Accepted Manuscript

Disseminated intravascular coagulation in pregnancy – insights in pathophysiology,

diagnosis and management

Offer Erez, Salvatore Andrea Mastrolia, Jecko Thachil

PII: S0002-9378(15)00335-X
DOI: 10.1016/j.ajog.2015.03.054
Reference: YMOB 10342

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 20 January 2015

Revised Date: 26 March 2015
Accepted Date: 29 March 2015

Please cite this article as: Erez O, Mastrolia SA, Thachil J, Disseminated intravascular coagulation in
pregnancy – insights in pathophysiology, diagnosis and management, American Journal of Obstetrics
and Gynecology (2015), doi: 10.1016/j.ajog.2015.03.054.

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 ACCEPTED MANUSCRIPT

Disseminated intravascular coagulation in pregnancy – insights in pathophysiology, diagnosis

and management

Offer EREZ1, Salvatore Andrea MASTROLIA1,2, Jecko THACHIL3

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Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health

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Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
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Department of Obstetrics and Gynecology, Azienda Ospedaliera Universitaria Policlinico di

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Bari, Universita' degli Studi di Bari "Aldo Moro", Bari, Italy
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Department of Haematology, Manchester Royal Infirmary, Manchester, UK
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Disclosure statement of any potential conflict of interest: The authors report no conflict of
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interest.
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Corresponding author

Dr. Offer Erez, MD

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Acting Director Maternal Fetal Medicine Unit

Department of Obstetrics and Gynecology "B"

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Soroka University Medical Center

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Faculty of Health Sciences, Ben Gurion University of the Negev

P.O.Box 151, Beer Sheva 84101, Israel

Phone +972-8-6400061

erezof@bgu.ac.il

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Abstract word count: 132

Manuscript word count: 5904

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Condensation: Disseminated intravascular coagulation in pregnancy

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Abstract

Disseminated intravascular coagulation (DIC) is a life-threatening situation that can arise from a

variety of obstetrical and non-obstetrical causes. Obstetrical DIC has been associated to a series

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of pregnancy complications including: 1) acute peripartum hemorrhage (uterine atony, cervical

and vaginal lacerations, and uterine rupture); 2) placental abruption; 3)

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Preeclampsia/eclampsia/HELLP syndrome; 4) retained stillbirth; 5) septic abortion and

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intrauterine infection; 6)amniotic fluid embolism; and 7) acute fatty liver of pregnancy. Prompt

diagnosis and understanding of the underlying mechanisms of disease leading to this

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complication in essential for favorable outcome. In the recent years novel diagnostic scores and
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treatment modalities along with bedside point-of-care tests were developed, and may assist

the clinician in the diagnosis and management of DIC. Team work and prompt treatment are
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essential for the successful management of patients with DIC.

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Keywords: Acute fatty liver of pregnancy, Endothelial dysfunction, HELLP syndrome,

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Hemorrhage, Score, Trophoblast.

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1. Introduction

Uncontrolled peripartum bleeding, resulting in disseminated intravascular coagulation (DIC), is

one of the leading causes for maternal mortality worldwide1. This is in spite of an adaptive

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physiologic mechanism that generates a physiologic prothrombotic state during gestation2, 3

and the advanced medical and surgical hemostatic capabilities that have evolved during the

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past decades for controlling acute obstetrical blood loss.

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The rate of DIC during pregnancy differ among cohorts and range from 0.03%4 to 0.35%5. A

series of pregnancy complications have been associated with DIC including: 1) acute peripartum

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hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine rupture); 2) placental
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abruption; 3) Pre-eclampsia/eclampsia/HELLP syndrome; 4) retained stillbirth; 5) septic
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abortion and intrauterine infection; 6)amniotic fluid embolism; and 7) acute fatty liver of

pregnancy1, 6. The proportion of each disorder varies among the different reports. In a cohort5
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including 24,693 pregnancies, among those who developed DIC, 49.4% had placental abruption,
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29.9% post-partum hemorrhage (PPH), 12.6% severe preeclampsia, and 5.7% had a uterine

rupture. While in a different cohort including 151,678 deliveries, the proportion of these
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complications in those who had DIC was, placental abruption 37%, postpartum hemorrhage or
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hypovolemia 29%, preeclampsia/HELLP syndrome 14%, acute fatty liver 8%, sepsis 6%, and
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amniotic fluid embolism 6%4. In most of these pregnancy complications, DIC is associated with

adverse maternal outcome including massive blood products transfusion, hysterectomy, and

even maternal death7. Therefore, prompt diagnosis and treatment are needed in order to

reduce the morbidity and mortality that is associated with DIC.

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In this review we aim to discuss 1) the pathophysiology of DIC focusing on the triad represented

by exaggerated activation of coagulation, consumption of coagulopathy and impaired synthesis

coagulation as well as anti-coagulation proteins ; 2) the diagnosis of DIC with special attention

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to the available scores adding prognostic value to the laboratory parameters in patients with

this dangerous condition or at risk for its development; and 3) the principles of the treatment of

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DIC, the latter is discussed extensively in the literature6, 8-17.

