Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review.

INTRODUCTION: Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data. METHODS: A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022. RESULTS: A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC. CONCLUSION: Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.

Reversal of direct oral anticoagulants: guidance from the SSC of the ISTH.

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development.

Current Diagnostic and Therapeutic Approaches in May-Thurner Syndrome in Children, Adolescents, and Young Adults: A Survey among Thrombosis Experts of the German Society of Thrombosis and Haemostasis.

May-Thurner syndrome (MTS) is a pelvic venous disorder involving compression of the left common iliac vein by the right common iliac artery, which results in predisposition for deep vein thrombosis. Although MTS is increasingly recognized in young patients, specific guidelines on diagnosis and management for children, adolescents, and young adults do not exist so far. The aim of this study was to assess current diagnostic and therapeutic practice in Germany, Austria, and Switzerland in children and young adults with thrombosis and MTS.We designed an online survey with 11 questions, which we sent via a mailing list to all members of the German, Austrian, and Swiss Society of Thrombosis and Haemostasis Research. Between July and October 2022, 33 specialists answered the questionnaire. Most participating specialists worked at pediatric hospitals (61%). Numbers of annually treated thromboses ranged from <5 (26%) to >30 (13%). Most specialists used venous ultrasound to diagnose deep vein thrombosis, 53% magnetic resonance imaging. Only 25% of specialists systematically screened for MTS in deep vein thrombosis. MTS was managed with anticoagulation (65%), iliac vein stent placement (32%), or balloon angioplasty (13%). In total, 31% of specialists reported to use more than one therapeutic method. Diagnostic and therapeutic approaches for MTS differed between specialists. Lack of standardization resulted in individualized and highly diverse management. Prospective observational clinical studies investigating the outcome of different management strategies including long-term follow-up on outcome and incidence of postthrombotic syndrome will help in defining patient groups who benefit most from revascularizing interventional strategies and developing standardized guidelines.

Clinical Course and Management of Patients with Emergency Surgery Treated with Direct Oral Anticoagulants or Vitamin K Antagonists-Results of the German Prospective RADOA-Registry.

(1) Background: The clinical management of anticoagulated patients treated with direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA) needing emergency surgery is challenging. (2) Methods: The prospective German RADOA registry investigated treatment strategies in DOAC- or VKA-treated patients needing emergency surgery within 24 h after admission. Effectiveness was analysed by clinical endpoints including major bleeding. Primary observation endpoint was in hospital mortality until 30 days after admission. (3) Results: A total of 78 patients were included (DOAC: 44; VKA: 34). Median age was 76 years. Overall, 43% of the DOAC patients and 79% of the VKA patients were treated with prothrombin complex concentrates (PCC) (p = 0.002). Out of the DOAC patients, 30% received no hemostatic treatment compared to 3% (1/34) of the VKA patients (p = 0.002), and 7% of the DOAC patients and 21% of the VKA patients developed major or clinically relevant non-major bleeding at the surgical site (p = 0.093). In-hospital mortality was 13% with no significant difference between the two treatment groups (DOAC: 11%, VKA: 15%; p > 0.20). (4) Conclusions: The 30-day in-hospital mortality rate was comparable between both patient groups. VKA patients required significantly more hemostatic agents than DOAC patients in the peri- and postoperative surgery period.

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure.

ABSTRACT: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered. OBJECTIVES: To analyze, in patients with VITT, the long-term course of anti-platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations. METHODS: 71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay. RESULTS: Platelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT. CONCLUSION: Once the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia.

