Keith R Mccrae

Keith R Mccrae
Cleveland Clinic · Taussig Cancer Institute

MD

About

322
Publications
24,500
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12,467
Citations
Citations since 2017
115 Research Items
4922 Citations
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201720182019202020212022202302004006008001,000
201720182019202020212022202302004006008001,000
Additional affiliations
February 2010 - present
Cleveland Clinic
Position
  • Professor of Molecular Medicine

Publications

Publications (322)
Article
C1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with...
Article
A dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer's disease, and sepsis. We previously showed that the 3E8 anti-HK antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) an...
Preprint
Full-text available
Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-speci...
Article
The antiphospholipid syndrome (APS) is the most common cause of acquired immune-mediated thrombophilia. This syndrome is broadly defined by the presence of arterial or venous thrombosis, or pregnancy morbidity, in the presence of high levels of antiphospholipid antibodies. Despite recognition of this disorder more than 50 years ago, a fundamental u...
Article
Background Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown.Objective We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients w...
Article
Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations and telangiectasia, with primary clinical manifestations of epistaxis and gastrointestinal bleeding and resultant anemia. HHT negatively affects health-related quality of life (HR-QoL); however, existing tools to measure HR-QoL are not HHT specific. Our obje...
Article
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy causing ischemic organ impairment. Blacks are overrepresented in iTTP cohorts in the United States but racial disparities in iTTP outcomes and response to therapy have not been studied. Using the United States Thrombotic M...
Article
Cancer immunotherapy has emerged as one of the most important new treatments for cancer in many years, moving rapidly to front-line therapy for several cancers. Cancer immunotherapy is based on treatment with immune checkpoint inhibitors (ICI), which are monoclonal antibodies directed toward immunoregulatory proteins including PD-1, PD-L1 and CTLA-...
Article
Full-text available
Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treat...
Article
Full-text available
Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with antiphospholipid antibodies. Dysregulation of the complement pathway has been implicated in APS pathophysiology. We report successful use of eculizumab, an anti-C5 monoclonal antibody, in controlling and preventing recurrent thrombosis in a refractory case of...
Article
Full-text available
Cancer is associated with an increased risk of venous thromboembolism (VTE). In the CASSINI study, ambulatory cancer patients with a Khorana risk score ≥2 had a reduced risk of VTE while receiving rivaroxaban. This analysis used blood samples from CASSINI to compare biomarker levels between patients with and without VTE. VTE occurred in 62 patients...
Article
Background: Venous thromboembolism (VTE) is an important immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICI) cancer therapy. To better understand the pathogenesis of ICI-induced VTE during ICI treatment, we utilized a murine model of cancer associated thrombosis (CAT) to examine the impact of ICI treatment on the...
Article
Human malaria is a complex disease and a leading cause of mortality in children under 5 years of age. Plasmodium falciparum (Pf) is the agent responsible for cerebral malaria. Parasite infected erythrocytes are sequestered in the brain vasculature, disrupting the blood-brain-barrier, and with systemic inflammation leading to progressive brain edema...
Article
Introduction Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by the development of arteriovenous malformations or telangiectasias that may affect any organ system, but are most prevalent in the nose and gastrointestinal tract. Nasal telangiectasia account for epistaxis, the most frequent manifestation of...
Article
Background: Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Cancer immunotherapy is linked to several inflammatory immune mediated adverse events. Inflammation plays a key role in thrombosis but the association between immunotherapy and venous thromboembolism (VTE) has not been thoroughly investigated. Here, we...
Article
ACKGROUND: Antiphospholipid syndrome (APS) is defined by arterial and/or venous thrombosis and/or pregnancy morbidity along with persistent circulating antiphospholipid antibodies (aPL). Central to APS pathogenesis are B cells that generate autoreactive antibodies, including anticardiolipin antibodies (aCL), and anti-β2-glycoprotein-I antibodies (a...
Article
Introduction Antiphospholipid syndrome (APS) is an autoimmune disorder caused by "antiphospholipid" antibodies (aPL) directed against β2-glycoprotein I (β2GPI). Although β2GPI is proposed to have both anti- and procoagulant properties in vitro, its physiological role in coagulation in vivo is not well understood. Previous studies have shown that β2...