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2. What is disseminated intravascular coagulation?

Disseminated intravascular coagulation (DIC) represents a life threatening condition which is

the endpoint of uncontrolled systemic activation of the hemostatic system, leading to a

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simultaneous widespread microvascular thrombosis, that can compromise the blood supply to

different organs, and may lead to organ failure18. This process is associated with increased

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degradation of coagulation factors as well as anticoagulation proteins, and followed by their

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impaired synthesis, leading to uncontrolled bleeding.

Acute, severe DIC is characterized by diffuse multi-organ bleeding, hemorrhagic necrosis,

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microthrombi in small blood vessels and thrombi in medium and large blood vessels12. This
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condition may occur in the setting of sepsis, major trauma, and obstetric calamities. The final
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scenario is represented by the exhaustion of coagulation/anticoagulation factors and platelets,

leading to profuse uncontrollable bleeding and often death.

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In contrast to the acutely ill patient with complicated severe DIC, other patients may have mild
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or protracted clinical manifestations of consumption or even subclinical disease manifested by

only laboratory abnormalities19. The clinical picture of sub-acute to chronic DIC is exemplified
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by the chronic hypercoagulability that may accompany malignancy, in particular with mucin-
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producing adenocarcinomas and acute promyelocytic leukemia. However, currently there are
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no reports in the literature regarding the occurrence of mild sub-acute DIC in pregnant women.

The development of DIC as a result of predisposing conditions can be a life-threatening

complication and is considered as one of the leading causes for maternal morbidity and

mortality worldwide7. However, it is important to emphasize that DIC is not a disease by itself;

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it is always secondary to an underlying disorder that causes the uncontrolled activation of

coagulation.

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3. What are the mechanisms leading to DIC during pregnancy?

The development of DIC during pregnancy can be either abrupt like in acute abruption or PPH

or continuous as can be observed in retained dead fetus. Of interest, obstetric complications

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such as placental abruption, amniotic fluid embolism, and acute fatty liver of pregnancy are

associated with severe early onset DIC that is accompanied by maternal coagulopathy. The DIC

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in obstetric hemorrhage activates coagulation and triggers fibrinolysis. Activation of fibrinolysis

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leads to the production of D-dimers and fibrin-degradation products. These will interfere with

platelet function and can impair myometrial contractility20.

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Clinical presentation of DIC may be the results of the following mechanisms:
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3.1 Endothelial dysfunction and platelet activation: Intact, dysfunctional, or activated cells, as

well as remnants of cell surfaces, inflammatory mediators and coagulation proteins are all part
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of an interplay in which uncontrolled activation of coagulation cascade leads to DIC21.

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Endothelial cells, platelets, but in some cases also leucocytes and cancer cells can participate in

the genesis of the process leading to DIC by releasing pro-inflammatory cytokines, propagating
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the activation of coagulation on their surface or inducing tissue factor (TF) expression on their
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membrane10, 22-28. A systemic inflammatory response that is associated with markedly increased
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circulating pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1 (IL-1) and

interleukin-6 (IL-6) can lead to exaggerated expression of TF by leukocyte and endothelial

cells24. This will generate an uncontrolled coagulation response that will eventually deteriorate

into DIC. Lastly, the initiation of coagulation leading to thrombin generation in DIC, is mediated

by the TF/factor VIIa pathway, also known as the extrinsic coagulation pathway12. The most

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significant source of TF is not completely clear in all situations. Tissue factor may be expressed

not only in mononuclear cells in response to pro-inflammatory cytokines (mainly IL-6), but also

by vascular endothelial or cancer cells27-29. Despite the potent initiation of coagulation by TF,

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the activation of coagulation cannot be propagated if the physiological anticoagulant pathways

function properly. However, in DIC all major natural anticoagulant pathways [i.e., anti-thrombin

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III, protein C system, and TF pathway inhibitor (TFPI)] appear to be impaired30. Plasma

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concentrations of antithrombin III, the most important inhibitor of thrombin, are markedly

reduced during DIC, due to a combination of consumption31, degradation by elastase from

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activated neutrophils32, and impaired synthesis10. A significant depression of the protein C
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system may further compromise an adequate regulation of activated coagulation33. This

impaired function of the protein C system is caused by a combination of impaired protein

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synthesis, cytokine-mediated down-regulation of endothelial thrombomodulin and a fall in the

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concentration of the free fraction of protein S (the essential co-factor of protein C), resulting in
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reduced activation of protein C33. Lastly, there seems to be a misbalance of TFPI function in

relation to the increased TF dependent activation of coagulation34.

