Warfarin dosage in a postpartum woman while breastfeeding: A case report.

Warfarin is the only oral anticoagulant recommended in women who are breastfeeding. Although warfarin is a compatible and recommended agent in the postpartum period and during lactation, little is known regarding changes to warfarin dose requirements in this patient population. Here, we report the case of a 40-year-old woman who transitioned from enoxaparin monotherapy back to warfarin at 2 months postpartum, while she was breastfeeding. Despite resuming warfarin at her previously therapeutic dose, her international normalized ratio (INR) remained subtherapeutic and required multiple dose increases. She ultimately required a 100% increase in her warfarin dose postpartum, compared to pre-pregnancy, to achieve a therapeutic INR. This case suggests patients may require higher warfarin doses postpartum, compared to pre-pregnancy, especially if breastfeeding. Clinicians should closely monitor these patients and adjust warfarin doses as necessary.

Outcomes of different perioperative management strategies of patients on chronic anticoagulation in elective total hip and knee arthroplasty: a systematic review.

INTRODUCTION: There are currently different management guidelines for patients undergoing elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) that are on long-term anticoagulation. The timing of discontinuation and restarting the anticoagulation is challenging during the postoperative care, which often involves general practitioners and physiotherapists. METHODS: The systematic review followed the PRISMA guidelines and included 3 databases: PubMed/MEDLINE, EMBASE, and Web of Science Core Collection. It was registered in the International Prospective Register for Systematic Reviews and Meta-analysis (PROSPERO) under the registration number: CRD42023408906. The risk of bias assessment was performed using the Methodological index for non-randomized studies (MINORS) criteria. RESULTS: Six retrospective studies involving 727 patients with therapeutic anticoagulation (1,540 controls) for elective THA, TKA and revision arthroplasty have been included. The follow-up ranged from 30 days to 1 year postoperatively. All studies evaluated outcomes of warfarin therapeutic anticoagulation versus prophylactic dosages of one or more of the following: warfarin, aspirin, low-molecular-weight heparin (LMWH) and unfractionated low-dose heparin (UFH). One study did not discontinue therapeutic anticoagulation. Two studies reported no significant differences in complications between groups, whilst 3 studies had significantly higher rates of superficial wound infections, revision surgeries, postoperative haematomas, and prosthetic joint infections (PJI). CONCLUSION: Different anticoagulation-related perioperative management strategies achieve different outcomes following elective arthroplasty in patients with therapeutic chronic anticoagulation. There is contradictory evidence regarding the need for the discontinuation of therapeutic warfarin. Retrospective data showed that individual risk stratification with multi-modal prophylaxis resulted in minimal complications. LEVEL OF EVIDENCE: Systematic Review of Level III studies.

Targeting ferroptosis for treating kidney disease.

Ferroptosis is a type of regulated cell death hallmarked by iron-mediated excessive lipid oxidation. Over the past decade since the coining of the term ferroptosis, advances in research have led to the identification of intracellular processes that regulate ferroptosis such as GSH-GPX4 pathway and FSP1-coenzyme Q10/vitamin K pathway. From a disease perspective, the involvement of ferroptosis in pathological conditions including kidney disease has attracted attention. In terms of renal pathophysiology, ferroptosis has been widely investigated for its involvement in ischemia-reperfusion injury, nephrotoxin-induced kidney damage and other renal diseases. Therefore, therapeutic interventions targeting ferroptosis are expected to become a new therapeutic approach for these diseases. However, when considering cell death as a therapeutic target, careful consideration must be given to (i) in which type of cells, (ii) which type of cell death mode, and (iii) in which stage or temporal window of the disease. In the next decade, elucidation of the true involvement of ferroptosis in kidney disease setting in human, and development of clinically applicable and effective therapeutic drugs that target ferroptosis are warranted.

Progression of Skin Ulcer Secondary to Calciphylaxis in a Patient With End-Stage Renal Disease (ESRD) on Hemodialysis and the Therapeutic Approach.

