Amniotic fluid embolism: literature review and an integrated concept of pathomechanism

doi:10.4236/ojog.2011.14034

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Open Journal of Obstetrics and Gynecology, 2011, 1, 178-183

doi:10.4236/ojog.2011.14034 Published Online December 2011 (http://www.SciRP.org/journal/ojog/

OJOG

Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJOG

Amniotic fluid embolism: literature review and an integrated

concept of pathomechanism

Mieczysław Uszyński

Department of Propedeutics of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland.

Email: [email protected]

Received 27 July 2011; revised 31 August 2011; accepted 22 September 2011.

ABSTRACT

Literature concerning procoagulant activity of the

amniotic fluid and pathomechanism of amniotic fluid

embolism (AFE) was surveyed and a new concept of

its pathogenesis, called the integrated concept of AFE,

was presented. According to this concept, two com-

ponents of the amniotic fluid are involved: 1) apop-

tosis-affected amniotic cells showing a special role in

the initiation of disseminated intravascular coagula-

tion (DIC) and 2) leukotrienes (formerly called slow-

reacting substances), inducing bronchial and pulmo-

nary vascular smooth muscle contraction. Although

each of these components initiates a different patho-

genic pathway, they both lead to the formation of a

mechanical barrier on blood flow through the lungs

(amniotic debris + microemboli) and/or functional

barrier (pulmonary vasoconstriction). An old dilem-

ma, concerning indications for heparin therapy in

AFE was recalled in the light of the new concept.

Keywords: Amniotic Fluid Embolism; Amniotic Cells;

Tissue Factor; Leukotriens; Disseminated Intravascular

Coagulation; Pulmonary Vasoconstriction

1. INTRODUCTION

Amniotic fluid embolism (AFE) is a rare but serious

condition that affects, according to earlier figures, 1 - 15

cases per 100,000 births, with a case fatality rate ranging

between 13% and 86%, whereas according to one of the

latest figures 7.7 per 100,000 births, with a case fatality

rate of 21.6% (for ref. see: [1]). It is most common dur-

ing labor (70%), although it may also develop after na-

tural delivery (11%) and during or after Cesarean section

(19%) [2].

AFE has been diagnosed since 1941, when two Ame-

rican gynecologists, Steiner and Lushbaugh [3], descri-

bed eight cases of sudden death of childbearing women

It was only after their publication that Meyer’s report of

1926 was noticed—the description also based on the pa-

thomorphology of the lung tissue [4].

Two clinical forms of AFE can be distinguished: 1)

typical, (classic) with three phases (phase 1—respiratory

and circulatory disorders, phase 2—coagulation distur-

bances of maternal hemostasis, phase 3-acute renal fai-

lure and acute respiratory distress syndrome (formerly:

adult respiratory distress syndrome, ARDS), and 2) aty-

pical, without the phase of respiratory-circulatory disor-

ders, beginning with hemostasis disorders in the mother

e.g. uterine hemorrhage or sometimes ARDS and renal

failure.

Three theories explain the pathomechanism of respi-

ratory-circulatory disorders and coagulation disturbances

in AFE, each of which have different premises. Briefly,

according to the mechanical theory, fetal squames and

other morphotic and amorphotic components of the fluid

act as a causative factor, blocking the pulmonary circu-

lation; the thromboplastin theory states that the obstruct-

tion is due to disseminated intravascular coagulation

(DIC), whereas according to the leukotriene theory, it is

leukotrienes that cause catastrophic pulmonary vasocon-

striction.

In the last 20 years, there have appeared case reports

of amniotic fluid embolism that cannot be explained by

any of the known theories. This mainly refers to the

cases of atypical embolism [5-8]. For instance, we can-

not explain the mechanism of isolated disseminated in-

travascular coagulation based on the leukotriene theory.