The APSANTICO Study: A Prospective Observational Study to Evaluate Antiphospholipid Antibody Profiles in Patients with Thromboembolic Antiphospholipid Syndrome (APS) after COVID-19 Infection and/or Vaccination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus discovered in December 2019 that causes coronavirus disease 19 (COVID-19) and various vaccinations have been developed. The extent to which COVID-19 infections and/or COVID-19 vaccinations alter antiphospholipid antibodies (aPL) in patients with thromboembolic antiphospholipid syndrome (APS) remains unclear. Eighty-two patients with confirmed thromboembolic APS were included in this prospective non-interventional trial. Blood parameters including lupus anticoagulants, anticardiolipin IgG- and IgM-antibodies, and anti-ß2-glycoprotein I IgG- and IgM-antibodies were assessed prior to and after COVID-19 vaccination and/or COVID-19 infection. No increases in aPL in the total study population were detected. In fact, low but significant decreases were observed for anticardiolipin IgG- and anti-ß2-glycoprotein I IgG-antibodies, while anticardiolipin IgM- and anti-b2-glycoprotein I IgM-antibodies slightly increased only in patients with COVID-19 infection and vaccination. Although the investigated patient group is known to have a high risk of recurrent thrombosis, only one arterial thrombotic event was diagnosed (1.2%, 1/82). This low recurrence rate was probably due to the high vaccination rates prior to infections and a high rate of effective anticoagulation. Our data show that COVID-19 infections and/or vaccinations do not deteriorate the clinical course of anticoagulated thromboembolic APS patients.

Pharmacokinetics of Phenprocoumon in Emergency Situations-Results of the Prospective Observational RADOA-Registry (Reversal Agent Use in Patients Treated with Direct Oral Anticoagulants or Vitamin K Antagonists Registry).

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days.

Bleeding Issues in Women Under Oral Anticoagulation.

In premenopausal women treatment with direct oral anticoagulants (DOACs) can be associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists. These findings come from retrospective or prospective single-center studies and post hoc analysis of regulatory studies in which HMB was not a predefined safety outcome. In most of these publications, there is a lack of information about the use of different contraceptive methods which can influence HMB. Another limitation is the various definitions of HMB, which makes comparison between studies regarding the incidences of HMB difficult.Therefore, prospective studies are urgently needed to investigate the severity and duration of unaffected menstrual bleeding under oral anticoagulation independently of oral contraceptives or intrauterine devices. An ongoing multicenter German registry is aiming to compare the incidence of unaffected HMB in consecutive women of reproductive age (18-50 years) treated with different DOACs because of venous thromboembolism.When HMB occurs during oral anticoagulation, management includes interruption or dose reduction of anticoagulation with the danger of recurrent venous thrombosis, switch to another oral anticoagulant, or additional use of the antifibrinolytic agent tranexamic acid with the potential risk of thrombosis. Concomitant use of either oral hormonal contraceptive therapy or hormone-releasing intrauterine systems can also reduce HMB.

Thromboembolic Antiphospholipid Syndrome (APS): Efficacy and Safety of Different Anticoagulants-Results of the APSantiCO Registry.

Background: The particular challenge in dealing with patients with thromboembolic antiphospholipid syndrome (APS) is to establish an adequate therapy regime, as patients suffer from an increased risk of relapse despite antithrombotic treatment (ATT). Vitamin K antagonists (VKA) are the standard medication of choice. The current data on the use of direct oral anticoagulants (DOAC) in APS patients remain limited. Methods: The results of the retrospective APSantiCO registry are presented. In 80 patients with APS, the efficacy and safety of different ATT regimens were analyzed. Results: At the time of inclusion, 43.8% of patients were treated with VKA and 36.3% with DOAC. Medication regimes changed several times and 279 treatment phases were further analyzed with a total treatment length of 7529 months. The incidence of recurrent arterial thrombosis was significantly larger in the DOAC group compared with the VKA group (p < 0.001), while the incidence of recurrent venous thrombosis was comparable between both groups, as was the incidence of bleedings. Heavy menstrual bleeding was the most frequently observed bleeding complication. Conclusions: The data suggest that DOAC may be an alternative to VKA for APS patients with venous thromboembolism, while VKA should be used in APS-related arterial thrombosis.

Intracranial bleeding under vitamin K antagonists or direct oral anticoagulants: results of the RADOA registry.

