Severe Hemoperitoneum From a Ruptured Ovarian Cyst in a Patient with Antiphospholipid Syndrome and Antithrombin III Deficiency: A Case Report

Introduction

Antiphospholipid syndrome (APS) is a multisystem autoimmune disorder defined by the presence of antiphospholipid antibodies, including anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies, and lupus anticoagulants. These antibodies promote arterial, venous, and microvascular thrombosis, frequently in association with early fetal loss [1]. The incidence of APS in the United States is estimated at 2.1 per 100 000 individuals, with a prevalence of 50 per 100 000 [2]. Mechanistic analyses have shown that the hypercoagulable state is driven by endothelial activation, upregulation of adhesion molecules (e.g., vascular cell adhesion molecule 1, intercellular adhesion molecule 1), antiphospholipid antibody-induced thrombocyte consumption, and myeloid lineage-mediated overexpression of tissue factor, accompanied by elevated levels of plasminogen activator inhibitor-1 [3]. APS is associated with substantial morbidity and mortality, primarily resulting from cerebrovascular events, deep vein thrombosis, and recurrent obstetric complications [1,3].

In exceptionally rare cases, APS may coexist with other thrombophilic disorders, such as antithrombin III (AT III) deficiency. AT III deficiency is a rare autosomal dominant condition, with a prevalence of 1: 2000 to 1: 3000, characterized by defective inhibition of thrombin (factor IIa) and factor Xa that increase the risk of venous thrombosis [4]. Combined thrombophilic conditions such as APS and AT III deficiency create a complex hypercoagulable state that warrants long-term anticoagulant therapy. However, during active hemorrhage, such as ovarian cyst rupture, management requires a careful balance between mitigating thrombotic risk and reversing anticoagulation. We report the first documented case of severe hemoperitoneum caused by a ruptured ovarian cyst in a patient with coexisting double-positive APS and hereditary AT III deficiency. This case highlights the clinical challenges and research implications of managing hemorrhagic conditions in the context of dual thrombophilias.

Case Report

A 28-year-old woman presented to the emergency department with a 24-h history of sudden-onset, intractable pelvic pain rated 8/10 in intensity, without radiation or associated vaginal bleeding. On arrival, she appeared acutely ill, with vital signs notable for hypotension (49/28 mmHg) and tachycardia (121 beats per minute). Physical examination revealed pronounced suprapubic tenderness with guarding, accompanied by nausea, vertigo, and visual disturbances. The patient denied trauma, fever, dysuria, hematuria, or gastrointestinal symptoms.

Her medical history included serologically confirmed APS, diagnosed in 2023 after hematologic evaluation for reproductive counseling and abnormal coagulation findings in the context of a strong family history of thrombophilia. She had persistently elevated anticardiolipin IgG and anti-β2 glycoprotein I IgG levels on 2 separate occasions, fulfilling the laboratory classification criteria for APS. Lupus anticoagulant was also positive at the initial assessment, reflecting a transient triple-positive profile; however, repeat testing confirmed stable double positivity as defined by the Sydney criteria. Hereditary AT III deficiency had been confirmed in 2019. Despite the absence of prior thrombotic or hemorrhagic events, warfarin therapy had been initiated on hematology recommendation due to the coexistence of APS and AT III deficiency. Although current guidelines do not support primary prophylaxis for either condition individually, their concurrence was considered to confer exceptionally high thrombotic risk. Other comorbidities included major depressive disorder and Hashimoto’s thyroiditis. Family history was notable for paternal AT III deficiency complicated by pulmonary embolism, whereas the maternal history was unremarkable. The patient reported no history of alcohol use, tobacco smoking, or substance abuse.

Home medications included thromboprophylactic warfarin (1.5 mg orally 3 times weekly and 1.0 mg orally on all other days), levothyroxine 75 μg daily, and extended-release bupropion hydrochloride 300 mg daily. Repeat testing on admission demonstrated lupus anticoagulant positivity, with elevated anticardiolipin IgG and anti-β2 glycoprotein I antibodies, although these findings may have been confounded by the concurrent warfarin therapy. Initial laboratory evaluation revealed a hemoglobin level of 11.5 g/dL, hematocrit of 33.1%, white blood cell count of 14.25×103/μL, platelet count of 280×103/μL, prothrombin time (PT) of 42.1 s, partial thromboplastin time (PTT) of 41.4 s, and an international normalized ratio (INR) of 4.35 (Figure 1). Given the patient’s persistent hemodynamic instability and worsening anemia, contrast-enhanced abdominopelvic computed tomography (CT) was performed, revealing a moderate-volume hemoperitoneum (Figure 2) with active bleeding in the cul-de-sac, consistent with hemorrhagic ovarian cyst rupture.