Calciphylaxis is a rare and severe medical condition characterized by the calcification of small blood vessels and soft tissues, leading to tissue damage, skin ulcers, and intense pain. It most commonly affects individuals with underlying health conditions such as kidney disease, particularly end-stage renal disease (ESRD), and is associated with high mortality rates. Understanding the diagnosis and management of calciphylaxis is crucial for improving patient outcomes. Diagnosing calciphylaxis can be challenging due to its rarity and overlapping symptoms with other skin conditions. Healthcare professionals typically use a combination of clinical evaluation and diagnostic tests to reach a conclusive diagnosis. The management of calciphylaxis is multifaceted and typically involves a collaborative effort between various healthcare specialists, including nephrologists, dermatologists, and wound care experts. The primary goals of treatment are to alleviate pain, promote wound healing, address underlying causes, and prevent further complications.

The Standard-Dose Heparin-Warfarin Remedy Partially Resolves Thrombi in the Right Superior Pulmonary Vein and Left Atrium and Ameliorates Type 2 Diabetes Mellitus.

Pulmonary vein thrombosis is common and underdiagnosed. Previously, we reported several cases of pulmonary vein thrombi (PVTs) using cardiac computed tomography (CT) and transesophageal echocardiography (TEE). We reported that warfarin and direct oral anticoagulants (DOACs) partially resolved PVTs; however, it is difficult to resolve all PVTs completely. Therefore, we evaluated the effects of standard-dose heparin-warfarin remedy on PVTs and left atrium (LA) thrombi using TEE and cardiac CT. A 64-year-old male with type 2 diabetes mellitus (T2DM) and hypertension was assessed for thrombi in the LA and pulmonary veins using TEE and 80-slice multidetector computed tomography (80-MDCT). After one month of standard-dose heparin-warfarin remedy, the patient's right superior pulmonary vein (RSPV) thrombi and expanded LA thrombi from the RSPV thrombi had partially resolved. The RSPV thrombi and the expanded LA thrombi from the RSPV thrombi were detected using cardiac CT and TEE; however, they were depicted as black areas on TEE. They periodically moved inward with the patient's heartbeats. Additionally, the standard-dose heparin-warfarin remedy ameliorated the patient's T2DM, and the remedy effect could be maintained for five months to some extent by administering a standard dose of warfarin. The standard-dose heparin-warfarin remedy can ameliorate not only T2DM but also diabetic complications such as diabetic nephropathy and gestational diabetes mellitus.

Evaluation of modified fixed dose four-factor prothrombin complex concentrate for warfarin reversal.

Non-activated four-factor prothrombin complex concentrate (4 F-PCC) has emerged as the preferred reversal strategy for patients on warfarin with life-threatening bleeding. Current dosing recommendations for 4 F-PCC require pre-treatment international normalized ratio (INR) and bodyweight values, resulting in ordering and administration delays. Studies have shown that alternative dosing regimens are safe and efficacious. This retrospective, single-center, pre- and post-protocol analysis was conducted to assess the efficacy of a pharmacist driven modified fixed-dose 4 F-PCC regimen versus package insert weight- and INR-based dosing regimen for warfarin reversal. The primary outcome was achievement of INR less than two. Secondary outcomes included dose and cost of 4 F-PCC, a time analysis, incidence of concomitant vitamin K administration, and incidence of thrombosis within seven days of 4 F-PCC. There were 195 patients included in the analysis, with 74 in the pre-cohort and 121 in the post-cohort. Baseline characteristics were similar between cohorts with the most common indication for warfarin use being atrial fibrillation (48.6% versus 47.1%) and reversal being intracerebral hemorrhage (68.9% versus 43.0%). Achievement of the primary endpoint occurred in 92% versus 95% (p = 0.097) of patients. A statistically significant difference was seen between cohorts regarding median dose and cost of 4 F-PCC administered (p < 0.001). Eleven thromboembolic events occurred with three events in the pre-cohort and eight events in the post-cohort (p = 0.453). A fixed-dose of 1500IU of 4 F-PCC was effective in reversing INR to less than two in most patients regardless of reversal indication with minimal thrombotic risks.

Postoperative anticoagulation management using subcutaneous unfractionated heparin for a patient with nonbacterial thrombotic endocarditis: a case report.