BACKGROUND AND PURPOSE: The use of direct oral anticoagulants (DOAC) has increased sharply and DOAC are the oral anticoagulant therapy (OAT) of choice for the majority of patients with newly-diagnosed atrial fibrillation. Intracranial hemorrhage is the most severe adverse event of OAT. Systematic data on the course of intracranial hemorrhage under DOAC compared to vitamin K antagonists (VKA) are warranted to enable shared decision making in AF patients needing OAT. METHODS: This is a secondary analysis of the patients with intracranial bleedings from the prospective multicenter emergency department-based RADOA registry, which collected data on patients admitted with major bleeding while taking VKA or DOAC. The primary endpoint was in-hospital mortality until day 30. We evaluated hematoma volume and short-term clinical outcomes in relation to the extent of active OAT according to coagulation parameters and OAT plasma levels measured by UPLC-MS/MS. RESULTS: Of 193 patients with major bleeding, 109 (56.5%) had intracranial hemorrhage [52.3% intracerebral (ICH), 33.9% subdural (SDH), 11.0% subarachnoidal (SAH)]. 64 (58.7%) were on VKA and 45 (41.2%) were on DOAC. On admission, we could confirm active anticoagulation in 97.7% of VKA-treated patients based on either INR > 1.3 or phenprocoumon levels and in 75.8% of DOAC-treated patients based on DOAC levels. Patients suffering an intracranial hemorrhage under VKA showed significantly larger hematoma volumes and a higher in-hospital mortality. Especially in intracerebral hemorrhage, we observed a higher initial severity and numerically greater proportion of early changes towards palliative therapy under VKA, which coincided with a numerically higher case fatality. CONCLUSIONS: We show significantly smaller hematoma volumes for ICH and SDH under DOAC in comparison to VKA and a significantly lower 30-day in-hospital mortality rate of DOAC-ICH, even before the introduction of specific antidotes. These data strongly support the use of DOAC whenever possible in patients requiring OAT. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; Unique identifier: NCT01722786.

Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations. METHODS: A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life (t 1/2), tested in repeat samples, were evaluated. RESULTS: A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients t ½ was 17.3 hours (95% confidence interval [CI]: 15.4-19.7) without significant difference in both groups (major bleeding: t ½ 16.7 hours, 95% CI: 14.7-19.3; urgent surgery: t ½ 19.7 hours, 95% CI: 15.2-27.9; p = 0.292). In apixaban-treated patients t ½ was 25.0 hours (95% CI: 22.9-27.6) with a longer t ½ after urgent surgery (t 1/2: 30.8 hours; 95% CI: 26.9-36.4) compared with severe bleeding (t 1/2: 20.8 hours; 95% CI: 18.8-23.2; p < 0.001). CONCLUSION: Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t ½.

Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.

OBJECTIVES: We assessed possible myocardial involvement in previously cardiac healthy post-COVID patients referred for persisting symptoms with suspected myocarditis. BACKGROUND: Prior studies suggested myocardial inflammation in patients with coronavirus-induced disease 2019 (COVID-19). However, the prevalence of cardiac involvement among COVID patients varied between 1.4 and 78%. METHODS: A total of 56 post-COVID patients without previous heart diseases were included consecutively into this study. All patients had positive antibody titers against SARS-CoV-2. Patients were referred for persistent symptoms such as chest pain/discomfort, shortness of breath, or intolerance to activity. All patients underwent standardized cardiac assessment including electrocardiogram (ECG), cardiac biomarkers, echocardiography, and cardiac magnetic resonance (CMR). RESULTS: 56 Patients (46 ± 12 years, 54% females) presented 71 ± 66 days after their COVID-19 disease. In most patients, the course of COVID-19 was mild, with hospital treatment being necessary in five (9%). At presentation, patients most often reported persistent fatigue (75%), chest pain (71%), and shortness of breath (66%). Acute myocarditis was confirmed by T1/T2-weighed CMR and elevated NTpro-BNP levels in a single patient (2%). Left ventricular ejection fraction was 56% in this patient. Additional eight patients (14%) showed suspicious CMR findings, including myocardial edema without fibrosis (n = 3), or non-ischemic myocardial injury suggesting previous inflammation (n = 5). However, myocarditis could ultimately not be confirmed according to 2018 Lake Louise criteria; ECG, echo and lab findings were inconspicuous in all eight patients. CONCLUSIONS: Among 56 post-COVID patients with persistent thoracic complaints final diagnosis of myocarditis could be confirmed in a single patient using CMR.

