EMORRAGIA COAGULAZIONE TROMBOSI L’EMERGENZA E OLTRE Ricoagulare il paziente scoagulato farmacologicamente Franco Manzato Mantova 17 Aprile 2010

Trattamento anticoagulante nei vari paesi Pengo V. J Tronb Trombolysis 2006

Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7,6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0,25 per 100 patient-years), 23 were major (1,1) and 125 were minor (6,2). Reversal of coagulopathy secondary to warfarin use There is widespread consensus that OAT-ICH (intracranial hemorrhage) is a lifethreatening situation that requires urgent reversal of anticoagulation. Despite the long history of use of anticoagulants and the serious nature of bleeding complications, there are no prospective randomized trials addressing the efficacy of various modalities of treatment aimed at reversing anticoagulation. Nonetheless, it is intuitive to assume that the anticoagulated state predisposes to hematoma expansion, which, in turn leads to poor outcome. As a corollary, it is also reasonable to suppose that rapid correction of the anticoagulated state might prevent or decrease the degree of hematoma expansion and thus improve outcome.

Farmacologia degli antagonisti della vitamina K Vitamina K reduttasi Vitamina K epossido reduttasi 2 Vitamina K (Phytonadione) 1 E’ importante sottolineare che l’effetto dei dicumarolici può essere superato da piccole dosi di vitamina K (phytonadione). Dosi troppo elevate di vitamina K possono provocare una resistenza ai dicumarolici per più di 1 settimana in quanto la Vit. K si accumula ne fegato e si rende disponibile per la K-reduttasi insensibile ai dicumarolici.

Antidoti agli antagonisti della vitamina K Sospensione dell’antagonista della Vitamina K Vitamina K (fitonadione) Plasma fresco congelato (FFP) Concentrati del Complesso Protrombinico (PCC) Fattore VII attivato ricombinante (rVIIa)

Coumadin (warfarina sodica) Sintrom (acenocumarolo) Assorbimento rapido Picco a 90 min. Legato all’albumina Si accumula nel fegato Metabolizzato dal fegato Emivita: 36 ore Scomparsa 4-5 gg INR più costante (F.VII) Formulazione: 5 mg Sintrom (acenocumarolo) Assorbimento rapido Picco a 90 min. Legato all’albumina Si accumula nel fegato Metabolizzato dal fegato Emivita: 10 ore Scomparsa 1-2 gg INR meno costante Formulazioni: 1 e 4 mg Discontinuation of warfarin Because of the long half-life of warfarin and its effects, it takes several days for reversal of anticoagulation after discontinuation of warfarin. Therefore, warfarin withdrawal alone is not a reasonable option in the setting of OAT-ICH.

Vitamina K Aumenta la sintesi endogena dei fattori K dipendenti By-passa l’enzima VKER Vie di somministrazione Sottocute Intramuscolo Per os Endovena Per una ricoagulazione urgente, la via endovenosa è da preferirsi perché si ha una sostanziale riduzione dell’INR entro 4 –6 ore. Rischio limitato di reazione allergiche (3/10.000). Somministrazione per infusione lenta (< 1 mg/min.)

Vitamina K La vitamina K impiega 24 ore per correggere la coagulopatia, se utilizzata da sola: è pertanto necessario, nell’emergenza, ricorrere ad una terapia concomitante Non è dimostrato che la correzione della coagulopatia riduca il rischio di sanguinamento

Conclusion: Low-dose oral vitamin K did not reduce bleeding in warfarin recipients with INRs of 4.5 to 10.0.

These data therefore suggest that patients with an INR<10 may be safely managed by withholding warfarin until the INR is within the therapeutic range. In patients with multiple risk factors for bleeding however vitamin K may still be considered… There are no data on the clinical impact of vitamin K in patients with an INR>10 but given the higher risk of bleeding and low thrombotic risk, vitamin K should be considered.

INR Bleeding ASTH Guidelines UK Guidelines 8th ACCP Guidelines 5.0 – 9.0 No bleeding Standard risk Cease warfarin High risk Cease warfarin, 1.0 – 2.0mg oral vit. K1 or 0.5 – 1.0mg vit. K1 iv. 1.0–2.5mg oral vit K > 9.0 2.5– 5.0mg oral vit. K1 or 1.0 vit. K1 iv. 1.0mg vit. K1 iv. Consider PCC (25-50 IU/Kg) and FFP (150-300 ml) 2.5–5.0mg oral vit K Any Major bleeding 5.0-10.0mg vit. K1 iv, PCC (25-50 IU/Kg)and FFP (150-300 ml) 5.0-10.0mg vit. K iv and PCC (25-50 IU/Kg) 10.0mg vit. K iv and FFP, PCC or rFVIIa

Plasma Fresco Congelato (FFP) Contiene tutti i fattori K dipendenti E’ “l’antidoto” più utilizzato negli USA Presenta molti importanti limiti: Ritardo per test di compatibilità AB0, riscaldamento, tempo di infusione. Richiede volumi notevoli con rischio di sovraccarico Pericolo di reazioni allergiche Rischio di Transfusion-Related Acute Lung Injury Emodiluizione con aggravamento del sanguinamento Frozen plasma remains an acceptable method for the reversal of warfarin anticoagulation. It must be remembered that the duration of action of FP is limited by the brief survival of coagulation factors, and vitamin K should be administered concomitantly to stimulate the synthesis of endogenous coagulation factors… and sustain warfarin reversal once the transient effect of FP is lost. Grobler C. Can J Anesth 2010

