Personalized Therapy and Clinical Outcomes for Congenital and Acquired Haemorrhagic Disorders, Thromboembolic Disease and Platelet Disorders

A special issue of Hematology Reports (ISSN 2038-8330).

Deadline for manuscript submissions: closed (8 April 2024) | Viewed by 18318

Special Issue Editor


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Guest Editor
Haemophilia Centre, Department of Medicine, University of Padua Medical School, 35128 Padova, Italy
Interests: hemophilia A and B; Von Willebrand disease; rare coagulation disorders; antipholipid antibodies (lupus anticoagulant, anticardiolipin antibodies); deep vein thrombosis and pulmonary embolism; venous thromboembolism; arterial thrombosis
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Special Issue Information

Dear Colleagues,

In recent years, several new drugs have been developed for the treatment of bleeding disorders, particularly in haemophilic patients. Recombinant coagulation factor concentrates FVIII / FIX extended half-life and new subcutaneous hemostatic agents are available. These innovative approaches have the advantage of being able to customize therapy based on the patient's hemorrhagic phenotype and pharmacokinetics. Even in patients with deep vein thrombosis and pulmonary embolism, the new oral anticoagulants have changed the management of these patients in both acute and long-term treatment. Advances in pharmacology have significantly influenced thrombotic outcomes, but a detailed assessment of the impact of non-thrombotic diseases on haemostasis and thrombosis is needed to better assess thrombotic risk and establish optimal treatment. Recent advances in our understanding of pathogenesis and diagnosis and new therapies for inherited and acquired platelet disorders have changed our approach in these patients as well.

This special issue aims to collect and publish original research articles and reviews demonstrating recent advance in our knowledge on new diagnostic and therapeutic approaches in these clinical conditions with particular regard to the personalization of the patient's treatment on the basis of his clinical characteristics, comorbidities and preference.

Dr. Ezio Zanon
Guest Editor

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Keywords

  • haemophilia
  • Willebrand disease
  • venous thromboembolism
  • deep vein thrombosis
  • pulmonary embolism
  • risk factors
  • inherited platelet disorders
  • thrombocytemia
  • thrombocytopenia
  • oral anticoagulant

Published Papers (10 papers)