Nonbacterial thrombotic endocarditis (NBTE) presents nonbacterial vegetation on cardiac valves. NBTE requires appropriate anticoagulant therapy to prevent recurrence after surgery. However, there has not yet been established evidence for anticoagulant therapy in NBTE, and low molecular weight heparin is not approved in Japan. We present a case of NBTE that was successfully managed with anticoagulant therapy using subcutaneous unfractionated heparin. A 59-year-old woman was diagnosed with NBTE on the mitral and tricuspid valve associated with breast cancer, underwent valve replacement. Warfarin and continuous intravenous unfractionated heparin were started. However, disseminated intravascular coagulation occurred after heparin was discontinued. Continuous intravenous unfractionated heparin injection was resumed immediately, and subcutaneous unfractionated heparin was administered before discharge. Postoperative echocardiography revealed no vegetation on the prosthetic valves thereafter. Subcutaneous unfractionated heparin therapy is useful to prevent the recurrence of NBTE as the anticoagulation in outpatients.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Potential Drug-Nutrient Interactions of 45 Vitamins, Minerals, Trace Elements, and Associated Dietary Compounds with Acetylsalicylic Acid and Warfarin-A Review of the Literature.

In cardiology, acetylsalicylic acid (ASA) and warfarin are among the most commonly used prophylactic therapies against thromboembolic events. Drug-drug interactions are generally well-known. Less known are the drug-nutrient interactions (DNIs), impeding drug absorption and altering micronutritional status. ASA and warfarin might influence the micronutritional status of patients through different mechanisms such as binding or modification of binding properties of ligands, absorption, transport, cellular use or concentration, or excretion. Our article reviews the drug-nutrient interactions that alter micronutritional status. Some of these mechanisms could be investigated with the aim to potentiate the drug effects. DNIs are seen occasionally in ASA and warfarin and could be managed through simple strategies such as risk stratification of DNIs on an individual patient basis; micronutritional status assessment as part of the medical history; extensive use of the drug-interaction probability scale to reference little-known interactions, and application of a personal, predictive, and preventive medical model using omics.

Small bowel intramural hematoma caused by warfarin: case report and literature review.

BACKGROUND: Intramural hematoma of the small bowel is a rare yet acute gastrointestinal condition typically linked with impaired coagulation function, often posing diagnostic challenges. It is principally encountered in patients undergoing prolonged anticoagulant therapy, specifically warfarin. CASE PRESENTATION: We reported a case of intramural hematoma associated with warfarin use. The patient was admitted to hospital with abdominal pain and had received anticoagulant therapy with warfarin 2.5 mg/day for 4 years. Laboratory examination showed decreased coagulation function, abdominal CT showed obvious thickening and swelling of part of the jejunal wall, and abdominal puncture found no gastroenteric fluid or purulent fluid. We treated the patient with vitamin K and fresh frozen plasma. The patient was discharged after the recovery of coagulation function. Then we undertaook a comprehensive review of relevant case reports to extract shared clinical features and effective therapeutic strategies. CONCLUSION: Our analysis highlights that hematoma in the small intestinal wall caused by warfarin overdose often presents as sudden and intense abdominal pain, laboratory tests suggest reduced coagulation capacity, and imaging often shows thickening of the intestinal wall. Intravenous vitamin K and plasma supplementation are effective non-surgical strategies. Nevertheless, in instances of severe obstruction and unresponsive hemostasis, surgical resection of necrotic intestinal segments may be necessary. In the cases we reported, we avoided surgery by closely monitoring the coagulation function. Therefore, we suggest that identifying and correcting the impaired coagulation status of patient is essential for timely and appropriate treatment.

Low recurrent thrombosis rates in single positive antiphospholipid syndrome regardless of type of anticoagulation.

