特発性血栓症（遺伝性血栓性素因によるものに限る。）

OBJECTIVE: To report a novel pathogenic frameshift mutation in the histidine-rich glycoprotein (HRG) gene causing hereditary thrombophilia, and to discuss its clinical implications for kidney transplantation decision-making. METHODS: A 42-year-old female with end-stage renal disease on maintenance hemodialysis presented with recurrent dialysis access thrombosis. Routine coagulation tests were normal, but decreased antithrombin and elevated D-dimer prompted genetic investigation. Whole-exome sequencing was performed to identify potential genetic etiologies. RESULTS: Whole-exome sequencing identified a previously unreported pathogenic frameshift mutation in the HRG gene: c.694delG (p.E232fs). This mutation explained the patient's prothrombotic phenotype. Given the significantly elevated risk of renal allograft thrombosis associated with this condition, a multidisciplinary risk assessment led to deferral of the planned kidney transplantation. CONCLUSIONS: This case highlights the critical role of early genetic testing in patients with unexplained recurrent thrombosis. Identifying a novel HRG mutation not only establishes a rare etiology of hereditary thrombophilia but also guides personalized management and high-stakes surgical decisions, such as deferral of organ transplantation to avoid graft loss.

Cerebral venous sinus thrombosis (CVST) is an uncommon cerebrovascular disorder with heterogeneous manifestations and may occasionally precede the diagnosis of an underlying malignancy. We report the case of a 24-year-old man who presented with recurrent fever, headache, pharyngodynia, and systemic inflammation initially attributed to a sinonasal or odontogenic infectious process. He subsequently developed binocular horizontal diplopia, left abducens nerve palsy, papilledema, severe headache, and nausea. Neuroimaging demonstrated extensive CVST involving the left internal jugular vein, bilateral transverse sinuses, and superior sagittal sinus, without ischemic, hemorrhagic, or tumoral brain parenchymal lesions. Thrombophilia testing identified heterozygous prothrombin G20210A as the only established inherited thrombophilic factor. Despite initial neurological stabilization, the patient developed a rapidly recurrent frontal calvarial, epicranial, and cranio-dural lesion extending toward the superior sagittal sinus, without brain parenchymal involvement or imaging evidence of leptomeningeal disease. Initial morphological assessment suggested Langerhans cell histiocytosis. However, comprehensive histopathological and immunohistochemical reassessment demonstrated diffuse strong CD30 expression, nuclear and cytoplasmic ALK positivity, CD43 expression, and focal epithelial membrane antigen and granzyme B positivity, while CD1a and S100 were negative. These findings established the diagnosis of systemic ALK-positive anaplastic large cell lymphoma with secondary extra-axial cranio-dural involvement. Systemic staging demonstrated disseminated nodal disease and a noncontiguous cranio-dural extranodal lesion, consistent with stage IV disease. Treatment with anticoagulation and six cycles of brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone resulted in a favorable neurological and oncological outcome, with no metabolically active or residual enhancing disease on follow-up imaging. This case emphasizes the importance of continued etiological investigation in young patients with extensive CVST and an atypical clinical course, even when plausible infectious and inherited thrombotic risk factors coexist.

Background: Hereditary thrombophilia testing is frequently performed outside guideline-supported indications, generating low-value results and diagnostic uncertainty. We evaluated the spectrum, laboratory validity, and appropriateness of thrombophilia testing in patients referred to hematology. Methods: This single-center retrospective cohort included 131 adults referred between September 2021 and November 2022 with a completed six-variant hereditary thrombophilia panel. Demographic, clinical, thrombotic, and laboratory data were reviewed, and testing appropriateness was assessed against the 2011 Turkish Society of Hematology guideline. Results: Ischemic stroke (25.2%), pulmonary embolism (21.4%), and recurrent pregnancy loss (16.0%) were the leading indications. Of 120 evaluable requests, only seven (5.8%) met guideline-supported criteria, and 42 (32.0%) were ordered during acute thrombosis. Factor V Leiden was associated with pulmonary embolism (48.6% vs. 22.1%, p = 0.003) and deep vein thrombosis (28.6% vs. 9.5%, p = 0.003), whereas ischemic stroke was less frequent among carriers (11.4% vs. 33.7%, p = 0.017). PAI-1, MTHFR c.1298A>C, and prothrombin G20210A showed no consistent associations. Of six low protein C results, only two were confirmed; none of eight low protein S results remained valid after timing and confirmation criteria were applied. Lupus anticoagulant was positive in 18 patients, yet only six underwent appropriately timed repeat testing, establishing four new antiphospholipid syndrome diagnoses. Conclusions: Most thrombophilia panels were ordered inappropriately, and test timing frequently compromised interpretability. Clinically meaningful information arose mainly from factor V Leiden and properly confirmed acquired thrombophilia testing. Targeted, indication-driven testing with strict attention to timing and confirmation should replace indiscriminate panel use.

