Navigating anemia and anticoagulation in elderly patients undergoing orthopedic surgery: strategies for preventing complications and implementing treatments.

BACKGROUND: Elderly populations face an increased risk of anemia, leading to elevated transfusion requirements during surgery, especially major orthopedic procedures. Anemia itself increases the risk of thromboembolic events, thus compounding complications in elderly individuals. Polypharmacy and the prevalent use of oral anticoagulants (OAC), particularly for atrial fibrillation, contribute to bleeding risks in this population. Data available in the literature on the peri-operative management of anemia in patients taking OAC is limited and often heterogeneous. MATERIALS AND METHODS: This narrative case-based review focuses on the peri-operative management of elderly patients on OAC undergoing major orthopedic surgery. PubMed/Medline was used to search for relevant literature. RESULTS: With reference to two cases, we critically evaluate the literature, and focus on risk factors, and preventive and therapeutic strategies as fundamental tools to reduce bleeding and correct anemia as soon as possible in elderly patients undergoing major orthopedic surgery. DISCUSSION: Peri-operative management of these patients, especially those on OAC, requires a balanced approach considering bleeding and thrombotic risks. Intravenous iron therapy and tranexamic acid emerge as valuable strategies in minimizing transfusion requirements and optimizing patients' outcomes.

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

STUDY QUESTION: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? SUMMARY ANSWER: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. STUDY DESIGN, SIZE, DURATION: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9). LIMITATIONS, REASONS FOR CAUTION: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. WIDER IMPLICATIONS OF THE FINDINGS: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NCT02385461.

Mortality and clinical outcome of Italian patients undergoing orthopaedic surgery: effect of peri-operative blood transfusion.

BACKGROUND: Blood transfusion is a relevant issue for elderly and frail patients, as they are often anaemic and have chronic diseases. Transfusion of red blood cells (RBC) can potentially affect morbidity and mortality of elderly patients undergoing major orthopaedic surgery. MATERIALS AND METHODS: We carried out a retrospective analysis of 2,593 patients undergoing major orthopaedic surgery between 2013 and 2017 in a single research institution in the Region of Apulia. The aims of the study were: 1) to describe the characteristics of transfused patients according to a restrictive or liberal strategy of transfusion and haemoglobin (Hb) triggers and targets; 2) to investigate the effect of RBC transfusion on mortality and complications. RESULTS: Older, women and patients with American Society of Anesthesiologists (ASA) score 3-4 were more often transfused. Those with lower admission Hb level had a higher risk of being transfused. Hb triggers were associated with the patients' age. A restrictive transfusion strategy was significantly more frequent in patients undergoing primary knee replacement and in those with higher estimated blood loss. We did not observe any significant difference of complications in patients transfused with a liberal vs restrictive strategy. Logistic regression correcting for potential confounders revealed that sex (males more than females), duration of stay in hospital, hip fracture and Charlson score >4 were good predictors of complications and/or mortality. Mortality was significantly higher in males and in older patients with ASA score 3-4. DISCUSSION: In this large cohort of Italian patients undergoing major orthopaedic surgery males were significantly more exposed than women to complications and in-hospital mortality. Furthermore, those undergoing urgent surgery because of hip fracture had a 3-fold higher chance of complications. Charlson score >4 and ASA 3-4 are good predictors of complications and mortality, respectively.

The curious incident of a cavum velum interpositum cyst in twins of a mother carrying May-Hegglin anomaly: a case report and short literature review.

