REVIEW (Derleme)

DISSEMINATED INTRAVASCULAR COAGULATION IN OBSTETRICS:

ETIOPATHOGENESIS AND UP TO DATE MANAGEMENT STRATEGIES

Sadik SAHIN1, Mustafa EROGLU1, Sermin TETIK2, Kadir GUZIN3

1 Department of Obstetrics and Gynecology, Zeynep Kamil Gynecologic and Pediatric Training and Research Hospital, Istanbul
2 Department of Biochemistry, Marmara University, Faculty of Phparmacy, Istanbul
3 Department of Obstetrics and Gynecology, Medeniyet University, Göztepe Education and Research Hospital, Istanbul

SUMMARY

Disseminated intravascular coagulation related to obstetric conditions is rarely seen but is associated with high
morbidity and mortality. Recently, pathophysiology of disseminated intravascular coagulation has not been understood
well and, therefore, effective and permanent treatment strategies are missing. In this review, we try to discuss the
etiology, current diagnostic approaches and management strategies of disseminated intravascular coagulation from
the perspectives of clinicians.

Key words: disseminated intravascular coagulation, morbidity and mortality, pregnancy

Journal of Turkish Society of Obstetrics and Gynecology, (J Turk Soc Obstet Gynecol), 2014; Vol: 11, Issue: 1, Pages: 42-51

OBSTETR‹DE YAYGIN DAMAR ‹Ç‹ KOAGÜLASYON:

ETYOPATOGENEZ VE GÜNCEL TEDAV‹ STRATEJ‹LER‹

ÖZET

Obstetrik nedenlere ba¤l› olarak geliflen yayg›n damar içi koagülasyon, nadir görülmesine ra¤men morbidite ve
mortalitesi oldukça yüksek seyreden klinik bir durumdur. Günümüzde yayg›n damar içi koagülasyonun patofizyolojisi
tam olarak ayd›nlat›lamam›fl olup, bu nedenle etkili ve kal›c› tedavi yöntemleri henüz gelifltirilememifltir. Bu derlemede,
klinisyenin bak›fl aç›s›yla obstetrik pratikte karfl›m›za ç›kan yayg›n damar içi koagülasyon de¤erlendirilmifl ve güncel
literatür bilgisi ›fl›¤›nda yayg›n damar içi koagülasyonun etyopatogenezi, tan›sal yaklafl›mlar› ve tedavi alternatifleri
tart›fl›lm›flt›r.

Anahtar kelimeler: gebelik, morbidite ve mortalite, yayg›n damar içi koagülasyon

Türk Jinekoloji ve Obstetrik Derne¤i Dergisi, (J Turk Soc Obstet Gynecol), 2014; Cilt: 11, Say›: 1, Sayfa: 42-51

INTRODUCTION pregnancy related conditon leading to bleeding with

high mortality and mobidity rates is dissemniated
At present time, obstetrical bleedings remain to be the intravascular coagulation (DIC).
worldwide's main cause of maternal mortality and early Dissemniated intravascular coagulation was first described
identification of factors leading to hemorrhage and rapid by Joseph DeLee in 1901 as a fatal hemorrhagic diathesis
management of the underlying pathological process is following placental abruption (2). The underlying
the key stone of the treatment(1). The most important pathophysiology in DIC is systemic activation of the

Address for Correspondence: Dr. Sad›k fiahin. Opr. Dr. Burhanettin Üstünel cad. no: 10, Üsküdar, ‹stanbul
Phone: +90 (532) 518 15 95
e-mail: [email protected]
Received: 12 May 2013, revised: 27 July 2013, accepted: 28 July 2013, online publication: 31 July 2013

DOI ID:10.5505/tjod.2014.93196 42
 Disseminated intravascular coagulation in obstetrics

coagulation cascade leading to extensive fibrin deposition Figure 1: The reasons of Disseminated Intravascular Coagulation

and subsequent microvascular thrombosis. Furthermore, (DIC).

