Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma.

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Severe thrombocytopenia in adults undergoing extracorporeal membrane oxygenation is predictive of thrombosis.

Extracorporeal membrane oxygenation (ECMO) provides lifesaving circulatory support and gas exchange, although hematologic complications are frequent. The relationship between ECMO and severe thrombocytopenia (platelet count <50 × 109/L) remains ill-defined. We performed a cohort study of 67 patients who received ECMO between 2016 and 2019, of which 65.7% received veno-arterial (VA) ECMO and 34.3% received veno-venous (VV) ECMO. All patients received heparin and 25.4% received antiplatelet therapy. In total, 23.9% of patients had a thrombotic event and 67.2% had a hemorrhagic event. 38.8% of patients developed severe thrombocytopenia. Severe thrombocytopenia was more common in patients with lower baseline platelet counts and increased the likelihood of thrombosis by 365% (OR 3.65, 95% CI 1.13-11.8, P = .031), while the type of ECMO (VA or VV) was not predictive of severe thrombocytopenia (P = .764). Multivariate logistic regression controlling for additional clinical variables found that severe thrombocytopenia predicted thrombosis (OR 3.65, CI 1.13-11.78, P = .031). Over a quarter of patients requiring ECMO developed severe thrombocytopenia in our cohort, which was associated with an increased risk of thrombosis and in-hospital mortality. Additional prospective observation is required to clarify the clinical implications of severe thrombocytopenia in the ECMO patient population.

Role of platelets in regulating activated coagulation factor XI activity.

Factor XI (FXI) has been shown to bind platelets, but the functional significance of this observation remains unknown. Platelets are essential for hemostasis and play a critical role in thrombosis, whereas FXI is not essential for hemostasis but promotes thrombosis. An apparent functional contradiction, platelets are known to support thrombin generation, yet platelet granules release protease inhibitors, including those of activated FXI (FXIa). We aim to investigate the secretory and binding mechanisms by which platelets could support or inhibit FXIa activity. The presence of platelets enhanced FXIa activity in a purified system and increased coagulation Factor IX (FIX) activation by FXIa and fibrin generation in human plasma. In contrast, platelets reduced the activation of FXI by activated coagulation factor XII (FXIIa) and the activation of FXII by kallikrein (PKa). Incubation of FXIa with the platelet secretome, which contains FXIa inhibitors, such as protease nexin-II, abolished FXIa activity, yet in the presence of activated platelets, the secretome was not able to block the activity of FXIa. FXIa variants lacking the anion-binding sites did not alter the effect of platelets on FXIa activity or interaction. Western blot analysis of bound FXIa [by FXIa-platelet membrane immunoprecipitation] showed that the interaction with platelets is zinc dependent and, unlike FXI binding to platelets, not dependent on glycoprotein Ib. FXIa binding to the platelet membrane increases its capacity to activate FIX in plasma likely by protecting it from inhibition by inhibitors secreted by activated platelets. Our findings suggest that an interaction of FXIa with the platelet surface may induce an allosteric modulation of FXIa.

Anticoagulation strategies in extracorporeal circulatory devices in adult populations.

Extracorporeal circulatory devices such as hemodialysis and extracorporeal membrane oxygenation can be lifesaving; however, they are also prone to pathologic events including device failure, venous and arterial thrombosis, hemorrhage, and an accelerated risk for atherosclerotic disease due to interactions between blood components and device surfaces of varying biocompatibility. While extracorporeal devices may be used acutely for limited periods of time (eg, extracorporeal membrane oxygenation, continuous venovenous hemofiltration, therapeutic apheresis), some patients require chronic use of these technologies (eg, intermittent hemodialysis and left ventricular assist devices). Given the substantial thrombotic risks associated with extracorporeal devices, multiple antiplatelet and anticoagulation strategies-including unfractionated heparin, low-molecular-weight heparin, citrate, direct thrombin inhibitors, and direct oral anticoagulants, have been used to mitigate the thrombotic milieu within the patient and device. In the following manuscript, we outline the current data on anticoagulation strategies for commonly used extracorporeal circulatory devices, highlighting the potential benefits and complications involved with each.