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All these anticoagulant pathways are linked to the endothelium, and it is likely that endothelial

cell activation and dysfunction are an important component of the imbalance between
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coagulation and anticoagulation systems. Of interest, experimental and clinical studies indicate
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that during DIC, the fibrinolytic system is largely suppressed at the time of maximal activation

of coagulation10, 11. This inhibition of fibrinolysis is caused by a sustained rise in the plasma

concentrations of plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of the

fibrinolytic system. Activation of platelets may also accelerate fibrin formation35. The

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expression of TF in monocytes is markedly stimulated by the presence of platelets and

granulocytes in a P-selectin dependent reaction29. This effect may be the result of nuclear

factor kappa B (NF-kB) activation induced by binding of activated platelets to neutrophils and

mononuclear cells36.

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During pregnancy maternal leukocytes are in a higher state of activation than in non-pregnant

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women37, and have characteristics akin to sepsis38. However, they are well controlled during

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pregnancy, and it has been proposed that the trophoblast plays a role in the maintenance of

the balanced systemic maternal inflammation during gestation39. Nevertheless, in cases of

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sepsis due to infectious agent or septic abortion and at least in some of the cases of amniotic
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fluid embolism40 this equilibrium is disturbed and the mother develops DIC.
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3.2 Trophoblast properties and activation of the coagulation system: During normal gestation
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the trophoblast has two hemostatic functions: 1) to allow the laminar flow of maternal blood in
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the intervillous space and prevent it from clotting during that time; and 2) to prevent bleeding

at the maternal fetal interface6. In order to address these contradicting challenges, the
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syncytiotrophoblast acquires endothelial-cell like properties (Figure 1). As a consequence: 1) In

human normal placenta syncytiotrophoblast strongly expresses TF, and its activity is higher if
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compared to human umbilical vein endothelial cells. On the contrary, the trophoblast is able to
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synthesize Protein C, Protein S and Protein Z as well as a specific inhibitor of the tissue factor

pathway known as TFPI-2 (Placental Protein 5)41-43 that will prevent unnecessary activation of

the coagulation cascade44-47; 2) The placenta produces PAI-2 in addition to the gradual increase

of PAI-1, observed during normal pregnancy and becomes markedly elevated in the third

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trimester in order to prevent fibrinolysis48. These changes are associated with relatively

unchanged tissue plasminogen activator (t-PA) concentrations, contributing to a state of

reduced clot lysis and a pro-thrombotic bias in the pregnant woman49. This mechanism is

(TAFI)50, 51.

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further mediated through thrombin activatable fibrinolysis inhibitor

The evidence brought herein supports the fact that any condition that disrupts the integrity of

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the throphoblast (Figure 2) can lead to a release of a large amount of potent TF that will

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activate the coagulation cascade and propagate an inflammatory response that can easily

become systemic leading to uncontrolled thrombin generation and subsequent development of

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DIC25, 52. There are several conditions that are associated with DIC in which the current evidence
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suggests that the systemic maternal response is the result of endothelial activation. The

classical one is abruption, especially that with concealed bleeding and fetal demise. These
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patients have a combination of consumption coagulopathy and discharge of thromboplastin

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(tissue factor) into the maternal circulation10.

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Although the DIC developed in patients with placental abruption is regarded as a problem of

consumption coagulopathy, it seems that there is more to it. Meaning, often patients with a
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retro placental clot have a much lower blood loss than those who developed PPH, yet the DIC

of in these patients is much more severe. A probable explanation is that this complication is
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associated to the release of pro-coagulating factors, such as thromboplastin, into the maternal
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circulation6. In addition, local hypoxia and hypovolemia trigger endothelial response leading to

increased expression of vascular endothelial growth factor, which causes an increased

endothelial expression of TF53. Evidence in support of this view is brought by Erez at al25 who

demonstrated that in women with fetal death, those who had abruption had a higher amniotic

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fluid of TAT complexes. These events result in consumption of coagulating factors, fibrin

deposition in microcirculation, and thrombus formation on maternal surface of the placenta at

the site of abruption. This is followed by fibrinolysis and release of fibrin degradation products

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further contributing to the development of DIC. Of interest, if the abruption in concealed or it is

severe enough to cause fetal demise, it is at much higher risk for the development of DIC, due

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to a continuous release of TF in the maternal circulation. The probable mechanism leading to

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this observation is similar to that observed in amniotic fluid embolism with systemic release of

TF that leads to systemic activation of coagulation and subsequent DIC. This view is supported

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by the experiment reported by Schneider54 which demonstrated that the intravenous injection
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of placental extracts into mice leads to the death of the animal through DIC, which can be

prevented by the administration of heparin54. The author identified thromboplastin as the

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causative agent through its effect on the clotting time and its chemical properties, and
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measured its activity by the one-stage prothrombin-time method54.