Article
Background- High molecular weight Kininogen (HK) is a nonenzymatic co-factor of the contact activation system. HK binds prekallikrein (PK) and FXI to surfaces in proximity to FXII, amplifying PK activation by FXIIa and the reciprocal activation of FXII by activated PK (PKa), as well as FXI activation of FXIIa. PKa cleavage of HK also liberates brad...
Article
Extracellular vesicles (EV) have been implicated in diverse biological processes, including intracellular communication, transport of nucleic acids, and regulation of vascular function. Levels of EV are elevated in cancer, and studies suggest that EV may stimulate thrombosis in cancer patients through expression of tissue factor. However, limited d...
Article
Full-text available
Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNA...
Article
Full-text available
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin...
Article
Full-text available
Introduction: A network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids. Methods: A systematic search of publication and clinical trial databases was con...
Article
Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in...
Preprint
Full-text available
Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success in treatment of HR repair deficient cancers has not translated to HR-proficient cancer. Our studies identify the mechanism of non-receptor lymphocyte-specific protein tyrosine k...
Article
Background Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied. Methods We conducted a retrospective cohort study of 1,686 individuals who received immunotherapy for a variety of malignancies to determine the incidence o...
Article
Full-text available
Background Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Little is known about the incidence of arterial TE (ATE) and venous TE (VTE) in patients with melanoma on immune checkpoint inhibitor (ICI) therapy. Methods We conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015...
Article
Introduction Thromboembolism (TE) is common in patients with non‐small cell lung cancer (NSCLC) and is associated with worse outcomes. Recent advances in the understanding of NSCLC have led to the identification of molecular subtypes such as ALK and EGFR mutations. The association of these subtypes with risk of TE has not been fully explored. Meth...
Article
Full-text available
Background Thrombopoietin receptor agonists (TPO‐RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. Objectives To develop expert consensus on when it is appropriate to consider tapering TPO‐RAs in ITP, how to taper patients off therapy, how to monit...
Article
Background: Clinical management of ITP depends on both disease severity and risk of bleeding. Treatment typically is considered when platelet counts (PC) fall below 30,000/µL, with a target PC of ≥50,000/µL to mitigate the risk of bleeding. The standard-of-care after failure of 1st line therapy (corticosteroids or intravenous immunoglobulin) has be...
Article
Background: The treatment paradigm for cancer associated thrombosis (CAT) has evolved over recent years from using low molecular weight heparin (LMWH) to direct oral anticoagulants (DOACs). Some randomized trials suggest decreased rates of recurrent venous thromboembolism (VTE) in CAT patients treated with DOACs compared to LMWH but also reported i...
Article
Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a con...
Article
Full-text available
Introduction:Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis in the presence of antiphospholipid antibodies. Recently, derangement in the complement pathway has been implicated in APS pathophysiology. Refractory cases of APS with recurrent and potentially fatal thrombosis have prompted use of the monoclonal ant...
Article
Introduction: In recent years, direct oral anticoagulants (DOACs) have been adopted as a treatment option for cancer associated thrombosis (CAT). Randomized trials comparing anti-Xa drugs to low molecular weight heparin (LMWH) showed treatment with DOACs conferred less risk of recurrent venous thromboembolism (VTE), but found higher rates of clinic...
Article
Background: Thrombopoietin receptor agonists (TPO-RAs) (e.g., romiplostim, eltrombopag, avatrombopag) are used to stimulate platelet production in patients with primary immune thrombocytopenia (ITP). While it was previously thought that patients would need to remain on a TPO-RA indefinitely, case reports and cohort studies have shown that some pati...
Article
Full-text available
Background Little is known about rates of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in patients with melanoma on ICI. We assessed incidence and outcomes of ATE and VTE in patients with melanoma receiving ICI. Methods We conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through Decem...
Article
Full-text available
Background SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated wi...
Article
Cancer-associated thrombosis is a leading cause of non-cancer death in cancer patients and is comprised of both arterial and venous thromboembolism. There are multiple risk factors for developing VTE, including cancer type, stage, treatment, and other medical comorbidities, which suggests that the etiology of thrombosis is multifactorial. While can...
