Fetal Thrombotic VasculopathyPerinatal Stroke, Growth Restriction, andOther Sequelae

Frederick T. Kraus, MD

KEYWORDS

� Fetal thrombotic vasculopathy � Clots � Placental oxygen � Fetal circulation

Key Features

ABSTRACT

FTV: POTENTIAL MORPHOLOGIC OR

CLINICAL ASSOCIATIONS AND SEQUELAE

Obstructive cord lesion or cord accident(common)

Admit to neonatal ICU; normal at discharge(common)

Neonatal encephalopathy (%)

Cerebral palsy (rare); includes cerebralinfarct, porencephalic cyst, hypoxic-ischemicencephalopathy

Stillbirth (uncommon)

Intrauterine growth restriction (uncommon)

C lots in the fetal circulation of the placentamay occlude or narrow the lumens of fetalvessels sufficiently to diminish the placental

oxygen and nutritional exchange, causing signifi-cant reduction in placental function. Whenextensive, growth restriction, neonatal encepha-lopathy, and stillbirth may occur. Propagation ofclots in other organs, such as brain, kidney, andliver, may affect the function of these organs,resulting in infarcts and neonatal stroke. Thisarticle presents an account of the placentalpathology and clinical sequelae of this condition,called fetal thrombotic vasculopathy.

Oligohydramnios

Maternal diabetes mellitus (common)

Maternal autoimmune disease (lupus, anticar-diolipin antibodies, and so forth) (uncommon)

Severe acute respiratory syndrome (rare)

Cytomegalovirus, Toxoplasma gondii (rare)

Transverse limb reduction (rare)

Maternal thrombophilic state (occurs equally innonthrombophilic mothers)

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OVERVIEW

Fetal thrombotic vasculopathy (FTV) is a vascularthrombotic condition causing obstruction ofarteries and veins in the fetal circulation of theplacenta, resulting in ischemic changes in the villiperipheral to the obstruction. When sufficientlyextensive, FTV may cause a reduction in functionalplacental reserve or in other cases may be associ-atedwith additional thrombotic or thromboembolicevents in the somatic vessels of the fetus itself.When extensive, the former condition can lead tofetal growth restriction or stillbirth, whereas thelatter may result in infarcts of various fetal struc-tures, such as the brain, kidney, or, rarely, anextremity, such as an arm or leg. As with intravas-cular clotting in general, causal factors of FTVinclude a combination of the triad of stasis (bycompression of cord or aberrant vessels); a throm-bophilic state, both genetic (eg, protein S or factorV Leiden) and acquired (anticardiolipin antibody

Department of Obstetrics and Gynecology, Washington UScott Avenue, St Louis, MO 63110, USAE-mail address: krausf@wudosis.wustl.edu

Surgical Pathology 6 (2013) 87–100http://dx.doi.org/10.1016/j.path.2012.10.0011875-9181/13/$ – see front matter � 2013 Elsevier Inc. All

and so forth); and vascular injury (inflammatoryand localized compression). The most seriousoutcomes include growth restriction, neurologicinjury, and perinatal death.

PREVALENCE

In an unselected series of 1153 deliveries, FTV wasidentified histologically in 11 placentas (1%),

niversity School of Medicine, Campus Box 8064, 4566

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eclinic

Box 1Risk factors for fetal thrombotic vasculopathy

Stasis: cord compression and cord hypercoiling

Maternal diabetes mellitus

Neonatal encephalopathy

Growth restriction

Stillbirth

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including 1 case of maternal gestational diabetesand 2 newborns small for gestational age; the re-maining 9 mothers and newborns were clinicallynormal.1 In a selected series of 2910 placentassubmitted for clinical indications from a total of19674 deliveries, 183 placentas (6%) had histo-logic FTV.2

