Purpose of Review Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. Recent Findings ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient’s pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Summary Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications—intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, with a high rate of mortality and morbidity. Even with the best current medical or surgical interventions, outcomes remain poor. The location and initial hematoma volume are strong predictors of mortality. Hematoma expansion (HE) is a further marker of poor prognosis that may be at least partly preventable. Several risk factors for HE have been identified, including baseline ICH volume, anticoagulation, and computed tomography angiography spot signs. Recent studies have shown the correlation of serum calcium (Ca++) levels on admission with HE. Low serum Ca++ level has been associated with larger hematoma volume at the time of presentation, HE, and worse outcome. Although the causal and mechanistic links between low serum Ca++ level and HE are not well understood, several mechanisms have been proposed including coagulopathy, platelet dysfunction, and higher blood pressure (BP) in the context of low serum Ca++ level. However, low serum Ca++ level might be only a biomarker of the adaptive response due to acute inflammatory response following acute ICH. The purpose of the current review is to discuss the evidence regarding the possible role of low serum Ca++ level on HE in acute ICH.

Sickle cell disease (SCD) is a hereditary blood disorder associated with many life-threatening comorbidities including cerebral stroke and chronic pain. The long-term effects of this disease may therefore affect the global brain network which is not clearly understood. We performed graph theory analysis of functional networks using non-invasive fMRI and high resolution EEG on thirty-one SCD patients and sixteen healthy controls. Resting state data were analyzed to determine differences between controls and patients with less severe and more severe sickle cell related pain. fMRI results showed that patients with higher pain severity had lower clustering coefficients and local efficiency. The neural network of the more severe patient group behaved like a random network when performing a targeted attack network analysis. EEG results showed the beta1 band had similar results to fMRI resting state data. Our data show that SCD affects the brain on a global level and that graph theory analysis can differentiate between patients with different levels of pain severity.

Objective: Oral anticoagulation (OAC) prescribed to AF patients for the prevention of cardioembolic complications likely has the added benefit of preventing venous thromboembolism (VTE). This study evaluated, among AF patients who are anticoagulated, whether type of OAC was associated with subsequent VTE risk. Methods: Non-valvular AF patients prescribed OACs between 2010 and September 2015 were identified via the MarketScan administrative claims databases. OACs included warfarin and direct OACs (DOACs: dabigatran, rivaroxaban, and apixaban). Incident VTE was defined by ICD-9-CM codes. Patients were matched on age, sex, CHA(2)DS(2)-VASc, and high-dimensional propensity scores. The final analysis included 117,912 AF patients. Results: In total, 1357 VTE events accrued over a mean follow-up of 484 days. In multivariable-adjusted, propensity score-matched Cox models, relative to new users of warfarin, risk of incident VTE was lower among new users of dabigatran [hazard ratio (95% confidence interval) = 0.55 (0.47-0.66)] and apixaban [0.51 (0.39-0.68)], but similar among new users of rivaroxaban [1.01 (0.87-1.19)]. In head-to-head DOAC comparisons, VTE risk was lower among users of dabigatran [0.48 (0.36-0.64)] and apixaban [0.61 (0.47-0.78)] vs rivaroxaban. Findings were mostly similar across patient sub-groups. Conclusions: In this large practice-based population of AF patients prescribed OACs for primary prevention of stroke and systemic embolization, subsequent risk of VTE was lowest among those prescribed apixaban and dabigatran, while risk was similar with prescriptions for warfarin and rivaroxaban. Among AF patients prescribed OACs, lowering the risk of VTE may be an additional benefit of apixaban and dabigatran, beyond the reduced bleeding risk observed in randomized clinical trials.

