Exam 3: AC Reversal Agents

Question 1

Reversal Agents: 4 types and 1 emerging agent

Answer 1

• antiplatelet = plt transfusion! duh.
• heparin = protamine
• vitamin K antagonists (will reverse Warfarin)
  
  • 3 and 4 factor PCCs
  • Vitamin K (slow - use the PCCs kind for emergencies)
• Direct thrombin inhibitors
  
  • idarucizumab (will reverse Dabigatran)
  • andexanet alfa (will reverse apixaban or rivaroxaban)
• Emerging agent: ciraparangtag - pretty much reverses it all
  
  • will reverse UFH, LMWH, fondaparinux, dabigatran, FXa
  • in clinical trials

Question 2

FFP

Answer 2

• variable but near-normal levels of coagulation factors, coagulation inhibitors, albumin, and immunoglobulins
• when you spin down blood, you either get RBCs or FFP

Question 3

cryoprecipitate

what’s in it?

when would you administer this?

Answer 3

• when you thaw FFP, this is the cold-insoluble precipitate that comes out of it
• contains fibrinogen, FVIII, vWF, and FXIII
  
  • (fibrinogen, factor 8, vWF, factor 13)
• So if a pt is low on fibrinogen what do you give?
  
  • fibrinogen concentrate, or cryoprecipitate

“You CRY(oprecipitate) if you’re working Friday the 13th….”

vWF always is with FVIII (F8), then fibrinogen of course

Question 4

factor concentrates

Answer 4

are either plasma-derived or recombinant (~ molecular cloning)

Question 5

PCC (google and picture on slide)

Answer 5

• Prothrombin Complex Concentrate
• is a solution that comes from FFP that is concentrated coagulation factors
  
  • II
  • VII
  • IX
  • X
  • XII
  • protein C
  • protein S

Question 6

Fresh Frozen Plasma (FFP)

Answer 6

• thawed FFP contains variable, but near-normal levels of procoagulant proteins, coag inhibitors, albumin, and immunoglobulins
• Large volumes of plasma transfusion (drawback) are not well tolerated in pts with limited cardiopulmonary reserve and can be assoc with transfusion-associated circulatory overload and acute lung injury (TRALI)
• the efficacy of transfusions is commonly assessed by PT/INR, PTT, fibrinogen level, plt count, and viscoelastic tests which range in turnaround times of 30-90 mins
• less expensive than PCCs

Question 7

fibrinogen content per vial for:

FFP

cryoprecipitate

plasma-derives fibrinogen (concentrate)

Answer 7

FFP: 0.5 g/250 mL

cryo: 0.3 g/20 mL

plasma-derived fibrinogen: 0.9-1.3 g/50 mL vial

Question 8

Universal donor and recipient

Answer 8

Donor: O neg

Recip: AB positive

Question 9

blood product compatibility and administration

Answer 9

• filter + warmer:
  
  • pRBCs
  • FFP
  • cryo
• filter only (NO WARMER)
  
  • plts (will get activated and get sticky!)

Question 10

factor concentrates:

plasma derived

recombinant

Answer 10

• were really created for factor deficiencies, not for the OR
• (bolded ones are the ones you’re commonly going to see)
• plasma-derived
  
  • factor VIII, vWF, Factor IX & XIII
  • Riastap fibrinogen concentrate (Factor I)
  • FEIBA - factor VIII inhibitor bypassing activity - mainly contains non-activated II, IX, and X and mainly activated VII along with heparin, AT, and PRO C&S)
  • Profilnine - factors II, IX, X
  • KCentra - factors II, VII, IX, and X
    
    • last 2 are PCCs?
• recominant
  
  • Factor VIIa, Factor IX

Question 11

RIastap Human Plasma-Derived Fibrinogen Concentrate

Answer 11

• fibrinogen concentrate is fractionated from blood and is stored at rm temp for up to 30 months
• can be quickly reconstituted and admin IV with no thawing or blood-type matching required
• fibrinogen concentrate is standardized in each vial (900-1300 mg per 50 mL vial)
  
  • should be as effective as cryoprecipitate (~150-300 mg in 20 mL vials) and superior to FFP (~150 mg in 100 mL vials)

Question 12

Factor complex concentrates: 2 kinds, clinical uses, and contraindications

(= PCCs)

Answer 12

• a biological product of pooled human plasma with therapeutic concentrations of factors II, VII, IX, and X
  
  • 4 Factor: K Centra (& FEIBA)
  • 3 Factor: Profilnine (but low amts of FVII)
• Clinical uses
  
  • reverses the effects of sign. vit K-antagonism coagulopathy
  • emergent or urgent surgery
  • clotting deficiency
• Contraindicated in DIC and HIT
• Think about using KCentra with head trauma!

Question 13

3 vs 4 factor concentrates

Answer 13

• Profilnine = 3-factor complex concentrate which was originally approved for tx of pts iwth hemophilia B (factor IX defic)
  
  • queen victoria
  • reserved mainly for cardiac cases
  • NOT indicated for warfarin or Factor Xa reversal
  • $1,265 per 1000 units x avg pt dose (1000-2000 units) = $1,265-2,530
  • pt may have a charge 4-5x higher
• KCentra = 4-factor complex concentrate, which is approved for reversal of Vitamin K antagonists (warfarin)
  
  • $1,400 per 1000 units x avg pt dose (2000-2500 units) = $2,800-3,500)

Question 14

Factor IX Complex (Profilnine):

what’s in it

dosing

Answer 14

• Contains concentrated factors of IX, II, X, and low levels of factor VII
  
  • does not contain heparin and contains no preservatives
• Dosing in based on temporarily increasing the plasma level of factor IX
  