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3.3 Hemorrhage: Acute obstetrical bleeding is being considered by many4, 6, 18, 23, 55-58
as a
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leading cause for DIC. This form of consumption coagulopathy is classically related to PPH as a

result of uterine atony, retained placenta or membranes, uterine rupture, placenta accreta, or
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severe cervical or vaginal lacerations5. In all of these cases, the mother is losing a large volume
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of blood and coagulation factors in a short time interval, and these patients are usually

hemodynamically compromised. Currently, there is a debate whether this form of consumption

coagulopathy is truly DIC or just a massive blood loss that depletes the patient's coagulation

factors and can lead to death due to exanguination9. However, massive maternal bleeding may

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not be that straightforward as pure loss of coagulation factors. During the time of parturition

and postpartum period there is substantial activation of coagulation cascade and generation of

thrombin as a result of the release of TF to the maternal circulation following the separation of

the membranes and the placenta59, 60. Thus, these women already have increased thrombin

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generation61 and indeed are regarded as high risk patients for the development of deep vein

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thrombosis during the puerperium62. The evidence brought herein, that parturients with PPH

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have a higher activation of coagulation cascade even above the physiologic threshold, suggest

that the clinicians who treat these patients must regard them as a high risk group for DIC, even

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though the fundamental pathology is a rapid and massive loss of blood as well as coagulation
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factors52. Therefore, patients with PPH need to be treated promptly, pharmacologically and/or

surgically, and by blood products as well as volume expanders to sustain the maternal
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circulation and maybe to prevent the subsequent development of DIC.

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3.4 Disruption of liver function

3.4.1 Acute fatty liver of pregnancy: Acute fatty liver of pregnancy is a rare, (an estimated
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incidence between 6 and 14 per 100,000 pregnancies63-65) but potentially fatal complication of

pregnancy. It is characterized by fatty microvascular infiltration of hepatocytes with progressive

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loss of liver function66, without alteration of the overall structure of the liver. Women who
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develop this complication have abnormal renal function67 and DIC68. The mechanisms in which

DIC develops in this complication is a combination of reduced liver production of fibrinogen as

well as coagulation proteins, and hemorrhage. Evidence in support of this view is presented by

Nelson et al69, who studied 51 women with acute fatty liver of pregnancy. Their hemostatic

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condition was classified according to the International Society of Thrombosis and Haemostasis

DIC score70, 71 and 80% of these women had unequivocal DIC defined as composite score of 5 or

greater. The authors studied the hepatic and hemostatic function of these patients including

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fibrinogen, fibrin–fibrinogen split products, coagulation studies, and cholesterol. Those who

developed DIC had abnormally low plasma fibrinogen concentrations that persisted for the first

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several days after delivery along with only mild to moderately elevated fibrin degradation

products69. At the same time, there was also evidence for continuing increased procoagulant

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consumption caused by ongoing DIC provided by the modestly elevated levels of fibrin

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degradation products in the face of depressed plasma fibrinogen concentrations. This
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observation was in contrast to that of patients with abruption in whom the fibrinogen

concentration recovered into normal range several hours after the acute event. Collectively, the
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continuous low fibrinogen concentration and abnormal function of the coagulation cascade is
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the result of the liver dysfunction associated with acute fatty liver of pregnancy, leading to a
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lower production of coagulation factors, anticoagulation proteins and fibrinogen by the liver.
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3.4.2 HELLP syndrome: this condition is an additional cause for DIC in obstetric patients that

may involve the liver. The relationship between acute fatty liver of pregnancy and HELLP
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syndrome has not been clearly established. There are obviously common clinical and biological
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features between these two entities68. Indeed, some authors66, 72 have suggested that acute

fatty liver of pregnancy and HELLP syndrome are the two faces of the same coin. However,

others73, 74
found that a difference in liver histopathology (fatty microvascular infiltration of

hepatocytes vs. fibrin deposition or hemorrhage in the periportal areas75, 76) makes an overlap

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between these two entities not possible. One of the major differences between acute fatty liver

of pregnancy and HELLP syndrome is the prevalence of DIC. In a study68 by Vigil-De Gracia, DIC

was present in >70% of patients with acute fatty liver of pregnancy and <15% of those with

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HELLP syndrome. Thus, although women with HELLP syndrome have a reduced production of

fibrinogen and other coagulating as well as anticoagulation factors which can lead to the

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development of DIC77, this is not the central feature of this disease. From the evidence brought

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herein, DIC is a central feature of acute fatty liver and in a way reflects the severity of the

hepatic injury, while in HELLP syndrome it is present in only a fraction of the patients probably

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those with a more severe form of the microangiopathic hemolytic anemia associated with this
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syndrome.
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4. How can we diagnose DIC?

Early and accurate recognition of DIC is the hallmark of success in the treatment of this dire

complication. Unfortunately, in the majority of the cases, the diagnosis of DIC is based on the

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clinical assessment of the patient. Indeed, there is no single laboratory or clinical test that is

sensitive and specific enough to diagnose DIC. Also the effect of the above mentioned

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pathologies on the coagulation profile of the patients and the risk to develop DIC is not evident

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in all cases4, 6, 8, 9, 23, 40, 78.

For these reasons, and the need to: 1) provide the clinician a tool for early identification of DIC;

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as well as 2) the need for a common language and definition of DIC, efforts have been made to
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create scoring systems to identify patients at high risk for this dangerous complication. All these
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scores use simple and readily available coagulation tests including platelet count, PT

prolongation, fibrinogen and fibrin split products/D-dimer concentrations.

