Hamostaseologie最新文献

In this article, our goal is to offer an introduction and overview of the diagnostic approach to inherited platelet function defects (iPFDs) for clinicians and laboratory personnel who are beginning to engage in the field. We describe the most commonly used laboratory methods and propose a diagnostic four-step approach, wherein each stage requires a higher level of expertise and more specialized methods. It should be noted that our proposed approach differs from the ISTH Guidance on this topic in some points. The first step in the diagnostic approach of iPFD should be a thorough medical history and clinical examination. We strongly advocate for the use of a validated bleeding score like the ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool). External factors like diet and medication have to be considered. The second step should rule out plasmatic bleeding disorders and von Willebrand disease. Once this has been accomplished, the third step consists of a thorough platelet investigation of platelet phenotype and function. Established methods consist of blood smear analysis by light microscopy, light transmission aggregometry, and flow cytometry. Additional techniques such as lumiaggregometry, immune fluorescence microscopy, and platelet-dependent thrombin generation help confirm and specify the diagnosis of iPFD. In the fourth and last step, genetic testing can confirm a diagnosis, reveal novel mutations, and allow to compare unclear genetics with lab results. If diagnosis cannot be established through this process, experimental methods such as electron microscopy can give insight into the underlying disease.

Congenital platelet disorders are rare and targeted treatment is usually not possible. Inherited platelet function disorders (iPFDs) can affect surface receptors and multiple platelet responses such as defects of platelet granules, signal transduction, and procoagulant activity. If iPFDs are also associated with a reduced platelet count (thrombocytopenia), it is not uncommon to be misdiagnosed as immune thrombocytopenia. Because the bleeding tendency of the different platelet disorders is variable, a correct diagnosis of the platelet defect based on phenotyping, function analysis, and genotyping is essential, especially in the perioperative setting. In the case of a platelet receptor deficiency, such as Bernard-Soulier syndrome or Glanzmann thrombasthenia, not only the bleeding tendency but also the risk of isoimmunization after platelet transfusions or pregnancy has to be considered. Platelet granule disorders are commonly associated with either intrinsically quantitative or qualitative granule defects due to impaired granulopoiesis, or granule release defects, which can also affect additional signaling pathways. Functional platelet defects require expertise in the clinical bleeding tendency in terms of the disorder when using antiplatelet agents or other medications that affect platelet function. Platelet defects associated with hematological-oncological diseases require comprehensive information about the patient including the clinical implication of the genetic testing. This review focuses on genetics, clinical presentation, and laboratory platelet function analysis of iPFDs with or without reduced platelet number. As platelet defects affecting the cytoskeleton usually show thrombocytopenia, but less impaired or normal platelet functional responses, they are not specifically addressed.

Objectives:  Trauma-induced coagulopathy (TIC) is common in severely injured patients and is associated with significant morbidity and mortality.

Method:  The association of two parameters of blood gas analysis (hemoglobin [Hb], base excess [BE]) with standard coagulation tests (SCTs) and rotational thrombelastometry (ROTEM) using the database of the TraumaRegister DGU between 2015 and 2022 was studied. In a stepwise approach, the occurrence of a TIC, the correlations between Hb/BE levels and SCT, as well as ROTEM were calculated respectively. Then we aimed to detect relations between different Hb/BE levels and the occurrence of TIC, using standard clotting studies and/or ROTEM respectively.

Results:  TIC occurred in 17.2% of the 68,996 primarily admitted adult patients with Injury Severity Score ≥9. A high correlation was found between Hb/BE and SCT. With a decrease in Hb and BE, the frequency of TIC increased and at an admission Hb <8 g/dL and BE < -6 mmol/L, >60% of patients presented with TIC. Clinical conditions associated with TIC were Glasgow Coma Scale ≤8, blood pressure ≤90 mmHg on the scene or at hospital admission, prehospital volume >1,000 mL, serious injuries to the head and/or the thorax and/or the abdomen and/or the extremities.