patients exhibit a tendency for severe bleeding associated

DIC
with the consumption of platelets and coagulation
factors(3,4). Clinically, DIC may lead to a wide range of
Obstetric causes Non-obstetric causes
pictures from unnoticed intravascular thrombosis and
Amniotic fluid embolism Sepsis
microvascular damage to uncontrollable bleeding. DIC Abruptio placenta Trauma
always evolves secondary to predisposing clinical Placenta previa and accreta Organ damage
condition(5). The real incidence of obstetrical DIC is Postpartum bleeding Leukemia
HELLP syndrome Vascular aneurysm
unknown since it represents a wide spectrum ranging
Preeclampsia/eclampsia Acute liver failure
from mild to severe. Various studies done showed that Septic abortion/intrauterine infection Toxic and immunological causes
the incidence of DIC in all pregnancies was 0.02-0.07 Acute fatty liver of pregnancy Narcotic drugs
%(6,7). Maternal mortality associated with DIC vary from ABO incompatibility
Transplant rejection
6 to 24% and postpartum hysterectomy, massive blood
transfusions and acute tubular necrosis are listed as the
main maternal morbidity indicators(7,8). Therefore, early
detection of these predictors of DIC and timely intervention In pre-eclampsia, the maternal inflammatory response
of this life-threatening condition is very important. formed against trophoblasts results in a systemic
endothelial dysfunction. Thus, vasodilator prostaglandins
decrease and thrombocyte aggregation and uteroplacental
CONDITIONS LEADING TO DISSEMINATED ischemia increases(15,16).
INTRAVASCULAR COAGULATION HELLP syndrome, is a syndrome characterized by
endothelial cell damage in the liver(17). It is believed
Obstetrical and non-obstetrical etiologies leading to DIC that substances originating in the placenta cause an acute
are listed in Figure 1. In a study reported by Darrien et inflammatory state in the hepatic endothelial cells(18).
al, the identified causes of obstetrical DIC were listed This inflammatory cascade is reported to be different
as placental abruption (%37), postpartum bleeding then the inflammatory mediators involved in the process
(%29), severe pre-eclampsia/HELLP syndrome leading to the DIC picture(19).
(Hemolysis, Elevated Liver Enzymes, Low Platelet Septic abortion causes DIC by triggering the release of
Count) (%14), acute fatty liver of pregnancy (%8), sepsis inflammatory substances which are eventually disrupting
(%6) and amniotic fluid embolism (%6)(8). Intrauterine the coagulation mechanism. Studies done showed that
fetal loss is also reported as a cause of DIC(9). endothelial dysfunction plays a key role in the
Placental abruption, is a pathology charaterized by pathophysiology of septic abortion(20).
rupture of the maternal decidual artery resulting in Amniotic fluid embolism, is a clinical condition that
hemorrhage into the deciudal-placental interface(10). could be observed during the delivery and postpartum
Although, the underlying pathophysiology is not fully upto 48hrs. It has been reported that 70% of the cases
understood, placental insufficiency and uteroplacental occurred pre-partum(21-24). Clinically, it's characterized
hypoperfusion are postulated to be the cause(11). It has as hypotension, cardiac arrhythmia, cyanosis, dyspnea,
also been shown that pro-inflammatory cytokines cause altered mental status and bleeding. Clark et al estimated
premature seperation of of the placenta(12). Studies the maternal mortality rate attributed to amniotic fluid
reported showed a positive relationship between the emboli as 61%(22). Recenly published studies, reported
degree of placental seperation and fibrin deposition as various rates ranging 6 - 44%(25,26).
well as thrombocytopenia suggesting that the coagulation Acute fatty liver is mostly reported in the third trimester
process initially starts in the placental bed (13) . and has a fulminant course. Studies done identified genetic
Similar to trauma patient, in postpartum bleeding, the deficiencies in the beta oxidation of fatty acids played a
severe amount of blood loss and subsequent role in the pathogenesis of acute fatty liver(27). Severe
consumption of coagulation factors is held responsible hepatic dysfunction and Anti-Thrombin III deficiency
for the development of DIC(14). are hypothesized to be involved in the course of DIC(28,29).

43 J Turk Soc Obstet Gynecol 2014;11:42-51

Sadik Sahin et al.

PATHOPHYSIOLOGY Physiological changes in the coagulation mechanisms

during pregnancy
Disseminated intravascular coagulation is a systemic During the pregnancy substantial changes take place
thrombohemorrhagic disorder developing secondary to in the hemostasis mechanism. Significant rise in the
certain clinical conditions. In order to understand the majority of the coagulation factors, and decrease in
changes it is essential to have a fund knowledge of the the level of natural anticoagulants and fibrinolytic
normal coagulation mechanisms. The coagulation activity are the most important physiological changes
cascade is demonstrated in Figure 2. The coagulant notable through pregnancy. These alterations lead to
response is initiated with the formation of Tissue Factor a state of hypercoagulability and an increased risk of
(TF) and subsequent binding to Factor VIIa. As a result, thrombembolism. Following the delivery, the period
Factor X is activated and thus prothrombin is converted of time when the placenta is being retrieved has the
to thrombin (Factor IIa)(30). Thrombin, plays a central highest level of thrombotic activity due to release of
role in coagulant, anticoagulant fibrinolytic, thromboplastic substances. Fibrinogen levels double
antifibrinolytic and antifibrinolytic mechanisms(31). during the pregnancy compared to prior to the
pregnancy. Also, D-Dimer levels rise during the
Figure 2: tPA: tissue plasminogen activator. pregnancy(32-34).
In response to activation of cytokines, release of pro-
Factor VIIa Factor XIIa
coagulant factors or exposure to pro-coagulant factors,
+
Tissue factor all predisposing factors leading to DIC initiate the
activation of the coagulation cascade as part of the
(-) systemic inflammatory response (35) . The DIC
Fibrinogen Factor Xa Activated pathogenesis is a complex mechanism in which the
Protein C
invivo increased thrombin production plays a central
role. Increased tissue factor production, anticoagulation
THROMBIN system dysfunction, insufficient fibrinolysis and
increased anionic phospholipid concentration leads to
development of DIC(36). The pathophysiology of DIC
is demonstrated in Figure 3.
Fibrin Thrombin activated tPA Protein C
fibrinolysis Figure 3: The Pathophysiology of Disseminated Intravascular
inhibitor
Coagulation (DIC).
Fibrin
(-) degradation
products

The coagulant response is initiated with the formation of Tissue Factor (TF) DIC
and subsequent binding to Factor VIIa. As a result, Factor X is activated and RELATED
CAUSE
thus Prothrombin is converted to Thrombin (Factor IIa).
ACTIVATION
Besides being a a procoagulant converting fribrinogen to fibrin, thrombin
COAGULATION
also controls anticoagulation by activating protein C. Fibrinolysis, is CASCADE
degradation of fibrin to fibrin split products via tissue plasminogen acticator

(tPA) activated by thrombin.