Thrombotic antiphospholipid syndrome (TAPS) is characterized by thrombosis and persistently positive tests for antiphospholipid antibodies or lupus anticoagulant (LAC). Triple-positive APS has the highest risk of recurrent thrombosis, but no studies have focused on recurrent thrombosis in patients with single-positive TAPS. We conducted a retrospective cohort study of patients with single-positive TAPS diagnosed at Lifespan Health System, Rhode Island, to determine the rates and risk factors for recurrent thrombosis. Between January 2001 and April 2022, 128 patients were assessed who had single-positive APS (LAC = 98, aCL = 21, aß2GPI = 9) and who had been followed for a total of 1453.8 patient-years (median follow-up 3.04 years). The initial antithrombotic regimen was warfarin in 44 %, a direct oral anticoagulant (DOAC) in 34 %, enoxaparin in 2 %, and no antithrombotic therapy or antiplatelet therapy only in 20 %. Recurrent thrombosis occurred in 16 (12.5 %) with a recurrent thrombosis rate of 3.08 per 100 patient-years. Systemic lupus erythematosus was the only variable significantly associated with recurrent thrombosis in a model adjusted for age, sex, body mass index, and type of positive APS test. All 16 patients with recurrent thrombosis were initially treated with warfarin, and, at the time of recurrent thrombosis, 13 patients remained on warfarin and three were off anticoagulation. In conclusion, the recurrent thrombosis rate in single-positive APS is low, and not all patients with a single-positive test may need indefinite anticoagulation with warfarin. Larger prospective studies are required to confirm this finding and establish optimal anticoagulation regimens for low-risk TAPS.

On-X aortic valve replacement patients treated with low dose warfarin and low dose aspirin.

OBJECTIVES: To assess if warfarin targeted to INR 1.8 (range 1.5-2.0) is safe for all patients with an On-X aortic mechanical valve. METHODS: This prospective, observational registry follows patients receiving warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus daily aspirin (75-100 mg) after On-X aortic valve replacement. The primary end-point is a composite of thromboembolism, valve thrombosis, and major bleeding. Secondary end-points include the individual rates of thromboembolism, valve thrombosis, and major bleeding, as well as the composite in subgroups of home or clinic-monitored INR and risk categorization for thromboembolism. The control was the patient group randomized to standard-dose warfarin (INR 2.0-3.0) plus daily aspirin 81 mg from the PROACT trial. RESULTS: A total of 510 patients were enrolled at 23 centers in the UK, United States, and Canada. Currently, the median follow-up duration is 3.4 years, and median achieved INR is 1.9. The primary composite end-point rate in the low INR patients is 2.31% vs 5.39% (95% confidence interval 4.12%-6.93%) per patient-year in the PROACT control group, constituting a 57% reduction. Results are consistent in subgroups of home or clinic-monitored, and high-risk patients, with reductions of 56%, 57%, and 57%, respectively. Major and total bleeding are decreased by 85% and 73%, respectively, with similar rates of thromboembolic events. No valve thrombosis occurred. CONCLUSIONS: Interim results suggest that warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus aspirin is safe and effective in patients with an On-X aortic mechanical valve with or without home INR monitoring.

Therapeutic drug monitoring of six contraindicated/co-administered drugs by simple and green RP-HPLC-PDA; application to spiked human plasma.

Therapeutic drug monitoring is an important clinical testing of the drugs to monitor their concentrations in plasma in order to guarantee their optimal impact, and to avoid any side effects resulting from drug-drug interactions. A green reversed-phase high-performance liquid chromatographic method using a photodiode array detector (RP-HPLC-PDA) was developed for the simultaneous determination of three carbapenem antibiotics (Imipenem, ertapenem, and meropenem) with the co-formulated drug (cilastatin) and contraindicated drugs (probenecid and warfarin) in spiked human plasma. The separation was achieved at 25 °C using a gradient elution of a mixture of mobile phase A: methanol and mobile phase B: phosphate buffer (pH 3.0). The photodiode array detector was adjusted at 220 nm. Bioanalytical method validation was carried out as per the FDA guidelines, and the method showed good linearity ranges for the six drugs that included their Cmax levels along with low limits of quantification. Based on the results, the method was found to be accurate and precise; with high % recovery and good % RSD, respectively. The method was successfully applied to spiked human plasma, signifying a good potential to be implemented in future TDM studies of these drugs when co-administered together.

Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy.

BACKGROUND: The direct oral anticoagulants (DOACs) are now commonly regarded as first line anticoagulants in most cases of venous thromboembolism (VTE). However, the optimal choice of subsequent anticoagulant in instances of first line DOAC failure is unclear. OBJECTIVES: To describe and compare outcomes with second line anticoagulants used after DOAC failure. METHODS: Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation (1st recurrent thrombosis) were included. RESULTS: In total, 166 patients after apixaban or rivaroxaban failure were included. Following DOAC failure (1st recurrent thrombosis), the subsequent anticoagulant was warfarin in 60 patients (36%), dabigatran in 42 patients (25%), and enoxaparin in 64 patients (39%). Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p < 0.01). The median follow-up time in our cohort was 16 months. There was no difference in 2nd recurrent thrombosis-free survival (p = 0.72) or risk for major bleeding event (p = 0.30) among patients treated with dabigatran, warfarin, or enoxaparin. CONCLUSIONS: In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience.

