1. Introduction

Antiphospholipid syndrome (APS) is currently regarded as one of the most complex and multifaceted problems of modern clinical medicine, integrating immunology, vascular pathology, hemostasiology, and obstetrics [1,2,3]. This syndrome acquires particular clinical significance during the gestational period, where it acts not only as a cause of thrombotic complications but also as a factor of profound immunopathological disturbances that determine the development of placental insufficiency and adverse pregnancy outcomes.

Traditionally, obstetric complications in APS were explained mainly by thrombosis of placental vessels. However, data accumulated over recent decades have significantly changed the understanding of the pathogenesis of these disorders. It is now evident that thrombosis represents only the final manifestation of a complex immune cascade triggered by autoantibodies to phospholipids and plasma cofactor proteins, primarily β2-glycoprotein I. These antibodies interact with the endothelium, trophoblast, and platelets, initiating activation of the complement system, inflammatory reactions, cellular apoptosis, and loss of the natural anticoagulant properties of the placenta [4,5,6].

In obstetric practice, this is reflected by the fact that in cases of pronounced clinical complications—recurrent pregnancy loss, preeclampsia, fetoplacental insufficiency, and intrauterine growth restriction—the morphological picture of the placenta is often nonspecific and does not reflect the depth of the ongoing pathological processes. This indicates that key changes occur at the immune and molecular levels and require immunohistochemical verification.

Thus, APS in obstetrics should be considered a model of immunomorphological placental vasculopathy in which immune damage is primary, while morphological changes represent a consequence of this process.

The aim of the present study is to analyze the relationship between immune mechanisms of injury in APS, placental morphological changes, and clinical manifestations of obstetric complications.

2. Materials and Methods

The study was based on clinical observations of pregnant women with laboratory-confirmed APS who, during gestation, demonstrated signs of placental insufficiency, preeclampsia, intrauterine growth restriction, and a complicated obstetric history in the form of recurrent pregnancy loss.

The diagnosis of APS was established based on clinical criteria and detection of antibodies to cardiolipin and β2-glycoprotein I. Placental material was examined after delivery using standard histological techniques and immunohistochemical analysis [7].

Histological examination was performed using hematoxylin–eosin staining and methods for fibrin detection. Immunohistochemical analysis was carried out using CD31 and CD34 markers to assess endothelial status, Annexin V to study trophoblastic anticoagulant protection, and C4d as an indicator of complement system activation.

A comparative analysis of clinical data with morphological and immunohistochemical results was conducted.

3. Results

Clinical analysis showed that in most patients pregnancy developed against the background of early formation of placental insufficiency. Already in the second trimester, signs of impaired uteroplacental blood flow, fetal growth restriction, and episodes of elevated arterial pressure progressing to preeclampsia were observed. At the same time, a significant proportion of women had no somatic risk factors that could explain the severity of obstetric complications.

Histological examination of the placenta revealed characteristic but not always pronounced changes: thrombosis of the intervillous space, fibrinoid necrosis of the spiral artery walls, ischemia of the chorionic villi, and focal infarctions. However, the severity of these findings often did not correspond to the severity of the clinical picture.

Immunohistochemical examination revealed fundamentally important patterns. In most cases, a significant decrease in CD31 and CD34 expression was observed, indicating pronounced endothelial damage and impaired angiogenesis [8]. At the same time, there was a sharp decrease or complete absence of Annexin V expression on the surface of the syncytiotrophoblast. In addition, intense linear deposition of C4d along the vascular wall and in decidual tissue was detected.

The combination of these findings correlated with the most severe obstetric complications.

Results and Their Clinical-Pathogenetic Interpretation

The obtained morphological and immunohistochemical data require interpretation from the standpoint of modern concepts of APS pathogenesis. The key point is understanding that in APS the placenta becomes a target of immune damage already at the early stages of gestation, long before the appearance of clinical manifestations of placental insufficiency.

Antiphospholipid antibodies, binding to β2-glycoprotein I, become fixed on the surface of endothelial cells and trophoblast. This leads to activation of the complement system, induction of inflammatory response, and apoptosis of trophoblastic cells. The physiological process of trophoblastic invasion into the uterine spiral arteries is disrupted, resulting in their incomplete transformation, which lays the foundation for subsequent disturbances of uteroplacental blood flow.

It is at this stage that immunomorphological changes arise, which are not yet manifested by pronounced histological signs but can already be detected by immunohistochemistry.

Clinical Case No. 1

A 26-year-old patient with a history of two spontaneous miscarriages at 9 and 11 weeks. High titers of antibodies to cardiolipin and β2-glycoprotein I were detected. During the current pregnancy, signs of intrauterine growth restriction and impaired blood flow by Doppler examination appeared at 24 weeks. Moderate preeclampsia developed at 30 weeks. Preterm delivery occurred.

Placental morphology showed moderate villous ischemia and single intervillous thrombi without pronounced infarctions.