Thrombin also regulates fibronolysis by activating the active fibrinolysis

inhibitor (TAFIa).
Intravascular fibrin Consumption of coagulation
Therefore, thrombin plays a cental role in coagulant, anti-coagulant, fibrinolytic
deposition factors and platelets
and anti-fibrinolytic mechanisms. Shows negative inhibition. bleeding

(Reference #65 is used in to build this figure). Deficiencies of coagulation

Microvascular thrombosis
factors and platelets

ORGAN FAILURE BLEEDING

J Turk Soc Obstet Gynecol 2014;11:42-51 44

 Disseminated intravascular coagulation in obstetrics

CLINICAL FINDINGS the hemostatic state provide information about the

clinical course. Prothrombin time (PT), activated partial
Disseminated intravascular coagulation is an aquired thromboplastin (aPTT) and thrombocyte count reflect
thromboembolic disease where the clinical findings the consumption and activation of thrombocytes(40).
usually depend on the underlying pathology. In the The laboratory finding showing fibrin production is
early stage (acute period), a massive thrombin made indirectly by measuring the fibrin degradation
production takes place as a result of exposure of blood product, D-Dimer(41). In a multicenter meta-analysis
to excessive amount of tissue factor. Subsequently the the most frequent encountered abnormal laboratory
coagulation cascade is triggered acutely(36). This findings in DIC were listed as thrombocytopenia,
condition can present itself with a clinical picture increased fibrin degradation products, prolonged PT,
varying from bleeding to thrombosis. End organ damage aPTT and low fibrinogen levels(42-46). In a study reported
at the microvascular level ensues as result of fibrin by Spero et al, thrombocytopenia was noted in 98% of
accumulation in the intravascular bed. The overall patients, while severe thrombocytopenia (<50 x 109/l)
conditon of patients' are often critical in disseminated was noted in 50% of patients(45). In another study, it
intrvascular coagulation along with parallellism between was postulated that low platelet counts could be an
the findings and severity of illness. Bleeding is usually indicator of increased thrombin production (47) .
the most frequent clinical finding. It manifests itself Thrombocyte aggregation related to thrombin is the the
usually as echymosis, petechia, mucosal oozing, main reason of thrombocyte consumption(48).
prolonged bleeding at vein pucnture sites, surgical Fibrin degradation products (FDPs) and D-Dimer are
incision sites and from various systems, especially the tests used in the diagnosis of DIC, however, a diagnosis
gastrointestinal system. Altered mental status, acute of DIC can not be established based only on an elevated
renal failure, hypoxia and hypovolemic shock may D-Dimer. Along with the rise in D-Dimer levels, a
occur as a result of blood loss(36,37). Although, rarely decrease in the thrombocyte counts and changes in the
seen, abdominal compartment syndrome may also be coagulation time have been accepeted as important
encountered in these patients. Abdominal compartment laboratory findings of DIC(49).
syndrome, is a condition in which tissue perfusion and A prolonged PT and aPTT is seen in 50-69% of
organ functions are adversely affected due to increased cases(50). This condition is related to the consumption
pressures in an enclosed anatomical space leading to of the coagulation factors. Since, a normal or even
dysruption of the circulation. It is a clinical picture shortened PT and aPTT level is seen in half of the
that presents itself as cardiovascular insufficiency, Disseminated Intravascular Coagulation cases, repeating
respiratory failure, renal dysfunction, increased intra- these test in the follow-up of these patients is highly
abdominal pressure and abdominal distension and important(51).
improves with prompt surgical decompression(38). Although, fibrinogen is a frequently used test in the
diagnosis of DIC, it is considered as a less specific
test(52). Fibrinogen is an acute phase reactant and
DIAGNOSIS plasma levels, therefore, may run for a long period of
time within normal limits independent of the
There is no single laboratory test to diagnose DIC. The consumption of coagulation factors. In a study, the
diagnosis is established based on clinical suspicion specificity of low fibrinogen levels in the diagnosis of
and supportive laboratory tests. The tests used include DIC was reported as 28% and hypofibrinogenemia
laboratory parameters indicative of procoagulant and was noted only in severe DIC cases (53). In another
fibrinolytic substance activation, inhibitor consumption study, 57% of DIC cases were noted to have normal
and organ damage or failure(36,39). fibrinogen levels(45). Therefore, measurement of serial
Disseminated intravascular coagulation is a dynamic fibrinogen levels in these patients is essential as it
process and the tests conducted reflect only the conditions provides us diagnostic clues.
at any given moment in time. In clinical circumstances In contrast to classical DIC cases, during pregnancy,
associated with this condition repeating these tests aids the reliability of tests used in the diagnosis of DIC is
in establishing the diagnosis. Tests used in assessing limited due to a rise in the serum levels of coagulation

45 J Turk Soc Obstet Gynecol 2014;11:42-51

Sadik Sahin et al.

