Cardio 2

Prothrombin Time (PT) Test

• measures how long it takes for blood to clot

• Normal time is 10—14 secs after coagulation initiated in lab.

• Clotting is induced by adding tissue factor.

• Measures factors l, II, V, VII, X

• INR= international normalizing ratio system.

• PT of 11-13 secs corresponds to INR of 0.8-1.1 (INR adjusts for diff test chemicals in diff labs)

Describe Active Protein C’s effects

inhibitory on factor VIII & V

What is unique about factor XII?

It is activated via damage to the body (like a cut)

What are the major blood cell types and their function?

• Platelets (Thrombocytes) — Clotting

• Erythrocytes (RBCs) — O2 transport

• Granulocytes — Innate Immune response, phagocytosis, inflamm response

• Lymphocytes — Humoral immune response; specific pathogen recognition & antibody production

What pts are candidates for antithrombic therapy for PAD

Symptomatic pts undergoing

• Non surgical intervention w/ or w/o h/o MI or stroke

• Surgical intervention, specifically…

  • Carotid artery stenting or RECENT ACS

  • Below-knee bypass grafting

  • amputation

What is the treatment done in Anti-thrombic therapy for symptomatic patients w/ no surgical intervention

• H/o previous MI or Stroke: Clopidogrel 75 mg

• No h/o MI or Stroke: ASA 81 mg OR Clopidogrel 75 mg

What is the treatment done in Anti-thrombic therapy for symptomatic PAD patients w/ surgical intervention?

• carotid Artery Stenting or RECENT ACS:

  • DAP Tx 1-6 months (ASA 81 mg + Clopidogrel 75 mg)

  • Then, either ASA 81 mg or Clopidogrel 75 mg

• Below-Knee Bypass Grafting (BKPG): ASA 81 mg

• Amputation: ASA 81 mg OR Clopidogrel 75 mg

Duration of VTE prophylaxis treatment in non-orthopedic surgery pts

Major general surgery = until hospital discharge

Same as ^ but prior VTE = 28 days

Major trauma = while immobile, up to 8 wks

[define]

ABI

A valuable tool for quickly, and non-invasively assessing for PAD

Abnormal ABI

≤ 0.9

Secondary prevention goals and txs for PAD

• Glycemic control

  • SGLT2 inhibitor or a GLP-I receptor agonist w/ proven CV benefit is rec'd

  • Goal: A1c <7% and appropriate cardioprotective agents

• Blood pressure management

  • goal: < 130/80 mmHg

• Lipid management

  • moderate or high intensity statin —> ezetimibe —> PCKS9i

  • Goal: LDL >70mg/dl

• Smoking cessation

  • Involve family

  • Discharge w/ NRT or Rx meds

  • Enroll in cessation programs

  • Use constant, motivational interviewing to assess progress towards cessation

  • Goal: Complete cessation of tobacco products using proactive tx approach

Core

Area where damage to brain is irrversible

Reperfusion therapy candidates

• Pts otherwise eligible for emergency reperfusion therapy except tht BP >185/110 mmHg

• Use labetalol, nicardipine, or clevidipine

Alteaplase monitoring

• Maintain BP at <180/105 mmHg during infusion

• Measure take neurologic assessments: q15 mins for first 2 hrs, q30 mins for 6 hrs following every hour until 24 hrs since administration Follow up CT at 24 hrs to ensure no bleeding

• Monitor for sudden change in mental status, s/sx's of bleeding or angioedema

When would you choose tenecteplase over alteaplase in thrombolytic therapy for AIS?

In pts w/o CI for IV fibrinolysis who are also eligible for mechanical thrombectomy

Alteaplase threapy for AIS doesnt have a well established safety & efficacy in pts w/

• Acute pericarditis or left atrial or ventricular thrombus and moderate stroke w/ mild disability

• Concomitant use of tirofiban or etifibatide

• Giant unruptured and unsecured intracranial aneurysm

When is alteplase therapy in patients consdiered reasonabled?

• W/in 3-4.5 hrs of sx onset, as good as 3 hr window in: >80 y/0, h/o DM & prior stroke

• Acute MI or MI within the past 3 mo

• GI/GU bleeding > 21 d ago

• History or active acute menhorrhagia w/o significant anemia or hypotenion

• Illicit drug use-associated stroke given no other exlcusion

• Initial BG of between 50-400 mg mg/dL

• Sickle cell disease

• Wake up stroke, and stroke of unclear time of onset >4.5 h since LKW

In what AIS patients is Alteplase threapy preferred?