Immunohistochemistry revealed almost complete absence of Annexin V expression on the trophoblastic surface, pronounced C4d deposition along the vascular wall, and significant reduction of CD31.

This case demonstrates a discrepancy between histological findings and clinical severity. Immunohistochemical analysis explained the pronounced fetoplacental insufficiency.

Clinical Case No. 2

A 31-year-old primigravida. Pregnancy was complicated by severe preeclampsia at 27 weeks. Preterm delivery occurred; the newborn had severe intrauterine growth restriction.

Histology revealed multiple placental infarctions, fibrinoid necrosis of spiral arteries, and thrombosis.

IHC showed a sharp decrease in CD34, absence of Annexin V, and total C4d deposition.

Here, morphology and immunohistochemistry fully corresponded to the severity of the clinical picture, confirming immune damage as the primary mechanism.

Clinical Case No. 3

A 29-year-old patient with recurrent pregnancy loss. The current pregnancy showed only moderate placental insufficiency. Delivery occurred at term.

Histology showed minimal changes.

IHC revealed moderate reduction of Annexin V and local C4d deposition.

This case shows that the degree of immunomorphological changes may vary and determine the clinical outcome.

Analytical Comparison

Comparison of clinical data with morphology showed that histological severity correlated with clinical severity in only 58% of cases, whereas immunohistochemical changes showed direct correlation in 86% of observations. This confirms that key processes in APS occur at the immune level and precede morphological manifestations.

Immune Cascade of Placental Damage in APS

1. Fixation of antiphospholipid antibodies on trophoblast and endothelium

2. Activation of the complement system (C4d)

3. Endothelial damage (decreased CD31, CD34)

4. Destruction of the Annexin V protective layer

5. Formation of a procoagulant surface

6. Thrombosis as the final stage

Thus, thrombosis is a consequence of immune damage, not its cause.

Decidual Tissue Morphology

Particular attention should be paid to changes in the decidual tissue. Signs of spiral artery vasculopathy, incomplete vascular transformation, fibrinoid changes, and complement deposition were observed. This confirms that the pathological process begins as early as the stage of placentation.

4. Discussion

The obtained data make it possible to reconsider traditional views on the pathogenesis of obstetric complications in APS. Immunohistochemistry demonstrates that the placenta is a target of primary immune injury. This explains cases in which anticoagulant therapy does not prevent the development of fetoplacental insufficiency, since it does not affect complement activation and immune inflammation.

Immunopathogenesis of Placental Disorders in Antiphospholipid Syndrome

Analysis of clinical, morphological, and immunohistochemical data makes it possible to construct an integrated model of the pathogenesis of placental insufficiency in antiphospholipid syndrome. A key element of this process is the interaction between antiphospholipid antibodies and β2-glycoprotein I, which has a pronounced tropism for phospholipid membranes of the endothelium and trophoblast. Fixation of immune complexes on the cell surface triggers a cascade of reactions, including complement activation, expression of adhesion molecules, release of pro-inflammatory cytokines, and induction of apoptosis.

An important stage is impaired trophoblastic invasion into the uterine spiral arteries. Under normal conditions, these vessels undergo profound transformation and become low-resistance channels that ensure adequate blood flow to the placenta. In APS, this process is disrupted due to immune-mediated trophoblastic damage, leading to persistence of vascular resistance and the development of chronic placental hypoxia [9].

In parallel, there is a loss of the protective anticoagulant Annexin V layer on the trophoblastic surface. Under normal conditions, this protein forms a barrier between the phospholipid membrane and coagulation factors. Its disruption converts the placental surface into a procoagulant state. Thus, thrombosis is the logical culmination of the immune process rather than its primary cause.

Clinical Case No. 4

A 28-year-old patient with a history of two early miscarriages. The current pregnancy was accompanied by marked placental insufficiency without clear signs of preeclampsia. At 34 weeks, decreased fetal movements occurred, followed by emergency delivery.

Histology: moderate ischemic changes, single thrombi.

IHC: pronounced C4d deposition, significant reduction of Annexin V, and moderate reduction of CD31.

Despite a relatively “mild” morphological picture, immunohistochemistry demonstrated an active immunopathological process explaining fetal compromise.

Clinical Case No. 5

A 33-year-old patient, pregnancy achieved after long-term infertility. Severe preeclampsia developed in the third trimester. Preterm delivery occurred.

Histology: multiple placental infarctions, marked fibrinoid necrosis of vessels.

IHC: almost complete absence of Annexin V, total C4d deposition, and pronounced reduction of CD34.

This case demonstrates the classic pattern of immunomorphological placental vasculopathy in which clinical presentation, morphology, and immunohistochemistry are fully interconnected.

The Role of the Complement System in the Development of Placental Insufficiency

Complement system activation is of particular importance in the pathogenesis of APS. Deposition of C4d along the vascular wall and within decidual tissue indicates that complement-mediated injury is one of the central mechanisms underlying impaired placental blood flow. Complement activation promotes leukocyte chemotaxis, endothelial damage, and amplification of inflammatory reactions, thereby aggravating placental ischemia.

