A safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is not uncommonly seen in pregnancy, either with the first episode or with the exacerbation of known disease. The management of TTP in pregnancy can be challenging if there is refractoriness to the use of therapeutic plasma exchange (TPE) and high-dose corticosteroids. Caplacizumab, a vWF-directed humanized antibody fragment, is approved for the treatment of acquired TTP but there is sparse data on its use in pregnant patients. Antenatal and peripartum haemorrhage is a theoretical concern with the use of the medication in the obstetric population. However, as options for treatment of TTP in the patients who have refractory disease are significantly limited, off-label use of caplacizumab to achieve disease control and prevent maternofetal morbidity and mortality is a reasonable consideration. This article described the successful use of caplacizumab in a pregnant patient with acquired TTP and the associated favourable outcome. The patient suffered an exacerbation following initial TPE and became refractory to both plasma exchange and high-dose corticosteroids. Off-label use of caplacizumab resulted in hematologic recovery and successful delivery of a healthy neonate. This case represents a contribution to the sparse literature on the use of this effective medication in an often-challenging clinical situation.

Hereditary thrombotic thrombocytopenic purpura acquired through liver transplantation: A case report.

A 62-year-old received orthotopic liver transplantation. Three weeks later, thrombotic microangiopathy developed. Testing revealed thrombotic thrombocytopenic purpura (TTP) characterized by low ADAMTS13 (A Disintegrin-like Metallopeptidase with ThromboSpondin type 1 motif 13) activity and no inhibitor of ADAMTS13 protein. Retrospective attainment of donor records revealed a TTP diagnosis, presumably hereditary TTP (hTTP), as an ADAMTS13 protein inhibitor was not mentioned. As the grafted liver does not produce ADAMTS13 protein, the recipient now functionally has hTTP and will likely need plasma transfusions indefinitely. While hTTP is extremely rare, it should be considered a contraindication to liver donation outside of exceptional circumstances. If a potential liver donor has TTP listed on medical history, attempts should be made to determine whether it is autoimmune or hereditary. An accurate medical history is critical as it is the only reliable way to identify hTTP, as outside of acute exacerbations of TTP, donors with hTTP can have normal laboratory values, including normal hemoglobin, platelets, and renal function.

Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency.

BACKGROUND: Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitriol deficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked. METHODS: To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time. RESULTS: After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p < 0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p = 0.002; phosphate decreased by -49.8 ± 15.4%, p < 0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy. CONCLUSION: In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia.

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort.

The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.

Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: results from a single center over a 10 year period.

Patients who undergo craniotomy for brain neoplasms have a high risk of developing venous thromboembolism (VTE), including deep vein thromboses (DVT) and pulmonary emboli (PE). The reasons for this correlation are not fully understood. This retrospective, single-center review aimed to determine the risk factors for VTE in patients who underwent neurosurgical resection of brain tumors at Northwestern University from 1999 to 2010. Our cohort included 1148 patients, 158 (13.7%) of whom were diagnosed with DVT and 38 (3.3%) of whom were diagnosed with PE. A variety of clinical factors were studied to determine predictors of VTE, including sex, ethnicity, medical co-morbidities, surgical positioning, length of hospital stay, tumor location, and tumor histology. Use of post-operative anticoagulants and hemorrhagic complications were also investigated. A prior history of VTE was found to be highly predictive of post-operative DVT (odds ratio [OR]=7.6, p=0.01), as was the patient's sex (OR=14.2, p<0.001), ethnicity (OR=0.5, p=0.04), post-operative intensive care unit days (OR=0.2, p=0.003), and tumor histology (OR=-0.16, p=0.01). Contrary to reports in the literature, the data collected did not indicate that the administration of post-operative medical prophylaxis for VTE was significant in preventing their formation (OR=-0.14, p=0.76). Hemorrhagic complications were low (2.2%) and resultant neurologic deficit was lower still (0.7%). The study indicates that patients with high-grade primary brain tumors and metastatic lesions should receive aggressive preventative measures in the post-operative period.