Article
Full-text available
Background Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso‐occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular w...
Article
Full-text available
The contact system is composed of Factor XII (FXII), prekallikrein (PK) and co-factor kininogen (HK). The globular C1q receptor (gC1qR) has been shown to interact with FXII and HK. We reveal the FXII fibronectin type II domain (FnII) binds gC1qR in a Zn2+ dependent fashion and determined the complex crystal structure. FXIIFnII binds the gC1qR trime...
Article
Full-text available
β 2 -glycoprotein I (β 2 GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound β 2 GPI to that in solution. β 2 GPI exi...
Article
Full-text available
Despite the publication in 2009 of a paper on ‘terms and definitions of immune thrombocytopenia’ (ITP), some unresolved issues remain and are reflected by the disagreement in the treatment suggested for primary ITP in adults. Considering that these disagreements could be ascribed to non-shared goals, we generated a ‘consensus’ on some terms, defini...
Article
Thromboembolism complicates disorders caused by IgG-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization and propagation of coagulation by ICs, is mediated through Fc gamma receptor IIa...
Preprint
Full-text available
Venous and arterial thromboses in patients suffering from the autoimmune disorder Antiphospholipid Syndrome (APS) are caused by the presence of antiphospholipid antibodies (aPL). Emerging evidence indicates that autoantibodies targeting the epitope R39-R43 in the N-terminal domain, Domain I (DI), of β 2 -glycoprotein I (β 2 GPI) are among the most...
Article
Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy. Heparin is generally avoided in patients with a history of HIT; however, it remains the anticoagulant of choice for cardiac surgery requiring cardiopulmonary bypass (CPB) because of limited experience with alternative anticoagulants such as direct thrombin...
Article
Background Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients. Objective These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinici...
Article
Full-text available
Objective: Patients with cancer are at high risk for developing primary but also recurrent venous thromboembolism (VTE). This study examined healthcare utilization (HRU) and costs related to VTE recurrence among cancer patients. Methods: Medical and pharmacy claims from the Humana Database were used to compare HRU (outpatient visits, emergency room...
Article
The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies including anti-beta-2-glycoprotein-I (anti-β2GPI) that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham...
Article
Background: Previous studies suggest isolated distal deep vein thrombosis (IDDVT) have a self-limited clinical course. However, these studies excluded cancer patients, who remain a high risk population. In addition, studies to evaluate the long-term clinical outcomes of IDDVT in cancer patients have been limited. Here, we report outcomes from our...
Article
Full-text available
Background: The propensity to develop venous thromboembolism (VTE) on the basis of individual tumor biological features remains unknown. Objectives: We conducted a whole transcriptome RNA sequencing strategy, focusing on a single cancer type (lung cancer), to identify biomarkers of cancer-associated VTE. Methods: Twelve propensity-matched pati...
Poster
Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder caused by "antiphospholipid" antibodies (aPL) directed against β2-glycoprotein I (β2GPI). However, there remains significant inconsistency in measurements of anti-β2GPI antibodies, possibly due to different sources of β2GPI. To address this issue and others, we have developed a...
Article
Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by abnormal blood vessel formation, recurrent and severe epistaxis, gastrointestinal bleeding, as well as pulmonary, hepatic and cerebral arteriovenous malformation (AVM). The pathogenesis of HHT appears to involve dysregulation of TGF-β...
Article
Introduction: Venous thromboembolism (VTE) is directly and indirectly associated with mortality in cancer patients. Cancer patients who experience VTE are known to be at higher risk for mortality than cancer patients without VTE, yet information regarding mortality based on differences in VTE risk level is limited in real-world data. The purpose of...
Article
Acetaminophen (APAP) toxicity is a common cause of acute liver failure (ALF). Dysregulation of coagulation is well documented in ALF patients. Recent reports indicate that small subset of ALF patients (~10%) exhibit spontaneous bleeding, while thrombotic complications are more frequent. Animal studies demonstrated that the inhibition of tissue fact...