CLINICAL FEATURES

Before delivery, FTV is clinically silent, with nopredelivery warning of its presence. As discussedpreviously, FTV occurs more frequently inplacentas selected for clinical study than in unse-lected pregnancies, but the factors involved inselection of placentas for pathologic study arediverse and nonspecific: maternal hypertensionand diabetes mellitus, fetal growth restriction,abnormal fetal heart rate during labor, and so forth.Ultrasound and other imaging techniques do notdetect FTV. When there seems to be some sortof fetal distress during labor, there is no way tosuggest that the actual cause of these symptomsis FTV until the placenta is examined. In mostcases, when FTV is identified on placental exami-nation, the newborn usually appears well, thereare no subsequent clinical abnormalities in thenursery, and the newborn goes home on schedule.Especially in more extensive or severe cases, FTVis associated significantly with neonatal encepha-lopathy,3 cerebral palsy,4 intrauterine growthrestriction,5 stillbirth, oligohydramnios, and fetalcardiac anomalies.6 Cerebral infarcts may be themost common specific cerebral lesion associatedwith placental FTV.7

Other fetal structural anomalies attributed tovascular disruption (including thrombi) includeporencephaly, cerebral infarcts, bowel atresias,gastroschisis, unilateral renal absence, cleftlip or palate, and transverse limb or digitreduction.8

RISK FACTORS

The most significant predisposing abnormalitiesare problems resulting in vascular stasis. Theseinclude cord prolapse, hypercoiling, and velamen-tous insertion.9,10 Large vessel thrombi havea similar effect. FTV is a major finding in cases ofstillbirth, even after the vascular featuressecondary to stillbirth itself are excluded.6 Ina study of 130 stillbirths in Australia, proved peri-natal cytomegalic inclusion infection occurred in20 cases; FTV was found disproportionately inmore (60%) of the cytomegalovirus casescompared with a smaller number (28%) of thenoninfected cases. FTV may occur more

frequently in association with maternal diabetesmellitus.1 Extensive FTV was discovered in theplacentas of 2 women convalescent in the thirdtrimester with severe acute respiratory syndromeduring an outbreak in Hong Kong11; the 2newborns were growth restricted.The possibility of a correlation between

placental FTV and parental or fetal thrombophiliashas been suggested by anecdotal observationsand some earlier studies.12–15 Later observations,controlled by comparing FTV cases with non-FTVcases, found similar proportions of maternalthrombophilias in the FTV and non-FTV cases.16–18

FTV and thrombophilias occur together, buta thrombophilia alone does not seem to increasethe prevalence of FTV.Box 1 summarizes risk factors for FTV.

GROSS FEATURES

Thrombi in the larger vessels of the chorionic plateare often visible on gross examination (Fig. 1).Distension of the chorionic plate vessels (Fig. 2)should prompt a search for thrombosed fetalvessels and for devascularized villi by selectingmultiple tissue blocks for histologic confirmation.Regions to select for this purpose include pale trian-gular regions with a base at the maternal surface(Fig. 3). Areas of villous parenchyma peripheral toan occluded vein are often darker red and con-gested. Older lesions may become firm and depig-mented, eventually with a gray-white color. Evenlarge lesions can often be indistinct and difficult torecognize. Formalin fixation may accentuate theappearance of lesions that were not apparent onsectioning of the fresh placenta.FTV is commonly associated with functionally

significant or potentially obstructive lesions ofthe umbilical cord, including velamentous inser-tion, hypercoiling, abnormally long cord, andeffects of compression and stasis, such as fetalvascular ectasia and major fetal vesselthrombosis.9,19

Box 2 summarizes the gross morphology ofFTV.

Fig. 1. A recent thrombuscaused expansion of alarge fetal artery in thechorionic plate, near thecord insertion, at the leftmargin.

Fig. 3. Multiple areas ofFTV form pale triangularareas with base at thematernal surface. Thisnewborn had severe neo-natal encephalopathy.Avascular villi from thisplacenta are shown inFig. 10.

Fig. 2. Note the distendedvessels in the chorionicplate, as seen in cross-sections of the placenta.Extensive FTV was presentin all 12 microscopicsections from widely dis-tributed areas, resulting indilatation and congestionofvesselsproximal tozonesofobstruction. (FromKrausFT, Redline RW, Gersell DJ,et al. Placental Pathology.Washington, DC: Americanregistry of Pathology;2004:144;withpermission.)

