Does recipient body mass index inform donor selection for allogeneic haematopoietic cell transplantation?

It is not known whether obesity has a differential effect on allogeneic haematopoietic cell transplantation outcomes with alternative donor types. We report the results of a retrospective registry study examining the effect of obesity [body mass index (BMI) > 30] on outcomes with alternative donors (haploidentical related donor with two or more mismatches and receiving post-transplant cyclophosphamide [haplo] and cord blood (CBU)] versus matched unrelated donor (MUD). Adult patients receiving haematopoietic cell transplantation for haematologic malignancy (2013-2017) (N = 16 182) using MUD (n = 11 801), haplo (n = 2894) and CBU (n = 1487) were included. The primary outcome was non-relapse mortality (NRM). The analysis demonstrated a significant, non-linear interaction between pretransplant BMI and the three donor groups for NRM: NRM risk was significantly higher with CBU compared to haplo at BMI 25-30 [hazard ratio (HR) 1.66-1.71, p < 0.05] and MUD transplants at a BMI of 25-45 (HR, 1.61-3.47, p < 0.05). The results demonstrated that NRM and survival outcomes are worse in overweight and obese transplant recipients (BMI ≥ 25) with one alternative donor type over MUD, although obesity does not appear to confer a uniform differential mortality risk with one donor type over the other. BMI may serve as a criterion for selecting a donor among the three (MUD, haplo and CBU) options, if matched sibling donor is not available.

Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature.

INTRODUCTION: Since the approval of emicizumab, a bispecific, factor VIII-mimetic antibody, for use in persons with congenital haemophilia A in 2018, there have been increasing case reports and case series of off-label use of emicizumab in other bleeding disorders, including acquired haemophilia A (AHA) and von Willebrand disease (VWD). AIM: We conducted a scoping review on the use of emicizumab in AHA and VWD, focusing on the clinical presentation and outcomes. METHODS: We conducted a comprehensive search in PubMed, EMBASE and Scopus up to July 15, 2021. The following criteria were applied to the studies identified in the initial search: patients had a diagnosis of AHA or VWD; and the study reported on the clinical outcome of emicizumab use. RESULTS: Seventeen studies were included in the final review for a total of 41 patients (33 AHA, eight type 3 VWD). The majority of AHA patients and all type 3 VWD patients were started on emicizumab for active/recurrent bleeds. The dosing regimen of emicizumab used varied significantly in AHA patients. All patients had a clinical response to emicizumab use. One AHA patient developed a stroke on emicizumab use in association with concomitant recombinant FVIIa use for surgery. Data on adverse events from emicizumab use were not specifically reported in 24.4% of patients (four AHA, six type 3 VWD). CONCLUSION: Based on published case reports and case series, emicizumab appears to be an effective haemostatic therapy for AHA and VWD. Larger confirmatory clinical trials are needed to confirm these findings.

Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies.

Rare cases of COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S-associated VITT patients are uniformly strongly positive in PF4-polyanion enzyme-linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4-dependent p-selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150 x 103 /µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4-polyanion ELISAs and functional assay are non-specific and detect all three conditions. Here, we report that a novel un-complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV-19, from both spontaneous HIT, HIT and commonly-encountered HIT-suspected patients who are PF4/polyanion ELISA-positive but negative in functional assays. In summary, Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis.

Short term efficacy of recombinant porcine factor VIII in patients with factor VIII inhibitors.

BACKGROUND: Antibodies against factor VIII (FVIII), seen in acquired (AHA) and congenital haemophilia A, lead to severe bleeding diatheses. Current first-line treatment includes bypass agents. Recombinant porcine sequence FVIII (rpFVIII) was developed as an alternative therapy. AIM: To describe our institutional experience with the use of rpFVIII. METHODS: A retrospective chart review of five patients treated with rpVIII between 2016 and 2019. RESULTS: Five patients (four AHA, one congenital haemophilia with inhibitors) were treated with rpFVIII. No patient had an adverse event during infusion. All patients initially exhibited a response evidenced by increased FVIII levels from baseline <1% to 81%-170%, normalization of the activated partial thromboplastin time (aPTT) and resolution of bleeding. However, all five patients were subsequently noted to have decreasing peak FVIII levels and aPTT prolongation, either within the initial treatment course or upon later re-administration. Resistance to rpFVIII was recognized after an average of 12.4 exposure days. Porcine FVIII inhibitor levels measured afterwards were present (detectable-170 Bethesda units) in all patients. Three out of four AHA subjects also developed an increase in the anti-human FVIII inhibitor titres after receiving rpFVIII. CONCLUSION: rpFVIII was safe and initially effective in all patients. However, its use is associated with development of an inhibitor to rpFVIII, decreasing its efficacy and duration of effect. Further, rpFVIII use may lead to an increase in patient anti-human FVIII inhibitor titres. A larger study is necessary to appropriately assess the incidence of these outcomes.