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Research

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12 pages, 1268 KiB  
Article
Platelet Microvesicles, Inflammation, and Coagulation Markers: A Pilot Study
by Antonio Gidaro, Alessandro Palmerio Delitala, Roberto Manetti, Sonia Caccia, Mark J. Soloski, Giorgio Lambertenghi Deliliers, Dante Castro, Mattia Donadoni, Arianna Bartoli, Giuseppe Sanna, Luigi Bergamaschini and Roberto Castelli
Hematol. Rep. 2023, 15(4), 684-695; https://doi.org/10.3390/hematolrep15040069 - 4 Dec 2023
Cited by 2 | Viewed by 1008
Abstract
Background: Platelet “Microvesicles” (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. Methods: We prospectively enrolled volunteers aged over [...] Read more.
Background: Platelet “Microvesicles” (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. Methods: We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor β (TGF-β), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. Results: A total of 246 individuals (median age 65 years (“IQR”54–72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-β, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. Conclusions: To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested. Full article
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17 pages, 1550 KiB  
Article
Changes in Hematologic Lab Measures Observed in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with C5 Inhibitors, Ravulizumab and Eculizumab: Real-World Evidence from a US Based EMR Network
by Jesse Fishman, Seth Kuranz, Michael M. Yeh, Kaylen Brzozowski and Herman Chen
Hematol. Rep. 2023, 15(2), 266-282; https://doi.org/10.3390/hematolrep15020027 - 21 Apr 2023
Cited by 3 | Viewed by 2631
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disorder, can be treated with C5 inhibitors (C5i) such as eculizumab or ravulizumab. This retrospective study is the first to describe real-world treatment patterns and changes in hematologic PNH-monitoring laboratory tests among C5i-treated US patients. [...] Read more.
Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disorder, can be treated with C5 inhibitors (C5i) such as eculizumab or ravulizumab. This retrospective study is the first to describe real-world treatment patterns and changes in hematologic PNH-monitoring laboratory tests among C5i-treated US patients. Data were extracted from TriNetX Dataworks Network and included patients with a PNH diagnosis between 1 January 2010, and 20 August 2021. Patients were stratified into three cohorts based on their C5i usage: eculizumab, ravulizumab (prior eculizumab), and ravulizumab (eculizumab naïve). Hematological markers (hemoglobin [Hb], lactate dehydrogenase [LDH], and absolute reticulocyte count [ARC]) and relevant clinical events (e.g., breakthrough hemolysis [BTH], complement-amplifying conditions [CAC], thrombosis, infection, and all-cause mortality) were captured any time within 12 months post-index treatment. Of the 143 (eculizumab), 43 (ravulizumab, prior eculizumab), and 33 (ravulizumab, eculizumab naïve) patients, mean age across cohorts was 42–51 years, 55–61% were female, 63–73% were White, and 33–40% had aplastic anemia. Among all cohorts 12 months post-C5i treatment, 50–82% remained anemic, 8–32% required ≥1 transfusion, and 13–59% had BTH, of which 33%-54% had CACs. Additionally, thrombosis was seen in 7–15% of patients, infection in 20–25%, and mortality in 1–7%. These findings suggest many C5i-treated patients experience suboptimal disease control. Full article
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6 pages, 234 KiB  
Article
Comparison of Response to Rituximab Therapy in Adults with Refractory Symptomatic Immune Thrombocytopenia According to the Presence of Accessory Spleen
by Fehmi Hindilerden, Ipek Yonal-Hindilerden, Mustafa Nuri Yenerel, Meliha Nalcaci and Reyhan Diz-Kucukkaya
Hematol. Rep. 2022, 14(3), 222-227; https://doi.org/10.3390/hematolrep14030030 - 5 Jul 2022
Viewed by 1930
Abstract
No data exist for the association between the presence of accessory spleen after splenectomy and response to rituximab in immune thrombocytopenia (ITP). We investigated the relationship between accessory spleen presence and rituximab response in splenectomized ITP patients. Fifteen chronic refractory ITP patients were [...] Read more.
No data exist for the association between the presence of accessory spleen after splenectomy and response to rituximab in immune thrombocytopenia (ITP). We investigated the relationship between accessory spleen presence and rituximab response in splenectomized ITP patients. Fifteen chronic refractory ITP patients were included. Four weekly doses of rituximab 375 mg/m2 were administered. All patients had undergone splenectomy before rituximab administration. Accessory spleen was detected in 5 of 15 patients (33.3%). Median age at diagnosis was significantly higher in patients with accessory spleen than those without accessory spleen (40 (range 25–68 years) and 26 (range 7–40 years), respectively; p = 0.049). There was a trend for older age at time of rituximab initiation in patients with accessory spleen compared to the other group (median 51 (range 43–75 years) and 42.5 (range 30–60 years), respectively; p = 0.066). Median follow-up duration was 96 months (range 40–98). We demonstrated a significant correlation between accessory spleen presence and older age. Accessory spleen presence correlated with higher platelet and WBC counts. We showed good inverse correlation between presence of accessory spleen and time to early response (ER) to rituximab while the rate of early response (ER), late response (LR), sustained response (SR) and overall response (OR) did not differ with respect to the presence of acessory spleen. Full article

Review

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12 pages, 923 KiB  
Review
Role of Therapeutic Anticoagulation in COVID-19: The Current Situation
by Mandeep Singh Rahi, Jay Parekh, Prachi Pednekar, Mayuri Mudgal, Vishal Jindal and Kulothungan Gunasekaran
Hematol. Rep. 2023, 15(2), 358-369; https://doi.org/10.3390/hematolrep15020037 - 5 Jun 2023
Cited by 3 | Viewed by 1923
Abstract
Thrombotic complications from COVID-19 are now well known and contribute to significant morbidity and mortality. Different variants confer varying risks of thrombotic complications. Heparin has anti-inflammatory and antiviral effects. Due to its non-anticoagulant effects, escalated-dose anticoagulation, especially therapeutic-dose heparin, has been studied for [...] Read more.
Thrombotic complications from COVID-19 are now well known and contribute to significant morbidity and mortality. Different variants confer varying risks of thrombotic complications. Heparin has anti-inflammatory and antiviral effects. Due to its non-anticoagulant effects, escalated-dose anticoagulation, especially therapeutic-dose heparin, has been studied for thromboprophylaxis in hospitalized patients with COVID-19. Few randomized, controlled trials have examined the role of therapeutic anticoagulation in moderately to severely ill patients with COVID-19. Most of these patients had elevated D-dimers and low bleeding risks. Some trials used an innovative adaptive multiplatform with Bayesian analysis to answer this critical question promptly. All the trials were open-label and had several limitations. Most trials showed improvements in the meaningful clinical outcomes of organ-support-free days and reductions in thrombotic events, mainly in non-critically-ill COVID-19 patients. However, the mortality benefit needed to be more consistent. A recent meta-analysis confirmed the results. Multiple centers initially adopted intermediate-dose thromboprophylaxis, but the studies failed to show meaningful benefits. Given the new evidence, significant societies have suggested therapeutic anticoagulation in carefully selected patients who are moderately ill and do not require an intensive-care-unit level of care. There are multiple ongoing trials globally to further our understanding of therapeutic-dose thromboprophylaxis in hospitalized patients with COVID-19. In this review, we aim to summarize the current evidence regarding the use of anticoagulation in patients with COVID-19 infection. Full article
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Other

