Rebalanced hemostasis in liver disease: a misunderstood coagulopathy

The combination of frequently abnormal hemostatic markers and catastrophic bleeding as seen with variceal hemorrhage has contributed to the longstanding misperception that chronic liver disease (CLD) constitutes a bleeding diathesis. Laboratory studies of hemostasis in liver disease consistently challenge this with global coagulation assays incorporating activation of the protein C pathway demonstrating rebalanced hemostasis. It is now recognized that bleeding in CLD is predominantly secondary to portal hypertension (rather than a coagulopathy) and additionally that these patients are at increased risk of venous thrombosis, particularly in the portal venous system. This narrative review describes the current understanding of hemostasis in liver disease, as well as the periprocedural management of hemostasis and anticoagulation for management of venous thromboembolism in patients with CLD.

Bleeding Milky Way!

Many people regard herbal plants as a safe natural product and routinely consume them for maintenance of healthy life or as home remedies without considering their potential health-threatening side effects. Here, we presented manifestations of milk thistle toxicity. The milk thistle’s flavonolignans, especially the silybin ingredient disturb the hemostatic process by dual anticoagulant and anti-platelet properties. This plant can inhibit serine proteases, including factors II and X as in the coagulation cascade as well as platelet activation by blocking adenosine diphosphate receptor and cyclooxygenase; hence, it causes bleeding diathesis.

Approach to clinically significant vascular anomalies in children

Vascular anomalies consist of tumours or malformations made up of abnormal growth or collections of blood vessels that can result in functional or cosmetic problems. While many vascular anomalies are present at birth, some do not appear until later in life, making diagnosis more challenging. Although many vascular anomalies are benign, some are associated with serious complications and may involve multiple organ systems. This article highlights the important features of clinically significant vascular anomalies to help physicians promptly identify and refer these cases to a specialised multidisciplinary team for evaluation and management. The discussion includes the various presenting complaints of vascular anomalies in children, namely rapidly growing birthmarks, painful lesions, seizures/neurological manifestations, bleeding diathesis, cardiac/airway abnormalities or part of an overgrowth syndrome.

Flow-Cytometry Evaluation of Cellular Surface FVIII in Blood Cells and Its Correlation with FVIII Activity and Coagulation

FVIII deficiency or inactivity leads to coagulation malfunction known as Hemophilia A (HA). FVIII overactivity on the contrary is commonly linked to a hypercoagulability state. In steady state, FVIII remains quiescent by forming a non-covalent complex with vWF, and upon coagulation cascade activation, thrombin liberates active FVIII (FVIIIa) from vWF. FVIIIa binds to the plasma membrane of the platelets and other blood cells via its C2 domain phospholipids binding motif to exert its coagulative role. Recently, we developed a reliable Flow-Cytometry (FC) platform for FVIII protein detection (Elnaggar M. et al, 2020). The assay is suitable to measure both intracellular and extracellular FVIII. When applied to human blood it showed that by overexpressing FVIII through a lentiviral-vector-based transduction, a high proportion of circulating FVIII is bound on leukocytes membranes. Leukocyte abundance is reported to be highly associated with thrombotic events but with no clear mechanistic explanation. Therefore, we sought to evaluate the percentage of FVIIIa bound on different leukocyte subsets (T cells, B cells, monocytes and granulocytes) in different clinical scenarios, including HA and other abnormal coagulation states and to correlate it to the plasmatic levels of FVIII. The analysis was conducted on 31 pediatric/young-adult subjects (median age 9y), including patients diagnosed with HA (n=8), patients with coagulopathies (von Willebrand Disease, menorrhagia and unexplained bleedings (n=11) and 1 patient with known high levels of FVIII), and patients without coagulopathies/healthy controls (n=11) referred to Hematology/Oncology clinic at Sidra Medicine-Qatar. Fresh blood samples were analyzed with a Sysmex XN1000 Hematologic Counter for complete blood count and with a BD-Symphony FC for the following surface markers: CD3/CD4/CD8/CD14/CD16/CD19/CD33/Live/Dead and for FVIII protein A2 domain (Ab clone GMA8024), after light-chain Zenon-labeling, with proper IgG controls, as described in the publication above. In parallel, plasma FVIII measurements were performed for clinical diagnostic purposes, and results were correlated. Expectedly, HA patients showed the lowest FVIII percentage in plasma (p<0.0001), while leukocytes' surface FVIII was generally low (on average <1%), trended to a lower rate in patients with coagulopathies and HA compared to healthy-controls and was significantly higher in the patient with hypercoagulability (p=0.0007). Surprisingly, among leukocytes' subpopulations, screened on patients with bleeding diathesis and HA subjects vs healthy-controls, only CD8-surface bound FVIIIa was significantly lower compared to healthy-controls (p=0.015 healthy-controls vs HA, and p=0,0093 healthy-controls vs bleeding diathesis). These results raise the possibility of a CD8-cell mediated controlled binding mechanism regulating FVIII availability in case of biological need of the protein, as bleeding. We did not find any significant correlation between leukocyte-surface bound FVIII and plasma FVIII level, and this further indicates that the differences in FVIIIa leukocyte surface binding are not directly proportional to FVIII availability in the circulation, rather actively regulated by a biological still unknown mechanism. While the study is still ongoing and recruiting other subjects with hypercoagulation state, we showed in this preliminary analysis that our in-house FC platform for FVIII protein detection screens in depth FVIII protein adherence to blood cells, may shed light on coagulation novel mechanisms, and potentially serve as a diagnostic and prognostic tool. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Extensive skin necrosis in an elderly woman on dabigatran

