Hem exam 1 Flashcards
What process is the formation of blood clots (partial or complete) within the blood vessels which limits the natural blood flow
thrombosis
What process is tightly regulated where the body attempts to maintain normal blood flow in vessels despite damage/trauma
hemostasis
What are the 4 simple steps of hemostasis process
constriction of blood vessel
formation of a temporary platelet plug
activation of the coagulation cascade
formation of a fibrin plug
What is primary hemostasis: blood vessel constriction
started by damage to endothelium of vessel
biomarkers released to promote vasoconstriction
platelet adhesion at site injury
release serotonin, ADP, and Ca2+
activation of glycoprotein receptors
platelet aggregation
platelet plug forms (very weak, only temporary)
What is secondary hemostasis: activation of the coagulation cascade
activation of clotting factors
conversion of prothrombin to thrombin
conversion of fibrinogen to fibrin
strong plug
How to remember:
intrinsic
extrinsic
common pathway
intrinsic: TENET
extrinsic: 7 (lucky 7)
common pathway: X (x marks the spot)
from there its small bills (2-thrombin, 1-fibrin)
Natural anticoagulants: protein C
inhibits factor VIIIa (8) and Va (5)
Natural anticoagulants: protein S
cofactor for protein C
Natural anticoagulants: antithrombin (ATIII)
inhibitors of factors Xa (10) and IIa (2)
Natural anticoagulants: TFPI
tissue factor pathway inhibitor (FVIIa) (7)
What has a short half life and what has a long half life
short: 7 and 10
long: 2, C, S, and 9
Factor 10 primarily activated the conversion of plasminogen into what
plasmin (this breaks down fibrin)
What kind of thrombosis is this:
platelets and injury to vessel wall activates
inflammation as a result of high LDL, infection, and hypertension
platelet rich
anti-platelet therapy
ischemic stroke, acute coronary syndrome
Arterial thrombosis
What kind of thrombosis is this:
clotting cascade activates
due to stasis or state of hyper-coagulability
fibrin rich
anticoagulant therapy
DVT, PE, cardioembolic stroke
Venous thrombosis
What are the 3 components that lead to a thrombus
hyper-coagulability
vascular damage
circulatory stasis
What type of VTE etiology is from an injury due to surgery, trauma, indwelling catheters, damage to valves, leading to venous stasis
vascular injury
What type of VTE etiology is from obesity, surgery, acute illness, paralysis, older ago
stasis
What type of VTE etiology is from malignancy, factor deficiency or mutations, pregnancy, nephrotic syndrome, medications
hypercoaguable states
What is the clinical presentation of DVT
unilateral leg pain
swelling
homan sign (back of knee pain)
tenderness
skin discoloration
ulceration
warmth
asymptomatic
What is the clinical presentation of PE
chest pain / tightness
SOB
tachypnea
tachycardia
syncope, dizziness
cardiogenic shock
hemoptysis
Pathophys and clinical presentation of ischemic stroke
stasis in atria
emboli from heart circulates to brain causing vessel occlusion
STROKE signs
Pathophys and clinical presentation of factor V leiden (FVL)
point mutation in F5 gene
insensitive to activated protein C
recurrent VTE or asymptomatic
Pathophys and clinical presentation of prothrombin 20210 mutation
point mutation
increased concentration of prothrombin in circulation
VTE or asymptomatic
Pathophys and clinical presentation of protein C and S deficiencies
PROC and PROS1 gene
upregulation of factors 8 and 5 leading to prothrombic state due to increased thrombin production
VTE, stroke, miscariage, warfarin induced necrosis
Pathophys and clinical presentation of antithrombin 3 deficiency
reduced levels of AT lead to uncontrolled thrombin generation and fibrin deposition