The pathology of sickle cell disease begins with the polymerization of intracellular hemoglobin under low oxygen tension, which leads to increased blood effective viscosity and vaso-occlusion. However, it has remained unclear how single-cell changes propagate up to the scale of bulk blood effective viscosity. Here, we use a custom microfluidic system to investigate how the increase in the stiffness of individual cells leads to an increase in the shear stress required for the same fluid strain in a suspension of softer cells. We characterize both the shear-rate dependence and the oxygen-tension dependence of the effective viscosity of sickle cell blood, and we assess the effect of the addition of increasing fractions of normal cells whose material properties are independent of oxygen tension, a scenario relevant to the treatment of sickle patients with blood transfusion. For untransfused sickle cell blood, we find an overall increase in effective viscosity at all oxygen tensions and shear rates along with an attenuation in the degree of shear-thinning achieved at the lowest oxygen tensions. We also find that in some cases, even a small fraction of transfused blood cells restores the shape of the shear-thinning relationship, though not the overall baseline effective viscosity. These results suggest that untransfused sickle cell blood will show the most extreme relative rheologic impairment in regions of high shear and that introducing even small fractions of normal blood cells may help retain some shear-thinning capability though without addressing a baseline relative increase in effective viscosity independent of shear.

Spontaneous intracerebral hemorrhage (ICH) is a devastating subtype of stroke that results in significant rates of mortality and morbidities. The initial hematoma volume, hematoma expansion (HE), blood pressure (BP), and coagulopathy are considered strong predictors of clinical outcomes and mortality. Low serum magnesium (Mg++) levels have been shown to be associated with larger initial hematoma and greater HE. Coagulopathy, platelet dysfunction, high BP, and increased inflammatory response might form the mechanistic link between low serum Mg++ levels, larger hematoma size and greater HE. However, randomized clinical trials administering intravenous Mg++ have shown no benefit over placebo in ICH patients. The confounding effect of hypocalcemia and a delay in Mg++ trafficking across the blood-brain barrier might explain the futile results for intravenous Mg++ therapy. In the current review, we will discuss the evidence regarding the possible role of low serum Mg++ level on HE in acute ICH.

Randomized clinical trials comparing direct oral anticoagulants (DOACs) to warfarin in cancer patients have not been performed. We evaluated the effectiveness and associated risk of DOACs vs warfarin, as well as comparisons of DOACs, in a large population of cancer patients with nonvalvular atrial fibrillation (AF). Using the MarketScan databases, we identified 16 096 AF patients (mean age, 74 years) initiating oral anticoagulant and being actively treated for cancer between 2010 and 2014. Anticoagulant users were matched by age, sex, enrollment date, and drug initiation date. Study end points were identified with diagnostic codes and included ischemic stroke, severe bleeding, other bleeding, and venous thromboembolism (VTE). Cox regression was used to estimate associations of anticoagulants with study end points. Compared with warfarin, rates of bleeding (hazard ratio [95% confidence interval]) were similar in rivaroxaban (1.09 [0.79, 1.39]) and dabigatran (0.96 [0.72, 1.27]) users, whereas apixaban users experienced lower rates (0.37 [0.17, 0.79]). Rates of ischemic stroke did not differ among anticoagulant users. Compared with warfarin, rate of VTE (hazard ratio [95% confidence interval]) was lower among rivaroxaban (0.51 [0.41, 0.63]), dabigatran (0.28 [0.21, 0.38]), and apixaban (0.14 [0.07, 0.32]) users. In head-to-head comparisons among DOACs, dabigatran users had lower rates of VTE than rivaroxaban users; apixaban users had lower rates of VTE and severe bleeding than rivaroxaban users. In this population of patients with AF and cancer, DOAC users experienced lower or similar rates of bleeding and stroke compared with warfarin users, and a lower rate of incident VTE.

Background: Bortezomib is a proteasome inhibitor that can lead to cell-cycle arrest and apoptosis. Bortezomib-based regimens are widely used as induction therapy of multiple myeloma (MM). Unlike lenalidomide (an immunomodulatory drug), the role of bortezomib in the consolidation and maintenance therapy of multiple myeloma is less clear. This study aims to examine the efficacy and safety of bortezomib-based regimens as consolidation/maintenance therapy in MM patients following induction therapy with or without autologous stem cell transplantation (ASCT).

