Excessive Subchorionic Fibrinoid Deposition as a Component of Massive Perivillous Fibrin Deposition: A Case With Maternal Immune Thrombocytopenia

Introduction

Maternal floor infarction (MFI), and massive perivillous fibrin deposition (MPFD) are placental disorders of uncertain etiology. MFI/MPFD occurs in .03–.5% of all placentas and is associated with significant adverse obstetric outcomes and risk of recurrence in subsequent pregnancies.^1-5 The morphology is characterized by a marked increase in perivillous fibrinoid deposition in the intervillous space with villous encasement. The distribution of the fibrinoid deposition in MFI and MPFD often overlaps, suggesting both conditions represent a final common pathway for a number of different inciting events, often involving maternal autoimmune/alloimmune diseases and/or a hypercoaguable state.^1,6

In MFI/MPFD, injured trophoblasts release tissue factors and/or other mediators that activate intervillous coagulation, in an attempt to seal syncytiotrophoblast defects. ¹ The amorphous, perivillous material is a mixture of maternal-derived laminated fibrin from the coagulation cascade and extravillous trophoblast-derived matrix substance, including fibronectin, basement membrane collagen, laminin, and major basic protein. ² The process is thought to begin near the basal plate (termed MFI) with further upward extension into the midzonal and subchorionic regions (then termed MPFD). As a result, encased villi in the basal zones tend to be more sclerotic than those in the mid zonal and subchorionic regions. ¹

We report a case of MPFD with excessive subchorionic fibrinoid deposition, occurring in the setting of maternal immune thrombocytopenia. We propose that this placental finding represents a component in the spectrum of MFI/MPFD that has received little attention to date.

Discussion

Diffusely positive immunostaining for C4d along the syncytiotrophoblast layer, as seen in our case, is evidence for an antibody-mediated immune reaction resulting in trophoblast injury,^1,2 and has been seen in some cases of MPFD. ³ In our patient, the differential was considered to be primary immune thrombocytopenia vs gestational thrombocytopenia. Immune thrombocytopenia is a heterogeneous disorder associated with platelet autoantibodies. ⁷ It is the most common cause of isolated thrombocytopenia in the first and early second trimesters and generally the platelet count is below 100,000/mm³. In comparison, gestational thrombocytopenia is the most common cause of thrombocytopenia in pregnancy, accounting for 75% of cases compared to 5% for immune thrombocytopenia. Gestational thrombocytopenia is characterized by a physiologic decline in the platelet count, greatest in the third trimester, but usually remaining above 70,000/mm³ throughout gestation. ⁸ With the above in mind, together with the C4d deposition in the placenta, immune thrombocytopenia was felt to be the more likely cause of the low platelet count in our patient.

Maternal immune thrombocytopenia carries a risk of postpartum hemorrhage. Less often, maternal anti-platelet antibodies are able to cross the placenta leading to fetal immune thrombocytopenia.^7,9 The associated placental pathologies include intervillous thrombi, infarcts and decidual vascular lesions. ¹⁰ Paradoxical thrombosis has been documented up to 8% of patients with immune thrombocytopenia ⁹ and the risk of this increases with pregnancy.^9,11 As well, antiphospholipid antibodies are identified in up to 75% of patients with immune thrombocytopenia. ¹¹ Lupus anticoagulant, an antiphospholipid antibody, was detected in our patient. The presence of these antibodies is a risk factor for thrombosis in patients with immune thrombocytopenia, even without antiphospholipid syndrome.

The question arises in our case whether the excessive subchorionic fibrinoid deposition is a part of the process of MPFD, or just a chance association. The morphology of subchorionic fibrin differs from MFI/MPFD, in that the thrombus in the subchorionic region is largely fibrin and pushes villi aside rather than encasing villi, a finding that is likely related to the relative scarcity of villi in this area.^6,12 We believe that the subchorionic fibrinoid deposition in our case goes beyond simply a fibrin deposit, and is more likely a part of the process of MPFD seen in the rest of the placenta. The subchorionic region is not typically regarded as a zone involved by MPFD. The progression of MFI/MPFD is considered to proceed from the basal plate toward midzonal region and then the subchorionic plate. ¹ However, in our case, villi encased by perivillous fibrinoid were more sclerotic in the subchorionic and basal zones, compared to the midzone, implying that the subchorionic zone was preferentially involved. The subchorionic region of the placenta is where maternal blood turns back toward the basal plate, leading to local eddies in flow and stasis, thereby increasing the chances of thrombus formation in this area. Fibrin as a major component of thrombus may leak out to adjacent villi. Perivillous fibrinoid deposition can then occur, as a secondary effect, at the edges of the thrombus material.^6,13,14 Villi displaced by the subchorionic thrombus undergo degenerative change by direct pressure effect. The damaged villous surfaces produce fibrinoid to repair such the injury. ¹⁵ In this respect, the pathogenesis of subchorionic fibrinoid deposition shares similarities with that of MFI/MPFD.

There is support from the literature to suggest involvement of the subchorionic region can be a part of MFI/MPFD. The concurrence of subchorionic cysts and MFI has been documented.^6,12,13 As well, two consecutive pregnancies in the same patient showed placentas with combined subchorionic cysts and MFI. ¹²

The actual sequence of cyst formation and fibrin deposition, however, is not clear. Serial ultrasound studies have suggested that subchorionic cysts are related to cystic change in areas of subchorionic fibrin. ¹² The proposed mechanism here involves extravillous trophoblasts, which are entrapped in the fibrin, producing major basic protein, which promotes cystic degeneration of fibrin.^13,16 On the other hand, cysts do not consistently occur within regions of fibrin deposition and it has been hypothesized that subchorionic cysts may lead to fibrin deposition, based on the observation that chorionic cyst fluid contains prothrombotic factors; hence, leakage of this fluid might trigger thrombosis. ¹⁷ A more practical view may be that subchorionic cysts and subchorionic fibrin may be present concurrently without one necessarily causing the other.

In any case, cystic degeneration is not generally seen in MFI/MPFD, nor was this seen in our case. One hypothesis is that macrophages in the fibrinoid play a role in removing degenerative products produced by extravillous trophoblasts, thereby subverting the process of cystic degeneration. ¹³ We did not identify macrophages in the fibrinoid deposits, either in the subchorionic region or the basal region, so we cannot comment on this mechanism. An alternative hypothesis might be that the cyst formation reflects degeneration of fibrin, given that fibrinolysis is part of the normal evolution of thrombi and can proceed over a relatively short period of time. In contrast, fibrinoid contains extracellular matrix material, remodeling of which is a slower process. Hence, fibrinoid material would be less susceptible to degeneration and, in that case, macrophages might not be so important in preventing cystic degeneration in MFI/MPFD.

In conclusion, we propose that the subchorionic fibrinoid deposition seen in our case is a part of the process of MPFD and, thus, this region of the placenta can sometimes be preferentially involved by this condition. The placenta in our case showed diffuse C4d deposition, including the subchorionic region, reflecting antibody-mediated trophoblast injury, an event that would lead to MPFD. MPFD is known to be associated with maternal autoimmune diseases,^1,6 but this has not previously been reported with immune thrombocytopenia, possibly because only some patients with this condition have paradoxical thrombotic events. We speculate that the excessive fibrinoid production in our case is linked to maternal anti-platelet autoantibodies. Whether excessive subchorionic fibrinoid deposition is a distinct pattern of MPFD related to immune thrombocytopenia requires study of placentas from additional patients with this hematologic condition.