Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal-maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11-79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal-fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe-moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules.

BACKGROUND: Despite pregnancy\'s hypercoagulable state, the correlation between inherited thrombophilia and thrombotic adverse pregnancy outcomes remains uncertain. The objective of this study was to determine the prevalence of inherited thrombophilic polymorphisms among asymptomatic pregnant individuals and to examine their potential correlation with adverse perinatal outcomes.
METHODS: in this single-center prospective study, 105 healthy pregnant women were included. Genotyping was conducted for factor V Leiden (FVL), prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and plasminogen activator inhibitor-1 (PAI-1), alongside the assessment of protein C (PC), protein S (PS), and antithrombin (AT) levels. The study analyzed the association between inherited thrombophilic polymorphisms and pregnancy complications linked to placental insufficiency, such as gestational hypertension (GH), preeclampsia (PE), intrauterine death (IUD), fetal growth restriction (FGR), and placental abruption.
RESULTS: The prevalence of identifiable thrombophilic polymorphism mutations was 61.9% (95% confidence interval-CI 52.4-70.8%), with the most common single mutation being PAI-1 4G/5G (12/105, 11.4%, 95% CI 6.4-18.5). The most frequent combined mutation was heterozygosity for MTHFR C677T and PAI-1 (12/105, 11.4%, 95% CI 6.4-18.5). Notably, no FVL homozygous carriers or single homozygous and heterozygous carriers for prothrombin polymorphisms were found. Additionally, no deficiencies in PC and AT were detected among participants. Except for homozygosity for PAI-1, none of the studied polymorphisms demonstrated a significant association with pregnancy complications linked to placental insufficiency.
CONCLUSIONS: The asymptomatic carriers of inherited thrombophilic polymorphisms do not have an increased risk of adverse perinatal outcomes.

Although the relationship between venous thromboembolism (VTE) and cancer has been a subject of study, knowledge of the contribution of thrombophilia to thrombosis in patients with cancer is still very limited. The aim of this article is to collect present knowledge on the contribution of inherited thrombophilia to VTE in cancer patients. We performed a search in Google Scholar and PubMed and selected 21 from 76 returned articles. Then we made a narrative review of the selected articles. We describe 11 studies on the contribution of inherited thrombophilia to VTE in cancer patients in general and 10 on that contribution in specific types of cancer: 1 in colorectal cancer, 4 in breast cancer, 1 in gynecologic cancer and 4 in hematopoietic malignancies. All studies investigate the relation of factor V Leiden (FVL) to VTE, 13 that of the prothrombin G20210A mutation (PTG20210A) and 7 studies also investigate other inherited thrombophilias, such methylenetetrahydrofolate reductase gene mutations, although only 2 investigate the contribution of deficiencies of the natural anticoagulants. Studies are very heterogeneous, in design and sample size and conclusions differ considerably. There is no consensus on the contribution of inherited thrombophilia to VTE in cancer patients except for acute lymphoblastic leukemia in children. Probably, that contribution is not the same for all types of cancer and more studies are needed to bring more knowledge on this subject.

OBJECTIVE: Thrombosis is an increasingly recognized complication of childhood malignancy and its treatment. The incidence and etiology of pediatric cancer-related thrombosis is still not well understood. The aim of this study was to evaluate the prevalence of common prothrombotic genetic conditions in children with cancer, the frequency of thrombosis, and the role of inherited thrombophilia in the development of thrombosis in a pediatric oncology population.
METHODS: Forty-seven children (36 treated for hematological malignancies and 11 for solid tumors) with a median age of 8.8. years (range 0.4 - 19.3 years) were included in the study. Genetic polymorphisms of Factor V Leiden (G1691A), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were determined by real-time polymerase chain reaction-based DNA analysis.
RESULTS: Four (8.5%) patients were heterozygous for Factor V Leiden, 3 (6.4%) were heterozygous for prothrombin G20210A mutation, and 3 (6.4%) were homozygous for MTHFR C677T mutation. All patients had implanted central venous catheters. Four (8.5%) children had documented thrombosis, three of which were in the upper venous system. Two of the four patients with thrombosis had Factor V Leiden heterozygosity.
CONCLUSIONS: Thrombosis is an important complication of childhood cancer. The risk of thrombosis may be increased in patients with Factor V Leiden. In the absence of consensus guidelines, our results support the recommendation for thrombophilia screening in children with cancer.