Fondaparinux Pre-, Peri-, and/or Postpartum for the Prophylaxis/Treatment of Venous Thromboembolism (FondaPPP).

We analyzed data for women who received fondaparinux for ≥7 days during pregnancy. The study retrospectively included women who received fondaparinux pre-, peri- and/or postpartum for ≥7 days for prophylaxis/venous thromboembolism (VTE) treatment at German specialist centers (2004-2010). Data on pregnancy, VTE risk factors, anticoagulant treatment, pregnancy outcome and adverse events were extracted from medical records. 120 women (mean age 31.5 years) were included. Among 84 women with prior pregnancies, 41.0% had ≥1 abortion. Anticoagulation was indicated for prophylaxis in 92.5% cases, including 82.5% women with an elevated VTE risk (82.8% thrombophilia, 34.2% VTE history). All women received low-molecular-weight heparin (LMWH) as first-line therapy; 3 also unfractionated heparin. Treatment changed to fondaparinux, due to heparin allergy (41.7%) or heparin-induced thrombocytopenia (10.0%). Fondaparinux was generally well tolerated. Adverse events included bleeding events (n = 5), abortion (n = 2), premature births (n = 2), stillbirth (n = 1), arrested labors (n = 2), injection site erythema (n = 4) and unspecified drug hypersensitivity (n = 6). No VTE events or increased liver enzymes occurred during treatment. In this retrospective study, fondaparinux was effective and well tolerated. Trial registration: ClinicalTrials.gov NCT01004939.

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants.

In 2018, the International Council for Standardization in Haematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alfa. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author's personal experience/expert opinion and (3) good laboratory practice.

Direct oral anticoagulants in point-of-care monitoring: an ex-vivo study.

BACKGROUND: Anticoagulatory activity of direct oral anticoagulants (DOACs) is not routinely measurable by point-of-care monitoring. Thus, the aim of this study was to evaluate the influence of dabigatran/rivaroxaban on point-of-care testing. METHODS: Samples from 34 participants under DOAC therapy were drawn at two time points. Before ingestion and two-to-three hours afterwards. Thrombelastometric (ROTEM) and aggregometric (Multiplate) measurements were performed. Dabigatran and rivaroxaban plasma levels were determined. RESULTS: Dabigatran and rivaroxaban plasma levels showed significant correlations with clotting time (CT) in EXTEM (r=0.765, P<0.0001; r=0.689, P<0.0001) and INTEM (r=0.792, P<0.0001; r=0.595, P<0.001). A positive correlation was identified between dabigatran ingestion and maximum-clot-firmness (MCF) (r=0.354, P<0.05) in the EXTEM test, pronounced in the absence of concomitant antiplatelet therapy (r=0.709, P<0.05). EXTEM-MCF positively correlated with the TRAP test in aggregometry (0.662, P<0.05), an effect not observed in patients treated with antiplatelet therapy. CONCLUSIONS: Prolongation of CT-EXTEM and CT-INTEM indicates delayed initiation of clot formation. The CT-EXTEM seems to facilitate qualitative monitoring of dabigatran. In contrast, qualitative monitoring of rivaroxaban by CT-EXTEM may be limited as rivaroxaban may affect the measurement at therapeutic plasma levels. It seems that clot formation is faster/firmer in the presence of increased dabigatran plasma levels. This can be attributed to a non-dose-dependent effect via increased fibrin polymerization and second to a dose-dependent effect via increased platelet sensitivity to thrombin.

