Les observations Mme P. (observation n° 1), âgee de 45 ans, a presente deux zones de necrose cutanee : l'une entourant le site implantable pour acces veineux central (figure 1a) (voie pour chimiotherapie en raison d'un cancer epidermoide du col uterin) ; l'autre au niveau de l'abdomen (figure 1b), en regard de la zone d'injection sous-cutanee de nadroparine [...]
Les observations : Mme P. (observation n° 1), âgee de 45 ans, a presente deux zones de necrose cutanee : l'une entourant le site implantable pour acces veineux central (figure 1a) (voie pour chimiotherapie en raison d'un cancer epidermoide du col uterin) ; l'autre au niveau de l'abdomen (figure 1b), en regard de la zone d'injection sous-cutanee de nadroparine calcique, Fraxiparine® (0,8 mL x 2/jour) (traitement d'une thrombose de la veine jugulaire droite et sous-claviere du cote du site implantable). L'interrogatoire de la patiente a permis de trouver une exposition anterieure a l'heparine : elle a recu pendant un mois de la nadroparine calcique (0,4 mL/jour) a titre prophylactique a la suite d'une fracture du perone deux mois auparavant et 30 000 UI/jour d'heparine non fractionnee par voie intraveineuse continue du fait d'une thrombose a l'extremite du site implantable, quinze jours auparavant. La numeration plaquettaire realisee en presence de l'anticoagulant EDTA (ethylene diamine tetraacetique) a montre une thrombopenie (106 x 109/L). L'absence d'amas plaquettaires a ete controle a partir du frottis sanguin. La numeration plaquettaire en presence de l'anticoagulant citrate etait similaire apres correction par le facteur de dilution. Devant ce tableau clinique (thrombopenie et necrose), la nadroparine calcique a ete arretee avant les resultats des tests biologiques (test d'agregation plaquettaire et test immunologique positifs). Un traitement par danaparoide, Orgaran® (750 UI x 6, voie IV) a ete mis en place, suivi d'un relais par antivitamine K (AVK). Le traitement par danaparoide a ete stoppe prematurement suite a l'apparition d'un erytheme cutane au niveau de l'injection. L'INR (international normalized ratio) etant egal a 1,9, seul le traitement par AVK a ete poursuivi. Une remontee des numerations plaquettaires a ete observee apres l'arret de nadroparine (figure 2). Mme W. (observation n° 2), âgee de 67 ans, a recu de la nadroparine, a posologie prophylactique (0,3 mL/ jour), a la suite d'une intervention pour adenocarcinome de l'ovaire. A J8, une reprise chirurgicale pour fistule du grele a ete necessaire. A J15, la patiente a presente aux points d'injection une necrose cutanee avec prurit, douleur et induration (figure 3). La numeration plaquettaire realisee en presence de l'anticoagulant EDTA (360 x 109/L) etait dans les valeurs de reference sans aucune variation par rapport a celle realisee avant l'injection d'HBPM (heparine de bas poids moleculaire) (figure 4). La diminution attendue des plaquettes a pu etre masquee par la thrombocytose liee a l'intervention chirurgicale. Bien qu'aucune thrombopenie ne soit presente, il a ete decide d'arreter l'administration de nadroparine, et de debuter un traitement par danaparoide, decision confortee par les resultats des tests biologiques : test d'agregation plaquettaire et test immunologique positifs.
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.
Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 109/L.
Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves.Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml.RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.