BACKGROUND: May-Hegglin anomaly is an autosomal dominant inherited condition, characterized by thrombocytopenia, giant platelets and Dohle-like bodies. Incidence is unknown and affected individuals can show from mild to moderate-severe haemorrhagic symptoms. The cyst of cavum veli interpositi (a virtual space filled with fluid within the third ventricle) is rarely reported in the foetal period. Furthermore, it is unclear whether isolated cavum veli interpositi cysts are a normal variant or developmental malformations. The simultaneous presence of these two anomalies was never described. CASE PRESENTATION: We describe a very rare case of a twin monochorionic pregnancy in a woman with the May-Hegglin anomaly, whose foetuses carried cavum veli interpositi cysts. Since childhood, our patient had shown macro-thrombocytopenia, deafness and bleeding (epistaxis and menorrhagia), but she was misdiagnosed until the age of 30 years when our Centre identified a de novo allelic variant in the gene MYH9 coding for the non-muscle myosin heavy chain IIa. Our patient bled neither during the pregnancy, nor in the peripartum period. Children are now eight-months-old and have never bled, although both inherited the MYH9 variant and have thrombocytopenia with giant platelets. Furthermore, none of them developed psychomotor disorders. CONCLUSIONS: To the best of our knowledge, this is the sixth case of twin pregnancy in a woman carrying May-Hegglin anomaly and the first one with cavum veli interpositi cysts in the neonates. We speculate that MYH9 could have, at least in part, played a role in the development of both conditions, as this gene has a pleiotropic effect.

Pulmonary embolism associated with transfusion after severe post-partum haemorrhage: is less more?

BACKGROUND: Transfusion of red blood cells is associated with superficial vein thrombosis (SVT) and venous thromboembolism (deep vein thrombosis and/or pulmonary embolism, VTE). The present study investigated the prevalence of SVT and VTE in women transfused in the peri-partum period. MATERIALS AND METHODS: We carried out an observational study in a tertiary level obstetrics department in the Apulia Region of Southern Italy to investigate VTE in women transfused during or after labour. The study included all women who delivered between January 1st and November 30th, 2018. A thrombotic event was defined as an admission with an ICD-9 code of SVT and VTE as a primary or secondary diagnosis. Maternal "near-miss" rate, as defined by the World Health Organization, was calculated and outcome of transfused women was recorded. RESULTS: From January 1st to November 30th, a total of 1,028 women delivered, 39% of them by caesarean section (CS). One-hundred and thirty-two women (12.8%) had been classified with one or more complication codes. Most complications occurred in women who underwent CS with an odds ratio (OR) of 7.0 (95% CI: 4.0-12.5; p=0.000). Twelve women (1.2%) were transfused in the peri-partum period, 7 of them had delivered by CS. The only thrombotic events recorded in the entire cohort of 1,028 patients were isolated pulmonary embolisms observed in 2 out of 12 transfused women. Overall, patients had received a mean of 7.5 units of packed red blood cells (1 patient also received 7 plasma units, while 1 patient also received 1 platelet unit). Consequently, the near-miss rate was 2.0/1,000 deliveries, which is not significantly different from that expected in Italy and in high-income countries. CONCLUSIONS: Pulmonary embolism is a life-threatening complication, which can be associated with transfusion in the peri-partum period.

Management of Patients Taking Oral Anticoagulants Who Need Urgent Surgery for Hip Fracture.

The number of hip fractures in anticoagulated patients is predicted to increase, due to people living longer. However, evidence regarding urgent perioperative management of elderly patients with hip fracture who take oral anticoagulants (vitamin K antagonists or direct oral anticoagulants) is scarce. In this article, the authors present a narrative review of the evidence to date supporting the urgent management of hip fracture in anticoagulated elderly patients. They discuss the complexity of managing the high risk of procedure-related bleeding and, at the same time, the high risk of thromboembolism. The role of a bridging procedure and the best strategy of anticoagulation reversal are also reviewed. Further studies are required to improve the evidence in urgent surgery, especially in frail elderly patients.

Antiphospholipid Antibodies in a General Obstetric Population: Clinical Impact on Pregnancy Outcome and Relationship with the M2 Haplotype in the Annexin A5 (ANXA5) Gene.