2. STUDY OBJECTIVE

The objectives of the study were to: 1) assess, based on

literature survey, thrombogenic potential of the amniotic

fluid; 2) discuss discrepancies between the existing theo-

ries of amniotic fluid embolism; 3) present a novel con-

cept of AFE which eliminates the discrepancies con-

cerning the pathomechanism of this complication and

takes into consideration new clinical and laboratory ob-

servations.

M. Uszyński / Open Journal of Obstetrics and Gynecology 1 (2011) 178-183 179

2.1. Historical Considerations Concerning the

Mechanism of AFE

a) Pioneer researchers of AFE, Steiner and Lushbaugh

[3], believed that cardiopulmonary collapse was caused

by disseminated pulmonary embolism of amniotic debris

of fetal origin (squamous cells, lanugo hairs, mucus th-

reads and fat droplets), and not by a biochemical mecha-

nism (mechanical theory of AFE).

b) Many authors—at first Weiner, Reid and Roby in

1949 [9], and later also others—based their explanations

on the presence of tissue factor (TF; formerly called tis-

sue thromboplastin), a procoagulant, in the amniotic

fluid. When the amniotic TF gets to the pulmonary arte-

rioles, it induces, as they thought, intravascular coagula-

tion. The microemboli block blood flow through the

lungs and what is more, consumption coagulopathy oc-

curs (in this way respiratory and circulatory disorders

were explained from the point of view of thromboplastin

theory).

c) The premises of the leukotriene concept of AFE

were first described in the years 1985 and 1986 [10,11],

though an overview of the theory contents was provided

in 1990 [12]. The animal studies revealed that infusion

of these substances resulted in severe pulmonary hyper-

tension followed by systemic hypotension with negative

inotropic effect and decreased cardiac output. It was

assumed that the action observed in animals could occur

in humans as well. According to this theory, metabolites

of the arachidonic acid cascade—mainly leukotrienes,

previously known as slow-reacting substance, but also

thromboxan A2 (TXA2) and others-cause catastrophic

pulmonary vasoconstriction in amniotic fluid embolism.

These metabolites either pass to the lungs with the am-

niotic fluid or are formed in loco after the fluid gets to

the pulmonary vessels.

The leukotriene concept of AFE has predominated

over the previous concepts. However, the search for po-

tent vasoconstrictors and bronchoconstrictors that could

induce embolic symptoms is still continued. Currently,

there are three or even four candidates: leukotrienes +

endothelin-1 + bradykinin + thrombin (see below). How-

ever, whether the action of these substances on the pul-

monary vessels and bronchi is synergistic still remains

unknown.

d) In 1995, hypoxia in AFE was suggested to stimu-

late local production (in the lungs) of endothelin-1 which

is a known potent vasoconstrictors and bronchoconstric-

tors (experimental studies) [13]. Later it was reported

that amniotic squames could also be the source of endo-

thelin-1 [14].

e) In 2005, the role of bradykinin in the pathogenesis

of respiratory and circulatory disorders in AFE was dis-

cussed [15]; bradykinin was suggested to cause contrac-

tion of smooth muscles of the lungs and bronchi, and to

impair pulmonary microcirculation. As far as kinins are

concerned, kininogenesis is a process associated with

coagulation and fibrinolysis. Two factors are a common

link, namely kallikrein and high-molecular kininogen

(HMK). Under the effect of kallikrein, three kinins are

formed from kininogen: Met-kallidin, kallidin and bra-

dykinin. Kinins are degraded by kininases. All compo-

nents of the kininopoietic system have been found in the

amniotic fluid [16]. The most active of the kinin group is

nanopeptide bradykinin.

f) In 2009, Zhou et al. [17] identified (described) the

presence of phosphatidylserine (PS) in amniotic cells

and showed its role in the process of thrombin produc-

tion. The involvement of amniotic cells in the generation

of thrombin is the key to the elucidation of DIC mecha-

nism in AFE (see further).