Objective Pain is a major issue in the care of patients with sickle cell disease (SCD). The mechanisms behind pain and the best way to treat it are not well understood. We studied how electroencephalography (EEG) is altered in SCD patients. Methods We recruited 20 SCD patients and compared their resting state EEG to that of 14 healthy controls. EEG power was found across frequency bands using Welch’s method. Electrophysiological source imaging was assessed for each frequency band using the eLORETA algorithm. Results SCD patients had increased theta power and decreased beta2 power compared to controls. Source localization revealed that areas of greater theta band activity were in areas related to pain processing. Imaging parameters were significantly correlated to emergency department visits, which indicate disease severity and chronic pain intensity. Conclusion The present results support the pain mechanism referred to as thalamocortical dysrhythmia. This mechanism causes increased theta power in patients. Significance Our findings show that EEG can be used to quantitatively evaluate differences between controls and SCD patients. Our results show the potential of EEG to differentiate between different levels of pain in an unbiased setting, where specific frequency bands could be used as biomarkers for chronic pain.

Sickle cell disease (SCD) is a red blood cell disorder that causes many complications including life-long pain. Treatment of pain remains challenging due to a poor understanding of the mechanisms and limitations to characterize and quantify pain. In the present study, we examined simultaneously recording functional MRI (fMRI) and electroencephalogram (EEG) to better understand neural connectivity as a consequence of chronic pain in SCD patients. We performed independent component analysis and seed-based connectivity on fMRI data. Spontaneous power and microstate analysis was performed on EEG-fMRI data. ICA analysis showed that patients lacked activity in the default mode network (DMN) and executive control network compared to controls. EEG-fMRI data revealed that the insula cortex's role in salience increases with age in patients. EEG microstate analysis showed patients had increased activity in pain processing regions. The cerebellum in patients showed a stronger connection to the periaqueductal gray matter (involved in pain inhibition), and negative connections to pain processing areas. These results suggest that patients have reduced activity of DMN and increased activity in pain processing regions during rest. The present findings suggest resting state connectivity differences between patients and controls can be used as novel biomarkers of SCD pain.

Ischemic stroke represents one of the leading causes of death and disability in both the United States and abroad, particularly for patients with prior ischemic stroke or transient ischemic attack (TIA). A quintessential aspect of secondary stroke prevention is the use of different pharmacological agents, mainly antiplatelets and anticoagulants. Antiplatelets and anticoagulants exhibit their effect by blocking the activation pathways of platelets and the coagulation cascade, respectively. Clinical trials have demonstrated the safety and efficacy of antiplatelets for noncardioembolic stroke prevention, while anticoagulants are more often used for cardioembolic stroke prevention. Commonly used antiplatelets include aspirin, clopidogrel, and aggrenox (aspirin plus extended-release dipyridamole). Furthermore, commonly used anticoagulants include warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. Each of these drugs has a unique mechanism of action, and they share some common adverse events such as gastrointestinal bleeding and intracranial hemorrhage in more serious cases. Consequently, physicians should carefully assess the benefits and risks of using different antiplatelet or anticoagulant therapies when managing patients with previous ischemic stroke or TIA. This review discuses the published literature on major clinical trials assessing the efficacy of different antiplatelet and anticoagulant drugs under varying circumstances and the subsequent guidelines that have been developed by the American Heart Association/American Stroke Association. Additionally, the role of imaging in stroke prevention is discussed.

Background: Pain is one of the major symptoms of sickle cell disease (SCD). Sickle pain can include both nociceptive and neuropathic components and can start from infancy. Unfortunately, pain management remains challenging in these patients partly due to the lack of understanding and tools to non-invasively map brain function. Pain can alter neural networks and in turn neuropathic changes can augment pain leading to chronic pain. To analyze brain function we have developed a non-invasive electroencephalography (EEG) coupled to functional magnetic resonance imaging (fMRI) to map how chronic pain affects neurological changes in the brain of SCD patients.