Antiphospholipid (aPL) antibodies are recognised risk factors for adverse obstetric outcomes. Recently, carriers of the M2 haplotype in the Annexin A5 gene have been shown to have a higher susceptibility to develop aPL antibodies. In a general obstetric population, we prospectively evaluated the possible relationship between: (1) aPL antibodies and M2 haplotype; and (2) aPL antibodies and/or M2 haplotype and obstetric outcomes. From a cohort of 3,097 consecutive pregnant women, 1,286 samples were analysed for the presence of both anti-cardiolipin and anti-human ß2-glycoprotein I antibodies; samples with available DNA (n = 606) were also investigated for the M2 haplotype. Overall, 41/1,286 (3.2%) women showed the presence of aPL antibodies. Among them, 2 (4.8%) experienced a pregnancy loss and 38 (92.7%) gave birth to live-born babies (p-value = non-significant vs. those without aPL antibodies). M2 haplotype was identified in 140 (23.1%) out of 606 women with DNA available: 3/140 (2.1%) M2 carriers and 17/466 (3.6%) non-carriers tested positive for aPL antibodies, respectively (p-value = non-significant). In total, 15/150 (10%) M2 and/or aPL antibody carriers, and 38/445 (8.5%) non-aPL antibody and/or M2 carriers suffered from obstetric complications, respectively (p-value = non-significant). No relationship between aPL antibodies and M2 haplotype was found. Furthermore, neither aPL antibodies nor the M2 haplotype is associated with obstetric complications.

Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype-phenotype relationship.

Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency.

Modulation of factors involved in placental haemostasis and angiogenesis by low-molecular-weight-heparins.

PURPOSE: In placentae from uneventful pregnancies a direct relationship between expression of tissue factor (TF) and tissue-factor pathway inhibitor type 2 (TFPI2) was found, as well as between TF and vascular endothelial growth factor (VEGF). Furthermore, placentae from gestational vascular complications (GVCs) lack these correlations. Aims of the present study are (1) to evaluate a possible role of low-molecular-weight-heparins (LMWHs) in the modulation of the expression of TF, TFPI, TFPI2 and VEGF in placentae from thrombophilic women and (2) to study the possible role of endothelium in the placental expression of markers involved in haemostasis and angiogenesis. METHODS: Fourteen pregnancies in thrombophilic women and 11 uneventful pregnancies in non-thrombophilic women were studied and placentae collected. From each placenta total RNA was obtained. Expression of TF, TFPI, TFPI2 and VEGF was evaluated. Human Vein Endothelial Cells were incubated with increasing doses of LMWH and expression of TF, TFPI and VEGF was measured. RESULTS: Expression of all the markers analyzed in placentae from treated pregnancies was similar to that observed in placentae from uneventful ones. A significant direct relationship between TF and TFPI2, as well as TF and VEGF, was observed in cases treated with LMWHs and controls. Furthermore, the expression of TF and its inhibitors and VEGF in endothelial cells was modulated by LMWH. CONCLUSION: Present data suggest that LMWH during pregnancy in thrombophilic women restores the relationship between markers of haemostasis and angiogenesis. Furthermore, the endothelium is likely to play an important role in this phenomenon.

Postpartum haemorrhage in a woman with essential thrombocythemia carrying calreticulin mutation: a case report.

Coagulation disorder associated with essential thrombocythemia may exacerbate the prothrombotic state physiologically occurring during pregnancy. We report a case of a severe postpartum haemorrhage in a 35-year-old woman previously diagnosed with essential thrombocythemia and carrying the somatic calreticulin mutation. She was referred to our Thrombosis and Haemostasis Unit for pregnancy management. A treatment with low-dose aspirin was prescribed until the labour started, as the platelets count raised above 1000 × 10/l. At the time of bleeding, no residual placenta was detected at the revision of the uterine cavity.Although the postpartum is a high-risk period for thrombotic events, we have to carefully evaluate in women with essential thrombocythemia the likelihood of developing a hemorrhagic complication.

Aspirin and heparin in pregnancy.