Comparative Analysis of Histology and Immunohistochemistry

The analysis showed that when the placenta is assessed only by histological methods, the true severity of the pathological process may be underestimated. Immunohistochemical methods reveal early and key pathogenetic mechanisms that are not yet accompanied by pronounced morphological changes.

This has important practical implications for interpreting cases of unexplained fetoplacental insufficiency.

Pathogenetic Model of Placental Disorders in APS

Based on the obtained data, the following sequence can be proposed: Immune fixation of antibodies → complement activation → endothelial and trophoblastic damage → loss of Annexin V → formation of a procoagulant surface → thrombosis → villous ischemia → clinical obstetric complications.

Practical Significance of the Findings

The identified immunomorphological correlations make it possible to: explain severe clinical manifestations in the presence of minimal histological changes; substantiate the need for placental immunohistochemical analysis in patients with recurrent pregnancy loss; and predict pregnancy outcomes based on the immunohistochemical profile.

Accumulated clinical, morphological, and immunohistochemical data allow a new perspective on the problem of placental insufficiency in APS. Whereas placental pathology was previously interpreted mainly as a consequence of thrombosis, it is now evident that thrombosis is only the final manifestation of a complex immunopathological process that begins much earlier and proceeds at molecular and cellular levels.

A crucial point is that immune injury to the placenta begins at the stage of early placentation. Impaired trophoblastic invasion into the uterine spiral arteries prevents the vessels from undergoing the necessary physiological transformation. They retain high vascular resistance, which subsequently creates conditions for chronic placental hypoperfusion. This process is not always accompanied by prominent early morphological changes; however, immunohistochemical studies can detect endothelial injury and complement activation before typical histological signs of ischemia develop.

Destruction of the Annexin protective layer on the trophoblastic surface is of fundamental importance. Under normal conditions, Annexin V forms a biological barrier that prevents contact between coagulation factors and the phospholipid membrane. In APS, this barrier is lost, shifting the placental surface toward a state of increased coagulation readiness. It is in this context that thrombotic changes subsequently develop and are morphologically recorded as intervillous thrombosis and placental infarctions.

Clinical observations convincingly demonstrate that the severity of obstetric complications often does not correspond to the extent of histological changes. In some cases, severe forms of fetoplacental insufficiency, preeclampsia, and intrauterine growth restriction occur in the presence of minimal morphological findings. In such situations, immunohistochemical analysis reveals pronounced signs of immune injury—complement component deposition, reduced expression of endothelial markers, and absence of Annexin V. This confirms that the true cause of placental dysfunction is rooted at the immune level.

Thus, in APS the placenta becomes a target organ for immune inflammation, endothelial dysfunction, and impaired angiogenesis. Morphological changes are merely consequences of these processes and reflect their late stages. Understanding this sequence fundamentally changes the approach to interpreting placental pathology in obstetric complications.

The obtained data have substantial practical relevance. They explain cases in which standard anticoagulant therapy does not prevent fetoplacental insufficiency because it affects thrombosis but does not influence complement-mediated injury and immune inflammation. This opens prospects for the development of new pathogenetically grounded approaches to prevention and treatment of pregnancy complications in APS.

Particularly noteworthy is the fact that immunomorphological changes are detected not only in the placenta but also in decidual tissue and spiral artery walls. This indicates that the pathological process begins long before a mature placenta forms and is associated with impaired placentation itself. Therefore, diagnosis of APS and correction of immune disturbances should be performed at early stages of pregnancy.

Analytical comparison of clinical data with immunohistochemical findings demonstrates a clear pattern: the more pronounced the reduction of Annexin V and endothelial markers combined with C4d deposition, the more severe the course of pregnancy and the higher the risk of an adverse outcome. This relationship may be considered a prognostic criterion for assessing the risk of obstetric complications.

Overall, the results confirm that APS in obstetrics should be viewed as a model of immunomorphological placental vasculopathy. The key element of this process is immune injury, whereas morphological changes represent its manifestation at the tissue level.

5. Conclusions

APS in obstetric practice is a complex immunopathological process based on endothelial and trophoblastic injury followed by complement activation and disruption of placental anticoagulant protection. Histological changes identified by routine examination reflect only late stages of this process and do not always correspond to the severity of clinical manifestations.

Immunohistochemical analysis makes it possible to detect early and key pathogenetic mechanisms of placental insufficiency in APS and has important diagnostic and prognostic value. The use of markers of endothelial injury, loss of Annexin V, and complement activation may be recommended for implementation in routine pathological examination of placentas in women with recurrent pregnancy loss and other obstetric complications [10].

Thus, shifting from a purely thrombotic interpretation of obstetric complications to recognition of their immunomorphological basis significantly deepens understanding of APS pathogenesis and opens new opportunities for improving diagnosis and pregnancy management.