Hem exam 1 Flashcards
1
Q
What process is the formation of blood clots (partial or complete) within the blood vessels which limits the natural blood flow
A
thrombosis
2
Q
What process is tightly regulated where the body attempts to maintain normal blood flow in vessels despite damage/trauma
A
hemostasis
3
Q
What are the 4 simple steps of hemostasis process
A
constriction of blood vessel
formation of a temporary platelet plug
activation of the coagulation cascade
formation of a fibrin plug
4
Q
What is primary hemostasis: blood vessel constriction
A
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)
5
Q
What is secondary hemostasis: activation of the coagulation cascade
A
activation of clotting factors
conversion of prothrombin to thrombin
conversion of fibrinogen to fibrin
strong plug
6
Q
How to remember:
intrinsic
extrinsic
common pathway
A
intrinsic: TENET
extrinsic: 7 (lucky 7)
common pathway: X (x marks the spot)
from there its small bills (2-thrombin, 1-fibrin)
7
Q
Natural anticoagulants: protein C
A
inhibits factor VIIIa (8) and Va (5)
8
Q
Natural anticoagulants: protein S
A
cofactor for protein C
9
Q
Natural anticoagulants: antithrombin (ATIII)
A
inhibitors of factors Xa (10) and IIa (2)
10
Q
Natural anticoagulants: TFPI
A
tissue factor pathway inhibitor (FVIIa) (7)
11
Q
What has a short half life and what has a long half life
A
short: 7 and 10
long: 2, C, S, and 9
12
Q
Factor 10 primarily activated the conversion of plasminogen into what
A
plasmin (this breaks down fibrin)
13
Q
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
A
Arterial thrombosis
14
Q
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
A
Venous thrombosis
15
Q
What are the 3 components that lead to a thrombus
A
hyper-coagulability
vascular damage
circulatory stasis
16
Q
What type of VTE etiology is from an injury due to surgery, trauma, indwelling catheters, damage to valves, leading to venous stasis
A
vascular injury
17
Q
What type of VTE etiology is from obesity, surgery, acute illness, paralysis, older ago
A
stasis
18
Q
What type of VTE etiology is from malignancy, factor deficiency or mutations, pregnancy, nephrotic syndrome, medications
A
hypercoaguable states
19
Q
What is the clinical presentation of DVT
A
unilateral leg pain
swelling
homan sign (back of knee pain)
tenderness
skin discoloration
ulceration
warmth
asymptomatic
20
Q
What is the clinical presentation of PE
A
chest pain / tightness
SOB
tachypnea
tachycardia
syncope, dizziness
cardiogenic shock
hemoptysis
21
Q
Pathophys and clinical presentation of ischemic stroke
A
stasis in atria
emboli from heart circulates to brain causing vessel occlusion
STROKE signs
22
Q
Pathophys and clinical presentation of factor V leiden (FVL)
A
point mutation in F5 gene
insensitive to activated protein C
recurrent VTE or asymptomatic
23
Q
Pathophys and clinical presentation of prothrombin 20210 mutation
A
point mutation
increased concentration of prothrombin in circulation
VTE or asymptomatic
24
Q
Pathophys and clinical presentation of protein C and S deficiencies
A
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
25
Pathophys and clinical presentation of antithrombin 3 deficiency
reduced levels of AT lead to uncontrolled thrombin generation and fibrin deposition
VTE, heparin resistance, stoke
26
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
27
What drugs can not be used in triple positive
DOACs
28
Pathophys and clinical presentation of hyperhomocysteinemia
variation in MTHFR gene
endothelial injury and inflammation
VTE, CVD
29
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
30
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
31
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
32
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
33
What is the heparin therapeutic range for its anti-Xa
0.3-0.7
34
What are the indirect parental anticoagulants
unfractioned heparin (UFH)
low molecular weight heparin (LMWH)
fondaparinux
35
What are the direct parental anticoagulants
argutraban
bivalriduin
36
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
37
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
38
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
39
Heparin chain must have ___ saccharide units to bind thrombin
18
40
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
41
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
42
Heparin dosing
prophylaxis: 5000-7500 SQ q8-12h
therapeutic: fixed dose or weight based
VTE: bolus of 80 units/kg*1, max 10,000, then start 18 units/kg/hr
ACS: bolus of 60 units/kg*1, max 4,000, then start 12 units/kg/hr
43
heparin ADE
bleeding, bruising
osteoporosis
hyperkalemia
elevated thransaminases
HIT
44
Enoxaparin and dalteparin MOA
accelerated factor Xa inhibition through conformational changes in antithrombin by pentasaccharide binding
45
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
46
What are the different Enoxaparin syringes
30, 40, 60, 80, 120, 150
47
Enoxaparin ADE
bleeding
osteoporosis
HIT
decreased risk compared to heparin
48
Dalteparin dosing
ppx: 5000 units qd
tx: 200 units/kg qd or 100 units/kg q12h
renal: crcl<30 AVOID
49
Dalteparin ADE
bleeding
elevated transaminases
HIT
50
Fondaparinux (synthetic heparin product) MOA
catalyzes factor Xa inhibition by binding antithrombin
