Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency-causing KNG1 variants, and estimated prevalence.

BACKGROUND: Severe high-molecular-weight kininogen (HK) deficiency is a poorly studied autosomal recessive contact system defect caused by pathogenic, biallelic KNG1 variants. AIM: We performed the first comprehensive analysis of diagnostic, clinical, genetic, and epidemiological aspects of HK deficiency. METHODS: We collected clinical information and blood samples from a newly detected HK-deficient individual and from published cases identified by a systematic literature review. Activity and antigen levels of coagulation factors were determined. Genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. The frequency of HK deficiency was estimated considering truncating KNG1 variants from GnomAD. RESULTS: We identified 48 cases of severe HK deficiency (41 families), of these 47 have been previously published (n = 19 from gray literature). We genotyped 3 cases and critically appraised 10 studies with genetic data. Ten HK deficiency-causing variants (one new) were identified. All of them were truncating mutations, whereas the only known HK amino acid substitution with a relevant phenotype instead causes hereditary angioedema. Conservative estimates suggest an overall prevalence of severe HK deficiency of approximately one case per 8 million population, slightly higher in Africans. Individuals with HK deficiency appeared asymptomatic and had decreased levels of prekallikrein and factor XI, which could lead to misdiagnosis. CONCLUSION: HK deficiency is a rare condition with only few known pathogenic variants. It has an apparently good prognosis but is prone to misdiagnosis. Our understanding of its clinical implications is still limited, and an international prekallikrein and HK deficiency registry is being established to fill this knowledge gap.

EHA Guidelines on Management of Antithrombotic Treatments in Thrombocytopenic Patients With Cancer.

In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.

Fibrinolytic Proteins and Factor XIII as Predictors of Thrombotic and Hemorrhagic Complications in Hospitalized COVID-19 Patients.

Introduction: In a prospective cohort of hospitalized COVID-19 patients, an extensive characterization of hemostatic alterations by both global and specific assays was performed to clarify mechanisms underlying the coagulopathy and identify predictive factors for thrombotic and hemorrhagic events during hospitalization. Materials and Methods: Intensive care unit (ICU; n = 46) and non-ICU (n = 55) patients were enrolled, and the occurrence of thrombotic and hemorrhagic events was prospectively monitored. At study inclusion, thromboelastometry together with the measurement of specific coagulation proteins and hypercoagulation markers was performed. Results: Patients (median age 67 years) showed significantly shorter clot formation time together with greater maximum clot firmness by thromboelastometry, increased levels of F1 + 2 and D-dimer, as biomarkers of hypercoagulability, and of procoagulant factors V, VIII, IX, XI, and fibrinogen, while FXIII was significantly reduced. The concentration of fibrinolytic proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in the overall cohort of patients. Many of these hemostatic alterations were significantly greater in ICU compared to non-ICU subjects and, furthermore, they were associated with inflammatory biomarker elevation [i.e., interleukin 6 (IL-6), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and procalcitonin]. After enrollment, 7 thrombosis and 14 major bleedings occurred. Analysis of clinical and biological data identified increased t-PA, PAI-1, and NLR values as independent predictive factors for thrombosis, while lower FXIII levels were associated with bleeding. Conclusion: This study demonstrates alterations in all different hemostatic compartments analyzed, particularly in severe COVID-19 conditions, that strongly correlated with the inflammatory status. A potential role of fibrinolytic proteins together with NLR and of FXIII as predictors of thrombotic and hemorrhagic complications, respectively, is highlighted.

Preoperative bleeding risk assessment with ISTH-BAT and laboratory tests in patients undergoing elective surgery: A prospective cohort study.

BACKGROUND: Patients with inherited haemorrhagic disorders may bleed during surgery. No questionnaire on bleeding diathesis has been yet validated for the preoperative period and current guidelines provide conflicting recommendations. AIM: We aimed to assess if preoperative assessment with ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assesment Tool) and laboratory screening tests is useful to identify mild previously undiagnosed bleeding disorders (BDs) and to predict bleeding complications in selected patients undergoing elective surgery. METHODS: Consecutive patients undergoing elective surgery received ISTH-BAT evaluation and laboratory screening for platelet count, Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Subjects with an abnormal ISTH-BAT and/or laboratory results underwent further testing, and they were compared with a 1:1 random gender-, age- and type of surgery- matched control group. RESULTS: Overall, 1502 consecutive surgical patients (1186 adults, 316 children) were enrolled. Of these, 83 (5.5%, 95% confidence interval 4.4-6.8) patients (37 adults and 46 children) had an abnormal ISTH-BAT, and/or prolonged PT and/or prolonged aPTT and/or low platelet count; of them, one subject had low von Willebrand factor level, three Factor XII deficiency and four anticardiolipin and/or antiB2GPI antibodies. No major bleeding was reported in these 83 patients and their controls. CONCLUSION: ISTH-BAT and laboratory screening tests do not accurately detect mild BDs in selected patients undergoing elective surgery.