Conclusion:  Almost one-sixth of patients present with a TIC at hospital admission. Blood gas analysis samples showed relevant correlations between Hb/BE levels and SCT. The combined closer inspection of Hb/BE and the clinical presentation of the patient is able to predict TIC in the majority of patients.

Background:  The risk of thrombosis and bleeding in myelofibrosis (MF) has been historically underappreciated. We sought to investigate potential molecular and clinical risk factors for venous (VTE) and arterial (ATE) thrombotic events as well as bleeding episodes.

Methods:  Data from 246 consecutive MF patients were analyzed. Driver mutations were tested in 191 patients.

Results:  In total, 181 mutations were found in 177 MF patients: 118 (61.8%) patients showed JAK2-V617F, 50 patients (26.2%) showed CALR, and 6 patients (3.1%) showed MPL mutations. Two patients were JAK2-V617F and MPL positive and one patient was positive for all three genes. Fourteen (7.3%) patients were triple negative. The JAK2-V617F allele burden was assessed in 63 JAK2-V617F-mutated patients, revealing a median of 35.6% (range: 5.0-96.0). At the time of MF diagnosis and during follow-up, 84 thrombotic events (52 VTEs and 32 ATEs) were observed, corresponding to 6.6% of patients per year. A significant association was found between JAK2-V617F mutation (OR: 2.5, 95% CI: 1.1-5.6) and prior VTE (OR: 7.6, 95% CI: 2.1-27.1) with an increased risk of VTE. Patients with prefibrotic MF had a higher rate of ATE than patients with overt MF. Hemorrhagic events occurred in 34 (13.8%) patients, corresponding to 3.8% of patients per year. Fibrosis grade 3 was associated with bleeding risk (OR: 3.4, 95% CI: 1.2-9.2, p = 0.02).

Conclusions:  The presence of the JAK2-V617F mutation, regardless of allele burden, and prior thrombosis were strongly associated with an increased risk of VTE. Patients with prefibrotic MF might be considered at high risk for developing ATE.

Thrombophilia management is based on the personal and family history of thrombosis. Current guidelines recommend performing thrombophilia testing only when the results will change clinical management. To investigate to what extent treatment recommendations changed following thrombophilia testing, clinical and laboratory data of 255 patients with and without venous thromboembolism who underwent thrombophilia screening were assessed retrospectively. A local score based on clinical indicators for thrombophilia was used to assess the pretest probability of thrombophilia. A total of 144 patients (57.6%) were found to have a clear thrombophilic phenotype, of which 78 were predicted to have definite thrombophilia and considered for indefinite anticoagulation; 66 were likely to have thrombophilia and were considered for indefinite or prolonged anticoagulation. Eighty-three (32.5%) could not be clearly classified and 28 (11%) were asymptomatic. A thrombophilic risk factor was diagnosed in 98 (38.4%) patients; this included 64 of 144 (44.5%) patients with a clear thrombophilic phenotype and 26 of 83 (31.3%) patients who could not be easily classified. Treatment recommendations changed in 57 of 255 (22%) patients following thrombophilia testing. Eight patients were switched from direct oral anticoagulants to vitamin K antagonists due to confirmed triple-positive antiphospholipid syndrome. In 49 patients, the anticoagulant dose was either increased (n = 3) or treatment was prolonged (n = 46) following diagnosis of high-risk thrombophilia. Clinically, assessing thrombophilia probability score before thrombophilia testing improves thrombophilia management recommendations.

Children with cancer have an increased risk for venous thromboembolic events (VTEs) compared to the healthy pediatric population. VTE rates in children with cancer vary among cancer types. Other VTE risk factors include central venous catheters and cancer therapies. VTE diagnosis relies on objective radiological imaging, and management to this date typically involves anticoagulant therapy. Low-molecular-weight heparins (LMWHs) are the most common choice. Evidence for primary VTE prevention is conflicting, and antithrombin replacement, LMWH, or apixaban have been studied. Recently, direct oral anticoagulants such as rivaroxaban or dabigatran were investigated for VTE treatment, showing promise in efficacy and safety. However, bleeding risks in this population need careful consideration, especially periprocedurally or with treatment-related thrombocytopenia. Prediction tools for VTE require adaptation for pediatric cancer patients. Progress in understanding and managing VTE in children with cancer is significant, with ongoing trials and real-world data contributing to improved strategies.