factors(54). In pregnancy, PT and aPTT levels shorten these methods, the coagulation is activated by spinning
based on the increase in coagulation factors. During the blood in a pool. For example, a sensor placed
pregnancy, even if the consumption of coagulation inside, enables accurate measurements of the speed
factors associated with DIC leads to prolongation of and structural strength of clot formation.
PT and aPTT levels, they may still be within normal Thus, activation of the coagulation systems,
limits. For this reason, serial measurements are vital thrombocyte functions and analysis of fibrinolysis can
in the diagnosis of evolving DIC (55). Similarly, be achieved. In contrast to conventional coagulation
physiological thrombocytopenia associated with tests, in the TEG system, other than tracking the elapsed
pregnancy should be considered while diagnosing DIC. time for the clot formation, the quality of clot formed
In serial analyses, the decline in platelet counts provides is assessed as well. Therefore, the hemostatic system
information about the increase in thrombin formation is analyzed both quantitatively and qualitatively.
and the associated development of DIC(56). Levels of Thromboelastography is a frequently prefered
Fibrinogen, an acute phase reactant, rise in pregancy. diagnostic method test as it can be performed at bedside,
In a study analysing 535 patients with an overt diagnosis i.e., point of care testing (POC testing). Clinically, it's
of non-pregnancy associated DIC, only 46 patients especially used in cardiac surgery and liver
(8.6%) were noted to have a low fibrinogen level (less transplantations(60). TEG, aids in rapid diagnosis of
than 1gm/L)(52). Considering the double fold increase DIC suspected cased, providing an opportunitty to
in baseline fibrinogen levels during pregnancy, it is address the dysfunction in the coagulation systems(61).
not surprising to encounter fibrinogen levels which are
within normal limits in patients with a suspicion of Scoring used in Disseminated Intravascular Coagulation
DIC(57). Furthermore, Fibrinogen levels are used as There is no single test to diagnose DIC. The
an indicator of the severity of portpartum bleeding(58). International Society of Thrombosis ve Hemostasis
Since, D-Dimer levels are already elevated in (ISTH) developed a scoring system for the diagnosis
pregnancy, only a significant rise in serial measurements of DIC thus easing the diagnosis and management(62).
may aid in the diagnosis of DIC(59). As a result of the The flow chart of this scoring system (Figure 4) is only
above mentioned reason, the yield of diagnostic tools appropriate for patients with an underlying disorder
used in DIC shows a difference in DIC associated with that can be associated with DIC. The scoring is done
obstetrical causes comapred with classical DIC. based on the thrombocyte count, Fibrin split products,
In methods, such as the thromboelastography (TEG) D-Dimer, prolonged aPTT and fibrinogen levels. A
and rotational TEG (ROTEG), the path from the score of 5 and higher is considered as overt DIC. The
initiation of clot formation to fibrinolysis, including DIC scoring by ISTH can be used in cases both with
thrombocyte functions is considered as a whole(39). In and wihout underlying infectious(63). Bakhtiari et al

Figure 4: International Society of Thrombosis ve Hemostasis (ISTH) DIC Scoring System.

DIC RELATED CAUSE

YES NO

Order coagulation tests Do not use this algorithm

* Prothrombin time
* Platelet count
* Fibrinogen level
* Fibrin degradation products

Prothrombin time Platelet count Fibrinogen level Fibrin degradation products

< 3 sc......0 SCORE >100x109......0 SCORE >1 g/L......0 SCORE Not increase......0 SCORE
> 3 - < 6 sc......1 SCORE 50-100x109......1 SCORE < 1 g/L......1 SCORE Growth medium......2 SCORE
> 6 sc......2 SCORE <50x109......2 SCORE Significant increase......3 SCORE

TOTAL SCORE
≥5 Compatible with Overt DIC: Repeat score daily
<5 Suggestive for non-overt DIC: Repeat next 1-2 days

J Turk Soc Obstet Gynecol 2014;11:42-51 46

 Disseminated intravascular coagulation in obstetrics

reported the sensitivity of the ISTH DIC scoring system without any further surgical or radiological intervention
as 97% and specifity as 91%. The strong relationship in 46% of the cases. In the same study, no adverse
betwen the scoring system and mortality has been effects, including thromboembolic events related to
demonstrated in a few studies. For every 1 point increase the use fibrinogen concentrate were noted(69).
in the score, ghe mortality was noted to rise between
1/25 to 1/29(64). Management of the Massive Bleeding
Obstetrical bleedings are the most common reason of
maternal mortality. In a healthy female, there may be no
TREATMENT alterations in vital signs until 10-15% of the blood volume
has been lost. Tachycardia is the first finding of bleeding.
The main goal of the treatment in DIC is to correct 30% of the blood volume may have been lost by the time
the underlying obstetrical cause. Once the precipitating that severe hypotension is noted (70). Management of
cuase is addressed DIC usually resolves. Besides, postpartum bleeding warrants medical, mechanical and
supportive treatment should be implemented to correct surgical interventions requiring significant amount of
the coagulation disorder(36). The following section blood and blood products(71).
comprises this part of the clincial management. In obstetrical bleedings, the replacement of blood and
blood products should be similar to the approach to
Replacement of Blood and Blood products trauma patients(72). Management of massive obstetrical
The decision for replacement of blood products is given bleeding is summarized in Table I. The purpose of
after consideration of laboratory results and the clinical management of bleeding is to maintain the patient
condition all toghether. In general, platelet suspensions normotensive, normothermic and ensure adequate
are administered to patients with platelet counts less than replacement of clotting factors. First of all, two large
50 x 109 and actively bleeding. In patients without bleeding, bore peripheral IV lines should be placed. Initiation
platelet transfusion is limited to patient's with a platelet of crystalloid or colloid fluids remains a controversy
count with less than 30 x 109 dir(65). There is no indication because colloid solutions may affect coagulation(73).
to transfuse coagulation factors and plasma if there is no Rapid transfusion of volume expanders may lead to
active bleeding. However, if the active bleeding occurs dilution of coagulation factors. Therefore, blood
is in the setting of prolonged PT and aPTT, then Fresh replacement should be implemented as soon as possible.
Frozen Plasma (FFP) should be administered at a dose O Rh negative blood transfusion must be started
of 10-20 ml/kg(65).Higher doses may be administered emergently and typed & screened, cross matched blood
based on response noted during serial follow-up testing. should be prepared within maximum 45 minutes(65).
If FFP's are not feasible due to concerns of fluids overload,
non-activated prothrombin complex concentrate (PCC) Table I: Management of Massive obstetrical bleeding (Reference
may be administered at 25-30 U/kg dose(66). Since this #65 is used in to build this figure).
concentrate, contains only Vitamin K dependent factors
Erythrocyte suspensions
it will replace the deficit partially. As it may worsen the * Firstly, use O Rh (-) erythrocyte suspensions (ES)
severity of the dissesminated intravascular coagulation * Cross matched ABO and Rh compatible blood should be
activated PCC should not be used, instead only non- available within maximum of 45 min
* Maintain circulating blood volume with ES as needed
activated PCC should be used(67). * Avoid hypothermia (use blood warmers)
In congenital isolated fibrinogen deficiencies with Fresh frozen plasma
* Transfuse one unit of plasma to every one unit of ES
levels less then 1gm/L, cryoprecipitate or fibrinogen
* PT & APTT values should be less than 1.5 times normal
factor concentrates should be used. Since the fibrinogen Platelet transfusion
consumption may be faster , fibrinogen concentrates * Transfuse one to two adult doses of platelets to every 8-10
units of ES
should be administered for values above 1gm/L in
* Platelet count should be >50x109/l
DIC. 4 gm of fibrinogen concentrates, increase serum Fibrinogen
fibrinogen levels to 1gm/L(68). In a study done on 30 * Cryoprecipitate (dose = two donation pools)
* Fibrinogen concentrates (4 g)
patients with acquired hypofibrinogenemia, i.e. * Fibrinogen level should be >1g/l
(<1.5g/lt), it was shown that the bleeding stopped