Attainment of Target in Therapeutic Range of International Normalized Ratio and Correlates Among Patients on Warfarin Therapy at Jimma Medical Center, Jimma, Ethiopia.

PURPOSE: Warfarin is effective therapy to prevent thromboembolic complications of venous thromboembolism, atrial fibrillation, and cardiac thrombus, among valvular heart diseases, including in patients treated with prostheses and/or repair. Its optimum effect is achieved when the international normalized ratio (INR) is in the target therapeutic range, but a subtherapeutic level increases risk of thromboembolism and complications. This study aimed to assess the attainment of target therapeutic range, proportion, and factors associated with subtherapeutic level of warfarin. METHODS: A hospital-based cross-sectional study was conducted at Jimma Medical Center in Jimma, Ethiopia, from October 1, 2020 through December 30, 2021. All patients on warfarin and attending Medical Follow-Up Clinics of Jimma Medical Center during the study period were included. Data were collected using structured questionnaires and then analyzed using EpiData Manager software, version 3.1 (EpiData Association). χ2 Tests and logistic regression models were used to assess relationships among variables. FINDINGS: Of 196 patients on warfarin, ∼60% were taking it for atrial fibrillation, followed by deep venous thrombosis, women accounted for 61.7% of patients, and mean (SD) age was 43 (7) years. Most patients (61.7%) lived in rural areas and 44.9% farmed to earn a living. Most of the study participants (51.5%) had a very low monthly income of less than USD50. Most of the patients (n = 107 [54.6%]) were advised on dietary selections while on warfarin and approximately two-thirds (n = 70 [65.4%]) were adherent to the advice. Most participants (n = 118 [60.2%]) were poorly adherent to warfarin therapy and more than two-thirds of them discontinued warfarin for financial reasons. Mean (SD) duration of warfarin therapy was 15.53 (18.92) months (range 1-90 months). Most of the respondents (n = 109 [55.6%]) had subtherapeutic INR and 21 (10.7%) were in the supratherapeutic range. Although the mean (SD) time in therapeutic range was 25.03% (24.17% [range 0-80%]), in most patients (n = 166 [84.7%]), it was <60%. Poor adherence (adjusted odds ratio = 6.13; 95% CI, 3.31-28.10), shorter duration of warfarin (<12 months; adjusted odds ratio = 0.104; 95% CI, 0.012-0.875), and presence of comorbidity (adjusted odds ratio = 0.035; 95% CI, 0.004-0.323) were significantly associated with subtherapeutic INR. IMPLICATIONS: Attainment of therapeutic INR among patients on warfarin therapy is suboptimal. This was evidenced by a significant number of patients with low time in therapeutic range, as well as INR. Poor adherence to warfarin therapy, shorter duration since initiation of warfarin, and presence of comorbid illnesses were significantly associated with subtherapeutic INR. This can lead to complications of atrial fibrillation, including thrombus formation and subsequent cardioembolic stroke, venous thromboembolism, and others, leading to morbidity, increased mortality, and poor quality of life. Therefore, providing health education and treatment for comorbidities may improve adherence, which may also improve attainment of therapeutic INR and reduce complications and improve quality of life.

Safety Issues of Herb-Warfarin Interactions.

Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from Hypericum perforatum, Zingiber officinale, Vaccinium oxycoccos, Citrus paradisi, and Punica granatum. In terms of PK-PD parameters, herbs, such as Coptis chinensis Franch. and Phellodendron amurense Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.

Antiphospholipid antibody positive Sneddon syndrome: a case report.

Sneddon syndrome may present with neurological findings such as transient ischemic stroke, strokes, seizures and/or headaches. However, a purplish, spider web-like skin finding called livedo reticularis may accompany the skin and precede neurological findings. Sneddon syndrome often affects women. Since it is vasculopathy affecting small and medium vessels, other organ findings may accompany. We present a 44-year-old Sneddon syndrome patient with monoparesis in her left lower extremity, livedo reticularis on her back and legs, and hypertension.