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Box 2Gross morphology of fetal thromboticvasculopathy

Large vessels: red or light brown occlusive ornonocclusive thrombi; distended vessel lumenssuggesting stasis and increased pressure

Placental cross sections: wedge-shaped areas,pale red-pink if recent; pale tan, if older (chronic)

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MICROSCOPIC FEATURES

The microscopic patterns of the vascular lesionsgrouped under the general term, fetal thromboticvasculopathy, vary, especially as the lesionsevolve over time. The appearance of the lesionsin the larger vessels of the chorionic plate andstem vessels differs from that of the lesions inthe capillaries of the terminal villi.Thrombi in larger vessels have an evolving

sequence similar to the histologic changes in throm-bosed veins and arteries in adults. Acutely, thevessel wall is distended; the clot becomes adherentas the endothelial cells lyse anddisappear and oftendevelops a layered appearance with strata of redcells alternating with leukocytes and fibrin (Fig. 4).The breakdown of the endothelial interface allowsred blood cells to extravasate and become distrib-uted in variable numbers into the vessel wall (Fig. 5).A variant early lesion is a focal accumulation of

fibrin, with or without edema, beneath the vascularendothelium of stem vessels, called fibrinous vas-culosis.20 In some cases, stem vessels become

narrowed by expanded subendothelial organizingmasses of connective tissue matrix, lesions calledintimal fibrin cushions (Fig. 6).21 Focal calcificationin these lesions is generally accepted as evidenceof increasing chronicity.Progressively, as thrombi age and become

chronic, spindle cells resembling fibroblasts appearwithin the thrombus, forming a pattern called septa-tion, in which the fragmenting red cells are dividedinto multilocular spaces (Fig. 7). Eventually thevessel lumen becomes obliterated, so that only anindistinct outline remains; red blood cells, distortedand fragmented, may persist even in the lumenand in the degnerated vascular wall (Fig. 8). Calcifi-cationmay occur focally in the vessel wall as well asin theclot itself (seeFigs.4and6).Histologicdistinc-tion between arteries and veins after these chronicalterations becomes difficult or impossible.Hemorrhagic endovasculopathy (HEV) is a vaso-

disruptive process affecting fetal vessels, from thelarger stem vessels down to fetal capillaries. Atearly stages, the integrity of the vessel wall is lostand fragmented endothelial nuclei persist, inter-mixed with masses of erythrocytes that spill outinto the villous stroma and dissect into the wallsof larger vessels. The stem vessel wall in HEVappears consistently disrupted with extravasationof red cells. The affected villi in HEV may appearfilled, even expanded, by stromal hemorrhage. Intime, the stem vessels of both FTV and HEV mayshow septation and the villi eventually becomeavascular and hyalinized.I have been able to show that villi in the distribu-

tion of a large placental vein showed the hemor-rhagic pattern of HEV (Fig. 9A),2 suggesting that

Fig. 4. Layered bloodelements formed progres-sively over a period ofseveral days in thisthrombus occluding alarge chorionic plate ves-sel. Note more recentstratification of red bloodcells alternating withlayers of fibrin and leuko-cytes at bottom left. Thereis an older pale blue gran-ular zone of calcificationnear the right margin(hematoxylin-eosin, orig-inal magnification �15).

Fig. 6. This chronic intimalfibrin cushion forms anexpanded mass withinthe wall of a large cho-rionicplateartery,bulginginto the lumen. A morerecent lesion would con-tain intramural fibrin orfibrinoid. An adherentmural thrombus maysometimes be present.Focal calcification, as inthis image, is common(hematoxylin-eosin, orig-inal magnification �300).

Fig. 5. Chorionic plateartery (right) occluded bythrombus several daysold, with prominent infil-tration by fibroblasts.Note the extravasationof red blood cells atthe endothelial margin.There are clumps of fibrinwithin the clot (hematox-ylin-eosin, original mag-nification �200).

Fig. 7. Septation in a stemartery is characterized bystrands of spindle-shapedfibroblastic cells that dissectinto the lumen, separatingclustersofredcells intosmallloculated spaces (hematox-ylin-eosin, original magnifi-cation �200). This is fromthe sameplacentaas showninFigs.4,5, and11. Thispro-cess begins multifocally inareas of stasis in approxi-mately 2 days and becomesextensive after 2 or moreweeks. (From Genest DR.Estimating the time ofdeath in stillborn fetuses: II.Histologic evaluation of theplacenta; a study of 71 still-borns.ObstetGynecol 1992;80:585–92;withpermission.)

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Fig. 8. This is an olderoccluded stem vessel,with completely obliter-ated lumen. Scattereddegenerating red bloodcells persist in the orga-nized central area (hema-toxylin-eosin, originalmagnification �100).

