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Placental Histopathologic Features in Patients With Thrombophilic Mutations

March 18, 2007

By Raspollini, Maria Rosaria; Oliva, Esther; Roberts, Drucilla J

Abstract

The purpose of this article is to review the histopathologic findings in the placenta of women with a known thrombophilic mutation. The findings range from normal to severe pathologic features including decidual vasculopathy, placental infarctions, syncytial knotting, maternal floor infarction, fetal thrombotic vasculopathy, vasculitis, and chronic villitis. They are, however, not pathognomonic of thrombophilic states, nor are necessarily markers of perinatal damage. The prospective evaluation of cases with known thrombophilic mutations and the application of tissue microarray examination of the placenta may allow identification of major histopathologic features and molecular parameters associated with maternal and/or fetal thrombophilic states. This may assist clinicians in their consultation with patients and optimize management in future pregnancies.

Keywords: Placenta, thrombophilia, decidual vasculopathy, fetal thrombotic vasculopathy, fetal outcome

Introduction

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 [3]. 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?

Literature review

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

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 [21]. 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.

Placental infarcts

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 [22]. 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. [23] 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. [24], 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

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 [25]. Sometimes, these changes are also observed in immature placentas. According to Kauffman and Scheffen [26], 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 [27]. 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) [28]. Placental massive perivillous fibrin deposition has been associated to thrombophilic states [29] and to antiphospholipid antibodies syndrome [30]. But it has also been observed an idiopathic elevation of maternal serum α-fetoprotein [31], 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 [32], sclerotic/avascular terminal villi (Figure 6A) [33,34], hemorrhagic endovasculitis (Figure 6B) [35,36], inflammatory damage to vessels, and meconium-induced myonecrosis [37] (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 [38]. 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 [39].

Hemorrhagic endovasculitis [40], 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 [36] to vessels (see below), thrombophilic mutations [43], diabetes mellitus [44], 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 [45]. Other less common conditions associated with FTV include perinatal liver disease [46] and discordant growth in twins [47]. 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 [48]. 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% [36].

Finally, vasculitis and chronic villitis are histopathologic features described and thought to be representative of a vascular- occlusive process [51].

Chronic villitis

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 [52].

Comments

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 [53]. Van Horn et al. [54] 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 [24], 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 [55]. Mousa and Alfirevic [56] 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 [58]. For instance, a histopathologic study of the product of conception from miscarriages associated with APL syndrome showed defective decidual endovascular trophoblast invasion [59]. 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 [65], the presence of circulating procoagulant microparticles [66], 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 [71]. In a case of a fetal thrombophilic mutation, Ariel et al. [73] 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 [74].

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 [37].

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 [76].

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 [77].

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 [74] 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.

References

1. Clark P, Brennand J, Conkie JA, McCall F, Green IA, Walker ID. Activated protein C sensitivity, protein C, protein S, and coagulation in normal pregnancy. Thromb Haemost 1998;79: 1166-1170.

2. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999;106:756-766.

3. Lane DA, Bayston T, Olds RJ, Fitches AC, Cooper DN, Miller DS, Jochmans K, Perry DJ, Okajima K, Thein SL, Emmerich J. Antithrombin mutation database: 2nd update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1997;77:197-211.

4. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96:45-49.

5. Kupferminc MJ, Rimon E, Asher-Landsberg J, Lessino JB, Many A. Perinatal outcome in women with severe pregnancy complications and multiple thrombophilias. J Perinat Med 2004;32:225-227.

6. Van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, Von Blomberg BM, Buller HR. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999;180:1146-1150.

7. Von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodics in patients with preeclampsia or HELLPsyndrome. Hemolysis, elevated liver- enzymes, low platelets. Thromb Res 2000;100:363-365.

8. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fair C, Lessino JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.

9. Kupferminc MJ, Many A, Bar-Am A, Lessing JB, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with a prevalence of thrombophilia. BJOG 2002;109:1373- 1376.

10. Van der Molen EF, Verbruggen B, Novakova I, Eskes TS, Monnens LA, Blom HJ. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy. BJOG 2000;107:785-791.

11. Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activate protein C and the Leiden mutation: High prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998;179:1565-1567.

12. Arias F, Romero R, Joist H, Kraus FT. Thrombophilia: A mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med 1998;7:277- 286.

13. Gharavi AE, Pierangeli SS, Levy RA, Harris EN. Mechanisms of pregnancy loss in antiphospholipid syndrome. Clin Obstet Gynecol 2001;44:11-19.

14. Gris JC, Ripart-Neveu S, Maugard C, Tailland ML, Brun S, Courtieu C, Biron C, Hoffet M, Hedon B, Mares P. Retrospective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) study. Thromb Haemost 1997;77:1096-1103.

15. Many A, Elad R, Yaron Y, Eldon A, Lessing JB, Kupferminc MJ. Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia. Obstet Gynecol 2002;99:684-687.

16. Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in woman with unexplained late fetal loss. New Engl J Mcd 2000;343:1015- 1018.

17. Preston FE, Rosendaal FR, Walzer ID, Briet E, Berntorp E, Canard J, Fontcuberta J, Makris M, Mariani G, Noteboom W. Increased fetal loss in women with heritable thrombophiHa. Lancet 1996;348:913- 916.

18. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: A meta-analysis. Lancet 2003;361:901-908.

19. Roque H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004;91:290-295.

20. Sarig G, Younis JS, Hoffman R, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with idiopathic pregnancy loss and it is associated with late pregnancy wastage. Fertil Steril 2002;77:342-347.

21. Klurfeld DM. Identification of foam cells in human atherosclerotic lesions as macrophages using monoclonal antibodies. Arch Pathol 1985; 109:445-449.

22. Benirschke K, Kaufmann P, Baerger R. Pathology of the human placenta. 5th ed. New York: Springer; 2006.

23. Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, Harpel PC. Pregnancy loss in the antiphospholipid-antibody syndrome- a possible thrombogenic mechanism. N Engl J Med 1997;337:154-160.

24. Many A, Schreiber L, Rosner S, Lessing JB, Eldor A, Kupferminc MJ. Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia. Obstet Gynecol 2001;98:1041-1044.

25. Faye-Petersen OM, Heller DS, Joshi W. Lesion of the chorioni\c villi involving the trophoblast. In: Handbook of placental pathology. 2nd ed. London, UK: Taylor & Francis; 2006.

26. Kauffman P, Scheffen I. Placental development. In: Polin RA, Fox WW, editors. Neonatal and fetal medicine-physiology and pathophysiology. Vol. I. Orlando, USA: Saunders; 1992. pp 47-55.

27. Kupferminc MJ. Thrombophilia and preeclampsia: The evidence so far. Clin Obstet Gynecol 2005;48:406-415.

28. Mandsager NT, Bendon R, Mostello D, Rosen B, Miodovnik M, Siddiqi TA. Maternal floor infarction of the placenta: Prenatal diagnosis and clinical significance. Obstet Gynecol 1994;83:750- 754.

29. Katz VL, DiTomasso J, Farmer R, Carpenter M. Activated protein C resistance associated with maternal floor infarction treated with low-molecular-weight heparin. Am J Perinatol 2002;19:273-277.

30. Sebire NJ, Backos M, Golden RD, Regan L. Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome. BJOG 2002;109:570-573.

31. Katz VL, Bowes WA, Sierkh AE. Maternal floor infarction of the placenta associated with elevated second trimester alpha fetoprotein. Am J Perinatol 1987;4:225-228.

32. Fox H. Thrombosis of the foetal arteries in the human placenta. J Obstet Gynaecol Br Commonw 1966;73:961-965.

33. Gruenwald P. Abnormalities of placental vascularity in relation to intrauterine deprivation and retardation of fetal growth: Significance of avascular chorionic villi. NY State J Med 1961;61:1508-1513.

34. Redline RW, Pappin A. Fetal thrombotic vasculopathy: The clinical significance of extensive avascular villi. Human Pathol 1995;26:80-85.

