products ± particularly ®brinopeptide A
Decreasing platelet counta
Increased serum ®brin degradation productsa
Most useful markers of severity and outcome.
638 E. A. Letsky
Non-Pregnant State
At Delivery
Rapid blood loss leads to
vasoconstriction to
compensate for drop in
blood volume.
Plasma volume increase
over next few days.
Hypervolaemia modifies
response. Remain
vasodilated even if loss
Fall in plasma volume due
to diuresis in puerperium.
Fall in haematocrit
proportionate to blood
Haematocrit gradually
increases as blood
volume returns to normal.
Figure 6. The unique maternal response to acute blood loss at parturition.
pattern emerges but there appear to be some signi®cant correlations of severity of the
disease process with both the Factor VIII complex.78 and antithrombin (AT).79
A readily available and sensitive indicator of activation of the coagulation system is
assay of ®brinopeptide A concentration in the plasma. Although in mild pre-eclampsia
patients may have a normal or only slight increase in ®brinopeptide A levels, marked
increases occur in patients with severe pre-eclampsia6 (Figure 5).
Most studies in pre-eclampsia have shown increased levels of FDPs in serum and
urine. Plasma levels of soluble ®brinogen±®brin complexes are also raised in preeclampsia compared with normal pregnancies. Once the disease process is established
the most relevant coagulation abnormalities appear to be the platelet count, Factor
VIII and FDPs. Those women with the most marked abnormalities in these parameters
su€er the greatest perinatal loss.80 In reality, most units use serial platelet counts to
monitor the activity of disease. It has been shown that coagulation abnormalities do
not occur unless the platelet count falls below 100 109/l.76
Following the reported association between thrombophilia factors, severe preeclampsia and intrauterine growth retardation (IUGR)81 it has been suggested that
investigation of pre-eclampsia should also include a search for defects in the naturally
occurring anticoagulants so that future pregnancies can be managed appropriately.
Acute fatty liver of pregnancy (AFLP)
AFLP is a rare complication of pregnancy included in this section because it is often, if
not always, associated with variable degrees of DIC ± which contributes signi®cantly to
its morbidity and mortality.33,82 Only the haematological aspects will be discussed here.
Early diagnosis and subsequent delivery are essential for improving survival of both
mother and child. Most patients have prodromal symptoms for at least 1 week before
jaundice develops. The Royal Free series83 draws attention to a characteristic blood
picture of neutrophilia, thrombocytopenia and normoblasts. Some of the blood ®lms
available for review also showed basophilic stippling and giant platelets and the authors
suggest that these appearances might help towards an early diagnosis of AFLP.
However, these features are not speci®c to AFLP and may be seen in any condition of
additional stress on a bone marrow already working to capacity in the last trimester of
DIC complicating severe liver failure is an extremely complex topic. In AFLP the
haemostatic defect is frequently resistant, probably owing to prolonged activation of
coagulation combined with very low to undetectable AT levels.33,84,85 The replacement
Disseminated intravascular coagulation 639
of AT with plasma or AT concentrate to shorten the period of DIC, and thereby
decrease morbidity and mortality of AFLP, has been suggested.33 AT concentrate has
also been used in the successful management of a patient with AFLP.85 Heparin
therapy can be very dangerous.86
Thrombotic thrombocytopenic purpura (TTP) and haemolytic-uraemic syndrome (HUS)
These conditions, extremely rare in pregnancy, share so many features that they have
been considered as one disease in the past, with pathological e€ects con®ned largely to
the kidney in HUS and being more generalized in TTP. Both are due to the presence
of platelet thrombi in the microcirculation that cause ischaemic dysfunction and microangiopathic haemolysis. They are included here because they can be confused with
severe pre-eclampsia.
Unlike severe pre-eclampsia, HELLP and AFLP, there is no evidence that prompt
delivery a€ects the course of HUS or TTP favourably. However, most clinicians would
recommend delivery if these conditions are present in late pregnancy so that the
mother can be treated vigorously without fear of harming the fetus. Therapeutic
strategies hinge on intensive plasma exchange or replacement. It is essential that the
correct diagnosis is made to obtain optimal outcome.
The pentad of fever, normal coagulation tests with low platelets, haemolytic
anaemia, neurological disorders and renal dysfunction are virtually pathogonomic of
TTP. The thrombocytopenia may range from 30 to 100 109/l. The clinical picture is
severe, with a high maternal mortality. A crucial problem when dealing with TTP is to
establish a correct diagnosis, because this condition can be confused with severe preeclampsia and HELLP syndrome, especially if DIC (very uncommon in TTP) is
triggered. All of these conditions are associated with thrombocytopenia and a
characteristic macroangiopathic blood ®lm with red cell fragments and burr cells.