47 J Turk Soc Obstet Gynecol 2014;11:42-51

Sadik Sahin et al.

A study done by Hishberg et al showed that dilutional another prospective study, the use of rFVIIa in patients
coagulopathy could be inevitable with more than 5units with postpartum bleeding was shown to prevent from
of blood tranfusion(74). In another study done, use of postpartum hysterectomy by 91%(83).
1:1 packed red blood cells and FFPs was demonstrated However, yet there are questions regarding the use of
to decrease the mortality(75,76). In another study, it was rFVIIa which need to be answered. First of all, the dose
reported that prophylactic administration of to be used in massive obstetric bleedings has not been
thrombocytes decreased the need for other blood standardized, yet. Various groups used doses ranging
products in massive bleedings. Therefore, the need for from 15 mcg/kg to 120mcg/kg(65). Secondarily, in cases
1-2 adult dosing thrombocyte replacement for every with platelet counts above 100x109 and less severe
8-10 units of blood is emphasized(77). coagulopathies the response to rFVIIa is higher. This
There is literature demonstrating that administration finding supports the replacement with blood products
of cyroprecipitates and fibrinogens for fibrinogen levels early on in the course to bring the response to rFVIIa
less than 1.5gm/L decreaeses bleeding(78,79). In a to a more adequate level. Acidosis and low fibrinogen
retropective study, the use of fibrinogen concentrates levels decrease the optimum response to rFVIIa(84). As
decreased the need for erythrocyte and thrombocyte a pre-hemostatic agent, rFVIIa may theoretically lead
suspesions, FFPs as well as led to a significant decrease to thromboembolic complications. Especially, in
in blood loss and improved coagulation factors. The hypercoagulable states like pregancy this could become
reported study includees mainly obstetrical cases and a problem of importance. In a recent review, only one
suported the use of fibrinogen factor concentrates in out of 48 patients who who were treated with rFVIIa
placental abruption and placenta previa(78). Serial developed a thromboembolic complication(85). Another
measurement of whole blood count and coagulation reason is that the costs of rFVIIa treatment are high.
parameters are essential in regards to whether to carrying However, if the surgical procedures and prolonged
on or hold further replacement of blood products. hospital stay including admission to the ICU are
Caution should be given to prevent development of considered as well it may balance out.
acidosis and hypothermia associated with transfusions. Although, rFVIIa seems to be an effective treatment
In massive transfusions, it has been shown that acidosis method in massive obstetrical bleedings there is need
hinders the union of the coagulation complex and that for further research in regards to optimum dosing,
hypothermia decreases thrombocyte activation(80). frequency and proper timing of use.
In massive obstetrical bleeding followign steps should
be ensured in order Pharmacological Treatment
1. The bleeding should be controlled with surgical The use of pharmacological agents inhibiting the coagulation
and radiological methods. and fibrinolytic systems in Disseminated Intravascular
2. The circulating blood volume should be replaced Coagulation is still controversial. Heparin will theoretically
with fluids and blood products and inhibit intravascular coagulation and subsequent fibrinolysis
3. Factors like, hypothermia and acidosis triggering through inhibition of the thrombin activity.
abnormal coagulation should be controlled. Heparin is especially recommended in DIC cases
The management of blood products should be done associated with thrombosis without stigmata of
as listed in Table I. bleeding. In patients considered for Heparin treatment,
fractionated heparin should be the treatment of choice
The role of activated Factor VII given its short half life and reversible actions and
The experience with the use recombinant Factor VIIa should be administered as continuous intravenous
(rFVIIa) in massive obstetrical bleedings is increasing. infusion at 10 µ/kg/hr. In these patients, the clinical
Gabriel et al discovered that rFVIIa levels above response should be taken into account rather then the
physiological limits are directly activating Factor X use aPTT in the monitorization of the anticoagulant
located on the surface of activated platelets(81). A study effect(36). The use of anti-fibrinolytic agents such as
reviewing the Northern Europian Obstetric records, Tranexamic asit and ß-aminocaproic acid is in general
demonstarted that the bleeding was effectively controlled contraindicated in DIC. However, these medications
in 83% of patints who were treated with FVIIa(82). In may be effective in life threatening bleedings(86).