Atrial fibrillation (AF) is a major risk factor for stroke in the elderly population. The use of anticoagulation in patients with AF greatly reduces the risk for stroke, but results in an increased risk of bleeding. Over the past several years, direct oral anticoagulants (DOACs, dabigatran, rivaroxaban, and apixaban) have been used in place of warfarin for stroke prevention in AF. We conducted a retrospective cohort study to assess the safety of DOACs in very elderly patients (75+) managed in a health care system encompassing both community and academic settings. We found that 36 % of patients had moderate to severe renal failure (estimated glomerular filtration rate < 59 ml/min/1.73 m(2)) at the time of DOAC initiation. 142 patients were followed for a mean of 2.56 years, and five experienced a major bleeding episode while on anticoagulation, for a rate of 1.37 per 100 person years. All major bleeding episodes were associated with a decline in GFR compared to baseline. There were 12 non-major bleeding episodes reported. HAS-BLED scores were similar for those patients who experienced bleeding complications compared to those who did not. 21 % of patients were prescribed an inappropriately low dose of DOAC based on approved recommendations. DOACs appear to be a safe form of anticoagulation in very elderly patients with AF. However, the decline in GFR among patients with major bleeding highlights the importance of routine renal function monitoring.

Sickle cell disease (SCD) is associated with impaired cognitive function, pain, cerebral stroke and other neural dysfunctions suggestive of altered brain function. The most common reason for hospitalization of SCD patients is pain. Sickle pain is unique compared to other clinical pain conditions because it includes chronic pain as well as acute pain due to vasoocclusive crisis. The neuropathic and nociceptive aspects of pain in SCD make pain treatment challenging. Opioids, the most common analgesics, are associated with liabilities, such as addiction and tolerance. As a result, patients are often under-treated because of a lack of an objective pain measurement system. We therefore sought to develop an unbiased pain quantification method using non-invasive imaging techniques to recognize the biomarkers of pain and altered brain function. We examined the brain network connectivity in SCD patients (N=14) and healthy controls (N=13) to identify altered activity between the two groups that can be used as biomarkers for chronic pain. All experimental procedures were approved by the IRB of the University of Minnesota, and all subjects gave written informed consent before participating in the study. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) were simultaneously recorded while the subjects were in a wakeful resting state. A 3T Siemens Trio whole-body scanner and a 16 channel head coil with an echo-planar imaging (EPI) sequence were used to acquire fMRI data. EEG data was recorded using a 64-channel EEG cap and MR-compatible amplifiers. Seed-based region of interest (ROI) analysis was performed on the fMRI data using Brain Voyager QX software. EEG informed fMRI (EEG-fMRI) was performed for power and microstate analysis using Matlab and SPM8 software. Statistical activation maps (p<0.001, uncorrected) were generated from general linear models (GLM) based on the time courses found from power and microstate analysis. Seeds were placed in the insula regions, and the functional connectivity between the left and right insula appeared to be stronger in SCD patients than in healthy controls. This result was verified in EEG-fMRI analysis. Activation of the insula and striatum regions positively correlated with the beta band in SCD patients, where healthy controls showed less activation in the insula in the same frequency band. Microstates corresponding to insula activation were observed in both healthy controls and SCD patients; however, activation seems stronger in SCD patients. Activation in the striatum regions was also observed in microstates for SCD patients, but not for healthy controls. These results show that the insula and striatum regions have greater activation in SCD patients compared to controls, and that patients have altered brain connectivity during resting state. Insula activation could be related to the salience network, a resting state network that is responsible for processing external input, or to pain processing. The insula and striatum are some of the common brain regions that have been shown to be active during painful stimuli. This altered activation could be caused by sickle pain and could be a potential biomarker of pain intensity. Due to the non-invasive nature of these quantitative data, this method can have applications in the unbiased objective quantification of pain and treatment outcomes. Altered connectivity observed in SCD patients can also be used to help better understand the neural pathophysiology of sickle pain and can lead to better management strategies for these patients. This work was supported in part by NIH grant U01-HL117664 and NSF IGERT grant DGE-1069104.

The risk of recurrent venous thromboembolism (VTE) must be weighed against the risk of bleeding in deciding to keep patients on extended anticoagulation with vitamin K antagonists (VKAs). Most of the studies of risk of bleeding on VKAs are randomized controlled trials of highly selected patients followed for less than 1 year. We sought to determine the rate of bleeding in ‘real world’ patients on long-term anticoagulation with VKAs for VTE. We conducted a retrospective cohort study of patients monitored at our anticoagulation clinic who were treated with prolonged anticoagulation (>1 year) for secondary VTE prevention to assess the incidence of significant bleeding in this population. We found that most of our patients had serious comorbidities, including diabetes, cancer and solid-organ transplantation. The overall rate of bleeding was 10 episodes per 100 person-years, with major bleeding 5.2 episodes per 100 person-years. The rate of significant bleeding while on long-term warfarin may be higher than what is anticipated based on outcomes from closely controlled trials.