Concentrati del Complesso Protrombinico (PCC) Company brand II VII IX X PC PS AT Hep Uman Complex D.I. (Kedrion) 25 - 20 6 0.06 3 Prothomplex-T® (Baxter) 35 30 13 <2 Octaplex® Octapharma 38 24 31 32 0.5 Confidex ® (Beriplex®) CSL Behring 16 29 41 0.6 Differenti tecniche di scambio ionico permettono la produzione di concentrati a tre o quattro fattori con una concentrazione finale 25 volte più alta del plasma normale. Ci sono evidenze che i PCC a tre fattori, da soli non sono efficaci

CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering. TRANSFUSION 2009

Dosaggio individualizzato è il più efficace PCC: dosaggio Ci sono controversie in letteratura sulla dose ottimale di PCC da utilizzare. Dosaggio individualizzato è il più efficace INR di partenza Peso del paziente INR desiderato

The number of patients reaching the target-INR 15 min after the dosage of PCC was significantly higher in the group treated with an individualized dosage, compared to the group treated with a standard dose, (89% versus 43%; p <0.001). Abstract Prothrombin Complex Concentrate (PCC) is indicated for the acute reversal of oral anticoagulation therapy. To compare the efficacy of a “standard”dosage of 20 ml PCC equivalent to about 500 IU factor IX (group A), and an “individualized” dosage based on a target-INR of 2.1 or 1.5, the initial-INR and the patient’s body weight (group B), we performed an open, prospective, randomized, controlled trial. The in vivo response and in vivo recovery of factor II, VII, IX and X in these patients on oral anticoagulation was determined. Ninety three patients (group A: 47; group B: 46) with major bleedings or admitted for urgent (surgical) interventions were enrolled. PCC and Vitamin K (10 mg) were administered intravenously. We evaluated the effect of treatment by the decrease of INR and the clinical outcome.

Transfusion Medicine Reviews, 2007:37-48

INR n. IU kg-1 < 4.0 26 25 4-6 7 35 > 6 10 50 Conclusions: PCC treatment serves as an effective rapid hemorrhage control resource in the emergency anticoagulant reversal setting. More widespread availability of PCC is warranted to ensure its benefits in appropriate patients. J Thromb Haemost 2008

PCC: può indurre trombosi? La presenza di piccole quantità di eparina/AT previene l’attivazione dei fattori in vitro E’ mantenuta la proporzione tra la concentrazione dei singoli fattori La presenza degli anticoagulanti K-dipendenti (PC e PS) La personalizzazione della dose sulla base del peso e dell’INR attuale. Un’infusione venosa lenta (2-3 ml/min)

The effects of PCC on coagulation lasts six to eight hours in the absence of major blood loss, and as discussed above, the effects of vitamin K administered concomitantly should start within 4-6 hours; therefore, repeat dosing is usually not required. Can J Anesth, 2010.

Uso del rVIIa Indicato per interventi chirurgici e/o sanguinamenti in emofilici, per inibitori dei singoli fattori, per la tromboastenia di Glanzmann, per gli alloanticorpi anti GP IIb/IIa,……per ricoagulare il paziente scoagulato?? Emivita troppo breve (2,8 h) per permettere alla VK di agire. Probabilmente servono più dosi One of the potential concerns with the use of rFVIIa is that it might correct the INR without correcting the underlying coagulopathy and the vitamin K dependent factors would still need to be replaced. The potential for thromboembolic adverse events (especially arterial) at higher doses and the high cost of the drug are additional considerations. Aiyagari Curr Opin Crit Care 2009

Based on this review, we conclude that rVIIa appears to rapidly correct the INR; however, its clinical impact on bleeding in patients taking warfarin remains unclear. This conclusion is based on the observation that currently available evidence consists mainly of small (1-16 patients), nonrandomized, retrospective, case series and case reports without adequate controls. We thus recommend against routine use of rFVIIa in acute warfarin reversal (Grade 2C).

Hemostatic therapy with rFVIIa reduced growth of the hematoma Conclusions: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 g of rFVIIa per kilogram of body weight (276 patients), or 80 g of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. N Engl J Med, 2008

Conclusioni INR Sanguinamento Intervento 5.0-9.0 No/non signif. Rischio standard Sospendere l’anticoagulante Rischio elevato Vit. K po: 1 – 2.5 mg; ≤ 5.0 mg se urgente > 9.0 Vit. K po: 2.5 – 5.0 mg; < 4.0 Sanguinamento maggiore Vit. K ev: 10 mg 4PCC* 25 UI kg-1 4.0-6.0 4PCC* 35 UI kg-1 > 6.0 4PCC* 50 UI kg-1 * Se 4PCC non è disponibile, utilizzare 3PCC + 150 – 300 ml di FFP