Dabigatran, a novel oral anticoagulant, is a direct thrombin inhibitor and is being increasingly used owing to the advantage of dosing without the need for laboratory monitoring. While extensive skin necrosis is known to be associated with oral anticoagulants such as warfarin and factor Xa inhibitors, dabigatran toxicity typically manifests with bleeding, especially in the elderly. We describe a 70-year-old woman who was prescribed dabigatran for the treatment of unprovoked deep venous thrombosis. She developed bleeding diathesis along with extensive skin necrosis and acute kidney injury shortly after commencing the drug. Haemodialysis was given in view of dabigatran toxicity and complications of kidney dysfunction which resolved promptly over a week. However, the patient succumbed to severe sepsis from secondary skin infections. It is crucial to closely monitor for signs of dabigatran toxicity, especially in the elderly patients.

Negative impact of socioeconomic deprivation on clinical outcomes after cryoablation for atrial fibrillation: 18-month study

Background Lower socioeconomic status has also been shown to associate with higher incidence of atrial fibrillation (AF), increased mortality and morbidity. However, the impact of socioeconomic deprivation on clinical outcomes post AF cryoablation has yet to be investigated. Aim To assess the impact of socioeconomic deprivation (as categorised by Scottish Index of Multiple Deprivation, SIMD) on the medical management and clinical outcomes of patients with AF post cryoablation. Methods A retrospective study of paroxysmal or persistent AF patients after cryoablation. Parameters included basic demographics, weight, past medical history (hypertension, heart failure, diabetes, stroke, myocardial infarction, sleep apnoea) and alcohol misuse. Medical treatment post ablation (Beta blocker, calcium channel blocker, flecainide, amiodarone, dronaderone, sotolol, anticoagulant use) were also recorded. Socioeconomic deprivation index, as per SIMD was recorded (1 – most deprived and 10 – least deprived), and accordingly placed into quintile (SIMD 1–2,3–4,5–6,7–8, 9–10). Follow-up for 18 months. Clinical outcome assessed was rate of readmission for symptomatic AF, rate of heart failure admission, stroke, bleeding diathesis and all-cause mortality. Results 383 patients were identified: 78 from the lowest quintile (SIMD 1–2), 68 (SIMD 3–4), 64 (SIMD 5–6), 62 (SIMD 7–8), and 111 from the highest quintile (SIMD 9–10). No statistical difference exists between age, gender or weight. Lowest socioeconomic quintile has higher incidence of heart failure (p=0.006) and hypertension (p=0.005) but other past medical history was no different. No difference in incidence of alcohol misuse. Medicine prescription was not different. Echo features: left ventricular function, atrial size and valvular dysfunction were not different between all groups. 18 months follow-up demonstrated that both readmission for symptomatic documented AF and recurrence of symptoms at 18 months were higher among patients of lowest socioeconomic quintile (Keplan Meier plot, p=0.014 and p=0.006 respectively). Stepwise multiple regression analysis also confirmed multiple socioeconomic deprivation as an independent predictor for more adverse clinical outcome (p=0.02). Risk of symptom recurrence at 18 months in patients from the least deprived background is less than one third as compared to the ones from the most deprived background (Odd-ratio 0.32 (0.17 - 0.59)) Risk of readmission for AF in patients from the wealthiest socioeconomic group is also less than a third as compared to those of most deprived social group (Odd-ratio 0.31 (95% CI 0.15–0.61)). Other clinical outcomes including risk of admissions for heart failure, stroke, bleeding diathesis and all-cause mortality was not statistically different across all groups. Summary After cryoablation, patients from the lowest socioeconomic group are more likely to experience symptoms recurrence and readmission for symptomatic AF FUNDunding Acknowledgement Type of funding sources: None.