Fig. 9. (A) Acute villouslesion. This instance ofmore extensive acuteintravillous hemorrhagewas traced to an occlusivethrombus in a large veinjust before joining theumbilical vein. (B) Acutevillous lesion. Fetal villouscapillary lesions of recent(2–4 days) duration showdisappearance of mostendothelial cells, extrava-sation, and fragmentationof red blood cells, ina region of stasis down-stream from a recent stemvessel thrombus (hema-toxylin-eosin, originalmagnification�300).

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Fig. 10. Old, chronic avas-cular hyalinized villi showmineralization inthebasallamina beneath the tro-phoblastic layer, visible inthis hematoxylin-eosin–stained section. Such hya-linized villous lesionswere extensive inmultiplesections of this placenta(hematoxylin-eosin, orig-inal magnification �200).This is the same sameplacenta as shown grosslyin Fig. 3.

Fetal Thrombotic Vasculopathy 93

this may be a variant of FTV in which the mainocclusive vessel is sometimes a large placentalvein. The clinical and pathologic features of typicalFTV and HEV have many similarities. The villi andvillous capillaries in the regions of placenta servedby the occluded veins or arteries no longer func-tion. In recent lesions (2–5 days), the capillaryendothelial cells are at first fragmented (see

Fig. 11. These villi, fromthe same placenta asshown in Figs. 4, 5, and7, show chronic villouschanges of FTV at themargin of a much largerlesion. The villi clusteredat left are avascular andhyalinzed, in contrast tosome adjacent normallyperfused villi at right.The fetus associated withthis placenta experiencedintrauterine death just 36hours before delivery.There were both old andrecent thrombi in thefetal vessels, andmultipleclusters of hyalinizedavascular villi were pre-sent in this placenta. Theintravascular clotting in-jury in this placenta began many days, possibly even weekduring the course of this carefully monitored pregnancy (h

Fig. 9B); then the red cells, also fragmented, areextravasated, sometimes extensively into thevillous stroma (see Fig. 9A). Ultimately, both capil-laries and red cells disappear (Fig. 10). In chronicvillous lesions (4–5 weeks), only an acellular hya-linzed core remains, surrounded by the villoustrophoblast, which remains viable (Fig. 11). Thetrophoblast layer survives because it is kept alive

s, before the fetal death. No symptoms were detectedematoxylin-eosin, original magnification �200).

Fig. 12. Avascular hyali-nized villi after Prussianblue stain for iron showdark blue linear depositsin the basement mem-branes beneath thetrophoblast layer (Prus-sian blue, original magni-fication �200).

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by the continued circulation of maternal blood inthe intervillous space. Iron is deposited in thebasement membrane beneath the trophoblast(Fig. 12) and in small clumps in the villous stromaas the red cells disappear.Box 3 summarizes the microscopic morphology

of FTV.

Box 3Microscopic morphology of fetal thromboticvasculopathy

Stem vessels, chorionic plate vesselsRecent thrombi are adherent to the vessel wall,the endothelium is gone, and there is focal orextensive red cell extravasation.

Older, chronic thrombi have a fibroblastic infil-trate into the thrombus, withmarked red bloodcell extravasation and fragmentation; areas offibrovascular sclerosis and endothelial cushionsare often calcified.

Distal chorionic villiIn recent lesions, variably sized clusters of villihave stromal-endothelial karyorrhexis and redblood cell extravasation. The intervillous spaceis normal and the syncytiotrophoblastic epithe-lium survives.

In chronic lesions, the clusters of villi are nowavascular with hyalinized stroma, but thetrophoblastic cover still persists. The basallamina beneath the trophoblast becomesmineralized (iron stain positive).