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8 pages, 6457 KiB  
Case Report
Factor VII Deficiency in Systemic Mastocytosis with an Associated Myeloid Neoplasm
by Giorgio Rosati, Sofia Camerlo, Alessandro Fornari, Valerio Marci, Barbara Montaruli and Alessandro Morotti
Hematol. Rep. 2024, 16(1), 132-139; https://doi.org/10.3390/hematolrep16010014 - 12 Mar 2024
Viewed by 661
Abstract
Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K deficiency or liver disease. Isolated acquired FVII deficiency is a rare occurrence and has been [...] Read more.
Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K deficiency or liver disease. Isolated acquired FVII deficiency is a rare occurrence and has been associated with inhibitors or auto-antibodies. Here, we describe a patient with polycythemia vera who developed systemic mastocytosis and FVII deficiency simultaneously. FVII deficiency was not caused by inhibitors and improved with antineoplastic treatment. Acquired FVII deficiency has been reported in cases of sepsis, possibly due to proteolytic degradation induced by the activation of monocytes or endothelial cells. Malignancies have been shown to cause a depletion in circulating FVII through the direct binding of cancer cells. This case report suggests a potential association between SM associated with a hematological neoplasm (SM-AHN) and acquired FVII deficiency. Further evaluations are recommended in patients with systemic mastocytosis to gain a better understanding of the relationship between pathological mast cells and clotting factor concentrations. Full article
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8 pages, 998 KiB  
Case Report
Manifestation of Pancytopenia Associated with COVID-19 as Paroxysmal Nocturnal Hemoglobinuria (PNH) and Aplastic Anemia (AA)
by Jeff Justin Aguilar, Vikram Dhillon and Suresh Balasubramanian
Hematol. Rep. 2024, 16(1), 42-49; https://doi.org/10.3390/hematolrep16010005 - 17 Jan 2024
Viewed by 1212
Abstract
We report two cases of pancytopenia in patients after recovering from a mild COVID-19, now presenting as paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. These cases illustrate a common pathway whereby a viral trigger causes the clonal expansion of a hematological disorder. Although [...] Read more.
We report two cases of pancytopenia in patients after recovering from a mild COVID-19, now presenting as paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. These cases illustrate a common pathway whereby a viral trigger causes the clonal expansion of a hematological disorder. Although the association of both cases with COVID-19 is temporal and COVID-19 may be an incidental diagnosis, the growing evidence related to the hematological effects of SARS-CoV-2 infection highlights the need for further investigation into the hematological consequences of COVID-19, particularly in the post-pandemic era. Full article
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6 pages, 231 KiB  
Case Report
Safe and Effective Administration of Caplacizumab in COVID-19-Associated Thrombotic Thrombocytopenic Purpura
by Antonella Bruzzese, Ernesto Vigna, Dario Terzi, Sonia Greco, Enrica Antonia Martino, Valeria Vangeli, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Rosellina Morelli, Antonino Neri, Fortunato Morabito, Francesco Zinno, Antonio Mastroianni and Massimo Gentile
Hematol. Rep. 2023, 15(3), 448-453; https://doi.org/10.3390/hematolrep15030046 - 20 Jul 2023
Viewed by 1298
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening, rare acute thrombotic microangiopathy (TMA), caused by a severe ADAMTS13 deficiency. As the COVID-19 pandemic rapidly spread around the globe, much data about the pathogenicity of this virus were published. Soon after the detection of [...] Read more.
Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening, rare acute thrombotic microangiopathy (TMA), caused by a severe ADAMTS13 deficiency. As the COVID-19 pandemic rapidly spread around the globe, much data about the pathogenicity of this virus were published. Soon after the detection of the first cases of COVID-19, it was clear that there was a wide range of COVID coagulopathy manifestations, such as deep venous thrombosis, pulmonary thromboembolism, and thrombotic microangiopathies. In the literature, little data have been reported about the association between TTP and COVID-19, and the treatment of COVID-19-associated TTP is still under debate. Here we present the case of a 46-year-old woman who developed a COVID-associated TTP, successfully treated with plasma exchange (PEX), steroids, and caplacizumab. Full article