VTE, heparin resistance, stoke
Pathophys and clinical presentation of antiphospholipid syndrome (APS)
APLA
upregulation of tissue factor, decreased nitric oxide, increased endothelial injury
DVT, PE, stoke, catastropic APS, miscarriage
What drugs can not be used in triple positive
DOACs
Pathophys and clinical presentation of hyperhomocysteinemia
variation in MTHFR gene
endothelial injury and inflammation
VTE, CVD
What lab monitoring:
time it takes plasma to clot after adding TF reagent
INR deeloped by WHO to standard values
INR= (patient PT/control PT)
mostly used for warfarin
PT/INR
What lab monitoring:
time it takes plasma to clot with reagent (not TF)
no standard
must calibrate range with reagent change
therapeutic range = 1.5-2.5*control
used for heparin, argotroban, bivalirudin
aPTT
What lab monitoring:
time it take whole blood to clot with a reagent (not TF)
range depends on lab/reagents
useful as a POC test when large doses of herparin used for cardiopulmonary bypass or cardiac catherizations
ACT
What lab monitoring:
measures in units the level of enzymatic activity
calibrated to measure levels based on the specific anticoagulant
no reagent/variability
normal range is 0
Anti-Xa
What is the heparin therapeutic range for its anti-Xa
0.3-0.7
What are the indirect parental anticoagulants
unfractioned heparin (UFH)
low molecular weight heparin (LMWH)
fondaparinux
What are the direct parental anticoagulants
argutraban
bivalriduin
What are the common indications when to use anticoagulants
VTE (DVT or PE)
ACS
mechanical circulatory support
bridging for a mechanical heart valve or a fib
hemodialysis
When to use anticoagulants with caution
thrombocytopenia (<100,000)
recent bleeding event
increased bleed risk
recent hemorrhagic stroke
concomitant antiplatelet use
severe liver disease
renal failure
bleeding disorders
elderly
What are the contraindications of anticoagulants
active significant bleeding
severe thrombocytopenia (<30-50)
heparin induced thrombocytopenia (HIT)
enoxaparin/fondaparinux BBW with neuraxial anesthesia or spinal punctures
Heparin chain must have ___ saccharide units to bind thrombin
18
heparin MOA
binds antithrombin and creates a conformational change that accelerates the rate which antithrombin inhibits clotting enzymes (factors 2 and 10a) which inactivates factors 9a, 11a, and 12a
What labs to monitor for heparin
aPTT (q6h after starting drip or rate change)
anti factors Xa
CBC
check AM labs once daily when therapeutic
Heparin dosing
prophylaxis: 5000-7500 SQ q8-12h
therapeutic: fixed dose or weight based
VTE: bolus of 80 units/kg1, max 10,000, then start 18 units/kg/hr
ACS: bolus of 60 units/kg1, max 4,000, then start 12 units/kg/hr
heparin ADE
bleeding, bruising
osteoporosis
hyperkalemia
elevated thransaminases
HIT
Enoxaparin and dalteparin MOA
accelerated factor Xa inhibition through conformational changes in antithrombin by pentasaccharide binding
Enoxaparin dosing
ppx: 30-40 mg daily SQ, BID in obesity and trauma
tx: 1 mg/kg q12h or 1.5 mg/kg qd
ACS dose based on weight/timing
RENAL: crcl<30 then VTE ppx=30 mg qd and tx is 1 mg/kg
What are the different Enoxaparin syringes
30, 40, 60, 80, 120, 150
Enoxaparin ADE
bleeding
osteoporosis
HIT
decreased risk compared to heparin
Dalteparin dosing
ppx: 5000 units qd
tx: 200 units/kg qd or 100 units/kg q12h
renal: crcl<30 AVOID
Dalteparin ADE
bleeding
elevated transaminases
HIT
Fondaparinux (synthetic heparin product) MOA
catalyzes factor Xa inhibition by binding antithrombin
Fondaparinux dosing
ppx: 2.5 mg qd (avoid if <50kg)
<50 kg: 5 mg qd
>100: 10 mg qd
renal: crcl<30 contraindiacted
Fondaparinux ADE
bleeding
elevated transaminases
Heparin, LMWH (Enoxaparin), Fondaparinux: monitoring labs and risk of HIT