A career in solving clinical-pathological conundrums: Heyde syndrome, anti-platelet factor 4 disorders, and microvascular limb ischemic necrosis.

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants).

The optimal antithrombotic strategy for post-stroke patients with atrial fibrillation and extracranial artery stenosis-a nationwide cohort study.

BACKGROUND: In post-stroke atrial fibrillation (AF) patients who have indications for both oral anticoagulant (OAC) and antiplatelet agent (AP), e.g., those with carotid artery stenosis, there is debate over the best antithrombotic strategy. We aimed to compare the risks of ischemic stroke, composite of ischemic stroke/major bleeding and composite of ischemic stroke/intracranial hemorrhage (ICH) between different antithrombotic strategies. METHODS: This study included post-stroke AF patients with and without extracranial artery stenosis (ECAS) (n = 6390 and 28,093, respectively) identified from the Taiwan National Health Insurance Research Database. Risks of clinical outcomes and net clinical benefit (NCB) with different antithrombotic strategies were compared to AP alone. RESULTS: The risk of recurrent ischemic stroke was higher for patients with ECAS than those without (12.72%/yr versus 10.60/yr; adjusted hazard ratio [aHR] 1.104, 95% confidence interval [CI] 1.052-1.158, p < 0.001). For patients with ECAS, when compared to AP only, non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy was associated with lower risks for ischaemic stroke (aHR 0.551, 95% CI 0.454-0.669), the composite of ischaemic stroke/major bleeding (aHR 0.626, 95% CI 0.529-0.741) and the composite of ischaemic stroke/ICH (aHR 0.577, 95% CI 0.478-0.697), with non-significant difference for major bleeding and ICH. When compared to AP only, warfarin monotherapy was associated with higher risks of major bleeding (aHR 1.521, 95% CI 1.231-1.880), ICH (aHR 2.045, 95% CI 1.329-3.148), and the composite of ischaemic stroke and major bleeding. With combination of AP plus warfarin, there was an increase in ischaemic stroke, major bleeding, and the composite outcomes, when compared to AP only. NOAC monotherapy was the only approach associated with a positive NCB, while all other options (warfarin, combination of AP-OAC) were associated with negative NCB. CONCLUSIONS: For post-stroke AF patients with ECAS, NOAC monotherapy was associated with lower risks of adverse outcomes and a positive NCB. Combination of AP with NOAC or warfarin did not offer any benefit, but more bleeding especially with AP-warfarin combination therapy.

Relationship of Warfarin and Apixaban with Vascular Function in Patients with Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with endothelial damage/dysfunction. Herein, we tested the hypothesis that brachial artery flow-mediated dilation (FMD) is superior in AF patients taking apixaban compared to warfarin. METHODS: AF patients on apixaban (n = 46; 67 [7] years; mean [standard deviation]; 15 women) and warfarin (n = 27; 73 [9] years (p < 0.01); 11 women) were recruited. Duplex Doppler ultrasound imaging was undertaken during baseline (2 min), cuff inflation (5 min), and following cuff deflation (3 min). FMD was defined as peak increase in brachial artery diameter following cuff deflation and analysed as percentage change in diameter, as a ratio of FMD, shear rate area under the curve (SRAUC; FMD-to-SRAUC), and using SRAUC as a covariate (FMDSR). RESULTS: Baseline artery diameter (4.96 [1.14] vs. 4.89 [0.88] mm), peak diameter (5.12 [1.17] vs. 5.14 [0.93] mm), and FMDSR (3.89 [3.62] vs. 4.80 [3.60] %) were not different between warfarin and apixaban (p > 0.05; analysis of covariance with age, CHA2DS2-VASc, years since AF diagnosis, number of diabetics, alcohol drinkers, and units of alcohol consumed per week as covariates). Stepwise multiple regression identified independent association of fibrillation, hypertension, and increased age with FMD. CONCLUSION: AF patients on warfarin and apixaban exhibit similar endothelium-dependent vasodilation. Increased blood pressure negatively impacts vasodilator capacity in AF patients.