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One key message is that the tests should be repeated to reflect the dynamic changes on the
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basis of laboratory results and clinical observations. In the order of relative importance in

patients with DIC, the tests are platelet count (decreasing), prothrombin time or PT
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(prolongation), fibrin-related marker (increasing) and fibrinogen (decreasing)13, 14, 79.

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Thrombocytopenia is the commonest laboratory diagnostic feature for DIC80. However, the
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platelet count may not always be very low and may even be in the normal range in patients

who have recently started developing DIC. On the other hand the gestational

thrombocytopenia of third trimester may confuse the thrombocytopenia of DIC. To determine

if the thrombocytopenia is due to DIC, a downward trend in the platelet count is most

important even if the count remains in the normal range. It is useful to bear in mind that

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thrombocytopenia in pre-eclampsia and hypertensive disorders of pregnancy may also be

related to platelet aggregation or increased adhesion to the vascular endothelium. This is

consistent with the finding that ADAMTS-13, the Von Willebrand cleaving protease enzyme

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that typically shows reduced concentration in thrombotic thrombocytopenic purpura, is also

lower in women with preeclampsia or HELLP syndrome in comparison to normal pregnant

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women35, 81-84. Stepanian et al81 suggested that it may even play a role in the pathophysiology

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of this obstetrical syndrome and, as a consequence, this might worsen the clinical course of

patients with DIC.

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A diagnosis of DIC is often considered when the PT and APTT are considerably prolonged.
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However, in pregnant women, normal ranges for these tests are considerably shorter than that

for the general population. For example, even after significant PPH (up to 1500 ml), due to
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uterine atony, genital tract trauma and retained placenta, PT and APPT were normal in 98.4%
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and 98% of cases, respectively, while in the case of placental abruption, they were normal in all
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cases85. Prolongation of PT and APTT may not occur until the underlying condition has

progressed considerably. This is especially in the case of APTT which can be shortened due to
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increased concentrations of factor VIII seen in pregnancy. It is important that in the correct

clinical context, attention is paid to prolongation of the PT and APTT even in the normal range
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as suggestive of thrombin generation and clinical worsening and treatment commenced when
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they are even mildly prolonged86.

Low fibrinogen concentration is often considered in the diagnostic algorithm for DIC. However,

due to the fact that it is an acute phase reactant, is very uncommon for the fibrinogen levels to

be low in pregnant women unless in the setting of massive PPH86. At the same time, in

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comparison with the other clotting factors, fibrinogen levels fall below the normal pregnancy

range sooner with reports suggesting a decrease in serum fibrinogen is an accurate biomarker

for progression from moderate to severe PPH87-89. The pivotal study in this area came from

Charbit et al87 who demonstrated that, in women with uterine resistant atony, a fibrinogen < 2

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g/l had a positive predictive value of 100% for progression to severe PPH, whilst a level > 4 g/l

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had a negative predictive value of 79%. For this reason, importance once again should be given

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to a decreasing fibrinogen level rather than an absolute value with a threshold value of 1.5 g/dl

or even higher recommended for replacement86. Fibrin degradation product measurements

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also have its problems in pregnancy since D-dimers are already raised even before pathological
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states set in. Repeated measurements showing increasing values may be helpful.

Point-of-care testing using devices like thromboelastography (TEG; Haemonetics, Braintree MA,
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USA), or thromboelastometry (ROTEM; TEM GmBH, Munich, Germany) is useful in the

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obstetrical coagulopathic disorders to achieve rapid results and decide intervention. Normal
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ranges have been published for women at the time of delivery compared to the standard

ranges90. Collins et al85 reported the ROTEM Fibtem A5 assay as a very useful marker for
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monitoring haemostasis in this setting. In addition, Sharma et al91 have proposed a

thromboelastographic score, studying 21 patients classified following the International Society

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for Haemostasis and Thrombosis (ISTH) score. They demonstrated that parameters arising from
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this technique may reach a sensitivity of 95.2%, specificity of 81.0%, with the highest receiver

operating characteristic area under the curve of all parameters of 0.957 for identifying overt

DIC. The use of thromboelastometry has been further evaluated in patients with DIC related to

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severe sepsis showing it can be a valuable tool in assessing whole blood coagulation capacity in

patients with severe sepsis with and without overt DIC92.

Data on thromboelastography and thromboelastometry in pregnant women are limited,

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especially during peripartum period and in women with PPH, so more research in this field is

needed. Moreover, preliminary data are encouraging, since these tests may be able to detect

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early alteration of coagulation pathways and hyperfibrinolysis93 allowing, in combination with

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the other diagnostic and prognostic means, like DIC scores, an adequate surveillance and,

eventually, a prompt intervention in obstetric not yet severely affected patients94.

