Tag Archives: hematology

NOACs – To bridge or not to bridge?

Periprocedural management of NOACs

 

See tables below to determine need for briding and/or interrupting NOACs:

 

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Simplified version:  (always interrupt if mod to high HR, consider bridging if high TR)d.JPG

 

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Reference:

Raval, Amish N. et al. “Management Of Patients On Non–Vitamin K Antagonist Oral Anticoagulants In The Acute Care And Periprocedural Setting: A Scientific Statement From The American Heart Association”. Circulation (2017): CIR.0000000000000477.

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Clotting Cascade and Anticoagulants

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Clotting cascade and anticoagulants.

 

Reference:

Raval, Amish N. et al. “Management Of Patients On Non–Vitamin K Antagonist Oral Anticoagulants In The Acute Care And Periprocedural Setting: A Scientific Statement From The American Heart Association”. Circulation (2017): CIR.0000000000000477.

Stroke in the Young Work-up

SITY work-up:

 

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Reference:

Singhal, A. B. et al. “Recognition And Management Of Stroke In Young Adults And Adolescents”. Neurology 81.12 (2013): 1089-1097.

Composition of PCC

A handy table:  composition of common prothrombin complex concentrates

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References:

Frontera, Jennifer A. et al. “Guideline For Reversal Of Antithrombotics In Intracranial Hemorrhage”. Neurocritical Care 24.1 (2015): 6-46.

Kiwon Lee, NeuroICU Book

FXa and “Universal” Reversal Agent Drug Targets

TWO REVERSAL AGENTS IN DEVELOPMENT:
  • Andexanet alfa = recombinant modified FXa decoy molecule
    • see previous blog
  • Ciraparantag = reverse many anticoagulants including the FXa inhibitors
    • developed by Perosphere
    • formerly known as “aripazine” or “PER977”
    • di-arginine piperazine
    • small (512 Da) synthetic molecule
    • binds to UFH, LMWH, fondaparinux, DOACs
    • inactivates anticoagulants via noncovalent hydrogen binding, blocks binding to target sites of FIIa and FXa
FXa and “Universal” Reversal Agent Drug Targets:
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Reference:

Milling, Truman J. and Scott Kaatz. “Preclinical And Clinical Data For Factor Xa And “Universal” Reversal Agents”. The American Journal of Emergency Medicine 34.11 (2016): 39-45.

Anticoagulation in Patients with Brain Metastases

Treatment:

  • Anticoagulate in patients with brain tumors and VTE except if risk of ICH is high: i.e.
    • melanoma mets
    • renal cell carcinoma mets
    • choriocarcinoma mets
    • thyroid carcinoma mets
  • treat x 3-6 months; long term if malignant gliomas
  • LMWH recommended versus warfarin
  • If risk of ICH high:
    • IVC filter if significant residual brain mets
    • if mets already removed / treated effectively and medical condition too unstable – anticoagulate

DVT Prophylaxis:

  • do not anticoagulate except in post-operative period
  • use SCDs with post-op LMWH or UFH 12-24 hours after surgery
  • cotninue prophylaxis until ambulation resumed

 

REFERENCE:

Uptodate. “Anticoagulant and antiplatelet therapy in patients with brain tumors.” Accessed 08/12/2016.

Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25:5490.

 

The Latest on DOACs (reversal and other important stuff to know)

 

DOACs target specific enzymes in the common pathway of coagulation cascade.  (vs warfarin which attenuates thrombin generation by decreasing levels of factors 2, 7, 9, 10).

Dabigatran has high affinity for thrombin, inactivates fibrin-bound as well as unbound thrombin, preventing conversion of fibrinogen to fibrin.

Rivaroxaban, apixaban and edoxaban directly inhibits free and clot-bound factor Xa without requiring cofactors, and suppress synthesis of new plasma thrombin but has no effects on the activity of existing thrombin.

Nonspecific Reversal Agents:

  1. Activated charcoal
    1. For acute intoxication (dabigatran studies) within 1-2h after intake of drug
    2. Efficacy not tested in clinical practice
  2. DDAVP
    1. Stimulates release of factor VIII and vWF from vascular endothelium
    2. One study (healthy volunteers), DDAVP infusion causes significant dose-dependent reduction in hirudin, induced prolongation of aPTT in vivo
    3. No clinical trials in bleeding patients on DTI
  3. PCCs (inactive)
    1. Inconsistent results
  4. PCCs (activated)
    1. Given at a dose of 50 or 100 IU/Kg reduces bleeding time in dabigatran-treated animal model
    2. Ex vivo study showed reversing impaired thrombin generation in healthy individuals treated with dabigatran
    3. Most reasonable alternative for reversing dabigatran (until recently) but weigh risk-benefit because of associated increased risk of thromboembolic complications
  5. rFVIIa
    1. no trial conducted to prove effect on reversal of dabigatran
    2. 4 case reports showed ineffective in dabigatran-induced bleeding in 3 patients
  6. Dialysis
    1. Low plasma protein binding (35%), so dabigatran can be dialysed in case of overdose, life-threatening bleeding or before emergency surgical situation
    2. Difficulty with establishing access in bleeding patient

 

Summary of DOACs:

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SPECIFIC REVERSAL AGENTS:

Idarucizumab is a humanized monoclonal Ab fragment (Fab) that binds free and thrombin-bound dabigatran.  Kidneys eliminate idarucizumab-dabigatran complex.  Idarucizumab binds to dabigatran with affinity 350x higher than binding affinity of dabigatran for thrombin.

Andexanet is a recombindnant modified human factor Xa decoy protein.  It binds to Factor Xa inhibitors in their active site with high affinity.  It binds and removes Factor Xa inhibitors.  This is assessed by measurement of thrombin generation and anti-factor Xa activity.

Aripazine PER977 binds specifically to UFH and LMWH through noncovalent H bonding and charge-charge-interactions.  It binds in a similar way to all 4 DOACs.  This drug reverses anticoagulant activity in ex-vivo human studies through aPTT and anti-Xa analysis.

 

 

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Idarucizumab and ANNEXA studies:

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Reference

Tummala, Ramyashree et al. “Specific Antidotes Against Direct Oral Anticoagulants: A Comprehensive Review Of Clinical Trials Data”. International Journal of Cardiology 214 (2016): 292-298. Web.