2.2. Formation and Composition of the

Amniotic Fluid (Remarks)

In the second half of the gestation period, amniotic fluid

is mainly a product of the fetus and only to a small ex-

tent generated by fetal membranes. Fetal excretions pass

directly to the fluid (primary urine, lung, oral and nasal

excretion). They contain epidermal cells, fetal lanugo

and sebaceous gland secretions from the fetal skin (ver-

nix caseosa), desquamated bronchial cells, nasopharyn-

geal cells and urinary tract cells as well as desquamated

cells of the umbilical cord and fetal membranes. In the

case of fetal distress (asphyxia, intrauterine infection),

meconium is excreted from the alimentary tract of the

fetus to the fluid [18,19].

2.3. Procoagulants and Anticoagulants

in Amniotic Fluid

In the past, as a rule, procoagulants, anticoagulants and

fibrinolytic components were searched only in the su-

pernatant, whereas sediment was treated as a biologi-

cally inactive material. The first report on the distribu-

tion of procoagulants in the two fluid fractions, i.e. su-

pernatant and sediment, appeared only in the last ten

years. It has been found that TF is a predominant pro-

coagulant in the supernatant, whereas other coagulation

factors show only a few percent of the global procoagu-

lant activity; TF and a few coagulation factors in an ac-

tive form (IIa, VIIa and Xa) were detected in sediment

[20].

The amniotic fluid does not contain fibrinogen ,factors

V and VIII, but it has all other procoagulants (coagula-

tion factors: II, TF, VII, IX, X-XIII, prekallikrein and

high molecular kininogen, HMK) and anticoagulants (ti-

ssue factor pathway inhibitor, TFPI; antithrombin, AT;

protein C and S; thrombomodulin, TM), which were i-

dentified by activity or antigen. The levels of procoagu-

M. Uszyński / Open Journal of Obstetrics and Gynecology 1 (2011) 178-183

180

lants and anticoagulants are very low as compared to the

plasma (3% - 5% of plasma value). The exception is TF,

whose level in the fluid is higher than in the plasma (for

ref. see: [21]). The higher-molecular weight (46,000)

form of TF predominates in amniotic fluid (in tissues

40,000 - 46,000) [20]. It is assumed that the major sour-

ce of TF in amniotic fluid is the cells of desquamated e-

pidermis of the fetus.

There is evidence for the functioning of the coagula-

tion cascade in amniotic fluid, although its range is in-

complete due to a lack of fibrinogen. However, high

thrombin markers (fragments of prothrombin F1 + 2 and

thrombin-antithrombin complexes, TAT) indicate that th-

rombin is generated there. Thrombin substrates in loco

include protein C and pro-TAFI (procarboxipeptydase B);

the anticoagulant called activated protein C (APC) and

thrombin activatable fibrinolysis inhibitor (TAFI), a spe-

ctacular link between coagulation and fibrinolysis, are

formed there (for ref. see: [21]).

Moreover, the fluid contains other enzymatic systems

having cascade dynamics, which can generate pathoge-

nic substances, such as leukotrienes (arachidonic acid

cascade) and kinins (kallikrein-kinin cascade). Also all

proteins of the fibrinolytic system and products suggest-

ing plasmin activation are found there (for ref see: [22]).

2.4. The Thrombogenic Role of

Amniotic Cells

The majority of amniotic cells are derived from exfolia-

tion of squamous epithelium of the skin, from the mu-

cous membranes of the fetus (respiratory, digestive and

urinary tracts), the umbilical cord and the amnion [19].

During pregnancy, amniotic cells gradually and inevita-

bly go to apoptosis, gaining the properties of a particular

type of procoagulant (procoagulant-like activity).