A novel somatic PLCG2 variant associated with resistance to BTK and SYK inhibition in chronic lymphocytic leukemia.

The treatment of chronic lymphocytic leukemia (CLL) has been transformed by the use of targeted small molecules inhibiting components of the B cell receptor (BCR) signaling pathway (Haematologica, 103, 2018 and e204; Curr Hematol Malig Rep, 14, 2019, 302). Chief among these is ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), which produces deep, durable responses in CLL with good tolerability (Haematologica, 103, 2018 and e204). Though prolonged exposure to the drug can exert selective pressure on CLL cells and allow for the emergence of drug-resistant clones, primary ibrutinib treatment failure is rare (Expert Rev Hematol, 11 and 2018, 185; N Engl J Med, 370, 2014 and 2352; N Engl J Med, 373, 2015 and 25, 2425; Blood, 128, 2016 and 2199). Activating mutations in the gene PLCG2, which encodes a downstream target of BTK, appear to enable constitutive BCR signaling and have been associated with ibrutinib resistance (Int J Cancer, 146 and 2020, 85; J Clin Oncol, 35, 2017 and 1437; Blood, 126, 2015 and 61). In recent years, novel investigational agents have targeted other components of the BCR pathway. Among these is entospletinib, an orally bioavailable, selective inhibitor of splenic tyrosine kinase (SYK) (Blood, 126, 2015 and 1744), which lies upstream of the enzyme phospholipase C-gamma-2 (PLCG2). Here, we describe a patient who was found to harbor a novel somatic variant of PLCG2 and experienced a lack of treatment response to both ibrutinib and entospletinib.

Diagnosis and management of hereditary haemochromatosis.

Hereditary haemochromatosis, one of the most common genetic disorders in the United States, can produce systemic iron deposition leading to end-organ failure and death if untreated. The diagnosis of this condition can be challenging as elevated serum ferritin may be seen in a variety of conditions, including acute and chronic liver disease, a range of systemic inflammatory states, and both primary and secondary iron overload syndromes. Appropriate and timely diagnosis of haemochromatosis is paramount as simple interventions, such as phlebotomy, can prevent or reverse organ damage from iron overload. The recognition of other aetiologies of elevated ferritin is also vital to ensure that appropriate intervention is provided and phlebotomy only utilized in patients who require it. In this review, we summarize the existing data on the work up and management of hereditary haemochromatosis and present a practical algorithm for the diagnosis and management of this disease.

The role of iron repletion in adult iron deficiency anemia and other diseases.

Iron deficiency anemia (IDA) is the most prevalent and treatable form of anemia worldwide. The clinical management of patients with IDA requires a comprehensive understanding of the many etiologies that can lead to iron deficiency including pregnancy, blood loss, renal disease, heavy menstrual bleeding, inflammatory bowel disease, bariatric surgery, or extremely rare genetic disorders. The treatment landscape for many causes of IDA is currently shifting toward more abundant use of intravenous (IV) iron due to its effectiveness and improved formulations that decrease the likelihood of adverse effects. IV iron has found applications beyond treatment of IDA, and there is accruing data about its efficacy in patients with heart failure, restless leg syndrome, fatigue, and prevention of acute mountain sickness. This review provides a framework to diagnose, manage, and treat patients presenting with IDA and discusses other conditions that benefit from iron supplementation.

Long-term remission rates after splenectomy in adults with Evans syndrome compared to immune thrombocytopenia: A single-center retrospective study.

