Afibrinolytics, Protamine, and DDAVP Flashcards
afibrinolytic medications uses
prevent lysis of fibrin, promotes clot formation (think spine surgeries)
-used to prevent and treat excessive bleeding as inhibitors or fibrinolysis.
interfere with formation of fibrinolytic enzyme plasmin from its precursor plasminogen by plasminogen activators (primarily t-PA and u-PA) which takes place mainly in lysine rich areas on surface of fibrin
2 types of afibrinolytic medications
lysine analogs: (tranaxamic acid, aminocaproic acid)
serine protease inhibitor: aprotinin, no longer avail
Epsilon Aminocaproic Acid (Amicar) MOA, uses
FDA approved for the use in the treatment of acute bleeding due to elevated fibrinolytic activity. inhibits proteolytic enzyme plasmin, enzyme responsible for fibrinolysis
-clinical uses include trauma, CPB, spinal infusions
Amicar Dosing Ranges
bolus followed by infusion
bolus 5-15g (pedes 75-150mg/kg)
infusions 1-2g/hr (pedes 5-30mg/kg/h)
Tranexamic Acid (TXA, cylokapron) MOA, uses
synthetic analog of amino acid lysine, inhibits fibrinolysis by competitively binding to lysine receptor sites on plasminogen. this prevents plasmin from binding to and degrading fibrin which preserves fibrin matrix struvture
parenteral TXA is effective in treating bleeding from multiple causes such as GI, surgical, and trauma
TXA t1/2, potency, route of admin, cases
t1/2 2 hours
8-10 times more potent than aminocaproic acid
given IV
ortho cases, bolus then redose versus spine cases- continuous gtt
TXA dosage/cost
10-15mg/kg IV (up to 1g) following infusion of 1-5mg/kg/h
cost of 1g is approx $50
TXA clinical uses (5 types of surgeries/populations)
non cerebral trauma (suggested to be beneficial within first 3 hours)
pedes (spine fusions, craniosynostosis)
ortho procedures (common in joint procedures)
cardiac (including with and without CPB)
obstetrics: in massive transfusion algorithm for this and trauma
CRASH 2 trial
20,011 adults with traumatic bleeding- showed TXA reduces death due to bleeding with no increase in vascular occlusive events.
in patients treated within 3h of injury, TXA reduced death due to bleeding by 1/3 but when given after 3h, it seemed to increase the risk.
WOMAN trial
world maternal antifibrinolytic trial (2017), death due to bleeding was significantly reduced in women given TXA, especially in women given tx within 3 hours of giving birth
TXA contraindications
active intravascular clotting (PE, DVT, embolic cerebral CVA)
anaphylaxis
SAH
TXA precautions
eliminated unchanged in urine, requires decreased dosing in patients with renal function impairment (change from 1g to .5g)
UTI- ureteral obstructions due to clot formation has been reported
hypotension with rapid IV injection
color vision defect- visual changes is an indicator of toxicity (1st sx)
seizure disorders with high dose
concomitant admin with factor concentrates
protamine
simple proteins obtained from sperm of salmon and certain other species of fish
positively charge alkaline protamine combines with negatively charged acidic heparin to form a stable complex void of anticoagulant activity
hematin-protamine complex is removed by reticuloendothelial system
protamine dosage
1-1.5mg for every 100U of heparin given
-guided also by last ACT and estimated amount of total IV heparin administered within last 2 hours
protamine adverse responses
hypotension (esp with rapid IV injection or whole 15mg)
pulmonary HTN (protamine heparin complex can result in complement activation and thromboxane release=pulmonary constriction)
-allergic reactions
allergic reactions to protamine: how to handle it
options are limited in a patient with a true known allergy
pretreatment with histamine receptor antagonists, followed by a slow trial
completely avoid protamine, and allow heparin effect to dissipate (take hours, risk for bleeding and blood transfusion)
administer alternative to heparin (ex bivalirudin)
patients at risk for true allergy to protamine
prior reaction to protamine
allergy to vertebrae fish (24.5x risk)
exposure to NPH insulin (8.2x risk)
DDAVP
d amino d arginine vasopressin (synthetic analogue of natural hormone arginine vasopressin)
causes release of endogenous store of FVIII and vWf
DDAVP dose
.3mcg/kg IV infusion over 15-30 minutes
- platelet adhesion increases within 30 minutes.