J Turk Soc Obstet Gynecol 2014;11:42-51 48

 Disseminated intravascular coagulation in obstetrics

REFERENCES dimethylarginine in pregnant women who subsequently develop

pre-eclampsia. Lancet 2003;361(9368):1511- 7.

1. Williams J, Mozurkewich E, Chilimigras J, Van De Ven C. 17. Redman CW. Platelets and the beginnings of preeclampsia.

Critical care in obstetrics: pregnancy-specific conditions. Best N Engl J Med 1990;323(7):478-80.

Pract Res Clin Obstet Gynaecol 2008;22(5):825-46. 18. Martin JN, Rose CH, Briery CM. Understanding and managing

2. DeLee JB. A case of fatal hemorrhagic diathesis, with HELLP syndrome: the integral role of aggressive glucocorticoids

premature detachment of the placenta. Am J Obstet Dis for mother and child. Am J Obstet Gynecol 2006;195(4):914-34.

Women Child 1901;44:785-92. 19. Fang CJ, Richards A, Liszewski MK, et al. Advances in

3. Bick RL. Disseminated intravascular coagulation: a review understanding of pathogenesis of HUS and HELLP. Br J

of etiology, pathophysiology, diagnosis, and management: Haematol 2008;143(3):336-48.

guidelines for care. Clin Appl Thromb Hemost 2002;8(1): 20. Boisramé-Helms J, Kremer H, Schini-Kerth V, Meziani F.

1-31. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol 2013;

4. Bick RL. Disseminated intravascular coagulation current 11(2):150-60.

concepts of etiology, pathophysiology, diagnosis, and treatment. 21. Högberg U, Joelsson I. Amniotic fluid embolism in Sweden,

Hematol Oncol Clin North Am 2003;17(1):149-76. 1951-1980. Gynecol Obstet Invest 1985;20(3):130-7.

5. Bick RL. Syndromes of disseminated intravascular coagulation 22. Clark SL, Hankins GD, Dudley DA, Dildy GA, Porter TF.

in obstetrics, pregnancy, and gynecology. Objective criteria Amniotic fluid embolism: analysis of the national registry.

for diagnosis and management. Hematol Oncol Clin North Am J Obstet Gynecol 1995;172(4 Pt 1):1158- 67.

Am 2000;14(5):999-1044. 23. Yang W, Zhou N, Zhou Y. The clinical analysis of 38 cases

6. Liang BL, Hong DH. Diagnosis and management of obstetric with amniotic fluid embolism [Chinese]. Zhonghua Fu Chan

acute disseminated intravascular coagulation. Zhonghua Fu Ke Za Zhi 2000;35(2):75-8.

Chan Ke Za Zhi 1992;27(3):147-9, 188. 24. Abenhaim HA, Azoulay L, Kramer MS, Leduc L. Incidence

7. Kor-anantakul O, Lekhakula A. Overt disseminated and risk factors of amniotic fluid embolisms: a population-

intravascular coagulation in obstetric patients. J Med Assoc based study on 3 million births in the United States. Am J

Thai 2007;90(5):857-64. Obstet Gynecol 2008;199(1):49.e1-8.

8. Rattray DD, O'Connell CM, Baskett TF. Acute disseminated 25. Sullivan EA, King JF. Maternal deaths in Australia 2000-

intravascular coagulation in obstetrics: A tertiary centre 2002. Maternal deaths series no. 2. Cat. no. PER 32. Sydney:

population review (1980 to 2009). J Obstet Gynaecol Can AIHW National Perinatal Statistics Unit; 2006.

2012;34(4):341-7. 26. Lewis G. The confidential enquiry into maternal and child

9. Kobayashi T, Terao T, Maki M, Ikenoue T. Diagnosis and health (CEMACH). Saving mothers' lives: reviewing maternal

management of acute obstetrical DIC. Semin Thromb Hemost deaths to make motherhood safer-2002-2005. The seventh

2001;27(2):161-7. report on confidential enquiries into maternal deaths in the

10. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol United Kingdom. London: CEMACH; 2007.

2006;108(4):1005-16. 27. Dey M, Reema K. Acute fatty liver of pregnancy. N Am J

11. Kramer MS, Usher RH, Pollack R et al. Etiologic determinants Med Sci 2012;4(11):611-2.

of abruptio placentae. Obstet Gynecol 1997;89(2):221-6. 28. Bacq Y. Acute fatty liver of pregnancy. Semin Perinatol 1998;

12. Han CS, Schatz F, Lockwood CJ. Abruption-associated 22(2):134-40.

prematurity. Clin Perinatol 2011;38(3):407-21. 29. Castro MA, Goodwin MT, Shaw KJ, et al. Disseminated

13. Ananth CV, Getahun D, Peltier MR et al. Placental abruption intravascular coagulation and antithrombin III depression in

in term and preterm gestations: evidence for heterogeneity in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996;

clinical pathways. Obstet Gynecol 2006;107(4):785-92. 174(1 Pt 1):211-6.

14. Hess JR. Blood and coagulation support in trauma care. 30. Hoffman M, Monroe DM. Coagulation 2006: a modern view

Hematol Am Soc Hematol Educ Program 2007;187-91. of hemostasis. Hematol Oncol Clin North Am 2007;21(1):1-11.

15. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive 31. Tetik S, Kaya K, Yardimci T. Effect of oxidized fibrinogen

maternal inflammatory response to pregnancy. Am J Obstet on haemostatic system: in vitro study. Clin Appl Thromb

Gynecol 1999;180(2 Pt 1):499-506. Hemost 2011;17(3):259-63.