Venous thromboembolism in high grade glioma among surgical patients: results from a single center over a 10 year period.

Patients with high-grade glioma are at elevated risk of venous thromboembolism (VTE). The relationship between VTE and survival in glioma patients remains unclear, as does the optimal protocol for chemoprophylaxis. The purpose of this study was to assessthe incidence of and risk factors associated with VTE in patients with high-grade glioma, and the correlation between VTE and survival in this population. Furthermore, we sought to define a protocol for perioperative DVT prophylaxis. This was a retrospective review of patients who underwent craniotomy for resection of high-grade glioma (WHO grade III or IV) at Northwestern University between 1999 and 2010. A total of 336 patients met inclusion criteria. 53 patients developed postoperative VTE (15.7 %). Median survival was 12.0 months and was not significantly different between VTE(+) and VTE(-) patients. Demographics and surgical factors were not significantly correlated with VTE development. Prior history of VTE was highly predictive of postoperative VTE (OR 7.1, p < .01), as was seizure (OR 2.4, p = .005). Increased duration of postoperative ICU stay was also a risk factor for VTE (p = .025). 25 patients in our study received prophylactic anticoagulation(pAC) with either heparin or enoxaparin. Early initiation of pAC was associated with decreased incidence of VTE (p = .042). There were no hemorrhagic complications in patients receiving pAC. VTE is a common complication in high-grade glioma patients. Early initiation of anticoagulation is safe and may decrease the risk of VTE. We recommend initiation of chemoprophylaxis on postoperative day 1 in patients without contraindication.

Venous thromboembolic disease.

Venous thromboembolism (VTE) remains a common and life-threatening complication among patients with cancer. Thromboprophylaxis can be used to prevent the occurrence of VTE in patients with cancer who are considered at high risk for developing this complication. Therefore, it is critical to recognize the various risk factors for VTE in patients with cancer. Risk assessment tools are available to help identify patients for whom discussions regarding the potential benefits and risks of thromboprophylaxis would be appropriate. The NCCN Clinical Practice Guidelines in Oncology for VTE provide recommendations on risk evaluation, diagnosis, prevention, and treatment of VTE in patients with cancer.

Age-related differences in disease characteristics and clinical outcomes in polycythemia vera.

The natural history and prognosis for young patients with polycythemia vera (PV) in the post-JAK2 V617F era are not well defined. Therefore, we retrospectively analyzed disease characteristics and clinical outcomes in 120 patients ≤ 45 years and 84 patients ≥ 65 years at diagnosis. Despite lower white blood counts (9.2 vs. 13.4 × 10(9)/L, p = 0.004) and a lower JAK2 V617F allele burden (51% vs. 66%, p = 0.015), younger patients with PV had comparable rates of vascular complications compared to older patients (27% vs. 31%, p = 0.64). However, splanchnic vein thrombosis occurred more frequently in younger patients (13% vs. 2%, p = 0.0056). Myelofibrotic and leukemic transformation, the most serious complications of myeloproliferative neoplasms (MPN), occurred with similar frequencies in young versus older patients (15% vs. 10%, p = 0.29). Prevention or delay of these complications is currently the most urgent challenge in the care of younger patients with PV.

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008).

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model.