Susoctocog-alfa (Obizur®) in the treatment of nine elderly patients with acquired haemophilia A: an Italian multicentre real world experience.

BACKGROUND: In 2016, a new recombinant B-domain deleted porcine FVIII (rpFVIII) was licensed in Italy for the treatment of acquired haemophilia A (AHA), but only a few cases of patients receiving this have been reported in the literature. Here we report the largest registry of the use of rpFVIII for the treatment of AHA. The objective of this retrospective study was to describe the efficacy and the safety of susoctocog-alfa for AHA. MATERIAL AND METHODS: We studied a population of nine patients, recruited in five Italian haemophilia centres presenting AHA, and treated with Obizur® as first- or second-line therapy. RESULTS: rpFVIII was used as a first-line therapy in one-third of the patients. The median delay between clinical onset and diagnosis was 16 days. Initial bolus of infused susoctocog-alfa was 100 IU/kg, lower than the recommended dose. The treatment was maintained for a median of four days. Only one patient with serious co-morbidities and recurrent infections was treated for 32 days. All patients reached a complete resolution of AHA, and no recurrences were reported. Two patients developed a low-titre inhibitor against rpFVIII, neither experienced any complications. DISCUSSION: In our real world experience, susoctocog-alfa was proven to be an effective and safe therapeutic option for patients with AHA, also at a lower than recommended dosage. In our report, the appearance of low-titre inhibitors against rpFVIII, was not found to be clinically significant.

Recurrence Risk after First Symptomatic Distal versus Proximal Deep Vein Thrombosis According to Baseline Risk Factors.

Background It remains unclear whether the distal location of deep vein thrombosis (DVT) is independently associated with a lower risk of recurrence in all patients, or represents a marker of the presence and severity of provoking factors for venous thromboembolism (VTE). Methods We investigated the impact of distal (vs. proximal) DVT location on the risk of developing symptomatic, objectively confirmed recurrent VTE in 831 patients with a first acute symptomatic DVT not associated with pulmonary embolism (PE), who were stratified by the presence of transient or persistent risk factors at baseline. The primary outcome was symptomatic, objectively diagnosed recurrent VTE, including proximal DVT and PE. Results A total of 205 (24.7%) patients presented with a transient risk factor, 189 (22.7%) with a minor persistent risk factor, 202 (24.3%) with unprovoked DVT, and 235 (28.3%) with cancer-associated DVT. One-hundred twenty-five patients (15.0%) experienced recurrent DVT or PE. The largest relative difference between patients with distal (vs. proximal) DVT was observed in the absence of identifiable risk factors (adjusted hazard ratio [aHR]: 0.11; 95% CI [confidence interval]: 0.03-0.45). In patients with cancer, distal and proximal DVT had a comparable risk of recurrence (aHR: 0.70; 95% CI: 0.28-1.78]). Conclusions The distal (vs. proximal) location of first acute symptomatic DVT represented, in the absence of any identifiable transient or persistent risk factors, a favorable prognostic factor for recurrence. In contrast, the prognostic impact of DVT location was weaker if persistent provoking risk factors for VTE were present, notably cancer.

Sex-specific differences in the distal versus proximal presenting location of acute deep vein thrombosis.

BACKGROUND AND AIMS: Women present with pulmonary embolism (PE) more often than men, while the opposite is true for proximal deep vein thrombosis (DVT). We investigated whether sex-specific differences exist in the presenting location of acute symptomatic DVT among patients without concomitant PE. METHODS: We tested our hypothesis in a meta-analysis of studies selected by systematically reviewing PubMed, Embase, and the grey literature. Thereafter, we analysed data of a single-center cohort including patients with first isolated acute DVT to assess the additional impact of age and provoking risk factors on the presenting location of DVT. RESULTS: We identified 7 studies for a total of 20,534 patients. The weighed pooled absolute difference in the proportion of distal DVT between women and men was +5.4% (95%CI: +0.7%; +9.5%), which corresponds to a pooled odds ratio (OR) of 1.30 (95%CI: 1.07-1.58). This difference was +6.5% (95%CI: +2.1%; +10.9%) for first distal DVT (OR 1.38; 95%CI: 1.11-1.72) and +5.3% (95%CI: +0.5%; +10.0%) for either first or recurrent distal DVT (OR 1.29; 95%CI: 1.03-1.61). In the cohort study, the larger difference in the proportion of distal DVT between women and men was observed among patients aged 51-70 (+9.5%; 95CI: +2.8%; +16.0% compared to those aged 18-50) or with unprovoked events (+8.5%; 95CI: -0.9%; +17.9%). CONCLUSIONS: Among patients with first symptomatic isolated acute DVT, women presented with distal DVT more often than men, whereas men had a higher proportion of proximal DVT events. This pattern appeared to depend on age and the absence of provoking risk factors for VTE.

Activated prothrombin complex concentrate (FEIBA®) for the treatment and prevention of bleeding in patients with acquired haemophilia: A sequential study.