  • 10-15 units/IBW kg; max dose of 1,000 units

“Pro-fil-nine, 9, “2”, 10 (some of 7) → 10 TO 15 (units/kg)”

Question 15

KCentra

Answer 15

• 1st FDA-approved 4-factor complex concentrate
  
  • contains antithrombotic proteins C and S and heparin 8-40 units in 500-unit vials in addition to factors II, VII, IX, and X
  • can’t give it to pts with HIT bc it contains heparin!
  • FDA approved for the tx of adult pts treated with vitamin K antagonists (ie. warfarin) with an INR >1.5, and are experiencing acute major bleeding
  • some data exists that Kcentra can help reverse factor Xa inhibitors like Xarelto (Rivaroxaban), and Eliquis (Apixaban), however at higher dosign (50 units/kg vs 20-30 units/kg)
  • pre-treatment INR dosing
    
    • if 2-<4 → 25 units/kg
      
      • not to exceed 2500 units
    • if 4-6 → 35 units/kg
      
      • not to exceed 3500 units
    • If >6 → 50 units/kg
      
      • not to exceed 5000 units
    • (After dose is calculated based on pt’s wt and INR, round to the nearest whole vial)

Question 16

KCentra not to be used for (7)

Answer 16

1. pts with INR <1.5 on VKAs
2. elective reversal of PO AC therapy pre-invasive procedure
3. tx of elevated INRs without bleeding or need for surgical intervention
4. massive transfusion coagulopathy
5. coag associated with hepatic dysfn
6. pts iwth DIC (Disseminated intravascular coagulation) and bleeding diathesis
7. pts with hx of HIT

Question 17

Recombinant Activated Factor VII (NovoSeven): uses
Dr. Funk’s favorite, so know it dammit

Answer 17

• rVVIIa is a form of blood factor VII. It’s a glycoprotein produced by recombinant DNA technology
• Was orig used for Hemophilia A (defic of VIII) or B (defic of IX), congenital factor VII defic
• Most of its use is off-label: prevention and tx of coagulopathy and major blood loss
  
  • PPH
  • trauma
  • reversal of various AC’s
  • high-risk cardiothoracic, spinal, transplant, or vasc surg
• rFVIIa can be associated with an increased risk of thrombosis in some settings, particularly in pts who do not have hemophilia

a = activated, so it’s ready to go! So as soon as it’s in the body it begins to work. (Zach’s question - ideally goes to the place in the body where it needs to work!)

Question 18

Recombinant Activated Factor VII (NovoSeven): MOA

Answer 18

• rFVIIa, which is the activated form of factor VII, bypasses factors VIII and IX and causes coagulation without the need for factors VIII and IX
• promotes hemostasis by activating the extrinsic pathway of the coagulation cascade
  
  • it forms a complex with TF (tissue factor) at the site of the injury, thereby activating coagulation factors IX and X - which leads to the formation of a hemostatic plug
• Theoretically, this mechanism localizes the action of Factor VIIa to the site of the injury and hence avoids the complications of thrombosis occurring in other vascular beds!

Question 19

Trauma and Factor VIIa

Answer 19

• rFVIIa was routinely used in severely wounded troops during the Iraq War
• 1999 - 1st published use was in trauma in a soldier with traumatic coagulopathy following a high-velocity gunshot wound to the IVC
• 2 pathways
  
  • site of tissue injury - combines with TF to directly activate factor X
  • plt surface

Question 20

Factor VIIa dosing

Answer 20

• dosing is all over the place
• difficult to randomize pts in life-threatening hemorrhage = limited studies
• clinical doses for rFVIIa in the literature range
  
  • 20 ug/kg to >200 ug/kg
  • 90 mcg/kg bolus (Duke’s dosing)
• Reconstitute with specified volume of sterile water for injection, USP
• re-dose can be q2hrs, as clinically indicated
• NovoSeven is supplied as 1 mg, 2 mg, and 5 mg vials
• A single dose for an 80-kg pts is ~ $8,000

(the 3x that Dr. Funk used it was in neurosurgery, with a neurosurgeon who had had experience with it in the military)

Question 21

Factor VII additional considerations

Answer 21

• RIsk of thrombotic adverse events
  
  • DIC, adv atherosclerotic dz, crush injury, septicemia or concomitant prothrombin complex concentrates (PCCs) have an increased risk of dev thrombotic events d/t circulating TF or predisposing coagulopathy
  • think about crush injury = little pieces of bone, will want to clot all over the place
  • think about septicemia = lots of inflammation, irritation, will want to clot in areas of inflammation
• Factor VII will not stop surgical hemorrhage, it’s a temporizing agent
• signficantly reduces the need for blood tx in pts with hemorrhagic shock from blunt trauma
• shouldn’t be given instead of other blood products, adequate FFP, cryo and plts need to be present for full effect
  
  • think about MOA: depends on plt and fibrinogen fn to work!
• T1/2: 2-2.5 hrs - the initial dose may require repeating until the bldg is controlled

Question 22

Factor Complex Concentrates Considerations (Summary)

Answer 22

• provide faster correction of coagulopathy (~30 mins) compared to FFP and vitamin K (>3 hrs)
  
  • takes extra time to match blood type and thaw
• the factors in plasma are relatively dilute and a large volume (10-15 mL/kg) is required for clinical reversal of PO ac’s
• less risk of [non]infectious transfusion rxns
  
  • extra wash, processing, antibodies are taken out that would still have been in FFP/cryo
• their action still dpeends on adequate []s of plts and fibrinogen
• []’d factors have varied T1/2s with prothrombin remaining active in plasma for up to 60 hrs, and factor X present for 30 hrs
• dosing with require hematology and pharmacy consultations - you will not be giving this alone!