16. Savvidou MD, Hingorani AD, Tsikas D et al. Endothelial 32. Bremme KA. Haemostatic changes in pregnancy. Best Pract

dysfunction and raised plasma concentrations of asymmetric Res Clin Haematol 2003;16(2):153-68.

49 J Turk Soc Obstet Gynecol 2014;11:42-51

Sadik Sahin et al.

33. DahlmanT, Hellgren M, Blomback M. Changes in blood 47. Neame PB, Kelton JG, Walker IR, Stewart IO, Nossel HL,
coagulation and fibrinolysis in the normal puerperium. Gynecol Hirsh, J. Thrombocytopenia in septicemia: the role of
Obstet Invest 1985;20(1):37-44. disseminated intravascular coagulation. Blood 1980;56(1):
34. O'Riordan MN, Higgins JR. Haemostasis in normal and 88-92.
abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 48. Akca S, Haji-Michael P, de MA, Suter P, Levi M, Vincent
2003;17(3):385-96. JL. Time course of platelet counts in critically ill patients.
35. Tetik S, Ak K, Sahin Y, Isbir S, Gulsoy O, Arsan S, Yardimci Crit Care Med 2002;30(4):753-6.
T. Postoperative statin therapy attenuates the intensity of 49. Carr, J.M., McKinney, M. & McDonagh, J. Diagnosis of dis-
systemic inflammation and increases fibrinolysis after coronary seminated intravascular coagulation. Role of D-dimer. Am J
artery bypass grafting. Clin Appl Thromb Hemost 2011;17(5): Clin Pathol 1989;91(3):280-7.
526-31. 50. Bick, R.L. Disseminated intravascular coagulation: objective
36. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the clinical and laboratory diagnosis, treatment, and assessment
diagnosis and management of disseminated intravascular of therapeutic response. Semin Thromb Hemost 1996;22(1):
coagulation: British Committee for Standards in Haematology. 69-88.
Br J Haematol 2009;145(1):24-33. 51. Asakura H, Ontachi Y, Mizutani T, Kato M., Ito T, Saito M.
37. Gando S, Iba T, Eguchi Y et al. A multicenter, prospective Decreased plasma activity of antithrombin or protein C is not
validation of disseminated intravascular coagulation diagnostic due to consumption coagulopathy in septic patients with
criteria for critically ill patients: comparing current criteria. disseminated intravascular coagulation. Eur J Haematol 2001;
Crit Care Med 2006;34(3):625-31. 67(3):170-5.
38. Çakmakç› M. Abdominal kompartman sendromu. T Klinikleri 52. Levi M, Ten CH. Disseminated intravascular coagulation. N
Cerrahi Dergisi 1998;3:51-4. Engl J Med 1999;341(8):586-92.
39. Ak K, Isbir C, Tetik S, Atalan N, Tekeli A, Aljodi M et al. 53. Levi, M., de, J.E., van der, P.T. & Ten, C.H. Disseminated
Thromboelastography based transfusion algorithm reduces intravascular coagulation. J Thromb Haemost 1999;82(2):
blood product use after elective CABG: A prospective randomized 695-705.
study. J Card Surg 2009;24(4):404-10. 54. O'Riordan MN, Higgins JR. Haemostasis in normal and
40. Tetik fi, Ak K, Yard›mc› KT. The factors effecting platelet abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol
function tests. Cumhuriyet T›p Der 2012;4:123-7. 2003;17(3):385-96.
41. Bick RL, Baker WF. Diagnostic efficacy of the D-dimer assay 55. Wallenburg HC, van Kessel PH. Platelet lifespan in normal
in disseminated intravascular coagulation (DIC). Thrombosis pregnancy as determined by a non-radioisotopic technique.
Research 1992;65(6):785-90. BJOG 1978;85(1):33-6.
42. Al-Mondhiry. Disseminated intravascular coagulation: 56. Neame PB, Kelton JG, Walker IR, et al. Thrombocytopenia
experience in a major cancer center. Thrombosis et Diathesis in septicemia: the role of disseminated intravascular
Haemorrhagica 1975;34(1):181-93. coagulation. Blood 1980;56(1):88-92.
43. Siegal T, Seligsohn U, Aghai E Modan M. Clinical and 57. Manten GT, Franx A, Sikkema JM, et al. Fibrinogen and high
laboratory aspects of disseminated intravascular coagulation molecular weight fibrinogen during and after normal pregnancy.
(DIC): a study of 118 cases. J Thromb Haemost 1978;39(1): Thromb Res 2004;114(1):19-23.
122-34. 58. Charbit B, Mandelbrot L, Samain E . The decrease of fibrinogen
44. Mant MJ, King EG. Severe, acute disseminated intravascular is an early predictor of the severity of postpartum hemorrhage.
coagulation. A reappraisal of its pathophysiology, clinical J Thromb Haemost 2007;5(2):266-73.
significance and therapy based on 47 patients. Am J Medicine 59. Nieuwenhuizen W. A reference material for harmonisation
1979;67:557-63. of D-dimer assays. Thromb Haemost 1997;77(5):1031-3.
45. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular 60. Tetik fi, Ak K. Platelet function tests on cardiovascular dieases:
coagulation. Findings in 346 patients. J Thromb Haemost from pathophysiology to clinical approach. Cumhuriyet Med J
1980;43(1):28-33. 2010;32:264-74.
46. Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. 61. Sharma P, Saxena R. A novel thromboelastographic score to
Plasma D-dimer levels and their relationship to serum identify overt disseminated intravascular coagulation resulting in
fibrinogen/fibrin degradation products in hypercoagulable a hypocoagulable state. Am J Clin Pathol 2010;134(1):97-102.
states. Br J Haematol 1989;71(1):65-70. 62. Taylor FB, Toh CH, Hoots WK, Wada H, Levi M. Towards

