March 18, 2007
Placental Histopathologic Features in Patients With Thrombophilic Mutations
By Raspollini, Maria Rosaria; Oliva, Esther; Roberts, Drucilla J
Keywords: Placenta, thrombophilia, decidual vasculopathy, fetal thrombotic vasculopathy, fetal outcome
Pregnancy is a hypercoagulable state due to an increased generation of thrombin and a decrease in the activity of anticoagulant and fibrinolytic factors [1,2]. Thus, the pregnant state is an independent risk factor for the development of deep venous thrombosis in women. This gestational hypercoagulable state accounts for about half of episodes of venous thromboembolism in the gestational and in the puerperal period.
A thrombophilic mutation may be present without inducing an abnormal hypercoagulable state leading to clinical thrombosis. Indeed individuals carrying a thrombophilic mutation do not develop thrombosis. It is believed that additional factors are requisite for the development of thrombosis. For example, infection/inflammation may represent an environmental factor, which coupled with pregnancy leads to an increased likelihood of thrombosis.
Thrombosis can reside in the intervillous space, maternal uterine circulation or the fetal compartment. The specific pathologic liaisons depend upon a combination of factors, including whether or not the fetus is a carrier of a thrombophilic mutation.
Specific mutations associated with heritable hypercoagulopathies include factor V Leiden, the G20210A mutation of the prothrombin gene, protein C and protein S deficiencies, and homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase (C677T MTHFR). An antithrombin III deficiency has long been identified . Among acquired risk factors, antiphospholipid antibody syndrome is the most common pre-thrombotic state.
A thrombotic event due to a thrombophilic mutation may become clinically manifest for the first time during pregnancy or in the postpartum period. In addition, a thrombophilic mutation may increase the risk for perinatal complications including preeclampsia [4-7], intrauterine growth restriction (IUGR) [8,9], and placental abruption [10,11]. Moreover, some studies have reported that maternally inherited and acquired thrombophilia contribute to the pathogenesis of fetal loss at different stages of gestation [12- 20].
This review focuses on the following key questions:
1. What are, if any, the placental findings in women with known thrombophilic mutations?
2. Are there placental histopathologic features pathognomonic of thrombophilic states?
3. Can studies of the placenta provide the clinician with additional information for the identification of patients who need screening for thrombophilic mutations?
4. Can a careful pathological examination of the placenta from women with thrombophilic states help in the management of future pregnancies?
The placenta may be completely normal in cases of either inherited or acquired maternal thrombophilia. However clinicians frequently report pregnancies complicated by preeclampsia, IUGR, placental abruption, or stillbirth in thrombophilic women, which may even follow previous uncomplicated pregnancies.
The histopathologic findings that can identify placentas delivered to women with known thrombophilia mutations are: (1) decidual vasculopathy, (2) thrombosis in vessels in the decidua basalis, (3) placental infarcts, (4) syncytial knotting, (5) maternal floor infarction, (6) fetal thrombotic vasculopathy and (7) vasculitis, and (8) chronic villitis.
Figure 1. Spiral artery with acute atherosis in a section of membrane roll. There are thickened hyalinized wall vessels, accumulation of large foamy macrophages, and fibrin deposition.
Decidual vasculopathy is a group of related pathologic changes diagnosed in the decidual segments of the spiral arteries. These lesions cause placental infarctions and abruptio. Initial changes include lack of physiologic conversion. Under normal conditions, the trophoblast infiltrates the wall of the decidual and the myometrial segments of the spiral artery. Destruction of the media is thought to be responsible for the refractoriness of the vessel wall to vasoconstrictive mediators. In pathological conditions, whenever the throphoblastic invasion is incomplete or limited, the myometrial vessels maintain the muscle component and this may predispose to reduction in uterine blood flow . Therefore, absence of physiologic transformation is characterized by: (a) lack of thromboblast invasion of the decidual and myometrial segment of the spiral artery, (b) absence of fibrinoid deposition and (c) persistence of the smooth muscle coat in the arteries.