INTRODUCTION: Tissue Factor (TF) expression is observed in many types of cancer, associated with more aggressive disease, and thrombosis. Alternatively-spliced human tissue factor (asHTF) has recently been identified in which exon 5 is deleted. asHTF is soluble due to the substitution of the transmembrane and cytoplasmic domains of exon 6 with a unique COOH-terminal domain. MATERIALS AND METHODS: We examine the expression and function of asHTF and full-length Tissue Factor ((FL)TF) in six human pancreatic cancer cells. Further, we transfected asHTF, (FL)TF, and control expression vectors into a non-expressing, human pancreatic cancer line (MiaPaCa-2). We studied the procoagulant activity of asHTF and (FL)TF and the effect on tumor growth in mice. RESULTS: asHTF is expressed in 5 of 6 human pancreatic cancer cell lines, but not in normal human fibroblasts, nor the MiaPaCa-2 line. (FL)TF conferred procoagulant activity, but asHTF did not. Transfected cells were injected subcutaneously in athymic mice. Interestingly, compared with control transfection, (FL)TF expression was associated with reduced tumor growth (mean 7 mg vs 85 mg), while asHTF-expression was associated with enhanced tumor growth (mean 389 mg vs. 85 mg). asHTF expression resulted in increased mitotic index and microvascular density. CONCLUSIONS: These data suggests that asHTF expression promotes tumor growth, and is associated with increased tumor cell proliferation and angiogenesis in vivo. Our results raise a new perspective on the understanding of the relationship between TF expression and cancer growth, by showing a dissociation of the procoagulant activity of (FL)TF and the cancer-promoting activity of asHTF.

Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.

OBJECTIVES: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). BACKGROUND: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). METHODS: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. RESULTS: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. CONCLUSIONS: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Adverse effects on hemostatic function of drugs used in hematologic malignancies.

The adverse effects of drugs used in the treatment of hematologic malignancies are among the many factors contributing to the increased risk of both thrombosis and bleeding. These effects most often occur when combination of drugs are given. Some, such as L-asparaginase, result in both bleeding and thrombosis. Consideration must be given also to the bleeding or prothrombotic risk of the underlying hematologic disorder. The commonly used drugs with adverse effects on hemostasis include L-asparaginase, corticosteroids, inhibitors of vascular endothelial growth factor, gemtuzumab ozogamicin, thalidomide, and immunomodulatory derivatives of Thalidomide, and the hematopoietic growth factors. In addition, the syndrome of thrombotic microangiopathy may be brought on by several other drugs. Thus, a full understanding of these adverse effects is necessary in treating these disorders.

Update on angiogenesis inhibitors.

PURPOSE OF REVIEW: A number of therapeutic agents have been developed which have anti-angiogenic potential. Here we present the most recent data from clinical trials with some of the promising inhibitors of angiogenesis. RECENT FINDINGS: Agents that target the vascular endothelial growth factor signaling pathway are the furthest along in clinical development. The last year has brought US Food and Drug Administration approval of bevacizumab (Avastin), a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody. Bevacizumab has demonstrated a survival advantage in combination with chemotherapy for patients with metastatic colorectal cancer. Other agents with early promising results include PTK787/ZK 222584 (Vatalanib), ZD6474, and BAY 43-9006 (Sorafenib). SUMMARY: Angiogenesis inhibitors show promise, but evaluation for optimal efficacy has been a problem, given that the mechanisms of action of these agents differ from conventional cytotoxic agents and surrogate markers for inhibition of angiogenesis are not available.

Hairy cell leukemia: survival and relapse. Long-term follow-up of purine analog-based therapy and approach for relapsed disease.

Since its initial description approximately 50 years ago, there has been an impressive evolution in therapies for hairy cell leukemia. Long-term follow-up with 2-cholorodeoxyadenosine and 2'-deoxycoformycin demonstrates that both agents result in a high complete remission rate and overall survival. Relapse rates appear to be between 20% and 30%. Therapeutic strategies for patients with relapsed disease include retreatment with a purine analog, rituximab, or the anti-CD22 pseudomonas exotoxin A immunoconjugate, BL-22.

Drug-induced thrombotic microangiopathy.

Drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP/HUS) has been recognized for several years. The most commonly implicated drugs are mitomycin-C, cyclosporine, quinine, and ticlopidine. As with idiopathic cases of TTP/HUS, basic science discoveries in the late 1990s now suggest that the likely mechanisms by which these agents lead to a thrombotic microangiopathy (TMA) include either an immune-mediated phenomenon involving the ADAMTS13 metalloprotease or direct endothelial toxicity. This article reviews the current understanding of the pathogenesis, the clinical and laboratory features, and the recommended treatments, prognosis, and outcomes of drug-associated TMA.