TTP is associated with abnormal patterns of multimers of von Willebrand (vWF)
factor in the plasma. A proteolytic enzyme present in normal plasma cleaves peptide
bonds in monomeric subunits of von Willebrand factor, thus degrading the large multimers. This proteolytic enzyme prevents the unusually large multimers from causing
vWF-mediated adhesion of platelets to sub-endothelium after vascular damage.87
Exciting new research by two groups of investigators has elucidated the role of
vWF-cleaving protease activity in TTP. In all the patients studied with acute single
episode TTP there was little or no vWF-cleaving protease activity associated with an
IgG auto-antibody during the illness but the activity returned to normal following
recovery.88 In patients with chronic relapsing TTP unusually large multimers of vWF
are found in the plasma, even between acute episodes, together with absence or low
levels of vWF-cleaving protease activity.89 What are the implications of these new
. The diagnosis of TTP which has been confused with severe pre-eclampsia and HELLP
syndrome may be facilitated by a single laboratory test measuring the vWF-cleaving
protease activity in the plasma and its inhibitor.
. This test will also help clinicians to distinguish between TTP and HUS, thought in the
past to be a spectrum of clinical expressions of the same disease. In HUS the levels of
vWF-cleaving protease are normal or approaching normal, and this also explains why
plasma exchange has disappointing results in HUS.
. The response of patients in the past to fresh frozen plasma component infusions
which contain the vWF cleaving protease activity is explained.
640 E. A. Letsky
. The fact that plasmapheresis is often required in the acute phase to achieve a response
is also clari®ed as this will remove auto-antibodies as well as the abnormal large vWF
In summary, objective diagnosis of TTP should now be facilitated by measurement of
vWF-cleaving protease and its inhibitor. The basis of treatment depends on supplying
the defective missing enzyme by infusion of plasma or cryosupernatant, preferably in
severe cases, by exchange transfusion. Virally inactivated plasma products retain vWFcleaving protease activity, ensuring the safety of this treatment.
As emphasized, DIC is always a secondary phenomenon, and the mainstay of
management is therefore to remove the initiating stimulus if possible.90 Low-grade
DIC may be con®rmed by ®nding increased FDPs and ®brin monomer complexes with a
falling platelet count in the presence of normal coagulation screening tests. With
rampant DIC and haemorrhage, increased thrombin time and a low ®brinogen level will
con®rm the coagulopathy and help to monitor the success of treatment measures.
Recovery will usually follow delivery of the patient provided the blood volume is
maintained and shock due to hypovolaemia is prevented. An eciently acting
Practice points
. to recognize the mother who has excessive blood loss peripartum in the early
stages so that appropriate replacement therapy will be given promptly in order to
prevent the development of DIC which is not present initially in the majority of
cases of abnormal obstetric haemorrhage
. to recognize low-grade DIC, particularly in pre-eclampsia and related syndromes,
by appropriate monitoring, and to take measures to deal with the trigger
. the management of DIC depends on dealing with the trigger and has to be
modi®ed depending on the speci®c problem
. the therapy of fulminant DIC with haemostatic failure should be automatic with a
frequently rehearsed protocol. Replacement therapy with crystalloids, colloids
and blood components is the same for massive obstetric haemorrhage, whether
or not there is coagulation failure initially
. for chronic low-grade DIC, rising FDPs and falling platelets are probably the best
rapidly available investigations. Serum ®brin monocomplexes and ®brinopeptides
may give additional supportive information. Examination of a blood ®lm may
reveal large platelets, indicating increased turnover and, less frequently, microangiopathic red cell changes
. for fulminant DIC, an FBC with platelets, a coagulation screen with particular
emphasis on the thrombin time and the ®brinogen concentration will identify
coagulation failure. Blood can be taken for FDPs but should be measured after the
emergency is over
Disseminated intravascular coagulation 641
Research agenda
. the evaluation of the measurement of thrombomodulin for the diagnosis of
placenta abruptio28
. the value of sub-endometrial vasopressin infusion during Caesarean section to
control intractable placental haemorrhage39
. regular audit of management of massive obstetric haemorrhage in every centre
with exchange of information because this problem does not lend itself to
randomized controlled trials
myometrium post-delivery will stem haemorrhage from the placental site. Measures
taken to achieve a ®rm contracted uterus will obviously contribute one of the most
important factors in preventing continuing massive blood loss. Supportive measures
must include urgent restoration of blood volume with a plasma substitute followed
rapidly by blood component therapy to replace blood loss and correct the coagulopathy.
Each obstetric unit must have frequent rehearsals and an established protocol for this
It is of interest that the maternal mortality of DIC associated with placental
abruption is less than 1%, whereas that associated with infection and shock is 50±80%.
The mortality rate reported in series of patients with DIC due to various aetiologies is
50±85% and the wide variation probably re¯ects the mortality rate of the underlying
disorder, not of DIC per se.33 There is no doubt that the major determinant of
survival is our ability to identify the underlying trigger and manage it successfully.
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