The apoptotically altered amniotic cells harbor an

aminophospholipid called phosphatidylserine (PS) (ex-

ternalization from the inner layer of the cell membrane),

which has a negative charge and thus can accumulate on

the cell surface factors that become positively charged

when interacting with calcium ions (Ca2+), i.e. the fac-

tors necessary to the formation of thrombin. The proxi-

mity and the surface (the platform) create conditions for

the coagulation factors to interact. Thus, the interaction

of TF with VIIa yields a TF/VIIa complex at first, and

then a triple tenase complex of TF/VIIa/X, which in the

presence of calcium ions transforms the proenzyme,

prothrombin, into the active serine enzyme, thrombin.

Although the action of amniotic thrombin is restricted in

normal conditions to the amniotic fluid, in AFE amniotic

cells act as ready foci of DIC.

The role of amniotic cells in the generation of throm-

bin is a discovery which is the key to elucidate the

mechanism of DIC in amniotic fluid embolism [17]. Al-

ready in 1970, Slunsky [23], a Czech/Austrian author, in

his book on AFE noticed that amniotic cells were fre-

quently found inside microthrombi. We now consider it

to be the effect of thrombin formed on amniotic cells and

transforming fibrinogen into fibrin in its closest vicinity.

Here, a cell-based model of hemostasis proposed by

Hoffman and Monroe [24] in 2001 should be recalled.

According to this model, the surface of fibroblasts and

platelets constitutes a platform for the process of throm-

bin generation—first thrombin is produced in ignition

amounts (initiation of coagulation), followed by subse-

quent phases (amplification and propagation), in which

thrombin is generated in the amount able to produce a

hemostatic plug. The surface of amniotic cells can thus

have a similar role in the process of initiation of coagu-

lation as the surface of fibroblasts and blood platelets.

Amniotic cells seem to compensate for the lack of blood

platelets in amniotic fluid.

2.5. The Phenomenon of Pathogenic Potential of

Amniotic Fluid

Since the turn of the 1940s/50s there has been a dispute

attempting to elucidate whether the amount of TF in am-

niotic fluid embolism can elevate significantly TF con-

centration in the mother’s blood and whether this a-

mount can induce DIC. Researchers have varied in their

opinions in this field.

In 1957 Schneider [25] wrote: “Plausible as this at fir-

st seems, proof of significant release of thromboplastin

is still lacking”. In 1972 Phillips and Davidson [26] con-

cluded their research with the following: “The amount of

procoagulant …is probably insufficient to cause signify-

cant intravascular coagulation…”. A spectacular calcula-

tion by Mac Millan of 1968 [27] stated that the patho-

genic amount of TF could be found in 7 liters of the fluid,

whereas the volume of a genuine embolus was estimated

at 10 ml - 100 ml. Meta-analysis of my own study of

2003 [28] showed that TF contained in 100 ml super-

natant could cause only a statistically insignificant in-

crease in TF concentration in maternal blood (not ex-

ceeding standard deviation).

Despite these reservations, there can be a positive an-

swer to the question concerning the pathogenicity of am-

niotic TF. The following hypothesis can be proposed:

There are two TF fractions in amniotic fluid: 1) free

fraction found in the supernatant and 2) TF-cell bearing

(harboring) fraction, bound to the apoptosis-affected

amniotic cells. Only the TF fraction found on the surface

of amniotic cells can be ascribed the role of the initiator

of coagulation. These cells—after reaching pulmonary

arteries (amniotic embolism)—immediately become the

foci of fibrinogen transformation into fibrin (coagula-

tion), since they already have thrombin, an active serine

M. Uszyński / Open Journal of Obstetrics and Gynecology 1 (2011) 178-183 181

enzyme, on their surface. On the other hand, the fraction

of “free TF”, i.e. TF found in the supernatant, does not

play a pathogenic role in amniotic fluid embolism.

Thus, the phenomenon of the thrombogenic potential

of amniotic fluid can be explained by integrated action

of three factors: 1) PS found on amniotic cells; 2) TF

and a few other coagulation factors that accumulate on

amniotic cells and form thrombin, and 3) the very am-

niotic cells which make a platform for thrombin genera-

tion.