Heparin: aPTT, anti-Xa, high
LMWH (Enoxaparin): anti-Xa, kinda high
Fondaparinux: n/a, +/-
Argatroban MOA
univalent inhibitor that directly targets the active site of thrombin, hepatic metabolism
Argatroban dosing
2 mcg/kg/min for HIT
hepatic impairment/critically ill: 0.25-1 mcg/kg/min
Argatroban ADE
bleeding
hypotension
INR prolongation
Argatroban monitoring with and without heparin
aPTT 2 hr after drip or change then once daily in AM
warfarin: hold Argatroban for 2-3 hr then check INR, or stop once INR >4 and recheck
Bivalirudin MOA
bidivalent inhibitor that directly targets the active site (N-terminus) and exosite 1 (C-terminus) of thrombin
Bivalirudin dose
HIT: 0.15-0.2 mg/kg/hr
reduce in renal impairment
Bivalirudin ADE
bleeding
hypotension
prolong INR
Bivalirudin monitoring with and without warfarin
aPTT 2 hr after drip or change then once daily in AM
warfarin: hold Argatroban for 2 hr then check INR, or stop once INR >2 and recheck
Apixaban MOA
directly inhibits Xa, prevents thrombin and fibrin formation
What are the direct and indirect factor Xa inhibitors
indirect: heparin, LMWH, fondaparinux
direct: apixaban, edoxaban, rivaroxaban
What are the direct and indirect thrombin inhibitors
indirect: heparin
direct: dabigatran, argatroban, bivalirubin
Heparin is a mixture of _________ glycosaminoglycans
sulfated (causing it to be highly acidic)
Heparin has a pentasaccharide sequence that has high affinity for AT (antithrombin) which is important for what activity
anticoagulant activity
Heparin has a contraindication for what kind of allergy
pork
Can haparin be used in pregnancy
yes
Heparin with >18 saccharide units inhibit what, while <18 inhibits what
> 18: thrombin
<18: Xa
AT helps regulate blood clot formation which inactivates several factors, its activity is increased when what binds to it
heparin
What does AT inhibit in the intrinsic and extrinsic pathways
intrinsic: 9,10,11,12
extrinsic: 7
Which binds to heparin AT or factor 10
AT because factor 10 only binds to AT so when there are smaller units then factor 10 is only inhibited
What is the antidote for heparin and how does it work
protamine (positive charge) completely reverse effect
binds to heparin and prevents it from activating antithrombin
What is the BBW for protamine
hypersensitivity (fish)
heparin and lmwh DDI
anticoag
antiplatelets
thrombolytics
Which crosses into breast milk deltaparin or enoxaparin
deltaparin
Does argatroban cross into breast milk
yes
hepatic metabolism by CYP3A4
Is dabigatran a prodrug? Can you use it in pregnancy
prodrug (oral use)
no pregnancy
dabigatran DDI
NSAID
Rifampin
Antacids
CCB
p-gp
dabigatran BBW
thrombotic events with premature discontinuation
dabigatran MOA
inhibitors reversibly bind to catalytic active site of thrombin which blocks the interaction of thrombin with its substrates
antidote for dabigatran
idarucizumab (IV)
fragments bind to its metabolites
can cause headache or constipation
Bivalirudin MOA
binds to N terminal and C terminal
transient inhibition of thrombin -> reversible inhibition
cleavage of NH2 restores thrombin catalytic site
inhibition of pro coagulant functions causes a decrease in formation of what
final blood clot
-inhibition clotting factor activation and activation of platelets
inhibition of anti coagulant functions causes an inhibition of what protein activation
protein C (serine protease)
Thrombin activation of clotting factors causes what
factor 5: accelerates formation of prothrombinase which accelerates formation of thrombin, and activates factor 13
Thrombin activation of platelets causes what
reinforces platelet aggregation
Can you use protamine in fondaparinux
no
fondaparinux MOA