UNASSIGNED: Kearns-Sayre syndrome (KSS) is classified as one of the mitochondrial DNA (mtDNA) deletion syndromes with multisystemic involvement. Additionally, the negative prognosis is associated with inherited thrombophilia, which includes the presence of homozygous Factor V G1691A Leiden mutation, MTHFR gene polymorphisms C677T and A1298C, and PAI-1 675 homozygous genotype 5G/5G.
UNASSIGNED: This case report presents a 48-year-old man with chronic progressive external ophthalmoplegia, bilateral ptosis, cerebellar ataxia, cardiovascular signs (syncope, dilated cardiomyopathy, and cardiac arrest) with electrocardiographic abnormalities (first-degree atrioventricular block and major right bundle branch block), endocrine dysfunction (short stature, growth hormone insufficiency, primary gonadal insufficiency, hypothyroidism, and secondary hyperparathyroidism), molecular genetic tests (MT-TL2 gene), and abnormal MRI brain images, thus leading to the diagnosis of KSS. The patient came back 4 weeks after the diagnosis to the emergency department with massive bilateral pulmonary embolism with syncope at onset, acute cardiorespiratory failure, deep left femoral-popliteal vein thrombophlebitis, and altered neurological status. In the intensive care unit, he received mechanical ventilation through intubation. Significant improvement was seen after 2 weeks. The patient tested positive for inherited thrombophilia and was discharged in stable conditions on a new treatment with Rivaroxaban 20 mg/day. At 6 months of follow-up, ECG-Holter monitoring and MRI brain images remained unchanged. However, after 3 months, the patient died suddenly while sleeping at home.
UNASSIGNED: The genetic tests performed on KSS patients should also include those for inherited thrombophilia. By detecting these mutations, we can prevent major complications such as cerebral venous sinus thrombosis, coronary accidents, or sudden death.

OBJECTIVE: Inherited thrombophilia testing in the acute inpatient setting is controversial and expensive, and rarely changes clinical management. We evaluated ordering patterns and results of inpatient inherited thrombophilia testing for patients who presented with an isolated acute ischemic stroke or transient ischemic attack (TIA) without concurrent venous thromboembolism.
METHODS: We retrospectively analyzed patients admitted for acute ischemic stroke or TIA between January 1st, 2019 and December 31st, 2021 at Thomas Jefferson University Hospitals in Philadelphia, PA and who underwent inherited thrombophilia testing during the hospital admission. Charts were reviewed to determine stroke risk factors, test results, and clinical management.
RESULTS: Among 2108 patients admitted for acute ischemic stroke or TIA (including branch and central retinal artery occlusions) during the study period, the study included 249 patients (median age 49.0 years, 50.2% female) who underwent inpatient testing for factor V Leiden, prothrombin G20210A variant, hyperhomocysteinemia, PAI-1 elevation, and deficiencies of protein C and S and antithrombin. 42.2% of patients had at least one abnormal test, and among the 1035 tests ordered, 14.3% resulted abnormal. However, 28% of abnormal tests were borderline positive antigen or activity assays that likely represented false positives. There was no significant difference in the likelihood of a positive test among patients without stroke risk factors vs those with risk factors (47.1% vs 40.9%, P = .428), nor any significant difference between those under vs over age 50 years (45.7% vs 38.3%, P = .237). No patients with an abnormal result had their clinical management changed as a result. Charges for the tests totaled $468,588 USD.
CONCLUSIONS: Inherited thrombophilia testing in the hospital immediately following isolated acute arterial ischemic stroke or TIA was associated with high rates of likely false positive results and was expensive. Positive results did not change clinical management in a single case.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a phenotype of pulmonary hypertension due to chronic and multiple organized thrombus. The therapeutic strategy for patients with CTEPH and comorbid protein S deficiency remains unknown due to its rarity. Case: We encountered a 49-year-old male patient with CTEPH and concomitant mild protein S deficiency (type III). We could successfully perform balloon pulmonary angioplasty without any major complications, including thromboembolism and bleeding, followed by standard-dose oral anticoagulation therapy instead of warfarin. Conclusion: A currently established standard therapeutic strategy for CTEPH, including pulmonary angioplasty, may be safe and effective even in patients with concomitant inherent coagulation abnormalities.

Thrombosis is an extremely dangerous complication in elderly patients with COVID-19. Since the first months of the pandemic, anticoagulants have been mandatory in treatment protocols for patients with COVID-19, unless there are serious contraindications. We set out to discover if genetic thrombophilia factors continue to play a triggering role in the occurrence of thrombosis in patients with COVID-19 with prophylactic or therapeutic anticoagulants. We considered the following genetic markers as risk factors for thrombophilia: G1691A in the FV gene, C677T and A1298C in the MTHFR gene, G20210A and C494T in the FII gene, and (-675) 4G/5G in the PAI-I gene. In a cohort of 176 patients, we did not obtain a reliable result indicating a higher risk of thrombotic complications when taking therapeutic doses of anticoagulants in carriers of genetic markers for thrombophilia except the C494T mutation in the FII gene. However, there was still a pronounced tendency to a higher incidence of thrombosis in patients with markers of hereditary thrombophilia, such as FV G1691A and FII G20210A mutations. The presence of the C494T (Thr165Met) allele in the FII gene in this group of patients showed a statistically significant effect of the mutation on the risk of thrombotic complications despite anticoagulant therapy.

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