- give slowly, causes hypotension
DDAVP pharmacology, t1/2, SE
shown to be more potent than arginine vasopressin in increasing plasma levels of factor VIII activity in patients with vWF
- change in structure of arginine vasopressin to DDAVP results in decrease in ADH and vasopressor action on smooth muscle
- excreted in urine, t1/2 3h in health patients and up to 9h in severe renal impairment
- hypotension is most commonly reported SE
DDAVP contraindications
hypersensitivity
patients with moderate to severe renal impairment
patients with hyponatremia (desmopressin may create a more dilution hyponatremia)
reversal agents: antiplatelets
platelet transfusion
reversal agents: heparin
protamine
reversal agents: vitamin K antagonists aka warfarin
3 and 4 factor PCC’s if emergent
vitamin K if urgent
reversal agents: direct thrombin inhibitors
Idarucizumab (reverses dabigatran) andexanet alfa (reverse apixaban or rivaroxaban)
reversal agents: emerging agent to know
ciraparangtag (reverses UFH, LMWH, fondaparinux, dabigatran, FXa)
Antithrombotic Agent: antiplatelets drug name(s) stop before procedure (days) monitoring reversal agents
drug names: ASA, 7 days P2Y12 receptor antagonists 7-14 days GPIIb/IIIa antagonists 24-72h monitoring: none reversal agents: platelet transfusion
Antithrombotic Agent: vitamin K antagonists drug name(s) stop before procedure (days) monitoring reversal agents
warfarin
2-5d
PT, INR
PCC, FFP, vitk
Antithrombotic Agent: heparins drug name(s) stop before procedure (days) monitoring reversal agents
unfractionated heparin, 6h, aPTT, protamine
LMWH, 12-24h, none required but fXA can be pulled, partially reversed by protamine
Antithrombotic Agent: pentasaccharide drug name(s) stop before procedure (days) monitoring reversal agents
fondaparinux
3 days (prophylactic dosing)
none required, but fXa levels can monitor
no reversal
Antithrombotic Agent: direct thrombin inhibitors drug name(s) stop before procedure (days) monitoring reversal agents
drug name: argatroban, 4-6h bivalirudin 3h monitoring: aPTT of ACT no reversal
dabigatran: 2-4d (longer if renal impairment), no required monitoring but thrombin time can be monitored, idarucizumab can reverse this.
Antithrombotic Agent: FXa inhibitors drug name(s) stop before procedure (days) monitoring reversal agents
rivaroxaban, apixaban, edoxaban
2-3d
none required, but fXa levels can be monitored
andexanet alfa for rivaroxaban and apixaban
what FFP contains
variable but near normal levels of coagulation factors, coagulation inhibitors, albumin, immunoglobulins
what cryoprecipitate contains
slowly thawing FFP leaves being a cold insoluble precipitate which contains fibrinogen, FVIII, vWF, and FXIII
factor concentrates can either be (2)
plasma derived or
recombinant
assessing efficacy of FFP transfusion
commonly via PT/INR, PTT, fibrinogen, platelet count, viscoelastic tests which range in turn around times of 30-90m
with what products do you use a filter and warmer
PRBC’s, FFP, cryo
with what products do you use a filter only and NO warmer
platelets
plasma derived factor concentrates (8)
4 standalone factors
Factor VII, vWF, factor IX, factor XIII
Riastap fibrinogen concentrate (factor I)
FEIBA (factor eight inhibitor bypassing activity, mainly contains non activated II and IX, and X and mainly activated VII)
Profilnine (factors of II, IX, X)
Kcentra (factors II, VII, IX, X)
recombinant factor concentrates
factor VIIa, factor IX
Riastap how long it can be stored does it require crossmatch what makes it different than cryo/ffp effectiveness
human plasma derived fibrinogen concentrate
fractionated from blood and stored up to 30 months
can be quickly reconstituted and administered IV with no thawing of blood type matching required
fibrinogen concentrate is standardized in each vial (900-1300mg/50mL vial) versus cryo/ffp is variable.