DIFFERENTIAL DIAGNOSIS

INTRAUTERINE FETAL DEATH

The histologic changes in vascular morphologyafter intrauterine fetal death, like the vascularchanges in FTV, result from cessation of bloodflow through the fetal vessels, except that thechanges are diffuse throughout the entireplacenta. The vascular changes are all approxi-mately the same age, however, which dependson the length of time between fetal death anddelivery. In contrast, the clusters of avascular villiof FTV form well-circumscribed clusters, sur-rounded by normally perfused villi. The endothelialcells fragment and the blood in larger stem vesselsafter fetal death is soon invaded by spindle-shaped fibroblasts, but the layered strata of leuko-cytes, fibrin, and red cells characteristic of thrombiin flowing blood does not occur. Red cells extrav-asate into the adjacent stroma. It takes approxi-mately 2 days for the early changes of FTV toappear in villi,22 so older, avascular hyalinzed villior other well-established FTV changes identifiedwithin a 48-hour interval between fetal death anddelivery (see Fig. 12) are truly pathologic FTVlesions, even though the stillborn (see Fig. 12description) died 36 hours before delivery.23

CHRONIC VILLITIS WITH OBLITERATIVE FETAL

VASCULOPATHY

The larger affected areas are grossly indurated,with a gray-tan color and irregular blotchy outlines

Fig. 13. These are cross-sections of a placentawith extensive localizedareas of chronic villitis.The affected areas arefirm, pale, and generallywell circumscribed, withfunctional placental villiin-between.

Fetal Thrombotic Vasculopathy 95

(Fig. 13). Stem villi involved by foci of chronic vil-litis may be infiltrated by the inflammatoryprocess, and blood vessels may become throm-bosed due to local endothelial injury (Fig. 14).The thrombi are generally limited to inflamedstem villi, but downstream avascular villi are notnecessarily always involved in the inflammatoryprocess. The inflamed villous stroma is infiltratedby predominately CD8-positive maternal T-lymphocytes and macrophages (predominatelyactivated Hofbauer-type fetal macrophages).24

Fig. 14. Chronic villitiscausing agglutination ofvilli at left. The occlusivestem vessel thrombusjust below center re-sulted in downstreamischemia of clusters ofavascular villi at right(hematoxylin-eosin, orig-inal magnification �100).

Groups of villli may become agglutinated by fibrinon the villous surfaces. Clusters of downstreamterminal villi are avascular and hyalinized, asseen with FTV. Unlike with FTV, there is noevidence of cord occlusion.

MESENCHYMAL DYSPLASIA

The placenta is usually enlarged; chorionic platevessels are conspicuously, even aneurysmally,dilated, tortuous, and often contain large mural

Fig. 15. Mesenchymaldysplasia. Dilated, aneu-rysmal stem vessels arepartially occluded bythrombi and surroundedby excessive amounts ofedematous mesenchyme(hematoxylin-eosin, orig-inal magnification �15).

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thrombi (Fig. 15). Many large, vesicular, swollen,edematous villi have an appearance suggestive ofmolar villi (Fig. 16). Placental ultrasound imagesareoften interpretedaspartial or complete hydatidi-form mole. There is an increased amount of edem-atous mesenchymal villous stroma. Trophoblastichyperplasia, a feature of partial or complete moles,is not present.25 The fetus, typically female, mayappear normal, but is often growth restricted, andsome fetuses are stillborn, depending on theamount of functioning placenta available to thefetus. There is an association with Beckwith-Wiedemann syndrome in approximately one-thirdof cases.

INFARCT

The intervillous space in FTV remains open andperfused by maternal blood, whereas the intervil-lous space of an infarct is collapsed as the villibecome adherent, separated only by thin strandsof fibrin. The syncytiotrophoblast cover ofinfarcted villi undergoes necrosis and disappears,whereas the trophoblast surface of villi in FTVremains viable. In time, all of the cellular compo-nents of an infarct undergo necrosis and nuclearstaining disappears throughout.Table 1 presents a summary of differential

diagnoses.

Fig.16. Mesenchymaldys-plasia. Many enlargedsubchorionic villi containabundant pale gray con-nective tissue; some havedilated stem vessels. Aprominent component ofmore normal villousparenchyma at left con-trasts with the markedlydysmorphic componentat the right. (Courtesy ofDeborah J. Gersell, MD,St. John’s Mercy MedicalCenter, St Louis, MO; withpermission.)