Serial testing at 20 h post-admission showed further deterioration, with a supratherapeutic INR of 7.08, as well as PT and PTT values of 67.4 s and 45.8 s, respectively. At 24 h, the hemoglobin level had declined to 6.3 g/dL (Figure 3), with a hematocrit of 18.9% and platelet count of 158×103/μL. Transvaginal ultrasonography confirmed the ovarian cyst and excluded torsion (Figure 4A), revealing heterogeneous echogenicities in the perihepatic space, Morrison’s pouch, and left paracolic gutter. The right ovary contained an ill-defined 4.0 cm echogenic focus without increased vascularity (Figure 4B); the left ovary (2.5×2.0×2.4 cm) and uterus (7.7×2.7×3.5 cm) were unremarkable. The patient was transferred to the intensive care unit for stabilization, where she received 4 units of packed red blood cells and 3 units of fresh frozen plasma (FFP). Anticoagulation was withheld due to the high risk of further hemorrhage.

Despite FFP administration, INR and aPTT values continued to rise, accompanied by worsening anemia and thrombocytopenia. Lactate dehydrogenase levels remained normal; peripheral smear examination revealed no schistocytes, excluding disseminated intravascular coagulation. Liver function test results were within normal parameters, excluding hepatic synthetic dysfunction. No heparin exposure was documented, and the smear showed no blasts or abnormal cellular forms suggestive of marrow pathology. CT-guided placement of a 10-French pigtail catheter via a transgluteal approach decompressed the 6.3×4.1 cm cul-de-sac hematoma. The procedure, performed under conscious sedation and local anesthesia, yielded 30 mL of dark red fluid. The catheter was flushed daily and removed when drainage decreased below 10 mL per day.

Follow-up non-contrast CT confirmed effective decompression with minimal residual pelvic blood. Warfarin therapy was cautiously reinitiated with serial INR monitoring. When a therapeutic range was achieved, CT confirmed complete resolution of hemorrhage and the absence of inflammatory changes (Figure 5). Final laboratory values included hemoglobin 12.9 g/dL, hematocrit 37.6%, white blood cell count 4.97×103/μL, platelet count 245×103/μL, PT 22.0 s, PTT 59.0 s, and INR 2.11. The patient was discharged in stable condition with scheduled outpatient follow-up.

Discussion

Ovarian cysts are fluid-filled sacs that originate from ovarian follicles or the corpus luteum, typically forming within the cortical stroma and commonly affecting women of reproductive age [5]. The right ovary is more frequently involved (63%), likely due to anatomical and hemodynamic asymmetries, including elevated right ovarian vein pressure from direct drainage into the inferior vena cava [6]. Most ovarian cysts are benign, asymptomatic, and self-limited; however, hemorrhagic rupture can result in hemoperitoneum, leading to visceral irritation and hemodynamic instability [6].

In the present case, cyst rupture caused hemodynamic compromise, which was further exacerbated by iatrogenic thromboprophylaxis for coexisting APS and AT III deficiency. The pathogenesis of APS involves persistent antiphospholipid antibody production, particularly anticardiolipin antibodies and lupus anticoagulants, which interact with phospholipid-binding proteins to activate endothelial cells, monocytes, and platelets. Transient antiphospholipid antibody-induced inflammation also activates complement, amplifying a prothrombotic cascade that promotes endothelial dysfunction, vasculopathy, thromboembolism, and miscarriage [7].

APS and AT III deficiency constitute distinct hypercoagulable states with overlapping clinical implications, even in the absence of conventional predisposing factors. AT III, a serine protease inhibitor, regulates coagulation by inactivating thrombin and factor Xa, with secondary inhibitory effects on factors IXa, XIa, and XIIa, thus limiting fibrin deposition and thrombus propagation [8]. In APS, endothelial dysfunction promotes upregulation of tissue factor and adhesion molecules, leading to local thrombin synthesis and platelet aggregation [9]. Simultaneously, monocyte activation and neutrophil activation induce cytokine release and the formation of neutrophil extracellular traps, further amplifying thrombogenesis [9].