14 pages, 333 KiB  
Conference Report
Managing Relevant Clinical Conditions of Hemophilia A/B Patients
by Massimo Morfini, Jacopo Agnelli Giacchiello, Erminia Baldacci, Christian Carulli, Giancarlo Castaman, Anna Chiara Giuffrida, Giuseppe Malcangi, Angiola Rocino, Sergio Siragusa and Ezio Zanon
Hematol. Rep. 2023, 15(2), 384-397; https://doi.org/10.3390/hematolrep15020039 - 7 Jun 2023
Cited by 1 | Viewed by 1646
Abstract
The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery [...] Read more.
The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated. Full article
7 pages, 577 KiB  
Case Report
A Case of Vancomycin-Induced Severe Immune Thrombocytopenia
by Shivani Shah, Ryan Sweeney, Maitreyee Rai and Deep Shah
Hematol. Rep. 2023, 15(2), 283-289; https://doi.org/10.3390/hematolrep15020028 - 24 Apr 2023
Cited by 2 | Viewed by 2421
Abstract
A male in his 60s presented with left lower extremity fractures following a vehicle accident. Hemoglobin, initially, was 12.4 mmol/L, and platelet count was 235 k/mcl. On day 11 of admission, his platelet count initially dropped to 99 k/mcl, and after recovery it [...] Read more.
A male in his 60s presented with left lower extremity fractures following a vehicle accident. Hemoglobin, initially, was 12.4 mmol/L, and platelet count was 235 k/mcl. On day 11 of admission, his platelet count initially dropped to 99 k/mcl, and after recovery it rapidly decreased to 11 k/mcl on day 16 when the INR was 1.3 and aPTT was 32 s, and he continued to have a stable anemia throughout admission. There was no response in platelet count post-transfusion of four units of platelets. Hematology initially evaluated the patient for disseminated intravascular coagulation, heparin-induced thrombocytopenia (anti-PF4 antibody was 0.19), and thrombotic thrombocytopenic purpura (PLASMIC score of 4). Vancomycin was administered on days 1–7 for broad spectrum antimicrobial coverage and day 10, again, for concerns of sepsis. Given the temporal association of thrombocytopenia and vancomycin administration, a diagnosis of vancomycin-induced immune thrombocytopenia was established. Vancomycin was discontinued, and 2 doses of 1000 mg/kg of intravenous immunoglobulin 24 h apart were administered with the subsequent resolution of thrombocytopenia. Full article
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5 pages, 433 KiB  
Brief Report
Triple-Negativity Identifies a Subgroup of Patients with Better Overall Survival in Essential Thrombocythemia
by Marco Santoro, Vincenzo Accurso, Salvatrice Mancuso, Mariasanta Napolitano, Marta Mattana, Giorgia Vajana, Federica Russello and Sergio Siragusa
Hematol. Rep. 2022, 14(3), 265-269; https://doi.org/10.3390/hematolrep14030037 - 24 Aug 2022
Cited by 1 | Viewed by 2480
Abstract
Essential thrombocythemia, as defined by the WHO in 2016, is a Philadelphia-negative chronic myeloproliferative neoplasm showing a better prognosis than polycythemia vera and myelofibrosis. In a variable percentage, patients with essential thrombocythemia show none of the known driver-gene mutations that may occur on [...] Read more.
Essential thrombocythemia, as defined by the WHO in 2016, is a Philadelphia-negative chronic myeloproliferative neoplasm showing a better prognosis than polycythemia vera and myelofibrosis. In a variable percentage, patients with essential thrombocythemia show none of the known driver-gene mutations that may occur on JAK2, CALR, and MPL genes. Such patients are classified as triple-negative and their clinical features and prognosis have not been described with precision yet. In this study, we evaluated some of the characteristics of this population by comparing them with those of patients with driver-gene mutated ET. Data from 266 consecutive essential thrombocythemia patients were analysed. Triple-negative patients had a significantly lower symptom load and a lower frequency of splenomegaly at diagnosis. The results show that the rate of thrombosis was equal in the two subgroups. Overall survival was slightly better in the triple-negative group of patients. Full article
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