Table 1Differential diagnosis of fetal thromboticvasculopathy

FTV VersusHelpful DistinguishingFeatures

Intrauterine fetaldeath

� Fetal vascular changesappear generallyuniform in all placentalsections

Chronic villitis � Patchy lymphohistio-cytic infiltrate in villi

� Inflammation in wallsof thrombosed vessels

Mesenchymaldysplasia

� Extreme vasculardistension: varicosities

� Scattered large hy-dropic mesenchymalvilli

� Vessel proliferation

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IMPACT ON OUTCOME

Placentas affected by FTV result in a 9-foldincrease in prevalence of stillbirth, a 6-foldincrease in cardiac abnormalities, and a 2-foldincrease in growth restriction,6 in comparisonwith normal placentas. The odds ratio for pretermbirth is also increased.6 Some newborns with FTVmay have clinical or autopsy evidence of throm-botic lesions elsewhere in the fetal circulation.Infarcts in the brain, which may occur before birth

Fig. 17. This cerebral in-farct has chronic histologicfeatures, associated withthrombi in the fetal circula-tion in the placenta, possiblytheresultofembolismtothemiddle cerebral artery. Thecentral necrosis, focal calcifi-cation,andmarkedastrocyticproliferation indicate at leastseveral days’ duration. Thenewborn had bradycardiaduring labor and severeneonatal encephalopathybut livedonly 2.5hours afterbirth; the placenta showedextensive chronic FTV withmanyclustersofavascularhy-alinized villi. Both the FTVand the cerebral infarctoccurred prenatally, longbefore the delivery (hema-toxylin-eosin,originalmagni-fication�100).

(Fig. 17), have been demonstrated in perinatalautopsies.2,26 In a study of 186 neonatal strokepatients in the Canadian Pediatric Ischemic StrokeRegistry, only 12 had placental pathologic exami-nations, but of these 12, 6 had thrombi in cord,chorionic plate vessels, or other features ofFTV.27 FTV is also an important cause ofhypoxic-ischemic encephalopathy, especiallywhen associated with obstructive umbilical cordproblems.28 An autopsy study of stillbirths thatcorrelated neuropathology with placentalpathology found that FTV correlated with neuronalinjury (nuclear karyorrhexis) in the brain.29

Instances of gangrene of an arm or leg associ-ated with FTV are rare,30 but dramatic, whenthey occur.31 Some cases of bowel atresia havealso occurred in this context, as a feature ofvascular disruption (Fig. 18).8 Placental veinthrombi appeared to have had some significancein the development of a case of twin reversed arte-rial perfusion sequence reported by Steffensenand colleagues.32 In a similar context, sudden,rapid onset of twin-twin transfusion syndromeoccurred as the result of a thrombus forming inone of the balancing AV anastomoses in a mono-chorionic twin placenta.33

Both fetal somatic thrombi and placentalthrombi (FTV) give no specific sign or symptomof their presence until fetal death occurs or growthrestriction becomes apparent. There may bereduction of amniotic fluid, but this is nonspecific,and growth restriction has many causes. FTV wasone of the main placental lesions (27% of cases of

Fig. 18. Esophageal atresiaassociated with extensiveplacental FTV. Very recentfetal death in uterooccurred at 32 weeks. Thelargest fetal vessels at thechorionic plate appeareddilated and congested.The cord had a singleumbilical artery and wastightly wrapped multipletimes about the left leg ofthe fetus, resulting in com-pression marks on the leg.There were several largestem vessel thrombi; bothold hyalinized villi andmore recent hemorrhagicvilli with extravasated redblood cells were present.Instances of atresia in thedigestive tract have beenattributed to vasculardisruptions, most likelycaused by thrombi. Unfor-tunately, attempts to relatebowel atresia to placentalpathology are not com-monly made.

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severe intrauterine growth restriction) causingreduced or reversed end diastolic blood flow, asdemonstrated by umbilical cord blood flowDoppler velocimetry.5

FTV may increase progressively as the processof intravascular thrombosis extends within theplacenta. Thus, FTV tends to reduce placentalfunction progressively without causing perceptibleinjury until the cumulative effects of reducedplacental reserve and the stress of labor onsetcombine to cause heart rate abnormalities, suchas bradycardia, fetal distress, and even late peri-natal stillbirth. It should be emphasized that FTV,as well as other pathologic processes that affectthe placenta, commonly begin long beforedelivery, but produce no symptoms, and, finally,as injury progresses, may produce nonspecificstress related alterations, such as bradycardia,

occur at onset of labor. Often it is at this stressfultime, hours before delivery, that the reducedplacental function finally causes acute injury tothe brain, kidneys, and other organs of the fetus,even though it is the older placental pathologiclesions that initiated the chain of events that culmi-nated in the serious injuries that the newborn mustface after delivery.Growth restriction is common when involvement

is more extensive. When the placenta is also smallfor gestational age, the cumulative effects ofreduced size and more extensive lesions mayenhance the destructive effects of reducedplacental function on the organs of the fetus.Long-term follow-up of newborns with FTV that

was not associated with either reduced placentalfunction, in the absence of symptomatic clots inthe somatic circulation is not available.