Since the 1970s, specialized hemophilia centers have been established to optimize the complex and costly treatment of patients with severe bleeding disorders. In 2019, the first GTH guidelines on the structural and process quality of hemophilia centers were published. On this basis, a procedure for the certification of hemophilia centers has been established under the technical leadership of the GTH. These GTH guidelines are essentially based on the European Guidelines for the Certification of Haemophilia Centers published in 2013, created by the European Haemophilia Network (EUHANET). In 2023, this European guideline was revised by the EAHAD Accreditation and Audit of Haemophilia Centers Working Group. On this background, the GTH guidelines have now been revised to take relevant updates to the European guidelines into account.

Cancer-associated thrombosis (CAT) is a common clinical problem in the treatment of cancer patients posing some unique challenges. These include the need to balance between the risk of recurrent thromboembolic events and bleeding complications in the individual cancer patient. A frequently encountered dilemma is the need for long-term anticoagulation in the setting of active malignancy. Until now, optimal duration, intensity, and type of anticoagulation in cancer patients remain an area of ongoing debate. In this case-based review, we present several challenging clinical scenarios and provide guidance on management. For optimal treatment results, CAT generally requires a multidisciplinary approach including specialists for thrombosis and hemostasis as well as hematology and oncology. Individual patient preferences should always be taken into account, especially in clinical situations with weak treatment evidence.

Background:  Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Standard treatment consists of bleeding control with bypassing agents and immunosuppressive therapy. Emicizumab is a bispecific antibody that mimics the function of activated FVIII irrespective of the presence of neutralizing antibodies. Recently, the GTH-AHA-EMI study demonstrated that emicizumab prevents bleeds and allows to postpone immunosuppression, which may influence future treatment strategies.

Aim:  To provide clinical practice recommendations on the use of emicizumab in AHA.

Methods:  A Delphi procedure was conducted among 33 experts from 16 German and Austrian hemophilia care centers. Statements were scored on a scale of 1 to 9, and agreement was defined as a score of ≥7. Consensus was defined as ≥75% agreement among participants, and strong consensus as ≥95% agreement.

Results:  Strong consensus was reached that emicizumab is effective for bleed prophylaxis and should be considered from the time of diagnosis (100% consensus). A fast-loading regimen of 6 mg/kg on day 1 and 3 mg/kg on day 2 should be used if rapid bleeding prophylaxis is required (94%). Maintenance doses of 1.5 mg/kg once weekly should be given (91%). Immunosuppression should be offered to patients on emicizumab if they are eligible based on physical status (97%). Emicizumab should be discontinued when remission of AHA is achieved (97%).

Conclusion:  These GTH consensus recommendations provide guidance to physicians on the use of emicizumab in AHA and follow the results of clinical trials that have shown emicizumab is effective in preventing bleeding in AHA.

In spite of my personal belief in the benefits of artificial intelligence (AI), reading Cathy O'Neil's book "Weapons of Math Destruction" left me feeling unsettled.1 She describes how flawed and unchecked algorithms are widely applied in areas that affect us all: hiring, credit scoring, access to education, and insurance pricing. In one example, a fixed percentage of teachers in a U.S. region was dismissed every year based on biased and opaque algorithms. The authors concluded that such algorithms act as "weapons of math destruction," perpetuate and amplify societal biases, act unethically, and harm vulnerable populations. The question arises as to what happens when we apply these algorithms to medicine? How do we know whether we are giving our patients the correct diagnosis or prognosis? Are we still sure that patients are receiving the appropriate treatment? Would we notice if the algorithms were geared more toward the needs of companies (make a lot of money) or health insurance companies (spend as little as possible)? In fact, evidence of bias and inequality of algorithms in medicine is already available.2 Due to these risks, some of my colleagues suggest that AI should be completely banned from medicine.