binds to and induces a conformational change in AT, then binds and inactivates factor 10
*it does not inactivate thrombin
fondaparinux DDI
NSAID
(also prolonged elimination in older than 75 y)
What do direct factor 10 inhibitors do
selective and reversible inhibition of factor 10
indirectly inhibits thrombin formation and platelet activation/aggregation by thrombin
Antidote for apixaban and rivaroxaban
Andexanet Alfa (IV)
binds to 10a inhibitors with high affinity, leading to release of endogenous FXa, which FXa can then resume normal function
Andexanet Alfa (IV) BBW
thrombosis, ischemic events, cardiac arrest, sudden death
direct factor Xa inhibitors DDI
NSAID
inducers and inhibitors of CYP3A4
direct factor Xa inhibitors BBW
increased risk of thrombotic events with premature discontinuation
not for pregnancy
Does warfarin cross the placenta
yes
(also takes 2-5 days for action onset leaving pt to maybe having to take something else prior to it working)
What warfarin mixture is more potent
S (warfarin is hydroxylated which is metabolized to alcohols by reductases)
What is the main target for Warfarin
VKOR (this enzyme takes the oxidized vitamin K and converts it to reduced active vit K which allows for clotting factors to get activated)
VKOE activity is required for post-translational modification of what clotting factors
2, 7, 9, 10, protein C and S
Warfarin side effects
bleeding from gums after brushing teeth
bruising
diarrhea
hair loss
Warfarin DDI
NSAIDs
fluconazole, omeprazole, lovastatin
antacids
foods rich in vit K
What are the antidotes for Warfarin
vit K (SOB, tachycardia, flushing, taste change)
fresh frozen plasma (FFP) (headache, nausea, itching)
recombinant factor VII
prothrombin complex concentrate (PCC)
-Feiba
-Kcentra
What factors does feiba, kcentra, and nocoseven (antidotes for warfarin) have
feiba: inactive 2, 9, 10, and active 7
kcentra: inactive 2, 7, 9, 10 and antithrombotic C and S
nocoseven : recombinant factor 7 (active)
What genetic mutations and polymorphisms contribute to genetic factors to warfarin dosing
CYP2C9: slow metabolism causing dose decrease
VKORC: larger doses needed
Which VKORC1 mutations cause a higher dose A or B
B require higher doses which is mainly seen in african americans, then europeans, then asians
A = decrease warfarin resistance = derease dose
B = increase warfarin resistance = increase dose
Apixaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
Apixaban dosing
NVAF: 5 mg BID or 2.5 mg BID* (meet 2/3 criteria: >80 yo, <60 kg, SCr >1.5)
DVT/PE: 10 mg BID x7 d then 5 mg BID
VTE ppx: 2.5 mg BID
THA/TKA: 2.5 mg BID for 10-35 d
Apixaban ADE
bleeding
Apixaban/Dabigatran/Rivaroxaban BBW
abrupt w/drawl increase risk of thrombotic events
spinal hematoma/epidural ICH
Dabigatran MOA
directly inhibits FIIa, prevents thrombin and fibrin formation
Dabigatran dosing (avoid if crcl <30 ml/min)
NVAF: 150 mg BID
DVT/PE: 150 mg BID after minimum 5 days parental AC
THA: 110 mg day if surgery then 220 mg d x10-35d
TKA: same as THA, off label use
Dabigatran ADE
bleeding
GI upset
What weight to use in DOACs
actual body weight to calculate CrCl
Edoxaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
Edoxaban ADE
bleeding
Edoxaban BBW
abrupt w/drawl increase risk of thrombotic events
spinal hematoma/epidural ICH
increase risk of ischemic events if CrCl >95 ml/min for AF
(do not use in <15 or >95 CrCl
Rivaroxaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
Rivaroxaban dosing
NVAF: 20 mg daily with largest meal (use 15 mg if CrCl 15-50)
DVT/PE: 15 mg BID x21 d then 20 mg d
VTE ppx: 10 mg d (avoid in <30 ml/min)
THA/TKA: 10 mg BID x10-35d
Rivaroxaban ADE
bleeding