Outgrowing the laboratory diagnosis of type 1 von Willebrand disease: A two decade study.

Von Willebrand Factor (VWF) levels are known to increase with age in the general population, but that effect is unclear in von Willebrand disease (VWD) patients. Thus, it is important to assess the trends of VWF levels with age, and the extent and rate of their normalization in patients with VWD. In a retrospective cohort study, we reviewed the medical records of 126 patients between 1996 and 2016 who met the NHLBI diagnostic criteria for type 1 VWD or "Low VWF" (LVWF). We followed all their historically documented VWF antigen (VWF:Ag), VWF activity (VWF:RCo), and Factor VIII (FVIII) levels longitudinally over time, correlating data with clinical setting at time of testing. The average duration of follow-up was 10.5 ± 3.7 years (SD). Out of the total study population, 27.8% achieved the primary outcome of complete normalization (CN) of both VWF:Ag and VWF:RCo levels, including 19.6% and 32.5% of those with VWD and LVWF, respectively. Linear regression demonstrated statistically significant positive trends of VWF:Ag, VWF:RCo, FVIII with time, calculated at 2.4, 1.4, and 1.4 U dL-1/year, respectively (P < .001 each). In the largest study population of VWD patients to date whose levels were followed longitudinally, there is a statistically significant rise in VWF:Ag, VWF:RCo, and FVIII levels observed with time. CN of both VWF:Ag and VWF:RCo levels was observed in almost a third of patients with VWD or LVWF, over an average of 10 years. Whether the bleeding phenotype also improves is unclear and requires further study.

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.

Eculizumab in the management of drug-induced thrombotic microangiopathy: A scoping review of the literature.

Drug-induced TMA (DI-TMA) is a thrombotic microangiopathy (TMA) caused by certain drugs, usually managed by drug discontinuation and supportive measures. Data on the use of complement-inhibition with eculizumab in DI-TMA is scarce, and its benefit in cases of severe or refractory DI-TMA is unclear. We conducted a comprehensive search in PubMed, Embase and MEDLINE databases (2007-2021). We included articles that reported on DI-TMA patients treated with eculizumab and its clinical outcomes. All other causes of TMA were excluded. We evaluated the outcomes of hematologic recovery, renal recovery, and a composite of both (complete TMA recovery). 35 studies fulfilled our search criteria, which included 69 individual cases of DI-TMA treated with eculizumab. Most cases were secondary to chemotherapeutic agents, and the most implicated drugs were gemcitabine (42/69), carfilzomib (11/69), and bevacizumab (5/69). The median number of eculizumab doses given was 6 (range 1-16). 55/69 (80 %) patients achieved renal recovery, after 28-35 days (5-6 doses). 13/22 (59 %) patients were able to discontinue hemodialysis. 50/68 (74 %) patients achieved complete hematologic recovery after 7-14 days (1-2 doses). 41/68 (60 %) patients met criteria for complete TMA recovery. Eculizumab was safely tolerated in all cases, and appeared to be effective in achieving both hematologic and renal recovery in DI-TMA refractory to drug discontinuation and supportive measures, or with severe manifestations associated with significant morbidity or mortality. Our findings suggest that eculizumab may be considered as a potential treatment for severe or refractory DI-TMA that does not improve after initial management, although larger studies are needed.

Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum.

The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidence-based recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternal-fetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital.

Beyond the guidelines: how we approach challenging scenarios in the diagnosis and management of von Willebrand disease.

Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.

Thrombotic microangiopathies: An illustrated review.

The thrombotic microangiopathies (TMAs) are a heterogenous group of disorders with distinct pathophysiologies that cause occlusive microvascular or macrovascular thrombosis, and are characterized by microangiopathic hemolytic anemia, thrombocytopenia, and/or end-organ ischemia. TMAs are associated with significant morbidity and mortality, and data on the management of certain TMAs are often lacking. The nomenclature, classification, and management of various TMAs is constantly evolving as we learn more about these rare syndromes. Thorough clinical and laboratory evaluation is essential to distinguish various TMAs and arrive at an accurate diagnosis, which is key for appropriate management. In this illustrated review, we focus on thrombotic thrombocytopenic purpura (TTP), Shiga toxin-associated hemolytic uremic syndrome, complement-mediated hemolytic uremic syndrome, hematopoietic cell transplant-associated TMA, and drug-induced TMA, and describe their incidence, pathophysiology, diagnosis, and management. We also highlight emerging complement-directed therapies under investigation for the management of complement-mediated TMAs.

How to manage bleeding disorders in aging patients needing surgery.

With improvements in medical care, the life expectancy of patients with bleeding disorders is approaching that of the general population. A growing population of older adult patients with bleeding disorders is at risk of age-related comorbidities and in need of various elective and emergent age-related procedures. The increased risk of thrombosis and volume overload in older adults complicates perioperative hemostatic management. Furthermore, antithrombotic treatment such as antiplatelet or anticoagulant therapy, which is frequently required for various cardiovascular interventions, requires a meticulous individualized approach. Evidence-based guidelines for the management of aging patients with bleeding disorders are lacking, largely due to the underrepresentation of older adult patients in clinical trials as well as the rarity of many such bleeding disorders. We discuss the current guidelines and recommendations in the perioperative hemostatic management of older adult patients with hemophilia and von Willebrand disease as well as other rare bleeding disorders. The optimal management of these patients is often complex and requires a thorough multidisciplinary and individualized approach involving hematologists, surgeons, anesthesiologists, and the specialists treating the underlying disorder.

Acquired von Willebrand syndrome in monoclonal gammopathy - A scoping review on hemostatic management.

BACKGROUND: Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management. METHODS: We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS-MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted. OBJECTIVES: To describe the clinical presentation and outcomes of different therapeutic approaches. RESULTS: Seventy-five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity <30 IU/dL (86.6%) and factor VIII levels <50 IU/dL (91.8%). Bleeding severity ranged from no bleeding (16.1%) to minor bleeding (46.4%) and major bleeding (37.5%). The overall clinical success rates for 1-deamino-8-D-arginine vasopressin (DDAVP), factor replacement therapy, and intravenous immunoglobulin (IVIG) were 43.8%, 33.3%, and 85.4%, respectively. The laboratory response rates for DDAVP, factor replacement therapy, and IVIG were 39.0%, 62.9%, and 88.6%, respectively. Several other treatments were also reported in small numbers, out of which myeloma-directed therapies, plasma exchange, recombinant factor VIIa, and antifibrinolytics appeared most successful, while immunosuppressive agents were largely ineffective. CONCLUSION: IVIG appears to be an effective treatment for AVWS-MGUS bleeding, conferring a high clinical success rate with measurable laboratory outcomes; albeit temporary. DDAVP and factor replacement therapy may be partially successful in controlling minor bleeds, but not major bleeds. Other less commonly used agents may be effective in certain cases, although data are limited.

Anticoagulation management post-transjugular intrahepatic portosystemic shunt in portal hypertension associated with myeloproliferative neoplasms.