• presenting w/in 3 h of sx onset (regardless of age or stroke severity)

• BP < 185/110 mmHg OR can safely lower BP to this lvl w/ hypertensive agents

• Blood glucose > 50 mg/mL

• no evidence of ischemic injury involving > 1/3 of MCA territory

• Present w in 3 — 4.5 h of sx onset AND:

  • ≤80 y.o

  • no h/o DM or prior stroke

  • NIHSS ≤25

  • Not taking OACs

What is anistreplase composed of?

Drug 1: Acetylated streptokinase (converted to active form in vivo)

Drug 2: Plasminogen protein in acetylated form

---

Active plasminogen is converted to plasmin by streptokinase, allowing plasmln to attack fibri

Heparin targets:

XIIa, XIa, Xa, IIa, Ia

Types of heparin-based anticoagulants

Unfractionated Heparin - 5-30kDa

Low molecular weight heparin - 3-8kDa

synthetic pentasaccharide - 1.7kDa

commercial heparin structure

Synthetic pentasaccharide (Fondaparinux) structure

Sulfate groups required for binding to antithrombin are circled

Selective: activates AT, which binds to & inhibits factor Xa

Two types of DTI

Bivalent: bind to active site and exosite-1 (a dock for substrate) of thrombin (exosite-2 is for heparin)

Univalent: bind to active site only

Bivalent DTIs

Hirudin - 65aa and lead compound

Lepirudin & Desirudin - nearly irreversible inhibition of thrombin

Bivalirudin - 20aa peptide, rapid onset, reversible

Argatroban Structure

colored portion bind to active site

SubQ due to low lipophilicity;

approved for prophylaxis & treatment in patients with HIT

Ximelagatran & melagatran STRUCTURE

orally active, withdrawn due to liver injury

Dabigatran (Pradaxa) Structre

orally active

Rivaroxaban (Xarelto) Structure

structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure.

Apixaban (Eliquis) Structure

Oral anticoagulants

Coumarin Derivatives & 1,3-Indandiones

Coumarin derivatives structure

AKA Vitamin K antagonist

Inhibition of vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and actor VII.

Warfarin (Coumadin) Structure

racemic preparation, though (S)-enantiomer is at least 4x more potent then (R)

Heparin MOA

• Antithrombin III (AT-3) is an enzyme that inhibits certain clotting factors

• Heparin acts as a scaffold that brings AT-3 into contact with the enzymes it inhibits—thrombin and Factor Xa

1,3-indanedione structure

Phenindione structure

Anisindione structure

Antiplatelet drugs

• Cyclooxygenase (COX-1) Inhibitors

• Phosphodiesterase (PDE3) Inhibitors

• Platelet P2Y Purinergic Receptor Antagonists

• GPIIb/IIIa (Integrin αIIbβ3) Antagonists

[Agents]

Cyclooxygenase (COX-1) Inhibitors

Aspirin

Triflusal

sulfinpyrazole

Indobufen

aspirin structure

Triflusal Structure

deacytelated metabolite is active

Note the 3 fluoride

Sulfinpyrazone Structure

Indobufen Structure

Phosphodiesterase (PDE3) Inhibitors

Inhibit degradation of cAMP

Dipyridamole

cilostazol

Anagrelide

Dipyridamole Structure

Used in combination with warfarin, alone has little, if any, benefit in the treatment of thrombotic conditions

Cilostazol Structure

quinolinone derivative, greater selectivity against PDE3A, also blocks adenosine uptake

Anagrelide Structure

Used for the treatment of essential thrombocytosis (ET), also

has been used in the treatment of chronic myeloid leukemia

Ticlopidine Structure

thienopyridines, pro-drugs:require cytochrome p450 activation, bind irreversibly

(S) Clopidogrel (Plavix) Structure

Thiophene ring must be opened!

thrombolytic agents

Convert plasminogen to plasmin, which in turn degrades fibrin

First gen thrombolytics

Stretokinase/streptase

Anistreplase - long half life

Urokinase - short half life

second gen thrombolytics

Alteplase - IV infusion, plasminogene activator

Prourokinase

3rd Gen Thrombolytics

Tenecteplase

the fastest thrombolytic agent used to treat acute MI

[Define]:

Anticoagulants

Anticoagulants are used to prevent blood clots from forming & to keep existing clots from becoming larger or expanding.

However, it does NOT break existing clots.

[Define]:

pulmonary embolism [PE]

when a piece of clot breaks off from a DVT, travels back to the heart and is pumped into the arteries of the lung.