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UMBILICAL CORD THROMBI

Cord thrombi may be evident grossly as localizedareas of fusiform enlargement or discoloration.Old thrombi may calcify. They may be associatedwith knots, torsion, amniotic bands, varices, infec-tion, compression, or velamentous insertion. Theumbilical vein is most commonly affected.

Thrombi in umbilical cord vessels may be partlyor completely occlusive. There is a strong associ-ation with fetal morbidity, including growth restric-tion, and two-thirds are stillborn. Heifetz34 foundan incidence of 1:1000 perinatal autopsies,increasing to 1:250 in high-risk pregnancies. Inan autopsy series of 317 consecutive stillbirths at15 to 40 weeks gestation, Avigliano andcolleagues35 found 32 cases with thrombi in cordvessels, an incidence of 1:10. The larger incidencein this report may be related to an acceptance offibrin identified only in phosphotungstic acid-he-motoxylin stains of cord as evidence of clots,even if lacking adherence and changes at theclot-endothelial interface in some cases; othersin this study did show loss of endothelium andextravasation of red cells at the inner vesselmargin. The umbilical vein was most ofteninvolved. Cord abnormalities (eg, knots and hyper-coiling) were present in 13 cases. Cord thrombiand FTV do occur together, but not invariably, inthis series, as well as in my experience.

REFERENCES

1. Pathak S, Lees CC, Hackett G, et al. Frequency and

clinical significance of placental histological lesions

in an unselected population at or near term. Virch-

ows Arch 2011;459:565–72.

2. Kraus FT, Acheen VI. Fetal thrombotic vasculopathy

in the placenta: cerebral thrombi and infarcts, coa-

gulopathies, and cerebral palsy. Hum Pathol 1999;

30:759–69.

3. McDonald DG, Kelehan P, McMenamin JB, et al.

Placental fetal thrombotic vasculopathy is associ-

ated with neonatal encephalopathy. Hum Pathol

2004;35:875–80.

4. Redline RW. Severe fetal placental vascular lesions

in term infants with neurologic impairment. Am J Ob-

stet Gynecol 2005;192:452–7.

5. Dicke JM, Huettner P, Yan S, et al. Umbilical artery

Doppler indices in small for gestational age fetuses.

Correlation with adverse outcomes and placental

abnormalities. J Ultrasound Med 2009;28:1603–10.

6. Saleemuddin A, Tantbirojn P, Sirois K, et al. Obstetric

and perinatal complications in placentas with fetal

thrombotic vasculopathy. Pediatr Dev Pathol 2010;

13:459–64.

7. Takenouchi T, Kasdorf E, Engel M, et al. Changing

pattern of perinatal brain injury in term infants in

recent years. Pediatr Neurol 2012;46:106–10.

8. Gilbert-Barness E, Van Allen MI. Vascular disrup-

tions. In: Gilbert-Barness E, editor. Potter’s

pathology of the fetus and infant. 2nd edition. St

Louis (MO): Mosby; 2007. p. 176–200.

9. Redline RW. Clinical and pathological umbilical cord

abnormalities in fetal thrombotic vasculopathy. Hum

Pathol 2004;35:1494–8.

10. Tantbirojn P, Saleemuddin A, Sirois K. Gross abnor-

malities of the umbilical cord: related placental

histology and clinical significance. Placenta 2009;

30:1083–8.

11. Ng WF, Wong SF, Lam A, et al. The placentas of

patients with severe acute respiratory syndrome:

a pathophysiological evaluation. Pathology 2006;

38:210–8.

12. Arias F, Romero R, Joist H, et al. Thrombophilia:

a mechanism of disease in women with adverse

pregnancy outcome and thrombotic lesions in the

placenta. J Matern Fetal Med 1998;7:277–86.