35. Sander CM, Gilliland D, Akers C, McGrath A, Bismar TA, Swart- Hills LA. Livebirths with placental hemorrhagic endovasculitis: Interlesional relationships and perinatal outcomes. Arch Pathol Lab Med 2002;126:157-164.

36. Sander CM. Hemorrhagic endovasculitis in the placenta. Am J Obstet Gynecol 1992;167:1483.

37. Roberts DJ, Oliva E. Clinical significance of placental examination in perinatal medicine. J Matern Fetal Neonatal Med 2006;19:255-264.

38. Redline RW, Ariel I, Baergen RN, Desa DJ, Kraus FT, Roberts DJ, Sander CM and the Society for Pdiatrie Pathology, Perinatal section, Fetal Vascular Obstruction Nosology Committee. Fetal vascular obstructive lesions: Nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004;7:443-452.

39. Redline RW, O’Riordan MA. Placental lesions associated with cerebral palsy and neurological impairment following term birth. Arch Pathol Lab Med 2000; 124:1785-1791.

40. Sander CH. Hemorrhagic endovasculitis and hemorrhagic villitis of the placenta. Arch Pathol Lab Med 1980;104:371373.

41. Sander CH, Kinnane L, Steven NG, Edit R. Hemorrhagic endovasculitis of the placenta: A review with clinical correlation. Placenta 1986;7:551-574.

42. Sander CH, Steven NG. Hemorrhagic endovasculitis of the placenta: An in-depth morphologic appraisal with initial clinical and epidemiologic observations. Pathol Annu 1984;19:37-79.

43. Debus O, Koch HG, Kurlemann G, Strater R, Vielhaber H, Weber P, Nowak-Gottl U. Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed 1998;78:F121-124.

44. Van Alien MI, Jackson JC, Knopp RH, Cone R. In utero thrombosis and neonatal gangrene in an infant of a diabetic mother. Am J Med Genet 1989;33:323-327.

45. Redline RW. Clinical and pathological umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol 2004;35:1494-1498.

46. Dahms BB, Boyd T, Redline RW. Severe perinatal liver disease associated with fetal thrombotic vasculopathy. Pediatr Dev Pathol 2002;5:80-85.

47. Redline RW, Shah D, Saker H, Schluchter M, Salvator A. Placental lesions associated with abnormal growth in twins. Pediatr Dev Pathol 2001;4:473-481.

48. Kraus FT, Acheen VI. Fetal thrombotic vasculopathy in the placenta: Cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999;30:759-769.

49. Brenner B. Inherited thrombophilia and fetal loss. Curr Opin Hematol 2000;7:290-295.

50. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96:45-49.

51. Salafia CM, Ernst LM, Pezzullo JC, Wolf EJ, Rosenkrantz TS, Vintzileos AM. Intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: Associated placental pathologic features. Am J Obstet Gynecol 1995;173:10491057.

52. Redline RW, Patterson P. Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells. Am J Pathol 1993;143:473-479.

53. Sikkema JM, Franx A, Bruinse HW, van der Wijk NG, Nikkels PGJ. Placental pathology in early onset pre-eclampsia and intra- uterine growth restriction in women with and without thrombophilia. Placenta 2002;23:337-342.

54. Van Horn JT, Crafen C, Ward K, Branch DW, Silver RM. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes. Placenta 2004;25:642-648.

55. Morssink LP, Santema JG, Willemse F. Thrombophilia is not associated with an increase in placental abnormalities in women with intra-uterinc fetal death. Acta Obstet Gynecol Scand 2004;83:348- 350.

56. Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod 2000;15:1830-1833.

57. Khong TY, Moore L, Hague WM. Thrombophilia and adverse pregnancy outcome. Hum Reprod 2000; 15:18301833.

58. Hustin J, Jauniaux E, Schaaps JP. Histological study of the materno-embryonic interface in spontaneous abortion. Placenta 1990;! 1:477-486.

59. Sebire NJ, Fox H, Backos M, Rai R, Paterson C, Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod 2002;17:1067-1071.

60. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med 1999;222:222-235.