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The acutely bleeding patient does not need any score evaluation but prompt infusion of blood

products according to preexisting protocols. However, in many cases, DIC develops gradually
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and through different underlying mechanisms that are described in the manuscript. In the latter
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group, using such a scoring system can alert the clinician that his patient is deteriorating and
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needs further attention and treatment. In addition, the introduction of such scoring system into

clinical work will help to validate the diagnosis and create a common language between
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clinician and researchers that will assist in the promotion of the understanding and

management of DIC during pregnancy. To address the task of facilitating the diagnosis of DIC, in
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those conditions that do not represent emergencies in which only a clinical diagnosis can be
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achieved, the use of scoring systems has been introduced. The first DIC score has been

recommended by the ISTH in 200170 showing a correlation between key clinical observations

and outcomes. Using the same parameters, the Japanese Association for Acute Medicine

(JAAM) published an additional score in 200595, offering a good predictive value for the

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diagnosis of DIC and the identification of critically ill non-pregnant patients. These scores can be

used not only as a diagnostic but also as prognostic tool. Thus, in the non-pregnant state a DIC

score is important in the diagnosis of patients with DIC and carries a diagnostic and prognostic

value71, 96-98.

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Since the physiologic hemostatic changes occurring in pregnancy affect the application of these

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scores to gestation, an adjusted score for the pregnant state was needed. Based on this

consideration Erez et al5, have recently constructed a pregnancy modified DIC score by using

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only three components of the ISTH DIC score (platelet count, fibrinogen concentrations and the

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PT difference) with an area the curve of 0.975 (p<0.001), and at a cutoff of ≥26 points had a
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sensitivity of 88% and a specificity of 96% for the diagnosis of DIC. At this cutoff, the pregnancy

modified DIC score showed a positive likelihood ratio of 22 and a negative likelihood ratio of
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0.125 (Table 1).

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In order to further validate these results, the performance of this DIC score was compared to
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that of a modified version of the DIC score adopted by the International Society of Thrombosis

and Hemostasis (ISTH) (D-Dimer was excluded from the score). Due to the differences in patient
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selection and definition, comparing the above mentioned score to that proposed by Terao99 in

2007 was not possible.

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Since abruption was the most prevalent cause for blood transfusion and DIC in their population,
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Erez et al5 used these patients for the comparison between the DIC scores. Out of 684 women

with abruption, 150 (21.93%) needed blood transfusion and 43 (6.29%) had DIC. The first

comparison was in the ability to identify patients with abruption who needed blood and blood

product transfusion. Their DIC score had an area under the curve of 0.98 (95% CI 0.96-0.99) at

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a cutoff point of 26 a sensitivity of 88% and a specificity of 96%. The modified ISTH score at a

cutoff point of 0.5 had an AUC 0.85 (95% CI 0.78-0.91), a sensitivity of 74%, and a specificity of

95%.

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The modified DIC score showed a high sensitivity and specificity to identify patients with DIC in

the general obstetric population. The positive Likelihood Ratio above 10 suggested a high

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probability that a positive test score would be really diagnostic for DIC. This is also correct for

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the negative Likelihood Ratio suggesting that a negative result is true, with a very low

probability of such patient having DIC (Figure 3).

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Two more studies have proposed the application of scores of parameters with diagnostic and
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prognostic value to obstetrical practice: 1) Terao et al99 suggested in 1987 a DIC score based on

77 patients with DIC identified in 100 centers in Japan, of which their score identified 70 (90%).
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The score included three main categories: a) etiology- stating whether there is a prominent
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etiology that can explain the development of DIC; b) clinical manifestation- including bleeding
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and organ dysfunction; and 3) laboratory tests- including PT, fibrinogen, FDP, and platelets; a

minimum score of ≥7 was needed for the diagnosis of DIC. However, this score was not
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validated in comparison to the normal obstetric

population, and it is currently not in wide clinical use; 2) Windsperger et al100 studied the utility
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fibrinogen/C-reactive protein (CRP) ratio as a diagnostic and prognostic tool for the
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development of overt DIC in patients with underlying HELLP syndrome. Their population was

containing 19,404 deliveries, with 111 cases of HELLP syndrome, who were divided two groups

as the diagnosis was based on the ISTH criteria. They also used D-dimer concentration. An overt

DIC developed in 11.7% of these patients with HELLP syndrome. This study showed that the

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fibrinogen/CRP ratio could differ significantly between patients who develop DIC and those who

do not, showing to be a better indicator for predicting a DIC than is the fibrinogen level. The

applicability of this parameter into clinical practice is limited by the very small amount of

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patients included who developed the studied condition. Moreover, following the study by Erez

et al5 we can no longer use coagulation parameters of non-pregnant patients in comparison to

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pregnant patients since curves are different and point of care tests perform differently during

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pregnancy, parturition and puerperium. The comparison of a scoring system that is not

adjusted to pregnancy, to laboratory testing taken during acute obstetrical complications such

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as HELLP syndrome needs to be taken with a grain of salt.
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5. What are the current treatments for obstetrical DIC?