Some cases of decidual vasculopathy are accompanied by atherosis in which there are lipid-laden macrophages in non-transported spiral arteries. The diagnosis of decidual vasculopathy includes vascular smooth muscle fibrinoid necrosis and 'foamy' histiocyte invasion - all evidence of vascular damage. The histology is typified by mural hyalinization with eosinophilic material accumulating in the vessel wall, a mononuclear infiltrate, and atherosis with foamy macrophages (Figure 1).
Thrombosis in the vessels of the decidua basalis
Proliferative activity of intimal and muscle cells along with damage to the vascular endothelium leads to thrombosis in the vessels of the decidua basalis (Figure 2). Fibrinoid necrosis of the vessel media may also occur.
Thrombosis of the decidual arteries, leading to necrosis and subsequent venous hemorrhage, may cause a retroplacental hematoma and result in chronic abruptio placentae. When thrombi cause the lumen obstruction of decidual vessels, this leads to a placental infarct. This appears as a firm and pale area of placental parenchyma that is histologically characterized by villous agglutination with collapse of the intervillous space, pyknosis and karyorrhexis of trophoblastic nuclei (Figure 3), and finally with ghost-like villi often within a thin layer of fibrinoid.
In third trimester placentas, the infarcts are usually a few millimeters in diameter. Infarcts can be observed in an otherwise normal pregnancy in post-term gestation. Conversely, confluent areas, multiple small lesions, or a more extensive distribution, should be regarded as pathologic and potentially clinically significant. In fact, when infarcts are randomly distributed, they are indicators of global ischemia to the placenta due to maternal underperfusion. Infarcts in any localization in first and second trimester placentas are usually considered pathologic findings.
Figure 2. The thrombosed chorionic plate vessel at the center is occluded by a recent thrombus.
The percentage of placental mass involved, especially in relation to the placental size (small placentas are less tolerant of even small infarcts than normal sized placentas), has clinical importance for the fetus. When infarcts involve a massive portion of the placenta, they can have serious clinical consequences such as fetal hypoxia, IUGR, pregnancy-induced hypertension, abruptio placentae, and neurological abnormalities . Placental infarctions can be observed in patients with vasculopathy associated with thrombophilic mutations, but have also been reported in women with complications of pregnancy: preeclampsia, diabetes mellitus, sickle cell hemoglobinopathies, smoking, and cocaine abuse, with known thrombophilic states.
Moreover, atherosis is not required for infarcts to occur. Rand et al.  found an interaction of the antibodies in antiphospholipid syndrome (APL) with annexin V, a placental anticoagulant protein that plays a key role in preventing intervillous thrombosis. Consequently, the observation that annexin V levels are reduced after antibody exposure suggests a possible mechanism for thrombosis in the intervillous space and may explain the association between recurrent pregnancy loss and APL.
Many et al. , comparing pathologic features of the placenta in women with different severe pregnancy complications, observed that infarctions are more frequent and large in the placenta of women with thrombophilic mutations than in those without thrombophilic states. Other pathologic parameters, such as vessel thrombosis, increased syncytiotrophoblast knotting, absent physiologic transformations in the spiral arteries or avascular villi were not statistically different.
Figure 3. Recent placental infarct. The trophoblastic nuclei are clustered and necrotic. The intervillous space is collapsed.
Figure 4. Trophoblastic nuclei of many villi are \clustered, forming trophoblastic knots.
Syncytial knotting results from excessive capillary proliferation and terminal villous branching (Figure 4), which is accelerated by hypoxia. The villous clustering and the increase in syncytial knot frequency for a given period of gestation are called 'Tenney-Parker changes', and they result in an increased chorionic villous surface area available for exchange . Sometimes, these changes are also observed in immature placentas. According to Kauffman and Scheffen , when more than 30% of tertiary villi possess syncytial knots, especially at an early gestational age, it is suggestive of a placental underperfusion.