[Define]:

embolus

a blood clot that's traveled/formed within the lung

[Agents]:

IV Direct Thrombin (Factor IIa) Inhibitors

1. lepirudin

2. argatroban (Novastan®)

3. bivalirudin (Angiomax®)

4. dabigatran (Pradaxa®)

[Contraindications]:

fondaparinus (Arixtra®)

CrCl <30 mL/min

[True/False]:

LMWHs can be used if patient has HIT from UFH

False

[should NOT use LMWHs if patient has HIT from UFH]

[Define]:

heparin-induced thrombocytopenia [HIT]

development of thrombocytopenia (a low platelet count <150,000/microL), due to the administration of various forms of heparin as an anticoagulant.

heparin sulfate exposure can cause anti-heparin antibody prodouction which can attack endogenous or injected heparin upon re-exposure.

Hemostasis vs. thrombosis

o Hemostasis: stoppage of blood loss after hemorrhage/injury

o Thrombosis: formation in arteries or veins WITHOUT overt hemorrhage. Usually a pathological state

What is the first/original cell in the process of hematopoeisis?

o Multipotential hematopoietic stem cell—can differentiate into any of the mature blood cell types

What are the 2 main lineages of cells produced by hepatopoesis?

o Myeloid and lymphoid

What's the difference between an arterial and venous thrombus?

o arterial thrombus ("white thrombus") has a high content of leukocytes (WBC) and platelets with modest levels of fibrins. A ruptured atheromatous plaque can often nucleate a coronary arterial thrombus.

o Venous thrombus ("red thrombus") has significant amount of platelets and fibrins, but less content of leukocytes.

How are clotting factors activated? How does that affect their nomenclature?

o Clotting factors exist in their inactive form (zymogens) in the blood, and are activated by proteolysis to their active form

o After activation, the clotting factors are named with an "a"—ex. Factor XI is a zymogen, and Factor XIa is the active form

Describe the progressive nature of the clotting cascade

o Different clotting factors are always activated in the same, progressive order

o Ex. in the intrinsic pathway, Factor 12 activates 11, which activates 9, which activates 10

Describe the amplifying nature of the clotting cascade

o Early factors in the cascade have lower concentration compared to later zymogens

o Ex. in the intrinsic pathways, there's only a low conc of Factor 12, but more 11 than 12, and more 9 than 11, etc.

What is the intrinsic vs. extrinsic clotting pathway?

Intrinsic pathway:

• Occurs when non-biological substance injures tissue Ex. if you cut your finger with a piece of glass

• ALL the ingredients necessary to initiate/complete clotting cascade are already within plasma itself—all the factors are "intrinsic"

Extrinsic pathway:

• Occurs in response to internal damage to epithelium.

• Damaged epithelium exposes tissue factor (TF), which is not normally exposed to the blood in intact arteries. Ex. when an artery ruptures, exposing TF to the blood

• TF is a lipoprotein that is NOT normally expressed, and it requires calcium for activation. Therefore, it's the "extrinsic" pathway since NOT all the ingredients necessary for the cascade are already present in the plasma

What is the final clotting factor? What does it do?

o The final clotting factor is prothrombin (Factor II), which is activated to thrombin (Factor IIa)

o Thrombin activates fibrinogen to fibrin, the material that actually makes up a blood clot

Which 2 clotting factors activate prothrombin to thrombin? How?

o Factor Xa and Factor Va work together to activate prothrombin. BOTH of them need to be involved for activation to occur

o Factor Va is embedded on the surface of platelets. This provides a docking site for Factor Xa and prothrombin. Once bound to Factor Va, Factor Xa cleaves prothrombin to thrombin

What 3 stages do platelets undergo during the clotting process?

o Adhesion

o Activation

o Aggregation

Activated platelets secrete what 3 substances? What do they do?

• TXA2 (thromboxane A2): upregulate expression of GPIIb/IIIa

• ADP: binds to ADP receptor on activated platelets --> stimulates platelet aggregation, changes platelet shape. Also upregulates expression of GP2b/3a

• 5-HT (serotonin): mildly activates resting platelets

True or false: the normal state of blood vessels promotes clotting and thrombus formation

False. The normal state of vessel endothelium is inhibitory for thrombus formation.

• Arterial & vascular endothelium have substantial stores of surface-bound heparin sulfates (heparin is an anti- thrombotic molecule).

• Vascular endothelium also contains activities that convert ADP to adenosine, which inhibits platelet fxn

• Disruption of vascular endothelium (by plaque rupture or trauma) exposes a substrate that supports thrombogenesis.

In Hemophilia A, there's a deficiency of ______.

In Hemophilia B, there's a deficiency of ______.