OBJECTIVE: Evans syndrome, the combination of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) or autoimmune neutropenia, is associated with a high rate of relapsed/refractory disease. There are limited data on the efficacy of splenectomy for this condition. We reviewed patient outcomes after splenectomy for Evans syndrome compared to ITP at our institution. METHODS: We performed a retrospective analysis of patients who underwent splenectomy for autoimmune cytopenias over a 23-year period with the intention of comparing disease relapse rates after splenectomy in patients with Evans syndrome and in those with ITP. RESULTS: During the study period, 77 patients underwent splenectomy for ITP and seven underwent splenectomy for Evans syndrome. In the Evans cohort, splenectomy led to an 85.7% initial response rate with a 42.8% rate of relapse within one year and a long-term (one-year) response rate of 42.8%. In the ITP cohort, the initial response rate was 90.9% with a long-term response rate of 70.1%. CONCLUSION: Our data suggest that long-term remission rates after splenectomy are lower in adults with Evans syndrome compared to those with ITP, although splenectomy may still be an acceptable treatment for certain patients with Evans syndrome. Our findings underscore the need for further research and development of additional therapeutic strategies for this patient population.

The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients.

Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.

Sleep-disordered breathing in patients with sickle cell disease.

Sickle cell disease is one of the most common hereditary hemoglobinopathies worldwide, and its vaso-occlusive and hemolytic crises cause considerable patient morbidity. A growing body of evidence has shown that sleep-disordered breathing, and in particular, obstructive sleep apnea, occurs at high frequency in the sickle cell population, and that there is significant overlap in the underlying pathophysiology of these two conditions. Through a variety of mechanisms including nocturnal hypoxemia and increased oxidative stress, production of pro-inflammatory cytokines, and endothelial dysfunction, sickle cell anemia and sleep-disordered breathing potentiate each other's clinical effects and end-organ complications. Here, we will review the shared pathophysiologic mechanisms of these conditions and discuss their clinical sequelae. We will also examine the results of studies that have been carried out with clinical intervention of nocturnal hypoxemia in patients with sickle cell disease in the attempts to overcome the complications of the disease. Finally, we will propose the areas of investigation that merit further investigations in future in patients with sickle cell disease and sleep-disordered breathing.

Molecular targeting in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogenous disease associated with distinct genetic and molecular abnormalities. Somatic mutations result in dysregulation of intracellular signaling pathways, epigenetics, and apoptosis of the leukemia cells. Understanding the basis for the dysregulated processes provides the platform for the design of novel targeted therapy for AML patients. The effort to devise new targeted therapy has been helped by recent advances in methods for high-throughput genomic screening and the availability of computer-assisted techniques for the design of novel agents that are predicted to specifically inhibit the mutant molecules involved in these intracellular events. In this review, we will provide the scientific basis for targeting the dysregulated molecular mechanisms and discuss the agents currently being investigated, alone or in combination with chemotherapy, for treating patients with AML. Successes in molecular targeting will ultimately change the treatment paradigm for the disease.

Intestinal dysbiosis and allogeneic hematopoietic progenitor cell transplantation.

The intestinal microbiota is a diverse and dynamic ecosystem that is increasingly understood to play a vital role in human health. Hematopoietic stem cell transplant recipients undergo prolonged exposure to antimicrobials, chemotherapeutic agents, and immunosuppressants, resulting in profound shifts in the gut microbiome. A growing body of research has revealed the ways in which these microbiologic shifts shape immune modulation, affecting susceptibility to infections and graft-versus-host disease, the two major post-transplant complications in this population. As transplant medicine becomes increasingly personalized, the potential for microbiome-modulating treatments holds immense potential. Strategies to preserve the intestinal microbiota, including targeted antibiotics, prebiotics and probiotics, and fecal microbiota transplant could mitigate some of the microbiologic shifts in stem cell transplant recipients, and reduce the incidence of peri-transplant morbidity and mortality.

Immunogenicity of Pfizer mRNA COVID-19 Vaccination Followed by J&J Adenovirus COVID-19 Vaccination in Two Patients with Chronic Lymphocytic Leukemia.