INTRODUCTION: A pro-coagulant state during pregnancy can be involved in the occurrence of gestational vascular complications (GVCs) and venous thromboembolism (VTE). AREAS COVERED: Antithrombotic drugs are used to prevent GVCs and VTE. Aspirin is not efficacious to prevent recurrences in women with previous early loss, while it can prevent pre-eclampsia in some groups of women. Heparins are not effective in the prevention of early recurrent loss and there is uncertainty about their efficacy in women carrying inherited thrombophilias. They could be efficacious in the prevention of GVCs in carriers of inherited thrombophilias, as GVCs have heterogeneous causes, and future studies have to focus on more homogeneous groups of patients. Not enough data are available regarding prophylaxis with heparins to prevent pregnancy-related VTE, but an accurate risk stratification of women during pregnancy and puerperium is crucial for administering prophylaxis in moderate-/high-risk women. Aspirin does not improve live births after assisted reproductive technologies, while heparins increase the number of clinical pregnancies and live births. EXPERT OPINION: Aspirin is efficacious in the prevention of GVCs in women at risk for pre-eclampsia and in those with antiphospholipid antibodies syndrome. Heparins could give benefit to women at risk for GVCs and/or pregnancy-related VTE.

Clinical utility of antithrombotic prophylaxis in ART procedures: an Italian experience.

BACKGROUND: The usefulness of antithrombotic prophylaxis in management of Assisted Reproductive Technologies (ART) is questionable. OBJECTIVES: We prospectively examined the contribution of an antithrombotic prophylaxis in influencing clinical pregnancy and live-birth in an unselected cohort of women approaching ART. PATIENTS/METHODS: 1107 women with fertility problems and a valid indication for ART were recruited. Baseline and follow-up information of obstetric outcomes and antithrombotic treatment were collected. RESULTS AND CONCLUSIONS: Median follow-up time was 34.5 months (range: 2-143). During the follow-up period, 595 (53.8%) women underwent ART (total 1234 cycles); 202 (33.9%) women achieved a pregnancy for a total of 255 clinical pregnancies. The concomitant use of LMWH and aspirin was significantly associated with a higher rate of clinical pregnancies (p: 0.003, OR: 4.9, 95% CI: 1.7-14.2). The pregnancy rate was also significantly increased by the use of LMWH alone (p: 0.005, OR: 2.6, 95% CI: 1.3-5.0). Carriership of inherited or acquired thrombophilia did not affect clinical outcomes of the ART. The efficacy of antithrombotic treatment was confirmed when the outcome " live-birth" was considered. Present data suggest a potential benefit of antithrombotic prophylaxis during ART in improving the number of live-births.

Markers of haemostasis and angiogenesis in placentae from gestational vascular complications: impairment of mechanisms involved in maintaining intervillous blood flow.

INTRODUCTION: Preeclampsia (PE) and fetal growth restriction (FGR) are multifactorial diseases, whose pathogenesis is largely unknown. A significant relationship between haemostasis and angiogenesis in placentae from uneventful pregnancies was previously shown. MATERIALS AND METHODS: RNA expression of haemostasis (TF, TFPI, TFPI-2, PAI-2, Anx V, TM) and angiogenesis (Ang-1, Ang-2, PlGF, VEGF) markers in placentae from PE (n=12), PE+FGR (n=17) and FGR (n=20) in respect of placentae from uncomplicated pregnancies (n=21) were investigated. RESULTS: Placentae from complicated pregnancies showed a significant lower expression (p

Occurrence of the JAK2 V617F mutation in the Budd-Chiari syndrome.

Myeloproliferative diseases represent a major risk factor for Budd-Chiari syndrome. In 32 patients with Budd-Chiari syndrome, the JAK2 V617F mutation was detected, in heterozygous state, in 11 individuals (34.4%; 95% confidence interval: 18.6-53.2). Eight patients with (72.7%; 95% confidence interval: 39.0-94.0) and six without (28.6%; 95% confidence interval: 11.3-52.2) the JAK2 V617F mutation had a diagnosis of myeloproliferative diseases before or at the occurrence of the venous thrombotic event. In three patients carrying the JAK2 V617F mutation, a myeloproliferative disease was not detected. Determination of the JAK2 V617F mutation may be useful to recognize patients with Budd-Chiari syndrome with or at risk for the subsequent development of overt myeloproliferative diseases.