Thrombotic lesions in the decidua basalis, placental infarcts, and syncytial knotting may represent lesions with a similar etiology. These features represent a histopathologic 'endpoint' of several processes and not thrombophilic states. Moreover, they are indicative of abnormal uteroplacental perfusion. Consequently, the histopathologic features related to an underlying maternal vascular disease, which are common in thrombophilia, are frequently difficult to differentiate from the lesions seen in other pathologies. Since preeclampsia is often associated with maternal thrombophilic mutations, so it is difficult to ascertain whether placental pathologic modifications are the results of one or the other or a combination of the two pathologies . In addition similar features can be observed in gestational diabetes.
Maternal floor infarction
Maternal floor infarction is characterized by a marked, diffuse increase in fibrin deposition along the decidua basalis and the perivillous space of the basal plate (Figure 5, A and B) . Placental massive perivillous fibrin deposition has been associated to thrombophilic states  and to antiphospholipid antibodies syndrome . But it has also been observed an idiopathic elevation of maternal serum α-fetoprotein , to congenital infection, and immune-mediated rejection. Maternal floor infarction is an uncommon but important cause of perinatal morbidity and mortality; it is associated with high rates of preterm birth, IUGR, intrauterine fetal demise (IUFD), and long-term adverse neurologic sequelae. In addition, it may recur in subsequent pregnancies.
Figure 5. (A) Massive perivillous fibrin deposits in a case of stillbirth at 23 weeks of gestation. (B) Massive perivillous fibrin deposits: the intervillous space is expanded and obliterated by a band of eosinophilic fibrin, which separates villi.
Fetal thrombotic vasculopathy and vasculitis
Fetal thrombotic vasculopathy (FTV) is histologically characterized by stem artery thrombosis, which may include occlusive or mural thrombosis , sclerotic/avascular terminal villi (Figure 6A) [33,34], hemorrhagic endovasculitis (Figure 6B) [35,36], inflammatory damage to vessels, and meconium-induced myonecrosis  (Figure 6C).
Occlusive thrombi, appearing in branches of the umbilical arteries and stem vessels within the placenta, cause regressive changes in fetal vessels distal to the thrombi. It must be remembered that the placenta has a double circulation, fetal and maternal, and both can undergo separate infarction. Underperfusion of the uteroplacental circulation from the maternal side will lead to villous infarcts, which are histologically characterized by crowded necrotic villi. With thrombi in the fetal circulation, areas with avascular villi are observed. The presence of avascular villi, conforming to the vascular distribution of a single villous tree, surrounded by an open maternal space, is probably the most objective and sensitive marker of fetal vascular occlusion in the placenta and allows for the diagnosis of FTV . Moreover, the presence of avascular villi as well as the presence of thrombi in the fetal circulation has been associated with a high incidence of fetal cerebral injury .
Hemorrhagic endovasculitis , a vasodisruptive alteration of fetal-placental blood vessels, is likely to be linked with thrombus formation resulting in extravasation of the fetal red blood cells (RBCs) into the vessel wall [41,42]. This is seen in cases of stillbirth, but it has also been observed in cases of severe hypoxemia and severe fetal heart failure. These lesions have been associated with many pathological conditions, such as inflammatory damage  to vessels (see below), thrombophilic mutations , diabetes mellitus , and anatomic anomalies, such as vascular anomalies accompanied by local trauma or stasis (for example true knots of umbilical cord), velamentous cord insertion, and umbilical cord entanglement . Other less common conditions associated with FTV include perinatal liver disease  and discordant growth in twins . Toxic damage to the myocytes of the fetal vessels (umbilical cord and placental vessels), such as in meconium-induced myonecrosis, has a direct action on the smooth muscle and hence causes collapse of the fetal vessels with severe damage to the baby.
Figure 6. (A) A clustered fibrotic avascular villi focus. (B) Hemorrhagic endovasculitis is characterized by endothelial injury, hemorrhage, erythrocyte fragmentation, and extravasation of red blood cells in the surrounding stroma. (C) Necrosis of the outer layer of vascular smooth muscle, in a meconium-stained placenta. The figure shows pyknotic nuclei and dense, eosinophilic, smudged appearance, cytoplasm.