CYP3A4 inducers can ________ DOAC concentrations and increase thrombotic events, while CYP3A4 inhibitors can _________ DOAC concentrations and increase bleeding risk
reduce
increase
P-gp inducers (reduce DOAC concentrations and increase thrombotic risk)
carbamazepine, phenytonin, rifampin, st johns wart (avoid DOAC)
P-gp/CYP3A4 inhibitors
clarithromycin, ketoconazole, itraxonazole, ritonavir (avoid DOAC or reduce eliquis dose)
Strong CYP3A4 inducers
phenobarbital, primidone (avoid apixaban, rivaroxaban)
SNTT for Warfarin
seven: short half life
nine: short half life
ten: long half life
two: long half life
The full effect of warfarin is depending on clotting factor 2 which is the longest, this causes the full INR to not be seen for how long
5-7 days
What is the most common bridging for warfarin
heparin or enoxaparin
overlap must continue for 24-48 hours after INR in therapeutic range and for minimum 5 days
Warfarin ADE
major or fatal bleeding
purple toe syndrome
microemboli
skin necrosis
decreased bone mineral density
bruising
Warfarin drug-disease interactions
hepatic dysfunction/alcohol abuse
end stage renal disease
anemia
acute decompensated heart failure
hyper/hypothyroidism
elderly
low body weight/obesity
malignancy
Warfarin DDI (FAB 5(F) + macrolides)
flagyl, amiodarone, bactrim, fluoroquinolone, macrolides
(amiodarone increase INR)
Warfarin drug-nutrition interactions
vit K consistency
malnutrition led to warfarin sensitivity
feeding tubes can increase warfarin requirements
stomach/intestine resections can increase or decrease warfarin sensitivity
How much of a percent to change warfarin dosing
10% change a week
double/half the dose if inpatient
What is the normal INR baseline
1
What is the warfarin INR goals
2-3 (AF, DVT, PE)
mechanical mitral valve/mechanical aortic valve + 1 risk factor (AF/HF) 2.5-3.5
How often to check INR in warfarin patients
monthly; every 2-3 months if patient is VERY stable
Warfarin other labs to check
CBC, liver function test, albumin
During titration phase in patient how often to check warfarin INR? During maintenance phase how often to check warfarin INR
2-3 days
1-2 weeks
ALWAYS check compliance
Warfarin education perals
tell everyone on warfarin even dentist
tell before you start/stop herbals or OTC
missed dose by 12 hours, skip and take at regular time
tell provider of doses missed dates
consistant vit K
monitor for bruising/bleeding or sings of clot
no alcohol
if hit head go to ER
avoid NSAID/aspirin
Types of DVT
upper extremity DVT
cerebral vein thrombosis
splanchnic thrombus
proximal DVT
distal DVT
superficial vein thrombosis
DVT diagnosis
treat until proven otherwise
ACs can cause major bleeding, avoid diagnosis if not reasonable certainty
DVT test/labs
elevated D-dimer (fibrin degradation prodcut)
venous duplex ultrasound/compression ultrasound
MRI/CT
DVT TX: acute phase nonpharm
rapid anticoag therapy
ambulation and compression stocking can help resolve pain and swelling
outpatient (hemodynamically stable, not on dialysis, not bleeding, no major trauma, compliant)
DVT TX: acute phase pharm
heparin, LMWH, fondaparinux
DOAC: apixaban (10 mg bid x7d), rivaroxaban (15 mg BID x21 d)
VKA: warfarin
DVT tx: chronic phase pharm
1: DOAC
2: warfarin (INR goal 2-3)
3: LMWH, fondaparinux (alt if pt cant take oral anticoag)
DVT complication: postthrombotic syndrome (PTS)
occur when blood flow not returned after thrombosis
chronic damage to venous valves
-edema, stass dermatitis, stasis ulcers, chronic pain
pulmonary embolism (sudden death)
Types of PE
submassive if systolic BP >90 but has 1:
-RV dysfunction (right heart strain)
-myocardial necrosis (elevated troponins)
massive if one:
-sustained hypotension (<90 mmHg for >15 min)
