Abstract
This is the first study to show a stepwise increase in venous thrombotic events according to COVID-19 coagulopathy (COVID-19-associated hemostatic abnormalities CAHA) staging and lung ...injuries assessed by chest computed tomography. Excess mortality and/or transfer to intensive care unit according to CAHA staging.
Background
Heparin‐induced thrombocytopenia (HIT) is a severe complication of heparin therapy associated with thrombosis that requires a quick diagnosis. Therefore, laboratory assays must provide an ...accurate and swift answer. This work aims to evaluate the performances of an ELISA assay, especially when combined with 4T risk score, and a functional assay.
Methods
Data were collected for 894 patients treated by heparin who underwent anticoagulant switch because of HIT suspicion and were examined by a multidisciplinary expert team who confirmed or ruled out HIT diagnosis. All patients were tested for anti‐PF4 IgG with Asserachrom HPIA IgG (ELISA), and 307 were tested with a platelet aggregation test done on platelet‐rich plasma (PRP‐PAT). The 4T risk score was available for 607 of them.
Results
HIT was diagnosed in 232 patients. 4T risk score had a 94.2% negative predictive value (NPV) for risk scores ≤3 and 77.3% for risk scores ≤5. The sensitivity of ELISA was 90.9%, its specificity 79.0%, and its NPV 96.1%. When combined with 4T risk score, its NPV reached 100% and 97% for risk scores ≤3 and ≤5, respectively. PRP‐PAT sensitivity was 70.4%, and its specificity was 92.3%. Combination of ELISA and PRP‐PAT had a 0.7% false‐negative rate.
Conclusion
This study shows that ELISA can rule out HIT with an excellent NPV, especially when combined with the 4T risk score. Nonetheless, it has low specificity; hence, it needs to be associated with a functional assay.
Heparin‐induced thrombocytopenia (HIT) is life‐threatening and requires an accurate diagnosis. Therefore, data were examined for 894 patients to determine the performances of laboratory diagnosis of HIT. ELISA had an excellent negative predictive value for low and intermediate (100% and 97.0%) 4T risk scores and the functional assay had a 70.4% sensitivity and 92.7% specificity. These findings support the combination of ELISA and functional assay, with a 0.7% false‐negative rate.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune ...thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild-to-severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)-polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA; (iv) occurring 5-30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccination. VITT's incidence is 1 per 100 000 vaccinated people irrespective of age and up to 1 in 50 000 for people <50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirus-vectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are thought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia.
Severe COVID-19 has been associated with a high rate of thrombotic events but also of bleeding events, particularly when the level of prophylactic anticoagulation was increased. Data on the ...contribution of platelets to these thrombotic events are discordant between reports, while the involvement of platelets in bleeding events has never been investigated. The objective of the present study was to assess platelet function during the first week of ICU hospitalization in patients with severe COVID-19 pneumonia. A total of 35 patients were prospectively included and blood samples were drawn on day (D) 0, D2 and D7. COVID-19 pneumonia was severe with a median PaO2/FiO2 ratio of 91 68-119 on D0. Platelets from these patients showed evidence of pre-activation and exhaustion with a significant reduction in the surface expression of GPVI, GPIb and GPIIbIIIa, together with a decrease in serotonin content. Platelets from patients with severe COVID-19 were hyporesponsive with a reduced maximal aggregation response to several platelet agonists and decreased adhesion to immobilized fibrinogen. Aggregation of washed platelets and plasma substitution experiments indicated that a plasma factor was at least partially responsible for this hyporeactivity of platelets. Blood flow experiments showed that severe COVID-19 platelets formed smaller, less stable aggregates on a collagen-coated surface, which could explain why some patients develop bleeding events. These findings should prompt us to carefully evaluate the risks and benefits of high-dose prophylactic anticoagulation, and to decrease the level of anticoagulation once the initial phase of the disease has resolved.
ClinicalTrials.gov identifier: NCT04359992.
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•Severe COVID-19 is associated with significant risks of thrombosis and bleeding•Platelets from patients with severe COVID-19 show signs of pre-activation at ICU admission.•Platelets from patients with severe COVID-19 are hyporeactive to several agonists.•Platelets hyporeactivity may be related to platelet exhaustion or to a plasmatic factor.•Platelets from patients with severe COVID-19 form smaller and unstable thrombi.
The obstetrical follow-up of patients with a severe hypofibrinogenemia requires a multidisciplinary collaboration because of potential maternal-fetal complications (recurrent miscarriages, ...intrauterine fetal demise, post-partum hemorrhage, thrombosis). We report the obstetrical management of a multiparous patient with a severe congenital hypofibrinogenemia associated with a platelet disorder (abnormal phospholipid externalization). A therapeutic strategy based on a biweekly administration of fibrinogen concentrates associated with enoxaparin and aspirin allowed the maintenance of pregnancy. But this last one got complicated by a placenta percreta requiring a salvage hysterectomy with an appropriate hemorrhage prophylaxis.
Background: The use of extending half-life (EHL) FVIII or FIX products is today a current strategy in Hemophilia A (HA) patients for improving prophylaxis and reducing the number of IV injections. Fc ...fusion technology is based on the use of the neonatal Fc receptor and endogenous Fc recycling pathway, thereby prolonging the half-life (T1/2) of rFVIII-Fc. A single dose phase 1/2 pharmacokinetic (PK) study performed in 16 severe HA patients demonstrated a prolonged T ½ of rFVIII-Fc equal to 18.8 hours (mean) compared to 12.2 hours with one conventional rFVIII (Malhangu et al. Blood 2014).