Despite anti-haemorrhagic therapy with proper doses of activated prothrombin complex concentrate (aPCC, Feiba®), patients with acquired haemophilia A (AHA) have a considerable risk of recurrent bleeding complications. Evidence in support of the benefit-to-risk ratio of prevention strategies with the use of lower doses of aPCC following the end of the initial treatment period is scarce and inconclusive. We report our experience in the management of 18 consecutive patients with AHA admitted to two Haemophilia centres in Italy. We managed the first 11 according to current guidelines (e.g., with conventional aPCC doses until bleeding resolution). Then, we decided to prolong the treatment beyond bleeding resolution with lower doses of the same concentrate (short-term prophylaxis) in the 7 additional patients. In these patients, the treatment was continued for as long as the titre of FVIII inhibitor was found to decrease by at least 50% when compared to the baseline one. We observed six relapses of bleeding in patients in whom aPCC was confined to the treatment of the qualifying bleeding episode, and none in patients to whom lower doses were administered until the pre-specified decrease in the titre of FVIII inhibitor was achieved. No patients experienced thrombotic complications during the study period. Prolonging the treatment with lower doses of aPCC beyond the initial phase in patients with AHA in whom the titre of FVIII inhibitor is still high is likely to safely prevent further bleeding complications.

A case of feverish neutropenia.

KEY CLINICAL MESSAGE: A case of feverish benign neutropenia occurring in a diabetic patient receiving pregabalin for peripheral neuropathy is reported. Although pregabalin-induced neutropenia is very rare, it is important to keep in mind that this drug like other anticonvulsants used for neuropathic pain, can cause severe neutropenia.

Thrombopoietin is not uniquely responsible for thrombocytosis in inflammatory disorders.

A few studies in patients with reactive thrombocytosis identified levels of the hormone higher than expected, and suggested that TPO behaves as an acute-phase protein and was responsible for increased platelet count. At the opposite, other studies did not find any significant rise of the hormone in patients who similarly developed reactive thrombocytosis. To gain further information on this topic, we compared TPO levels and platelet counts in two series of patients hospitalized for acute illnesses: one with strong elevation of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and the other with normal values. Within the group of subjects with high ESR and CRP, 38 had normal platelet counts, while 15 had thrombocytosis. No thrombocytosis was observed in control patients. Patients with high acute phase indexes had significantly higher TPO levels and platelet counts than control patients. We identified significant positive correlations between ESR and CRP, and between TPO and CRP. Interestingly, no significant relationship between platelet counts and TPO levels was find. When we grouped patients with acute-phase reaction according to absence or presence of thrombocytosis, we found similar TPO values. Conversely, positive correlations between platelet count and IL-6 and between TPO and IL-6 have been identified. All together our results confirm that TPO acts as an acute phase protein but exclude the possibility that it is uniquely responsible for thrombocytosis of inflammatory disorders, which might recognize in IL-6 a credible candidate as a cooperating factor.

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations.

BACKGROUND AND OBJECTIVES: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. DESIGN AND METHODS: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. RESULTS: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. INTERPRETATION AND CONCLUSIONS: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.

Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients.

BACKGROUND AND OBJECTIVES: The Italian Gruppo di Studio delle Piastrine recently developed a diagnostic algorithm to assist clinicians in the diagnosis of inherited thrombocytopenias. This algorithm is based on the simplest possible diagnostic investigations and can also be used in centers that are not highly specialized. The aim of the present study was to validate this diagnostic algorithm by applying it to a case series of genetic thrombocytopenias. DESIGN AND METHODS: The diagnostic algorithm was applied retrospectively to 46 consecutive patients observed during the last five years at a single institution. Twenty-eight were affected by defined illnesses or their variants, while 18 had a disorder that did not fit the criteria for any known genetic thrombocytopenia. The study was based on the evaluation of clinical records and laboratory tests. RESULTS: The diagnostic algorithm recognized: 4 homozygous and 4 heterozygous Bernard-Soulier syndromes, 11 MYH9-related diseases, one von WillebrandOs disease type 2B, one gray platelet syndrome and one X-linked thrombocytopenia with thalassemia. Moreover, it identified 4 patients with the clinical and laboratory features of heterozygous Bernard-Soulier syndrome not caused by mutations in the coding region of the GPIbalpha, GPIbbeta, GPIX or GPV genes, and two patients with the clinical phenotype of MYH9-related disease but without MYH9 mutations. Since the diagnostic flow chart did not allow prompt recognition of two subjects with MYH9-related disease, we introduced a small change to the previously proposed flow chart to obviate this defect. INTERPRETATION AND CONCLUSIONS: The diagnostic algorithm correctly diagnosed 26 of 28 patients with known disorders or phenotypic variants of known disorders. By a simple modification of the investigation sequence, its sensitivity reached 100%. The algorithm also identified 18 patients with new, as yet uncharacterized forms of genetic thrombocytopenia.