-obstructive shock (requires inotropic support)
PE diagnosis
if suspected, treat until proven otherwise
ACs can cause major bleeding, avoid diagnosis if not reasonable certainty
PE labs/tests
Elevated D-dimer
ventilation/perfusion (V/Q) scan
computed tomography pulmonary angiography (CTPA)
PE tx: acute phase nonpharm
rapid anticoag therapy
assess for hemodynamic instability (<90 mmHg, HR >110 BPM, O2 <90%)
only low risk treated outpatient
PE tx: acute phase thrombolytics
only for massive PE
reduced elevated PA pressure and normalizes RV dysfunction
major bleed risk but multisystem failure outweighs risk
alteplase 100 mg IV over 2 hours
for DVT: no improvement, consider extensive proximal DVT
IVC filter
only for contraindication to AC
remove 90-120 d once bleeding resolves, then start conventional AC therapy
may be permanent with chronic VTE
risk of dislodgment, migration, perforations, hemorrhages
EKOS
catheter directed thrombolysis
alteplase: 0.5-2 mg/hr for 2-15 h (depend on clot)
resume AC after procedure
Thrombectomy/Embolectomy
PE last line
for contraindications to thrombolytic therapy, failed thrombolytics, or likely to die before thrombolysis
suction out clot or incision in blood vessel to remove clot
DVT/PE tx duration
first provoked VTE: 3 months
first unprovoked VTE: at least 3 months (6-12 if risk)
second/recurrent VTE: indefinite
cancer related: continue until cancer remission
VTE goals of therapy
prevent thrombus extension
prevent embolization
reduce recurrence risk
prevent long term complications
prevent death
Test for predicting who needs VTE ppx
PADUA
very low risk - ambulation only
low risk - GCS and EPC cuffs
moderate to high - LMWH, UFH, fondaparinux, rivaroxaban (score >/= 4)
VTE nonpharm therapy
ambulation
graduation compression socks (GCS)
EPC/IPC cuffs (18 h/d)
VTE PPX for acute medically III pharm
UHF: 5000 u SQ q8012h (7500 for obese)
enoxaparin: 30-40 mg sq qd (avoid in dialysis)
fondaparinux: 2.5 mg sq qd (CI if crcl <30)
rivaroxaban: 10 mg po qd
VTE PPX for orthopedic surgery
TKA/THA: ASA 81 mg or DOAC, up to 35 days, could use UFH, fondaparinux, warfarin
Hip frature: LMWH, UFH, up to 35 days, could use ondaparinux, warfarin
(cardio, general, neuro) LMWH, UFH no long term
TX vs PPX in VTE
tx: have clot or suspected clot (symptoms, elevated d-dimer), full therapeutic higher dosing
ppx: have risk factors for clot, no current clot, prophylactic, lower dosing
ESRD VTE patients are at increased bleed risk due to platelet dysfunction. They are also at an increase thrombotic risk due t the activation of what
clotting cascade, increase homocysteine, decreased levels of protein C and S
Agents to use for ESRD
warfarin
UFH (IV)
Apixaban
Enoxaparin monitoring in ESRD
steadt state (4-5 doses)
0.7-1.0 mg/kg/d
check at trough level (30-60 min before next dose)
goal through: <0.5 units/mL
Agents to use for pregnancy
LMWH
UFH (IV)
LOWWWWW dose heparin (<5 mg if in 2nd or 3rd trimester)
Enoxaparin monitoring in pregnancy
increase eGRF causes faster clearance
1 mg/kg q12h may increase to q8h
goal aXa: 0.6-1.0 units/mL
Agents to use for cancer
Apixaban (w/out GI lesions)
LMWH (w/ GI lesions)
UFH (IV)
Cirrhosis in DVT is caused by what
coagulation factor deficiencies
thrombocytopenia
vik K deficiencies
decreased protein C, S, and antithrombin
Agents to use for cirrhosis
enoxaparin
UFH (IV)
(warfarin if INR is not elevated at baseline)
Agents to use for obesity
Apixaban
Rivaroxaban
Warfarin
UFH (IV)
Enoxaparin monitoring in obesity
0.7-1.0 mg/kg/q12h (cap at 120-150 mg)
check peak level (4 hours after dose)
peak goal: 0.6-1 units/mL
Agents to use for antiphospholipid syndrome: anticoagulation
Warfarin
LMWH
UFH (IV)
(no DOACs because its triple positive)