61. Redman CW, Sargent IL. Placental debris, oxidative stress and pre-eclampsia. Placenta 2000;21:597-602.

62. Roberts JM, Hubel CA. Is oxidative stress the link in the two- stage model of pre-eclampsia? Lancet 1999;354:788789.

63. Hempstock J, Jauniaux E, Greenwold N, Burton GJ. The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol 2003;34:1265-1275.

64. Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblast oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal pregnancies. Am J Pathol 2003; 162: 115-125.

65. Vincent T, Rai R, Regan L, Cohen H. Increased thrombin generation in women with recurrent miscarriage. Lancet 1998;352:116.

66. Laude I, Rongieres-Bertrand C, Boyer-Neumann C, WoIfM, Mairovitz V, Hugel B, Freyssinet JM, Frydman R, Meyer D, Eschwege V. Circulating procoagulant microparticles in women with unexplained pregnancy loss: A new insight. Thromb Haemost 2001;85:18-21.

67. Kwak JY, Beer AE, Kirn SH, Mantouvalos HP. Immunopathology of the implantation site utilizing monoclonal antibodies to natural killer cells in women with recurrent pregnancy losses. Am J Reprod Immunol 1999;41:91-98.

68. Laird SM, Tuckerman EM, Cork BA, Linjawi S, Blakemore AI, Li TC. A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update 2003;9:163174.

69. Giordano P, Laforgia N, Di Giulio G, Storelli S, Mautone A, Iolascon A. Renal vein thrombosis in a newborn with prothrombotic genetic risk factors. J Perinat Med 2001;29: 163-167.

70. Grow JL, Fliman PJ, Pipe SW. Neonatal sinovenous thrombosis associated with homozygous thcrmolabile methylenetetrahydrofolate reductase in both mother and infant. J Perinatol 2002;22:175-178.

71. Khong TY, Hague WM. Biparental contribution to fetal thrombophilia in discordant twin intrauterine growth restriction. Am J Obstet Gynecol 2001; 185:244-245.

72. Stance J, Bove KE, Bofinger M, Needham D, Saldana LR, Mutema GK, Meyer R. Premature closure of foramen ovale and renal vein thrombosis in a stillborn twin homozygous for methylene tetrahydrofolate reductase gene polymorphism: A clinicopathologic study. J Perinat Med 2000;28(l):61-68.

73. Ariel I, Anteby E, Hamani Y, Redline RW. Placental pathology in fetal thrombophilia. Hum Pathol 2004;35:729733.

74. Gonen R, Lavi N, Attias D, Schliamser L, Borochowitz Z, Toubi E, Ohel G. Absence of association of inherited thrombophilia with unexplained third-trimester intrauterine fetal death. Am J Obstet Gynecol 2005;192(3):742-746.

75. Vern TZ, Alls AJ, Kowal-Vern A, Longtine J, Roberts DJ. Frequency of factor V (Leiden) and prothrombin G20210A in placentas and their relationship with placenta! lesions. Hum Pathol 2000;31:1036-1043.

76. Dizon-Townson DS, Miller C, Sibai B, Spong CY, Thorn E, Wendel G Jr, Wenstrom K, Samuel P, Cotroneo MA, Moawad A, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005; 106:517-524.

77. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314: 253-257.

78. Fowler JM, Ramirez N, Cohn DE, Kelbick N, Pavelka J, Ben Shachar I. Correlation of cyclooxygenase-2 (COX-2) and aromatase expression in human endometrial cancer: Tissue microarray analysis. Am J Obstet Gynecol 2005; 192:12621271.

79. Nocito A, Bubendorf L, Tinner EM, Suess K, Wagner U, Forster T, Kononen J, Fijan A, Bruderer J, Schmid U, et al. (Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Anabitarte M, Hering F, Hardmeier T, Schoenenberger AJ, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Casser T, Sauter G). Microarray of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 2001;194:349-357.

80.Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, Kallioniemi OP, Kononen J. Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res 2000;60: 6617-6622.

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: djroberts@partners.org

Copyright Taylor & Francis Ltd. Feb 2007

(c) 2007 Journal of Maternal – Fetal & Neonatal Medicine. Provided by ProQuest Information and Learning. All rights Reserved.




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