Article
Introduction Venous thromboembolism (VTE) is the second leading cause of mortality among cancer patients and is potentially preventable through the use of anticoagulation therapy. Risk models exist to guide use of prophylactic therapy but have low positive predictive value. New biomarkers are needed, particularly in intermediate-risk cancer types....
Article
Background: Immune thrombocytopenia (ITP) is an autoimmune disorder causing reduced platelet counts <100,000/µL, with potential bleeding consequences and reduced quality of life. Treatment is generally reserved for adults with platelet counts <30,000/µL. Methods: ITP patients from the Platelet Disorder Support Association were recruited to complete...
Poster
Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigate...
Article
Background Venous thromboembolism (VTE) is a common complication in cancer care and can be predicted based on validated risk assessment tools. Innovative new therapeutics in non-small cell lung cancer (NSCLC) have changed practice patterns and mortality, and new predictors of VTE are therefore needed to better identify high risk patients in this se...
Article
Introduction Randomized trials of venous thromboembolism (VTE) treatment in cancer have primarily focused on the initial 6-month period and the risk/benefit of additional anticoagulant therapy beyond this time point has not been fully evaluated. Current guidelines recommend continuing full dose anticoagulation after 6 months in patients who have on...
Article
Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder caused by "antiphospholipid" antibodies (aPL) directed in part against β2-glycoprotein I (β2GPI). Though β2GPI is proposed to have numerous anti- and procoagulant properties in vitro, its effect in vivo is not well studied. Β2GPI binds thrombin via exosite 1 and exosite 2 and i...
Article
Introduction Immuno-oncology shows significant promise in the treatment of malignancy but is associated with a variety of immune-related adverse events. We previously reported that venous thromboembolism (VTE) occurred in over 20% of patients treated with checkpoint blockade. We therefore have attempted to identify biomarkers/risk factors for VTE i...
Article
Disclosures: Chaturvedi: Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Streiff:Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Portola: Consultancy, Honoraria; Roche: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-San...
Conference Paper
Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create t...
Article
Full-text available
Purpose Anticoagulant therapy for at least 3–6 months is currently recommended for treatment of venous thromboembolism (VTE) in patients with cancer, but the optimal duration of treatment is unknown. This study examines the association between the duration of anticoagulation treatment and VTE recurrence in cancer patients. Methods The Humana claim...
Article
Full-text available
Introduction Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM). Methods This was an open label phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had prog...
Article
Full-text available
Compared to age‐matched controls, cancer patients have increased risk of bleeding when treated with anticoagulation. However, there are little data regarding bleeding as it relates to anticoagulant choice and other risk factors. We evaluated the 6‐month incidence of bleeding among patients treated with anticoagulation and bleeding risk factors. Dat...
Article
Background: Abnormal red cell distribution width (RDW), reflecting heterogeneity of red blood cell (RBC) size, is associated with cardiovascular disease outcomes. However, whether RBC size itself, expressed as mean corpuscular volume (MCV), provides additional prognostic value is unclear. We therefore investigated the relationship between outcomes...
Article
Full-text available
Objective: Standard of care for cancer-related venous thromboembolism (VTE) has been low molecular weight heparin (LMWH), but oral anticoagulants are also widely prescribed. This study compared VTE-related healthcare resource utilization and costs of cancer patients treated with anticoagulants. Methods: Claims data from Humana Database (1/1/2013-05...
Article
Background The homologous plasma proteins prekallikrein (PK) and factor XI (FXI) circulate as complexes with high molecular weight kininogen (HK). While evidence supports an interaction between the PK‐HK complexes and vascular endothelium, there is conflicting information regarding FXI binding to endothelium. Objective To study the interaction bet...
Article
Full-text available
The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Complement is a system of enzymes and regulatory proteins of the innate immune system that plays a key role in the inflammatory response to pathogenic stimuli. The complement and coagulation pathways are c...
Article
Full-text available
Background Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and hospitalization in cancer patients. Objectives To evaluate the feasibility of an electronic alert to identify and screen at‐risk individuals and gather rates of early detection of deep vein thrombosis (DVT). Patients/Methods An alert was built into the electroni...