51
Fondaparinux dosing
ppx: 2.5 mg qd (avoid if <50kg)
<50 kg: 5 mg qd
>100: 10 mg qd
renal: crcl<30 contraindiacted
52
Fondaparinux ADE
bleeding
elevated transaminases
53
Heparin, LMWH (Enoxaparin), Fondaparinux: monitoring labs and risk of HIT
Heparin: aPTT, anti-Xa, high
LMWH (Enoxaparin): anti-Xa, kinda high
Fondaparinux: n/a, +/-
54
Argatroban MOA
univalent inhibitor that directly targets the active site of thrombin, hepatic metabolism
55
Argatroban dosing
2 mcg/kg/min for HIT
hepatic impairment/critically ill: 0.25-1 mcg/kg/min
56
Argatroban ADE
bleeding
hypotension
INR prolongation
57
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
58
Bivalirudin MOA
bidivalent inhibitor that directly targets the active site (N-terminus) and exosite 1 (C-terminus) of thrombin
59
Bivalirudin dose
HIT: 0.15-0.2 mg/kg/hr
reduce in renal impairment
60
Bivalirudin ADE
bleeding
hypotension
prolong INR
61
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
62
Apixaban MOA
directly inhibits Xa, prevents thrombin and fibrin formation
63
What are the direct and indirect factor Xa inhibitors
indirect: heparin, LMWH, fondaparinux
direct: apixaban, edoxaban, rivaroxaban
64
What are the direct and indirect thrombin inhibitors
indirect: heparin
direct: dabigatran, argatroban, bivalirubin
65
Heparin is a mixture of _________ glycosaminoglycans
sulfated (causing it to be highly acidic)
66
Heparin has a pentasaccharide sequence that has high affinity for AT (antithrombin) which is important for what activity
anticoagulant activity
67
Heparin has a contraindication for what kind of allergy
pork
68
Can haparin be used in pregnancy
yes
69
Heparin with >18 saccharide units inhibit what, while <18 inhibits what
>18: thrombin
<18: Xa
70
AT helps regulate blood clot formation which inactivates several factors, its activity is increased when what binds to it
heparin
71
What does AT inhibit in the intrinsic and extrinsic pathways
intrinsic: 9,10,11,12
extrinsic: 7
72
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
73
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
74
What is the BBW for protamine
hypersensitivity (fish)
75
heparin and lmwh DDI
anticoag
antiplatelets
thrombolytics
76
Which crosses into breast milk deltaparin or enoxaparin
deltaparin
77
Does argatroban cross into breast milk
yes
hepatic metabolism by CYP3A4
78
Is dabigatran a prodrug? Can you use it in pregnancy
prodrug (oral use)
no pregnancy
79
dabigatran DDI
NSAID
Rifampin
Antacids
CCB
p-gp
80
dabigatran BBW
thrombotic events with premature discontinuation
81
dabigatran MOA
inhibitors reversibly bind to catalytic active site of thrombin which blocks the interaction of thrombin with its substrates
82
antidote for dabigatran
idarucizumab (IV)
fragments bind to its metabolites
can cause headache or constipation
83
Bivalirudin MOA
binds to N terminal and C terminal
transient inhibition of thrombin -> reversible inhibition
cleavage of NH2 restores thrombin catalytic site
84
inhibition of pro coagulant functions causes a decrease in formation of what
final blood clot
-inhibition clotting factor activation and activation of platelets
85
inhibition of anti coagulant functions causes an inhibition of what protein activation
protein C (serine protease)
86
Thrombin activation of clotting factors causes what
factor 5: accelerates formation of prothrombinase which accelerates formation of thrombin, and activates factor 13
87
Thrombin activation of platelets causes what
reinforces platelet aggregation
88
Can you use protamine in fondaparinux
no
89
fondaparinux MOA
binds to and induces a conformational change in AT, then binds and inactivates factor 10
*it does not inactivate thrombin
90
fondaparinux DDI
NSAID
(also prolonged elimination in older than 75 y)
91
What do direct factor 10 inhibitors do
selective and reversible inhibition of factor 10
indirectly inhibits thrombin formation and platelet activation/aggregation by thrombin
92
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
93
Andexanet Alfa (IV) BBW
thrombosis, ischemic events, cardiac arrest, sudden death
94
direct factor Xa inhibitors DDI
NSAID
inducers and inhibitors of CYP3A4
95
direct factor Xa inhibitors BBW
increased risk of thrombotic events with premature discontinuation
not for pregnancy
96
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)
97
What warfarin mixture is more potent
S (warfarin is hydroxylated which is metabolized to alcohols by reductases)
98
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)
99
VKOE activity is required for post-translational modification of what clotting factors
2, 7, 9, 10, protein C and S
100
Warfarin side effects
bleeding from gums after brushing teeth
bruising
diarrhea
hair loss
101
Warfarin DDI
NSAIDs
fluconazole, omeprazole, lovastatin
antacids
foods rich in vit K
102
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
103
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)
104
What genetic mutations and polymorphisms contribute to genetic factors to warfarin dosing
CYP2C9: slow metabolism causing dose decrease
VKORC: larger doses needed
105
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
106
Apixaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
107
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