Individuals with chronic lymphocytic leukemia (CLL) have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role a heterologous boost would have in patients who did not respond to the initial two-dose mRNA vaccine series. SARS-CoV-2 specific immune responses, including antibodies and memory B-cells, CD4 and CD8 T-cells were assessed prior to vaccination, as well as postinitial vaccination series and post-third dose in two subjects. One subject seroconverted, had RBD-specific memory B-cells and spike-specific CD4 T-cells while the other did not. Both subjects had a spike-specific CD8 T-cell response after the original mRNA vaccination series that was further boosted after the third dose or remained stable. The results of this study, however small, are especially promising to CLL individuals who did not seroconvert following the initial mRNA vaccination series.

Immunogenicity of Pfizer mRNA COVID-19 vaccination followed by J&J adenovirus COVID-19 vaccination in two CLL patients.

IMPORTANCE: Individuals with Chronic Lymphocytic Leukemia have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role heterologous boost would have in patients who did not respond to the recommended two-dose mRNA vaccine series with a SARS-CoV-2 specific immune response. OBJECTIVE: To characterize the immune response of two CLL patients who failed to seroconvert after initial mRNA vaccine series following a third, heterologous, COVID-19 vaccination with Ad26.COV2.S. DESIGN: Two subjects with CLL were enrolled in an IRB-approved observational longitudinal cohort study of the immune response to COVID-19 vaccination. After enrollment, they received a third vaccination with Ad26.COV2.S. Blood was drawn prior to original vaccination series, four weeks after mRNA vaccination, and again four weeks after third vaccination. SETTING: Eligible subjects were approached by oncologist overseeing CLL treatment and informed about study, at time of enrollment subjects consented to join the cohort study. PARTICIPANTS: Sixteen subjects enrolled in the larger CLL cohort study, of whom two subjects received a third COVID-19 vaccination and were included in this analysis. Subject 1 is CLL treatment naive, while Subject 2 is currently on active treatment. MAIN OUTCOMES AND MEASURES: SARS-CoV-2 specific immune response, including plasma antibodies, memory B-cells, CD4 and CD8 T-cells were assessed prior to vaccination (baseline) as well as post vaccination series and post third dose. RESULTS: Of the two subjects who received Ad26.COV2.S doses, Subject 1 seroconverted, had RBD-specific memory B-cells as well as spike-specific CD4 T-cells while Subject 2 did not. Both subjects had a spike-specific CD8 T-cell response after original mRNA vaccination series that was further boosted after third dose (Subject 1), or remained stable (Subject 2). CONCLUSIONS AND RELEVANCE: The results of this study, however small, is especially promising to CLL individuals who did not seroconvert following initial mRNA vaccination series. Especially those that are treatment naive, not currently in active treatment, or who may consider vaccination before beginning active treatment.

Heparin Resistance Is Common in Patients Undergoing Extracorporeal Membrane Oxygenation but Is Not Associated with Worse Clinical Outcomes.

Extracorporeal membrane oxygenation (ECMO) protocols generally require systemic anticoagulation with heparin to prevent circuit thrombosis. The prevalence, risk factors, and outcomes of heparin resistance in this setting are ill-defined. To better understand the prevalence and clinical consequences of heparin resistance in this population, we conducted a retrospective analysis of all patients treated with ECMO at a single academic medical center between 2016 and 2019. Univariate and multivariate analyses were used to evaluate predictors and outcomes of heparin resistance. Of 67 patients in our study, 50.7% met the threshold for heparin resistance for at least 1 day, which was managed in all cases with increases in heparin dose. Patients with heparin resistance were more likely to be male (82.4% vs. 48.5%, p = 0.005) and to have a higher mean platelet count (132 vs. 104 × 103/mL, p = 0.027) compared with those without heparin resistance. Multivariate logistic regression found no significant association between the development of heparin resistance and rates of thrombosis, hemorrhage, or overall survival. Additional prospective studies are required to clarify the clinical implications of heparin resistance in this population.