The basic principles for treating obstetrical DIC include6, 13, 14, 86: management of the underlying

condition which predisposes to DIC; supportive care with blood products and related measures;

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regular clinical and laboratory surveillance; seeking assistance from the relevant specialists at

the earliest.

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5.1 Management of the underlying condition which predisposes to DIC. DIC is an intermediary

mechanism of disease and is always secondary to an underlying process. This hypothesis is

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supported by the fact that the mortality of DIC associated with placental abruption is less than
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1% whereas that associated with sepsis related to obstetrical cases is 50-80%13. For this reason,
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appropriate management of the primary condition is paramount in limiting the excess thrombin

generation.
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5.2 Supportive care with blood products and related measures. The term consumption

coagulopathy, often classically used for DIC, suggests the need for replacement of blood
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components in the management of DIC. The following principles are considered in this context:
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in relation to the coagulation factors, their reduction has to be considered in relation to their
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haemostatic levels, especially if the patient is bleeding; in the case of platelets, since an

element of platelet dysfunction exists, this may contribute to the bleeding; fibrinogen as an

acute phase reactant has recently been shown to play an important role in hemostasis in

obstetrics as discussed before; an adequate hemoglobin concentration needs to be maintained

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since severe anemia can worsen the rheology by being unable to push platelets towards the

endothelium and also reducing oxygen delivery to already compromised tissues.

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The thresholds for transfusing blood components are those recommended by the harmonized

guidance from the ISTH, except in the case of fibrinogen14, 86. In bleeding patients or those who

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need interventions, this should be started in the following conditions: fibrinogen less than 1.5

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g/L (Two pools of cryoprecipitate should raise the fibrinogen level by 1.0 g/l in the absence of

continued bleeding. If available, fibrinogen concentrate may be used); platelets less than 50 x

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109/L (one to two adult doses of platelets), but if on-going hemorrhage is occurring, a higher
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threshold of 75 x 109/L may be a starting point; PT and APTT prolonged outside normal ranges

(15-30 ml/kg of fresh frozen plasma, higher volumes likely to replace more coagulation factors
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and is preferred if volume overload is not a concern).

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The evidence on different recommendation transfusion protocols for blood products is

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available in the literature101-105 and we suggest the interested reader to refer to them, since a

more thorough evaluation of these protocols is beyond the scope of this review.
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Moreover, an interesting and novel view regarding transfusion protocols deserves to be

mentioned in order to be critically evaluated by the interested readers. This is brought by

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Pacheco et al106 that suggested how transfusion protocols may not be able to sustain patients
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with massive bleeding since crystalloid resuscitation may actually worsen bleeding before

achieving surgical control of hemorrhage increasing the intravascular hydrostatic pressures

(favourishing a dilutional coagulopathy) and by dislodgement of fresh clots at sites of

endothelial injury. Following the evidence107, shared by patients with trauma and obstetric

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patients with massive bleeding, of an early coagulopathy occurring before dilution and

consumption of clotting factors, they suggest a less aggressive crystalloid therapy and an early

administration of fresh frozen plasma, platelets and packed red blood cells in a condition of

acute bleeding not yet associated with catastrophic clinical signs106.

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Tranexamic acid has had resurgence in recent years for the management of massive

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haemorrhage. In the obstetrical setting, the multinational WOMAN trial is likely to improve the

evidence regarding this issue (www.thewomantrial.lshtm.ac.uk). In their recently published

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review, Sentilhes et al108, underlined the presence of little evidence regarding the employment
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of tranexamic acid in the treatment of PPH due to the lack of adequately powered and high-

quality randomized controlled trials on this topic109. Moreover, the updated World Health
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Organization (WHO) guidelines for PPH treatment101 state a possible use of tranexamic acid in
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case other measures (uterotonics, uterine massage, fluid resuscitation) fail, and this is
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suggested in the UK as ‘recommended for consideration’ in cases of intractable PPH110.

A similar conclusion in terms of lack of evidence has been suggested by Wikkelsø et al111 for the
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use of preemptive treatment with fibrinogen concentrate for severe PPH in patients with

normofibrinogenaemia.
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Prothrombin complex concentrates are avoided for the reasons that they may promote
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thrombotic process and do not replace all the clotting factors, especially factor V. It is not an

uncommon practice worldwide to administer recombinant activated factor VII (rFVIIa) in

patients who have massive PPH. However, World Health Organization guidelines advise against

the use of this product outside the context of clinical trials112. Recombinant activated factor VII

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has been identified as global hemostatic agent. Its use in massive PPH decreased maternal

mortality due to hemorrhage113. A recently published randomized controlled trial114, including

eighy-four women with severe PPH unresponsive to uterotonics, evaluated the use of human

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rFVIIa in these patients. The authors found that this molecule reduces the need of specific

second-line therapies (interventional hemostatic procedures, blood transfusions) in about one

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third of the patients, with the occurrence of non-fatal venous thrombotic events in one every

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20 patients. Guidelines suggest its use before proceeding to hysterectomy for massive PPH. A

review including 99 cases115 of DIC treated with rFVIIa, of which 32 were due to massive PPH,

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showed a median dose of 67.2 mg/kg to be effective in controlling hemorrhage. It was also
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found useful in DIC related to malignancy while in the presence of metabolic acidosis the

efficacy of rFVIIa in DIC is much lower. Thus, the timing of its administration during the course
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of the management of DIC should be considered carefully.