FTV lesions that are grossly extensive and involve 40-60% of the placental mass usually cause sudden fetal death. Small foci of FTV may be asymptomatic, unless the fetus is growth-restricted, the placenta itself is small for gestational age, or thrombi are also present in somatic vessels of the newborn, such as in cerebral or in renal vessels.
Heritable alterations of coagulative factors, such as factor V Leiden deficiency, have been reported in the pathogenesis of thrombi of the fetal-placental vessels . The most frequent mutations in the Caucasian population are factor V Leiden mutation, the prothrombin gene, and the C677T MTHFR mutation [49,50]. Thrombi may be found in vessels of the chorionic plate or within stem vessels in the placenta. The placenta shows, in the distribution of occluded stem vessels, a wedge-shaped pale region that is triangular in cross- section. The incidence of FTV is estimated to be as high as 0.9% .
Finally, vasculitis and chronic villitis are histopathologic features described and thought to be representative of a vascular- occlusive process .
Chronic villitis is an inflammation of the villous stroma, often with chronic intervillositis and vasculitis. Histologie features include villous stroma and adjacent intervillous space infiltrated by a polymorphous inflammatory composition of neutrophils, lymphocytes, monocyte-macrophages, and occasional eosinophils (Figure 7). Common accompanying features include fetal stem villous vasculitis, villous necrosis, diffuse perivillous fibrin deposition, and villous infarcts. Chronic inflammation is not pathognomonic of thrombophilic mutations. Chronic inflammatory damage may be due to rare congenital infection or immuno-mediated processes.
As a consequence of vasculitis, vessels of the placenta may become a thrombogenic focus. Thrombi can embolize downstream to the villi, resulting in a fetal thrombotic vasculopathy. In addition, the thrombi can reach the fetus through the umbilical vein. The brain and kidney circulations are the most likely sites of embolization. An inflammatory infiltrate, which may be related to an infection or to a vascular-occlusive process, may lead to the release of cytokines that stimulate a systemic response with a fetal septic-like picture. Another cause of chronic villitis may be the maternal immune regulated rejection of fetal semiallograph .
It may be reasonable to expect unique lesions in a placenta delivered to a woman with a thrombophilic mutation and an obstetrical complication. Some studies have demonstrated that such lesions exist; others have not. Most reports have included a small numbers of cases that have either not specified the location or the dimension of the lesions. A careful pathologic evaluation of the placenta in the case of clinical symptoms of gestational complication or fetal compromise is useful for the understanding of the final outcome. Frequent complications of pregnancy, such as gestational diabetes or preeclampsia, or the presence of an acquired and/or hereditary thrombophilic state, may lead to the same placental lesions.
Figure 7. Extensive areas of chronic villitis of unclear etiology. There is a polymorphous inflammatory composition of primarily mononuclear inflammatory cells sometimes mixed with rare neutrophils.
A few studies examining the histopathologic features of placentas comparing thrombophilic associated and not-thrombophilic associated complications of pregnancy failed to show significant differences between the two groups . Van Horn et al.  observed similar placental histopathological findings in antiphospholipid and antiphospholipid-like antibody syndrome pregnancies. There is no possibility of differentiating between the two entities from a pathologist's point of view.
It has been reported that placentas delivered to women with thrombophilic mutations have more extensive infarcts than those of women without thrombophilic mutations , but the presence of infarcts in the placenta is not characteristic of any thrombophilic state. In addition it has been seen that in cases of IUFD, thrombophilia is not associated with an increase in specific placental abnormalities . Mousa and Alfirevic  also reported no relationship between placental histology and thrombophilia in women with severe preeclampsia/eclampsia, placental abruption, IUGR or unexplained stillbirth. This observation has been confirmed by Khong et al. [57\].