Whole-Exome Sequencing Identified a Novel Homozygous Frameshift Mutation of HPS3 in a Consanguineous Family with Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder with an autosomal recessive inherited pattern. It is mainly characterized by deficiencies in lysosome-related organelles, such as melanosomes and platelet-dense granules, and leads to albinism, visual impairment, nystagmus, and bleeding diathesis. A small number of patients will present with granulomatous colitis or fatal pulmonary fibrosis. At present, mutations in ten known genetic loci (HPS1–11) have been identified to be the genetic cause of HPS. In this study, we enrolled a consanguineous family who presented with typical HPS phenotypes, such as albinism, visual impairment, nystagmus, and bleeding diathesis. Whole-exome sequencing and Sanger sequencing were applied to explore the genetic lesions of the patient. A novel homozygous frameshift mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 was identified and cosegregated in the family members. Furthermore, real-time PCR confirmed that the mutation decreased the expression of HPS3, which has been identified as the disease-causing gene of HPS type 3. According to ACMG guidelines, the novel mutation, resulting in a premature stop codon at amino acid 442, is a pathogenic variant. In summary, we identified a novel mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 in a family with HPS. Our study expanded the variant spectrum of the HPS3 gene and contributed to genetic counseling and prenatal genetic diagnosis of the family.

Adrenal hemorrhage and hemorrhagic masses; diagnostic workup and imaging findings

Adrenal hemorrhage (AH) is a rare condition. It can be traumatic or non-traumatic. Most common causes are septicemia, coagulopathy or bleeding diathesis, and underlying neoplasms. Other reported less common causes of AH are COVID-19 and neonatal stress. Clinical diagnosis of AH is challenging due to its non-specific presentation and occurrence in the setting of acute medical illness. Therefore, most cases are diagnosed incidentally on imaging. Having high clinical suspicion in the proper clinical setting for AH is crucial to avoid life-threatening adrenal insufficiency that occurs in 16–50% of patients with bilateral AH. We discuss the clinical situations that predispose to AH, review the imaging features on different imaging modalities, highlight a variety of clinical cases, imaging features that should be concerning for an underlying neoplasm, and outline the potential role of interventional radiology in management of AH.

Hemoadsorption Treatment with CytoSorb® in Probable Hemophagocytic Lymphohistiocytosis: A Role as Adjunctive Therapy?

Acute hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, with an annual incidence of 1 : 800,000 people. The disease is characterized by a cytokine storm, with concomitant macrophage and natural killer (NK) cell activation; death can occur from multiple organ failure or complications such as bleeding diathesis. Therefore, HLH treatment remains a challenging one. We hereby present a case of a 76-year-old man with severe HLH in whom hemoadsorption was successfully applied. Due to the failure of the immunomodulatory therapy , continuous venovenous hemodiafiltration therapy with the CytoSorb® adsorber was successfully applied for 48 hours. Upon therapy discontinuation, the biological and clinical condition reverted, unfortunately evolving towards the patient’s death.