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Concerns have been raised about the potential of arterial thrombosis associated with its use. It
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has been found that its use is associated with two-times increased risk for arterial thrombosis

but not with venous thrombosis55. In addition, one must take into account the high cost of this
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treatment.
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5.3 Regular clinical and laboratory surveillance. Since DIC is a dynamic process, close
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monitoring of the patient is crucial in order to evaluate clinical improvement or worsening, to

assess whether the process of DIC is abated or not and notice the development of

complications including organ failure, allowing prompt intervention.

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Repeated monitoring of the laboratory values including full blood count for hemoglobin and

platelet count and clotting screen including fibrinogen is needed.

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5.4 Seeking assistance from the relevant specialists at the earliest. DIC is a complex condition

where dysfunction in multiple organ systems contributes to the pathophysiology and as such,

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the obstetrician should not be left alone in managing the patients but he should be involved as

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the part of a group of physicians from different specialties. As a consequence, attending

surgeons, intensive care specialists, and hematologists, but also all the people involved in the

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patient care, including nurses and support staff has to take part to the case management
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(Figure 3).
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6. Conclusions

DIC is a life-threatening situation that can arise from a variety of obstetrical and non-obstetrical

causes. Prompt diagnosis and understanding the underlying mechanisms of disease leading to

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this complication in essential for favorable outcome. In the recent years novel diagnostic scores

and treatment modalities along with bedside point-of-care tests were developed, and may

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assist the clinician in the diagnosis and management of DIC. Team work and prompt treatment

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are essential for the successful management of patients with DIC.

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Table 1. Comparison among the pregnancy modified DIC score by Erez et al. and the other DIC scores in current clinical use.

Parameters ISTH score JAAM score Modified ISTH score

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Platelet count (10 /L) > 100 = 0 < 80 or > 50% decrease < 50 = 1
within 24 hours = 3

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< 100 = 1 50–100 = 2
≥ 80 but < 120 or >30%
< 50 = 2 decrease within 24 100–185 = 2
hours = 1

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> 185 = 0
> 120 = 0

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Fibrin-related markers no increase: 0 ≥ 25 = 3
(e.g. soluble fibrin
monomers/fibrin moderate increase: 2 ≥ 10 = 1 /

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degradation products)
strong increase: 3 < 10 = 0
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Prothrombin time < 3 sec = 0 ≥ 1.2 = 1 < 0.5 = 0
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(value of patient/normal ≥ 3 sec but < 6 sec.= 1 < 1.2 = 0 0.5–1 = 5

value)
≥ 6 sec = 2 1.0–1.5 = 12
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> 1.5 = 25
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Fibrinogen level (g/L) > 1.0 = 0 3.0 = 25

< 1.0 = 1 3.0–4.0 = 6

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/ 4.0–4.5 = 1

> 4.5 = 0
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SIRS criteria ≥3=1

/ 0-2 = 0 /

Calculated score > 5: compatible with ≥ 4: suggestive of > 26 high probability

overt DIC; repeat disseminated for DIC
scoring daily intravascular
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< 5: suggestive (not

affirmative) for non-
overt DIC; repeat next
1-2 days

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ISTH, International Society for Thrombosis and Haemostasis; JAAM, Japanese Association for Acute Medicine; SIRS, Systemic
inflammatory response syndrome

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Figure 1. Comparison between normal endothelium (top) and placental trophoblast (bottom).

The placenta is in a heightened state of coagulation activation through increased tissue factor

(TF) production. This increases prothrombin (II) to thrombin (IIa) conversion for cleavage of

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fibrinogen into fibrin. Increased amounts of activated thrombin activatable fibrinolysis inhibitor

(TAFIa) is generated, which together with increased levels of plasminogen activator inhibitors

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(PAI) 1 and 2, reduce fibrinolytic activity that would normally occur through tissue plasminogen

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activator (tPA)-induced generation of plasmin (Pm) from plasminogen (Pg) in generating fibrin-

degradation products (fdp). The bold arrows signify increased generation and the dotted arrows

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signify inhibition. From: Disseminated intravascular coagulation in obstetric disorders and its
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acute haematological management. Blood Rev 2009;23:167-76.With permission.
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Figure 2. Disruption of trophoblast integrity, as classically observed in placental abruption,

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leading to a release of a large amount of tissue factor in maternal circulation. This can activate
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the coagulation cascade and propagate an inflammatory response that can easily become

systemic leading to uncontrolled thrombin generation and subsequent development of DIC.

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Figure 3. Algorithm summarizing diagnosis and treatment of DIC.

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