should be as effective as cryo and superior to FFP
factor complex concentrates
biological product of pooled human plasma with therapeutic concentrations of factors II, VII, IX, X
4 factor: Kcentra
3 factor: profilnine (low amounts of FVII)
clinical uses of FCC’s (3)
reverses effects of significant vitamin K antagonism coagulopathy (use Kcentra for this)
emergent or urgent surgery
clotting deficiency (congenital)
contraindications of FCC’s
DIC and HIT
profilnine
3 factor complex concentrate originally approved for treatment of patients with hemophilia B (factor IX deficiency). reserved mainly for cardiac cases, not indicated for warfarin or factor Xa reversal
Kcentra
4 factor complex concentrate which is approved for reversal of vitamin K antagonists
which factors are in profilnine
IX, II, X, low levels of VII. does not contain heparin or any preservatives
profilnine dosing
based on temporarily increasing plasma level of factor IX
10-15 units/IBW kg, max dose of 1000 units
which factors are in Kcentra
antithrombotic proteins C and S and heparin 8-40 units in 500-unit bills in addition to factors II, VII, IX, X
when to use Kcentra
FDA approved for tx of adult patients treated with vitamin K antagonists with an INR >1.5 and experiencing acute major bleeding
do not use Kcentra for
patients with INR <1.5 on VKA’s
elective reversal of oral anticoagulant therapy pre invasive procedure
treatment of elevated INR without bleeding or need for surgical intervention
massive transfusion coagulopathy
coagulopathy associated with hepatic dysfunction
patients with DIC and bleeding diathesis
patients with hx of HIT
preop INR 2-3.9, kcentra dose, dose max
25 units/kg
dont exceed 2500 units of factor IX
preop INR 4-6, kcentra dose, dose max
35 units/kg
dont exceed 3500 units of factor IX
preop INR >6, kcentra dose, dose max
50 units/kg
dont exceed 5000 units of factor IX
Recombinant activated factor VII (NovoSeven) (rFVIIa) chemical makeup uses uses off label risk associated with factor VII factors it bypasses how it promotes hemostasis
form of blood factor VII
glycoprotein produced by recombinant DNA technology
used in hemophilia A (deficiency of VIII) or B (deficiency of IX) congenital factor VII deficiency
most of its use is off label for the prevention and tx of coagulopathy and major blood loss (postpartum hemorrhage, trauma, reversal of various anticoagulants, high risk cardiothoracic, spinal, transplant, or vascular surgery)
-can be associated with increased risk of thrombosis in some settings, particularly in patients who do not have hemophilia
-bypasses factors VIII and IX and causes coagulation without the need for these factors
-promotes hemostasis by activating extrinsic pathway of coagulation cascade
rFVIIa and extrinsic pathway
promotes hemostasis by activating extrinsic pathway of coagulation cascade. forms a complex with TF at the site of injury, thereby activating coagulation factors IX and C which leads to the formation of a hemostatic plug
trauma and factor rVIIa: 2 pathways
site of tissue injury combine with TF to directly activate factor X
platelet surface
factor VIIa dosing
administration instructions
redosing
vial sizes
20mcg/kg to over 200mcg/kg range
90mcg/kg IV bolus
reconstitute with specified volume of sterile water for injection, USP
redosing can be every 2 hours as clinically indicated
supplied in 1mg, 2mg, and 5mg vials
expensive
factor VII and risk of thrombotic adverse events
DIC, advanced atherosclerotic disease, crush injury, septicemia or concomitant tx prothrombin complex concentrates have increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulatopahy
will factor VII stop surgical hemorrhage
no, but it will significantly reduce the need for blood transfusions in patients with hemorrhagic shock from blunt trauma
should you give factor VII over other blood products?
no, you need adequate FFP, cryo, and platelets for full effect of this drug
factor VII t1/2
2-2.5h for initial dose, may require repeating units bleeding is controlled
FCC considerations (6)
provide faster correction of coagulopathy (~30 minutes) compared to FFP and vitamin K (>3h).
factors in plasma are relatively dilute and large volume (10-15ml/kg) is required for clinical reversal of oral anticoagulants
less risk of infectious and noninfectious transfusion reactions
action still depends on adequate concentrations of platelets and fibrinogen
concentrated factors have varied half lives with prothrombin remaining active in plasma for up to 60h and factor X present for 30 hours
dosing will require hematology and pharmacy consultations