13. Khong TY, Hague WM. Biparental contribution to fetal

thrombophilia in discordant twin intrauterine growth

restriction. Am J Obstet Gynecol 2001;185:244–5.

14. Redline RW, Pappin A. Fetal thrombotic vasculop-

athy: the clinical significance of extensive avascular

villi. Hum Pathol 1995;26:80–5.

15. Vern TZ, Alles AJ, Kowal-Vern A, et al. Frequency of

Factor V Leiden and Prothrombin G20210A in

placentas and their relationship with placental

lesions. Hum Pathol 2000;31:1036–43.

16. Ariel IB, Anteby E, Hamani Y, et al. Placental

pathology in fetal thrombophilia. Hum Pathol 2004;

35:729–33.

17. Leistra-Leistra MJ, Timmer A, van Spronsen FJ, et al.

Fetal thrombotic vasculopathy in the placenta:

a thrombophilic connection between pregnancy

complications and neonatal thrombosis? Tropho-

blast Research. Placenta 2004;25(Suppl A):S102–5.

18. Mousa HA, Alfirevic Z. Do placental lesions reflect

thrombophilic state in women with adverse preg-

nancy outcome? Hum Reprod 2000;15:1830–3.

19. Parast MM, Crum CP, Boyd TK. Placental histolog-

ical criteria for umbilical flow restriction in unex-

plained stillbirth. Hum Pathol 2008;39:948–53.

20. Scott JM. Fibrinous vasculosis in the human

placenta. Placenta 1983;4:87–100.

21. De Sa DJ. Intimal cushions of foetal placental veins.

J Pathol 1973;110:347–52.

22. Genest DR. Estimating the time of death in stillborn

fetuses: II. Histologic evaluation of the placenta;

a study of 71 stillborns. Obstet Gynecol 1992;80:

585–92.

23. Redline RW. Villitis of unknown etiology: noninfec-

tious chronic villitis in the placenta. Hum Pathol

2007;38:1439–46.

Kraus100

24. Parveen Z, Tongson-Ignacio JE, Fraser CR, et al.

Placental mesenchymal dysplasia. Arch Pathol Lab

Med 2007;131:131–7.

25. Kaiser-Rogers KA, McFadden DE, Livasy CA, et al.

Androgenetic/biparental mosaicism causes placental

mesenchymaql dysplasia. J Med Genet 2006;43:

187–92.

26. Thorarensen O, Ryan S, Hunter J, et al. Factor V Lei-

den 19 mutations: an unrecognized cause of hemi-

plegic cerebral palsy, neonatal stroke, and placental

thrombosis. Ann Neurol 1997;42:372–5.

27. Elbers J, Viero S, MacGregor D, et al. Placental

pathology in neonatal stroke. Pediatrics 2011;127:

e722–9.

28. Wintermark P, Boyd TK, Gregas MC, et al. Placental

pathology in asphyxiated newborns meeting the

criteria for therapeutic hypothermia. Am J Obstet

Gynecol 2010;203(6):579.e1–9.

29. Chang KT, Keating S, Costa S, et al. Third trimester

stillbirths: corrlative neuropathology and placental

pathology. Pediatr Dev Pathol 2011;14:345–52.

30. Hoyme HE, Jones KL, Van Allen MI, et al. Vascular

pathogenesis of transverse limb reduction defects.

J Pediatr 1982;101:839–43.

31. Kraus FT, Redline RW, Gersell DJ, et al. Placental

Pathology. Washington, DC: American Registry of

Pathology; 2004.

32. Steffensen TS, Gilbert-Barness E, Spellacy W, et al.

Placental pathology in trap sequence: clinical and

pathogenetic implications. Fetal Pediatr Pathol

2008;27:13–29.

33. Nikkels PG, Van Gemert MJ, Sollie-Szarynska KM,

et al. Rapid onset of severe twin-twin transfusion

syndrome caused by placental venous thrombosis.

Pediatr Dev Pathol 2002;5:310–4.

34. Heifetz SA. Thrombosis of the umbilical cord; anal-

ysis of 52 cases and literature review. Pediatr Pathol

1988;8:37–54.

35. Avagliano L, Marconi AM, Candiani M, et al. Throm-

bosis of the umbilical vessels revisited. An observa-

tional study of 317 consecutive autopsies at a single

institution. Hum Pathol 2010;41:971–9.