The aim of the present study was to analyze PK data collected with Elocta® in “real life” i.e. in a large cohort of patients treated in 13 different French hemophilia care centers, and results were compared to those obtained with conventional FVIII, when available. Importantly, this study was performed without any involvement of Sobi, the pharmaceutical company that provides Elocta® in France.
Patients and methods: 113 severe Hemophilia A (HA) patients with the following characteristics were included: mean age 30 years (range 3 - 70); weight 65 Kg (17-125); total FVIII-Fc dose injected 2650 IU (500-5750); FVIII-Fc IU/Kg: 41 (25 - 59); VWF Ag 98% (41-279). The FVIII recovery (R) was calculated as follows: (body weight (Kg) x observed increased in FVIII (%))/administered dose (IU/Kg). The T1/2 was calculated with the following formula: Ln2/((Ln FVIII% T1 - Ln FVIII%T2)/T2 - T1)), with T1 ≥ 4 hours and T2 ≥ 24 hours.
Results were compared to those performed with conventional FVIII (non EHL-FVIII) in 48 patients (Advate® n = 14, Refacto® n = 2, Helixate®/Kogenate®/Kovaltry® n = 29, Factane® n = 3)
Results: rFVIII-Fc activity measured by one stage clotting assay (OSA) was 20% lower than those obtained with chromogenic assay (CSA) in samples with FVIII levels higher than 20%, but this difference was lower than 10% when FVIII levels < 20%. Therefore, rFVIII-Fc recovery (R) always appeared lower when measured with OSA (Mean 2.38, range 1.33 - 5.7) than with CSA (mean 2.82, ranges 1.35 - 5.5) (p < 0.0001). No correlation was found between this recovery and age, weight, injected doses or VWF Ag levels. Mean T1/2 measured with rFVIII-Fc equaled 15 hours whatever the measurement method used (OSA or CSA), and was strongly correlated with vWFAg levels (R2 = 0.57). Using OSA, significantly lower recovery (1.86 vs. 2.49, p = 0.0002) and T1/2 values (11.75 vs. 15.13 hours, p = 0.0004) were measured in children (< 10 years, n = 19) compared to adults. Similar differences were evidenced with data obtained by CSA (recovery : 2.26 vs. 2.93, p = 0.0009 and T1/2 : 11.4 vs. 15.6 h, p = 0.004, n = 14 children < 10 years).
PK parameters of FVIII-Fc were compared to those obtained with non EHL-FVIII (rFVIII or pdFVIII) in 47 patients (mean T1/2 equal to 10.0 hours; range 5.3 - 21.2), and half-lives of these two categories of products were well correlated (r2 = 0.57). However, the apparent benefit provided by FVIII-Fc was variable from one patient to another, with a mean T1/2 rFVIII-Fc / T1/2 FVIII ratio ranging from 0.6 to 2.4 (mean 1.4). Interestingly, the increase in T1/2 with FVIII-Fc was lower than 20% only in patients previously treated with BHK-derived rFVIII i.e. Helixate®/Kogenate®/ Kowaltry® (n=10). Whatever the FVIII injected (FVIII-Fc or other non EHL-FVIII), the T1/2 measured was also strongly correlated to vWF levels, which were significantly lower in patients for whom the mean T1/2 rFVIII Fc / T1/2 FVIII ratio was > 1.3 (mean 79% vs 116% in the others, p=0.017).
Conclusion: This study is the first to report PK data obtained with rFVIII-Fc (Elocta®) in a large group of HA patients. Our results confirm the benefit of rFVIII-Fc in most HA patients, adults or children, but also emphasize the impact of vWF on half-life of rFVIII-Fc or conventional non EHL-FVIII. Indeed, the benefit of rFVIII-Fc clearly appears higher in patients with lower vWF levels, with a more significant prolongation of T1/2.
No relevant conflicts of interest to declare.
Glanzmann thrombasthenia (GT) is a rare congenital platelet function disorder associated with a severe bleeding diathesis. Thrombotic manifestations remain a rare condition. We report here the first ...case of recurrent venous thromboembolism (VTE) successfully treated with apixaban in a patient with GT. Our patient’s morbid obesity was an additional challenge.
The Key Clinical Question was to determine if direct oral anticoagulants are suitable for patients with both obesity and GT.
In our patient, the first episode of VTE occurred after the use of a low dose of activated recombinant factor VII for a minor procedure, whereas the second was unprovoked. Administration of rivaroxaban very quickly led to the appearance of bleeding symptoms and subsequently led to poor compliance and extension of deep vein thrombosis. The patient was switched to apixaban, with very good efficacy and safety over the cumulative 18 months of use.
The last updated guidelines now recommend the use of rivaroxaban and apixaban for management of VTE in patients with obesity. Regarding patients with GT, there is still insufficient data on the use of direct oral anticoagulants. Management of thrombotic manifestations in these patients remains a rare and complex condition and could be improved by the creation of a specific international registry.
•Glanzmann thrombasthenia (GT) is a rare inherited bleeding disorder.•Thrombotic manifestations, such as venous thromboembolism, are rare in patients with GT.•We present an obese patient with GT and recurrent venous thromboembolism successfully treated with apixaban.•The choice of the anticoagulant treatment to be given was a real challenge.
The use of enhanced half‐life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data ...obtained with efmoroctocog alfa (rFVIII‐Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non‐EHL FVIII. The in vivo recovery (IVR) of rFVIII‐Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half‐life (T1/2) of rFVIII‐Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII‐Fc vs non‐EHL FVIII showed a T1/2 ratio of 1.4 in favour of rFVIII‐Fc, regardless of the patient's age. However the relative increase in T1/2 with rFVIII‐Fc was lower than 30% in one‐third of patients evaluated, particularly when the previous FVIII administered was a BHK‐derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.
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