BackgroundInherited thrombophilia, particularly Factor V Leiden (FVL) mutation, globally, stands as a known contributing factor for venous thromboembolism (VTE). However, there are minimal case-control studies about the genetic composition and risk of these mutations within the Kurdistan Region of Iraq (KRI). This study's goal was to analyze the frequency and clinical significance of FVL, Prothrombin G20210A, and MTHFR C677T mutations in patients from Sulaymaniyah province.MethodsWithin this prospective case-control study, we analyzed 147 unselected patients (aged 18-49) with documented VTE (DVT, PE, or PVT) and 100 age and sex matched healthy controls. Molecular analysis was performed using multiplex PCR and reverse hybridization.ResultsIn the patient cohort, 55.8% had at least one prothrombotic mutation. The frequency of FVL was 14.3% in the patient cohort compared to 8% in the control group. FVL carriers showed a remarkably higher rate of recurrent thrombosis compared to non-carriers (71% vs. 40%; p = 0.041). Furthermore, FVL carriers had a five-fold increased risk for recurrent DVT (OR 5.4, 95% CI 0.778-37.505) and were significantly more likely to have a positive family history (p = 0.005). While MTHFR C677T was highly prevalent in both groups (48% patients, 49% controls), it was not identified to be an independent risk factor for VTE.ConclusionFVL is classified as a strong contributing factor for recurrent thrombosis in Sulaymaniyah. The high regional prevalence of FVL shows the need for targeted genetic screening in young patients, presenting with unprovoked or recurrent DVT, particularly when a family history is present.

BACKGROUND: The predictive value of serum Anti-Müllerian Hormone (AMH) for overall reproductive potential remains controversial, particularly with respect to obstetric and perinatal outcomes. The aim of this study was to evaluate the association between AMH levels and adverse maternal and neonatal outcomes in a large cohort of women diagnosed with recurrent pregnancy loss (RPL). METHODS: This retrospective observational cohort monocentric study included women assessed for RPL at a tertiary referral center between 2014 and 2023. Patients were stratified according to serum AMH levels (<0.7 vs. ≥0.7 ng/mL). Pregnancy and perinatal outcomes were evaluated using composite adverse neonatal outcomes (CANO), including birth weight <2500 g, neonatal intensive care unit admission, 5-minute Apgar score <7, birth weight below the 10th percentile, stillbirth and perinatal death. Composite adverse maternal outcomes (CAMO) included emergency cesarean section, operative vaginal delivery, postpartum hemorrhage, and intensive care unit admission. Descriptive and inferential statistical analyses were performed. Logistic regression models were used to investigate factors associated with adverse maternal and neonatal outcomes. RESULTS: During the study period, 453 women were evaluated for RPL. Serum AMH levels were available for 281 women (62.0%), and pregnancy outcome data were available for 123 women (44.1%). Among these, 11 women (8.7%) experienced a miscarriage, while 112 (90.3%) achieved a live birth. Women with AMH <0.7 ng/mL (N.=60; 13.25%) were significantly older (P<0.001), had a higher number of previous miscarriages (P=0.03), and a higher prevalence of hereditary thrombophilia (P=0.005). Among ongoing pregnancies, women with low AMH showed a higher prevalence of thyroid disorders (P=0.025) and lower antral follicle count (P=0.016). Multivariable analysis demonstrated no significant association between AMH levels and composite adverse neonatal or maternal outcomes, while labor induction was independently associated with a reduced risk of adverse neonatal outcomes. CONCLUSIONS: In women with recurrent pregnancy loss, low AMH levels were not associated with an increased risk of adverse maternal or neonatal outcomes. Labor induction appeared to exert a protective effect on neonatal outcomes. Prospective studies are warranted to confirm these findings and to support periconceptional counseling in this population.