Incidence and severity of postthrombotic syndrome after iliofemoral thrombosis - results of the Iliaca-PTS - Registry.

Background: Deep venous thrombosis (DVT) and in particular, iliofemoral thrombosis (IFT) can lead to recurrent thrombosis and postthrombotic syndrome (PTS). Data on the prevalence, predictors and outcome of IFT are scarce. Patients and methods: We retrospectively searched our database of outpatients who had presented with DVT and IFT including the iliac veins from 2014 until 2017. In addition, we performed a prospective registry in a subgroup of patients with IFT. These patients received duplex ultrasound, magnetic resonance venography and measurement of symptom-free walking distance using a standardized treadmill ergometry. The severity of PTS was analyzed using the Villalta-Scale (VS) and quality of life was assessed using the VEINES-QOL/Sym Questionnaire. Results: 847 patients were retrospectively identified with DVT and 19.7% (167/847) of these presented with IFT. 50.9% (85/167) of the IFT-patients agreed to participate in the prospective registry. The majority of these patients (76.5%: 65/85) presented with left-sided IFT. In 53.8% (35/65) May-Thurner syndrome was suspected. 27.1% (23/85) underwent invasive therapy. Moderate or severe PTS (VS ≥ 10) occurred in 10.6% (9/85). The severity of PTS is correlated with a reduced quality of life (ρ (CI 95%) = -0.63 (-0.76; -0.46); p < 0.01). None of the patients presented with a venous ulcer at any time. A high body mass index was a significant predictor (OR (CI 95%) = 1.18 (1.05; 1.33), p = 0.007) for the development of clinically relevant PTS (VS ≥ 10) and venous claudication. Conclusions: Every fifth patient with DVT presented with an IFT. The majority developed left sided IFT. Every 10th patient developed moderate or severe PTS (VS ≥ 10). A high body mass index was predictive for the development of PTS and venous claudication.

Severe Hemorrhage Associated With Oral Anticoagulants.

BACKGROUND: Few data have been published to date on outcomes after the common clinical experience of severe hemorrhage in orally anticoagulated patients. METHODS: A prospective, multicenter observational study was carried out to investigate outcomes and management in a series of consecutive patients who sustained a severe hemorrhage under treatment with vitamin K antagonists (VKA) or direct oral anticoagulant drugs (DOAC). The primary endpoint was in-hospital death up to and including day 30 after hospital admission. The secondary endpoints were the duration of bleeding, in-hospital death due to hemorrhage (as defined by the study physician examining the patient's records), the use of antagonists, the extent of supportive measures used to stop the hemorrhage, and an assessment of causality. Consecutive patients were recruited until a predefined number of patients was reached in both groups. RESULTS: Among 193 patients with severe hemorrhage, 97 had been taking a VKA, and 96 had been taking a DOAC. 13.0 % (95% confidence interval [8.6; 18.5]; 25/193) of the overall group patients died in the first 30 days after hospital admission, including 17.5% ([10.6; 26.6]; 17/97) in the VKA group and 8.3% ([3.7; 15.8]; 8/96) in the DOAC group (p = 0.085). The median duration of bleeding was 19.8 hours in the VKA group and 27.8 hours in the DOAC group (p = 0.632). The in-hospital mortality due to hemorrhage was higher in the VKA group than in the DOAC group (15.5% [15/97] versus 4.2% [4/97]; p = 0.014). Only the use of prothrombin complex concentrates (PCCs) lowered the median duration of hemorrhage in the two patient groups. In 35% (68/193) of the patients, the hemorrhage was caused by an external influence, most commonly a fall. CONCLUSION: The in-hospital mortality was higher among patients treated with VKA than among patients treated with DOAC, although the difference failed to reach statistical significance.