Erythrocytosis and thromboembolic events in transgender individuals receiving gender-affirming testosterone.

Erythrocytosis is a well-recognized consequence of exogenous testosterone, however its prevalence and contributions to thrombosis remain unknown in the context of gender-affirming hormonal therapy. We undertook a retrospective study of transgender and non-binary (TGNB) adults receiving exogenous testosterone. In the retrospective sample, 923 transgender individuals receiving testosterone were identified with 519 having documented pre- and post-testosterone hemoglobin and hematocrit (Hgb/Hct). The mean peak Hgb/Hct was 15.7 g/dL, and 47.0%. Mean time-to-peak Hgb/Hct was 31.2 months; 7.8% developed a hemoglobin >17.5 g/dL, whereas 20% developed a hematocrit of >50%. Testosterone dose reduction occurred in 42% of patients with erythrocytosis and 4.8% underwent phlebotomy. Thromboembolic events occurred in 0.9%, of which 80% had developed erythrocytosis by either Hgb or Hct, including two cases each of superficial and calf vein thrombosis as well as one ischemic stroke. We then performed an analysis of 14,294,784 hospitalizations from the 2016-17 US National Inpatient Sample (NIS), which identified 4141 admissions involving transgender individuals. Of those, seven had erythrocytosis with one concurrent venous thromboembolic event. Hematocrit >50% occurs in up to 20% of transgender individuals receiving testosterone. Despite the high incidence of erythrocytosis, thromboembolic events and hospitalizations involving erythrocytosis were uncommon.

Management of Anticoagulation in Pregnant Women With Mechanical Heart Valves.

IMPORTANCE: Mechanical heart valves (MHVs) pose significant thrombogenic risks to pregnant women and their fetuses, yet the choice of anticoagulation in this clinical setting remains unclear. Various therapeutic strategies carry distinct risk profiles that must be considered when making the decision about optimal anticoagulation. OBJECTIVE: We sought to review existing data and offer recommendations for the anticoagulation of pregnant women with MHVs, as well as management of anticoagulation in the peripartum period. EVIDENCE ACQUISITION: We performed a literature review of studies examining outcomes in pregnant women receiving systemic anticoagulation for mechanical valves, and also reviewed data on the safety profiles of various anticoagulant strategies in the setting of pregnancy. RESULTS: Warfarin has been shown to increase rates of embryopathy and fetal demise, although it has traditionally been the favored anticoagulant in this setting. Low-molecular-weight heparin, when dosed appropriately with close therapeutic monitoring, has been shown to be safe for both mother and fetus. CONCLUSIONS: We favor the use of low-molecular-weight heparin with appropriate dosing and monitoring for the anticoagulation of pregnant women with MHVs. Data suggest that this approach minimizes the thrombotic risk associated with the valve while also providing safe and effective anticoagulation that can be easily managed in the peripartum period.

An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate.

Importance: Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary threshold-typically assessed in a single-arm study. Objective: To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval. Design, Setting, and Participants: A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018. Exposures: Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted. Main Outcomes and Measures: The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response. Results: Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02). Conclusions and Relevance: Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.

The contact pathway and sepsis.

The contact pathway factors XI (FXI) and XII (FXII) have been demonstrated to be largely dispensable for hemostasis, as their absence results in a mild to absent bleeding diathesis. A growing body of literature, however, suggests that the contact pathway contributes to the pathologic host response to certain infectious organisms that produces the often-fatal syndrome known as sepsis. The contact pathway factors serve as a central node connecting inflammation to coagulation, and may offer a potentially safe therapeutic target to mitigate the morbidity and mortality associated with sepsis. Herein, we summarize published in vivo and in vitro data that have explored the roles of the contact pathway in sepsis, and discuss potential clinical applications of novel FXI- and FXII-inhibiting drugs currently under investigation.