To date, only 3 cases of concurrent APS and AT III deficiency have been documented. Phan et al. reported a 45-year-old woman with catastrophic APS-like disease and AT III deficiency who ultimately died of extensive thrombosis. Barham et al. described a 28-year-old man with severe hemoptysis and recurrent thromboembolic events [10,11]. More recently, Kowalczewska et al. reported a 13-year-old girl with APS and newly diagnosed AT III deficiency who developed recurrent ischemic strokes despite rivaroxaban therapy and ultimately required emergent mechanical thrombectomy, which led to a favorable outcome [12].

None of the prior reports involved acute hemorrhage requiring anticoagulation reversal, which represented the central challenge in the present case. A comparable clinical dilemma was described by Yokus et al. in a 31-year-old woman with APS and hemophilia B who developed postpartum deep vein thrombosis and pulmonary embolism after warfarin discontinuation [13]. Initiation of enoxaparin and aspirin precipitated diffuse alveolar hemorrhage, prompting anticoagulation cessation, transfusion support, targeted imaging, and eventual reintroduction of low-molecular-weight heparin (LMWH) at half dose, followed by 2.5 mg of warfarin when hemostasis had been achieved [13]. Similar to our case, management required ongoing reassessment of thrombotic and hemorrhagic risk, highlighting the need for individualized, adaptive anticoagulation strategies in patients with dual coagulopathies.

Warfarin remains the cornerstone of long-term anticoagulation for patients with APS and AT III deficiency, supported by robust efficacy data from both United States and European guidelines [14–16]. In cases of refractory APS or warfarin resistance, adjunctive agents such as low-dose aspirin, statins, hydroxychloroquine, or LMWH may be considered [1,17]. However, LMWH efficacy largely depends on AT III activity, rendering it suboptimal in AT III deficiency. Short-term administration of exogenous AT III can temporarily restore antithrombin activity in perioperative or acute settings, but it remains largely impractical for long-term therapy [14]. Direct oral anticoagulants (DOACs) act independently of AT III, presenting a theoretical advantage in AT III deficiency; however, supporting evidence is limited to isolated case reports [18–22]. In contrast, meta-analyses suggest that DOACs are less safe in high-risk APS subgroups, particularly those with triple antiphospholipid antibody positivity [21,22].

In the present case, management initially focused on hemodynamic stabilization and temporary discontinuation of anticoagulation due to active bleeding and a markedly supratherapeutic INR. Supportive care included fluid resuscitation, serial hematologic monitoring, and transfusion of packed red blood cells and FFP to counteract acute blood loss. Although guidelines recommend 4-factor prothrombin complex concentrate for rapid warfarin reversal, FFP was selected as a plasma-based alternative providing broader factor replacement and intravascular volume expansion. Both agents offer only transient correction in ongoing hemorrhage; however, PCC carries a higher thromboembolic risk, which is particularly concerning in patients with high-risk antiphospholipid antibody profiles and concomitant AT III deficiency [23]. Hemoperitoneum was managed with CT-guided placement of a 10-French percutaneous pigtail catheter to relieve intra-abdominal pressure.

Upon resolution of bleeding, anticoagulation was reinitiated in a stepwise manner with repeat imaging and serial INR monitoring. Alternative agents such as LMWH and DOACs were avoided due to suboptimal AT III levels and insufficient safety data in high-risk APS, respectively. The coexistence of APS and AT III deficiency presents a critical therapeutic dilemma – ensuring durable anticoagulation to prevent thrombosis while minimizing hemorrhagic risk. Both the present case and the report by Yokus et al. emphasize the importance of early risk stratification, multimodal imaging, hemodynamic support, and individualized anticoagulation strategies. Given that evidence remains limited, prospective trials evaluating DOACs in APS and AT III deficiency separately are imperative to clarify evidence-based approaches for managing complex hypercoagulable states.

Conclusions

APS and AT III deficiency are rare hypercoagulable disorders that, when present together, pose substantial clinical challenges. Management requires personalized, dynamically reassessed strategies to balance thrombotic risk against iatrogenic hemorrhagic potential. Although vitamin K antagonists remain the cornerstone of therapy, emerging case-based evidence suggests that DOACs represent a feasible alternative in selected patients, particularly those with AT III deficiency. This case highlights the importance of early risk stratification, structured anticoagulation planning, and close hemodynamic monitoring during acute hemorrhagic events in hypercoagulable patients. Given the inherent limitations of a single-patient report, future research should focus on generating robust, disease-specific data regarding DOAC efficacy to inform risk-adjusted management protocols. Beyond immediate therapeutic considerations, this case illustrates the paradox of hemorrhage in dual hypercoagulable disorders, underscoring its clinical significance and contribution to existing literature.