The use of combined hormonal contraceptives has been reported to increase the level of C-reactive protein (CRP). We assessed the effect of hormonal contraceptive use on inflammatory cytokines including CRP, monocyte chemotactic protein-1, soluble tumor necrosis factor (sTNF), interleukin-6 (IL-6), and soluble CD40 ligand. We used 79 female subjects (19 to 30 years old) who were combined oral contraceptives users (n=29), combined vaginal contraceptive users (n=20), and nonusers (n=30) with CRP values of ≤1 (n=46) or ≥3 (n=33). Information on medical history, physical activities, and dietary and sleeping habits were collected. Both oral and vaginal contraceptive users had higher levels of CRP (P<0.0001), compared to nonusers. Only oral contraceptive users exhibited elevated sCD40L (P<0.01). When comparing the groups with CRP ≤ 1 and CRP ≥ 3, levels of IL-6 and sTNF-RI were positively correlated with CRP among oral contraceptive users. We did not observe the same elevation for other inflammatory biomarkers for the CRP ≥ 3 group among vaginal contraceptive users. The clear cause of elevation in CRP level due to the use of different hormonal contraceptive formulations and methods is not well understood. Longitudinal studies with larger sample size are required to better assess the true cause of CRP elevation among hormonal contraceptive users.

Antiphospholipid antibody syndrome (APS) is a multisystem disorder characterized by vascular thrombosis and presence of circulating autoantibodies. The presence of APS can predispose to macrovascular as well as microvascular thrombotic events. Renal involvement is a common occurrence especially in the background of systemic lupus erythematosus. Skin appears to be another frequent target organ and a significant proportion of patients may present with skin lesions at the time of diagnosis. We present the case of a patient who presented with skin necrosis secondary to antiphospholipid antibody syndrome despite being on therapeutic anticoagulation and then developed dystrophic calcification secondary to her renal insufficiency. This complex skin condition eventually leads to her demise, as she was not a candidate for surgical management of these lesions. Why is this important? This case brings to our attention the need to consider calciphylaxis as a cause of ecchymotic-appearing skin lesions in dialysis patients on warfarin in patients with antiphospholipid antibody syndrome.

The international normalized ratio (INR) can be unreliable in patients with lupus anticoagulants (LACs) or other conditions affecting baseline testing. Alternative methods to assess anticoagulation on warfarin through measures of vitamin K-dependent factor activity by clot based or chromogenic assays may be necessary. In this patient population, the ideal method is unknown. Thirty-six patients stable on warfarin with LAC or unreliable INR testing had an INR, a prothrombin time-based clotting assay for factor II (FII) activity, and a chromogenic assay for factor X (CFX) activity were performed simultaneously. Eighty-nine sets of measurements were obtained of which 83 sets included all three assays. CFX and FII levels were well correlated (r = 0.92) in all patients and in 26 patients with a documented antiphospholipid antibody (r = 0.93). Parallel testing was seen in 99% of FII assays. Sixty-one percent of CFX and 57% of FII were within the therapeutic range. In 32 CFX and FII pairs wherein assessment of anticoagulation was discordant, 16 CFX agreed with INR and 13 FII agreed with INR (McNemar's, chi(2) = 0.14, P = 0.7). The number of times tests were discrepant was not statistically different between CFX and FII (P = 0.36). CFX and FII activity are well correlated in patients that require alternative monitoring of warfarin. Either test can be used in this population.

American Journal of HematologyVolume 89, Issue 6 p. E1-E101 AbstractsFree Access Abstract Proceedings of the 2014 Thrombosis and Hemostasis Summit of North America First published: 10 May 2014 https://doi.org/10.1002/ajh.23759Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume89, Issue6June 2014Pages E1-E101 RelatedInformation