3. NEW CLINICAL OBSERVATIONS

During the last 20 years some new, spectacular and ef-

fective diagnostic and therapeutic methods have been

described, which inspires revision of the common views.

This refers to e.g. the case of embolism after Cesarean

section reported by Esposito et al. in 1991 [29] and dur-

g Cesarean section described by Stanten et al. in 2003

[30]. In both cases, circulation arrest occurred and since

standard resuscitation procedure was ineffective, after

full heparinisation, cardiopulmonary bypass was insti-

tuted with a successful result. In the former case [29],

massive embolisation to the lung (pulmonary perfusion

scan) and embolus in the pulmonary artery with high

concentration of fetal squames (thromboembolectomy)

were detected, in the latter [30]—although the lumen of

the pulmonary arteries was free, transesophageal echo-

cardiogram showed catastrophic pulmonary vasoconstri-

ction. In both cases severe consumption coagulopathy was

observed.

These descriptions can be interpreted in the following

way: 1) disseminated intravascular coagulation (DIC)

takes place not only in pulmonary arterioles, but can also

reach the bifurcations and even the trunk of the pulmo-

nary artery, with fetal squamous cells and fibrin forming

“primary + secondary” embolic material (case 1); 2) two

pathogenic routes may exist alongside (catastrophic DIC

and catastrophic pulmonary vasoconstriction), and

therefore both routes should be considered during thera-

py (case 2); 3) full heparanisation was performed in car-

diopulmonary bypass procedure, which undoubtedly fa-

cilitated the maintenance and recovery of pulmonary va-

scular patency; 4) The process of DIC was already pre-

sent at the very beginning of the complication and if so,

only a targeted and immediate treatment could reduce

this process (pathogenetic treatment).

3.1. An Integrated Concept of Amniotic

Fluid Embolism

In the integrated concept of amniotic fluid embolism

(Figure 1), two amniotic fluid components, i.e. the apo-

ptosis-affected amniotic cells and leukotrienes play a role.

Figure 1. The mechanism of respiratory and circulatory disor-

ders in amniotic fluid embolism: two pathogenic pathways (A)

leading to catastrophic blockade of lung function (B), and cli-

nical sequels (C).

Each of these components induces different pathogenic

pathway (chain) in pulmonary vessels: 1) the apop-

tosis-affected cells become foci of thrombin, which leads

to DIC (DIC pathway); 2) leukotrienes and other me-

tabolites of arachidonic acid cascade, and possibly coex-

isting with them vasoactive substances, e.g. amniotic

endothelins, kinins and shock neurotransmitters, as well

as thrombin generated in the coagulation foci cause

catastrophic pulmonary vasoconstriction together with a

chain of sequels due to anoxia (the leukotriene pathway).

The obstruction of blood flow through the lungs is a

direct cause of cardio—pulmonary collapse. The blocka-

de occurs due to the following: 1) blood flow through

the lungs is hindered or blocked by amniotic cells and

amniotic debris found in pulmonary arteriolar circulation

(mechanical action per se); moreover, the blockade is

enhanced by secondary embolic material produced in the

process of DIC (fibrin accumulating around amniotic

cells); 2) pulmonary vasoconstriction caused by leukot-

rienes and/or other substances. Both types of disorders

have the same “onset time”.

3.2. Clinical Remark

In the light of the integrated concept of amniotic fluid

embolism, an old dilemma, i.e. indication for heparin

therapy in amniotic embolism, should be recalled. The

use of heparin or alternative medications (streptokinase,

recombinant tissue plasminogen activator, trasylol) should

be discussed and decided by appropriate scientific socie-

ties. “Full heparinization”—the management mentioned

in the casuistic reports cited can be indicated as a direc-

tion to follow. Literature reports on some signals con-

M. Uszyński / Open Journal of Obstetrics and Gynecology 1 (2011) 178-183

182

cerning controlled heparin therapy in the first phase of

typical embolism (for ref. see: [31]).

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