J Turk Soc Obstet Gynecol 2014;11:42-51 50

 Disseminated intravascular coagulation in obstetrics

definition, clinical and laboratory criteria, and a scoring practices around the globe and a suggestion for a common
system for disseminated intravascular coagulation. J Thromb massive transfusion protocol. J Trauma 2006;60(6 Suppl):S91-
Hemost 2001;86(5):1327-30. 6.
63. Gando S, Wada H, Asakura H, Iba T, Eguchi Y, Okamoto K. 76. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of
Evaluation of new Japanese diagnostic criteria for disseminated blood products transfused affects mortality in patients receiving
intravascular coagulation in critically ill patients. Clin Appl massive transfusions at a combat support hospital. J Trauma
Thromb Hemost 2005;11(1):71-6. 2007;63(4):805-13.
64. Bakhtiari K, Meijers JC, Levi M. Prospective validation of 77. Johansson PI, Stensballe J, Rosenberg I, et al. Proactive
the international society of thrombosis and haemostasis scoring administration of platelets and plasma for patients with a
system for disseminated intravascular coagulation. Crit Care ruptured abdominal aortic aneurysm: evaluating a change in
Med 2004;32(12):2416-21. transfusion practice. Transfusion 2007;47(4):593-8.
65. Thachil J, Toh CH. Disseminated intravascular coagulation 78. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, et
in obstetric disorders and its acute haematological management. al. Fibrinogen concentrate substitution therapy in patients
Blood Rev 2009;23(4):167-76. with massive haemorrhage and low plasma fibrinogen
66. Josic D, Hoffer L, Buchacher A. Manufacturing of a prothrombin concentrations. Br J Anaesth 2008;101(6):769-73.
complex concentrate aiming at low thrombogenicity. Thromb 79. Wikkelsoe AJ, Afshari A, Stensballe J, Langhoff-Roos J,
Res 2000;100(5):433-41. Albrechtsen C et al. The FIB-PPH trial: fibrinogen concentrate
67. Preston FE, Laidlaw ST, Sampson B. Rapid reversal of oral as initial treatment for postpartum haemorrhage: study protocol
anticoagulation with warfarin by a prothrombin complex for a randomised controlled trial. Trials 2012;13:110.
concentrate (Beriplex): efficacy and safety in 42 patients. Br 80. Meng ZH, Wolberg AS, Monroe 3rd DM. The effect of
J Haematol 2002;116(3):619-24. temperature and pH on the activity of factor VIIa: implications
68. Kreuz W, Meili E, Peter-Salonen K. Efficacy and tolerability for the efficacy of high-dose factor VIIa in hypothermic and
of a pasteurised human fibrinogen concentrate in patients with acidotic patients. J Trauma 2003;55(5):886-91.
congenital fibrinogen deficiency. Transfus Apher Sci 2005; 81. Gabriel A, Li X, Monroe DM. Recombinant human factor
32(3):247-53. VIIa, (rFVIIa) can activate FX on activated platelets. J Thromb
69. Weinkove R, Rangarajan S. Fibrinogen concentrate for acquired Haemost 2004;2(10):1816-22.
hypofibrinogenaemic states. Transfus Med 2008;18(3):151-7. 82. Sobieszczyk S, Breborowicz GH, Platicanov V, et al.
70. Wise A, Clark V. Strategies to manage major obstetric Recombinant factor VIIa in the management of postpartum
haemorrhage. Curr Opin Anaesthesiol 2008;21(3):281-7. bleeds: an audit of clinical use. Acta Obstet Gynecol Scand
71. Kayabasoglu F, Guzin K, Aydogdu S, Sezginsoy S, Turkgeldi 2006;85(10):1239-47.
L, Gunduz G. Emergency peripartum hysterectomy in a tertiary 83. Franchini M, Lippi G, Franchi M. The use of recombinant
Istanbul hospital. Arch Gynecol Obstet 2008;278(3):251-6. activated factor VII in obstetric and gynaecological
72. Stainsby D, MacLennan S, Thomas D, Isaac J, Hamilton PJ. haemorrhage. BJOG 2007;114(1):8-15.
BCSH guidelines on the management of massive blood loss. 84. Haynes J, Laffan M, Plaat F. Use of recombinant activated
Br J Haematol 2006;135(5):634-41. factor VII in massive obstetric haemorrhage. Int J Obstet
73. Van der Linden P, Ickx BE. The effects of colloid solutions Anesth 2007;16(1):40-9.
on hemostasis. Can J Anaesth 2006;53(6 Suppl):S30-9. 85. Butwick AJ. Postpartum hemorrhage and low fibrinogen
74. Hirshberg A, Dugas M, Banez E, Scott B, Wall M, Mattox levels: the past, present and future. Int J Obstet Anesth 2013;
K. Minimizing dilutional coagulopathy in exanguinating 22(2):87-91.
hemorrhage: a computer simulation. J Trauma 2003;54(3): 86. Novikova N, Hofmeyr GJ. Tranexamic acid for preventing
454-61. postpartum haemorrhage. Cochrane Database Syst Rev 2010;
75. Malone DL, Hess JR, Fingerhut A. Massive transfusion (7):CD007872.

51 J Turk Soc Obstet Gynecol 2014;11:42-51