The observation of similar placental histopathologic features in different pathologies may indicate a common ground. Defective placentation, characterized by thinner and fragmented trophoblast shell and reduced cytotrophoblast invasion of the lumen at the tips of the spiral artery, is possibly the common denominator of these pathologies . For instance, a histopathologic study of the product of conception from miscarriages associated with APL syndrome showed defective decidual endovascular trophoblast invasion . The excessive entry of maternal blood into the intervillous space is hypothesized to exert a direct mechanical effect on the villous tissue and an indirect oxidative stress effect, which results in cellular dysfunction and damage. There is much evidence that placental oxidative stress may play a key role in the pathogenesis of preeclampsia [60-62] and there are studies indicating that it may also contribute to early pregnancy failure [63,64]. This mechanism is close to the pathophysiology of placental damage associated to an increased hypercoagulable state , the presence of circulating procoagulant microparticles , and the role of cytokines and immune cells in recurrent miscarriage [67,68].
The fetus may inherit the thrombophilia trait from the mother or from the father [69-72]. Case reports frequently found in literature on this topic, underline the difficulties encountered in studying these associations. A study concerning a case of discordant twin IUGR, for example, reported that one dizygotic twin inherited thrombophilic genes from both the father and the mother. This twin suffered from IUGR with placental fetal thrombotic vasculopathy; its co-twin inherited only one gene from its mother and was neither growth restricted nor had associated placental vasculopathy . In a case of a fetal thrombophilic mutation, Ariel et al.  observed that this state was not associated to fetal vascular lesions of the placenta, even in the context of maternal underperfusion.
Many genetic factors of the mother and the father and their interaction along with the other pathological conditions may determine different histopathological features and different clinical courses of the pregnancy. Finally, the interaction between the genetic factors of the mother and those of the father probably become more important in certain ethnic subgroups for the high prevalence of some mutations .
At the beginning of this review we aimed to answer some key questions. What follows are the answers based on a literature search and personal experience.
In thrombophilic women, the placenta may be normal, but it may also show findings such as those described above. However, these features are not pathognomonic of patients with thrombophilic mutations, nor do they identify perinatal damage strictly associated with a thrombophilic state.
Further investigation is needed to answer the third question regarding the possibility of identifying the histopathological pictures that may justify the clinical study of the mother or the newborn. The observation that placentas with fetal thromboembolic events are more frequently found in patients with a hereditary thrombophilic mutation has been disputed [73,75].
We suggest that infants with clinical diagnoses of congenital embolie stroke and visceral infarcts be evaluated for thrombophilia and certainly strongly recommend that the placentas be examined in such cases. A careful examination of the placenta, especially in cases of unexpected unfavorable perinatal outcome, may lead to the evaluation of a thrombophilic state in the mother and/or in the newborn .
A large study on factor V Leiden mutation showed that carrier status does not confer a higher risk of adverse perinatal outcome and pregnancy complications .
Also considering the possible confounding influence of gestational concomitant pathologies such as diabetes and hypertension, it is still difficult at the present time to answer the third question addressed (i.e., the role of placental studies for the identification of patients who may need screening for thrombophilic mutations). It should also be considered that currently a further confounding factor might be the therapeutic regimen and drugs administered during pregnancy. Some drugs, such as aspirin or heparin, may undoubtedly modify the clinical course of pregnancy and placental features .
Further analysis is required regarding the last question. The careful prospective evaluation of cases homogeneous for thrombophilic risk factors, clinical pathology and therapeutic regimen, and perhaps ethnic groups  may allow the pathologist, in the future, to identify some characteristic histopathologic and molecular parameters associated with maternal or fetal thrombophilic mutations. Particularly, an application of tissue microarray that has been widely used in cancer research to identify molecular signatures with diagnostic and/or prognostic significance [78-80], may allow systematic studies of the placenta.
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MARIA ROSARIA RASPOLLINI1, ESTHER OLIVA2, & DRUCILLA J. ROBERTS2
1 Department of Human Pathology and Oncology, University of Florence School of Medicine, Florence, Italy and 2 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
(Received 27 November 2006; revised 5 December 2006; accepted 18 December 2006)
Correspondence: Drucilla J. Roberts, MD, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Tel: +617 724 1415. Fax: +617 726 7474. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Feb 2007
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