Portal hypertension (pHTN) complicates myeloproliferative neoplasms (MPNs), and usually occurs due to Budd-Chiari syndrome or splanchnic vein thrombosis. Current management modalities for MPN-associated pHTN include anticoagulation, transjugular intrahepatic portosystemic shunt (TIPS), and orthotopic liver transplant. Data on the thrombotic and bleeding outcomes of this practice is of poor quality, and whether direct oral anticoagulants (DOACs) are effective in this setting is unknown. We describe failure of DOACs to prevent post-TIPS complications in two case reports of patients with MPN-associated pHTN and review the associated literature. We conducted a comprehensive search in Embase (embase.com), Scopus (scopus.org), and PubMed for existing data on MPN-associated pHTN post-TIPS procedure. Four studies (n = 251) of patients with pHTN post-TIPS were eligible (MPN, n = 143). A review of the literature suggests that patients with MPN-associated pHTN may be at higher risk for post-TIPS complications including stent thrombosis and stenosis, compared with other causes of thrombotic pHTN. DOAC use has not been studied in this setting. While further studies to guide optimal management of MPN-associated pHTN post-TIPS are needed, available evidence suggests that life-long anticoagulation is warranted. DOACs should not be considered standard of care because of lack of evidence of efficacy.

History of drug use in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use. The medical charts of 232 patients were reviewed. Recipients of matched unrelated donor (MUD) or matched related donor (MRD) transplants were included. Drug use was defined by either metabolic evidence or provider documentation prior to transplant. Transplants were MUD (n = 148) or MRD (n = 84). Median follow-up duration was 15.5 months. There were 35 (15%) patients in the drug use group and 197 (85%) patients in the control group; 49% and 60.4% were in remission at the time of transplant, respectively. In univariate analysis, drug use was associated with a 3-year cumulative incidence of NRM of 43% vs 29% for the control group (p = 0.048), and an HR of 1.75, (95% CI: 1.02-2.99). After controlling for age, sex, disease status, and graft type, drug use was associated with a hazard ratio (HR) of 1.6 (95% CI: 0.95-2.92) for NRM, and an HR 1.2 (95% CI: 0.74-1.94) for OS. Larger cohorts may be needed to further evaluate this association.

Estrogen and thrombosis: A bench to bedside review.

Estrogen, in the clinical setting is used primarily for contraception and hormone replacement therapy. It has been well established that estrogen increases the risk of both arterial and venous thrombosis. While estrogen is known to induce a prothrombotic milieu through various effects on the hemostatic pathways, the exact molecular mechanism leading to those effects is not known. The most common clinical presentation of estrogen-related thrombosis is venous thromboembolism (VTE) of the deep veins of the legs or pulmonary vessels, usually within the first few months of use. Estrogen has also been associated with increased risk of "unusual site" thromboses, as well as arterial thrombosis. Women at high-risk of thrombosis need careful evaluation and counseling for contraception, pregnancy, menopausal hormonal therapy and other estrogen-related conditions or treatments in order to lower the risk of thromboses. We review the most recent evidence on management of high-estrogen states in women at high-risk of thrombosis, as well as emerging data on unique populations such as transgender women. More studies are needed to better understand the pathophysiology of hormone-related thrombosis, as well as more comprehensive techniques to stratify risks for thrombosis so as to enable tailoring of recommendations for each individual.

Central venous catheter-related thrombosis in children and adults.

Central venous catheters (CVC) have revolutionized the care of patients requiring long-term venous access. With increasing use of CVCs, the incidence of catheter-related thrombosis (CRT) has been on the rise. CRT constitutes 10% of all deep venous thromboses (DVT) in adults and 50-80% of all DVTs among children. The incidence of CRT varies significantly based on patient characteristics, catheter-related factors and the steps involved in the process of catheter insertion. Multiple risk factors have been associated with a higher risk of CRT, including older age, hospitalization, CVC insertion in the subclavian vein, left-sided CVC insertion, longer duration of catheter, catheter-to-vein ratio > 0.45, and type of CVC. A majority of patients with CRT are asymptomatic. Duplex ultrasound is the initial diagnostic modality of choice, though other modalities like CT angiography and MRV may be necessary for certain CRT locations. Current guidelines recommend maintaining a catheter unless nonfunctional or unneeded, in addition to systemic anticoagulation. Data guiding anticoagulant management specific to upper extremity VTE is lacking, and practice is mostly extrapolated from data on lower extremities. Further studies are required to establish evidence-based guidelines in the management of adults and children with CRT, and in particular the role of direct oral anticoagulants. In this review, we describe the knowledge gaps that exist in multiple aspects of CRT and the need for large collaborative studies to improve the care of patients with CRT.

The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management.

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.