108
Apixaban ADE
bleeding
109
Apixaban/Dabigatran/Rivaroxaban BBW
abrupt w/drawl increase risk of thrombotic events
spinal hematoma/epidural ICH
110
Dabigatran MOA
directly inhibits FIIa, prevents thrombin and fibrin formation
111
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
112
Dabigatran ADE
bleeding
GI upset
113
What weight to use in DOACs
actual body weight to calculate CrCl
114
Edoxaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
115
Edoxaban ADE
bleeding
116
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
117
Rivaroxaban MOA
directly inhibits FXa, prevents thrombin and fibrin formation
118
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
119
Rivaroxaban ADE
bleeding
120
CYP3A4 inducers can ________ DOAC concentrations and increase thrombotic events, while CYP3A4 inhibitors can _________ DOAC concentrations and increase bleeding risk
reduce
increase
121
P-gp inducers (reduce DOAC concentrations and increase thrombotic risk)
carbamazepine, phenytonin, rifampin, st johns wart (avoid DOAC)
122
P-gp/CYP3A4 inhibitors
clarithromycin, ketoconazole, itraxonazole, ritonavir (avoid DOAC or reduce eliquis dose)
123
Strong CYP3A4 inducers
phenobarbital, primidone (avoid apixaban, rivaroxaban)
124
SNTT for Warfarin
seven: short half life
nine: short half life
ten: long half life
two: long half life
125
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
126
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
127
Warfarin ADE
major or fatal bleeding
purple toe syndrome
microemboli
skin necrosis
decreased bone mineral density
bruising
128
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
129
Warfarin DDI (FAB 5(F) + macrolides)
flagyl, amiodarone, bactrim, fluoroquinolone, macrolides
(amiodarone increase INR)
130
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
131
How much of a percent to change warfarin dosing
10% change a week
double/half the dose if inpatient
132
What is the normal INR baseline
1
133
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
134
How often to check INR in warfarin patients
monthly; every 2-3 months if patient is VERY stable
135
Warfarin other labs to check
CBC, liver function test, albumin
136
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
137
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
138
Types of DVT
upper extremity DVT
cerebral vein thrombosis
splanchnic thrombus
proximal DVT
distal DVT
superficial vein thrombosis
139
DVT diagnosis
treat until proven otherwise
ACs can cause major bleeding, avoid diagnosis if not reasonable certainty
140
DVT test/labs
elevated D-dimer (fibrin degradation prodcut)
venous duplex ultrasound/compression ultrasound
MRI/CT
141
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)
142
DVT TX: acute phase pharm
heparin, LMWH, fondaparinux
DOAC: apixaban (10 mg bid x7d), rivaroxaban (15 mg BID x21 d)
VKA: warfarin
143
DVT tx: chronic phase pharm
1: DOAC
2: warfarin (INR goal 2-3)
3: LMWH, fondaparinux (alt if pt cant take oral anticoag)
144
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)
145
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)
146
PE diagnosis
if suspected, treat until proven otherwise
ACs can cause major bleeding, avoid diagnosis if not reasonable certainty
147
PE labs/tests
Elevated D-dimer
ventilation/perfusion (V/Q) scan
computed tomography pulmonary angiography (CTPA)
148
PE tx: acute phase nonpharm
rapid anticoag therapy
assess for hemodynamic instability (<90 mmHg, HR >110 BPM, O2 <90%)
only low risk treated outpatient
149
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
150
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
151
EKOS
catheter directed thrombolysis
alteplase: 0.5-2 mg/hr for 2-15 h (depend on clot)
resume AC after procedure
152
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
153
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
154
VTE goals of therapy
prevent thrombus extension
prevent embolization
reduce recurrence risk
prevent long term complications
prevent death
155
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)
156
VTE nonpharm therapy
ambulation
graduation compression socks (GCS)
EPC/IPC cuffs (18 h/d)
157
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
158
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
159
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
160
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
161
Agents to use for ESRD
warfarin
UFH (IV)
Apixaban
162
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
163
Agents to use for pregnancy
LMWH
UFH (IV)
LOWWWWW dose heparin (<5 mg if in 2nd or 3rd trimester)
164
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
165
Agents to use for cancer
Apixaban (w/out GI lesions)
LMWH (w/ GI lesions)
UFH (IV)
166
Cirrhosis in DVT is caused by what
coagulation factor deficiencies
thrombocytopenia
vik K deficiencies
decreased protein C, S, and antithrombin
167
Agents to use for cirrhosis
enoxaparin
UFH (IV)
(warfarin if INR is not elevated at baseline)
168
Agents to use for obesity
Apixaban
Rivaroxaban
Warfarin
UFH (IV)
169
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
170
Agents to use for antiphospholipid syndrome: anticoagulation
Warfarin
LMWH
UFH (IV)
(no DOACs because its triple positive)