In Von Willebrand Disease, there's a deficiency of ______.

o In Hemophilia A, there's a deficiency of Factor VIII

o In Hemophilia B, there's a deficiency of Factor IX

o In Von Willebrand Disease, there's a deficiency of Von Willebrand factor

Which type of hemophilia is x-linked?

o Hemophilia A

What is Von Willebrand factor? What role does it play in the clotting process

o VW factor is only exposed when the endothelium is disrupted/damaged—not usually present in intact arteries

o VW factor is embedded in the wall of the blood vessel. It provides a docking site for platelets to start forming the clot—helps with the adhesion phase

o VW factor is also involved in activation of Factor VIII. Thrombin can't activate Factor VIII to Factor VIIIa until Factor VIII is bound to VW factor

What role does vitamin K play in the clotting process? How does warfarin interfere with this pathway?

o Several key clotting factors (II, VII, IX, X) must be modified with gamma carboxyglutamic acid residues in order to be activated

o Normally, reduced vitamin K participates in a redox reaction that creates gamma carboxyglutamic acid residues and turns reduced vitamin k into oxidized vitamin K. Then, oxidized vitamin K is reduced back to its original form by vitamin K reductase and turns into reduced vitamin K again by vitamin K reductase. This recycles the vitamin K and allows the process to continue

o Warfarin inhibits vitamin K reductase (both of them) --> inhibits gamma carboxyglutamic acidification --> inhibits activation of several clotting factors

What genotyping should pts receive starting warfarin? Why?

o Genotype CYP2C9, which metabolizes warfarin

o Genotype VKORC1, which activates vitamin K

o Pts with certain variants in these genes may have a very different response to warfarin

Aspirin MOA

o COX-1 inhibitor --> inhibits production of TXA2

What alternative can be used in pts with low CYP2C19 metabolizers who cannot be treated with clopidogrel?

o Prasugrel

What are fibrinolytic agents? Name some examples

These are clot busters—activate plasminogen to plasmin, which directly degrades fibrin

o Tissue plasminogen activator (TPA)

o Recombinant forms of TPA (alteplase, duteplase, reteplase, tenecteplase)

o Streptokinase

What is thrombocytopenia? What is thrombocytosis?

o Thrombocytopenia: Decreased/low platelet count (

For UFH, LMWH, and fondaparinux, compare their ability to inhibit Factors Xa and IIa (thrombin)

o All 3 can inhibit Xa

o UFH inhibits thrombin strongly; LMWH inhibits thrombin but not as strongly as UFH; fondaparinux cannot inhibit thrombin

UFH therapeutic monitoring (for IV infusion)

o Very close monitoring required because of its unreliable PK --> unpredictable pt response

o There are 2 values that can be used to monitor the therapeutic effect: aPTT or antiXa

o Values should be measured at baseline, then 6 hrs after initiating or changing a dose

o If the aPTT/antiXa value is too low, that means there's not enough anticoagulation --> increase the infusion rate

o If too high, that means there's too much anticoagulation --> decrease the infusion rate

Does UFH or LMWH have more variable PK?

o UFH has much more variable PK, and therefore requires more monitoring

o LMWH has a much cleaner PK profile

Name the 3 LMWHs (brand and generic)

o Enoxaparin (Lovenox)

o Dalteparin (Fragmin)

o Tinzaparin (Innohep)

Describe safety and therapeutic monitoring for LMWH. Is it required for all pts? What values do we look at? Why?

• Unlike UFH, therapeutic monitoring is NOT necessary for all pts, since PK is much more predictable.

• But can choose to monitor in pts who might have altered PK or higher risk (ex. older pts, altered renal function, body weight extremes, etc.)

  • If therapeutic monitoring, you can monitor anti-Xa levels (CANNOT measure aPTT, like for UFH)

• ALL pts should receive safety monitoring.

  • Monitor CBC with platelets (in case of bleeding risk).

  • Monitor serum creatinine (since LMWH is renally cleared and must be renally dose-adjusted)

Does fondaparinux affect platelet function? Why or why not?

o No. Fondaparinux doesn't have any direct effect on thrombin activity --> no effect on platelet function

Fondaparinux monitoring

o NO routine coagulation testing required

o Evaluate baseline CBC, then periodically after

o Evaluate baseline kidney function in pts at risk of developing renal failure

What pregnancy category is fondaparinux?

o B

Which of the following can be used in pts with a history of HIT? UFH, LMWH, fondaparinux

o Only fondaparinux

Warfarin inhibits the activation of which 4 clotting factors?

The SNOT factors:

• VII (T1/2 = 4-6 hrs)

• IX (T1/2 = 21-30 hrs)

• X (T1/2 = 27-48 hrs)

• II (T1/2 = 42-72 hrs)

Which isomer of warfarin is more potent?

o S isomer is more potent than R

Which CYPs metabolize the S isomer of warfarin?

o 2C9

Which CYPs metabolize the R isomer of warfarin?

o 1A2, 3A4

What would be the effect on anticoagulation if warfarin was concomitantly administered with a 2C9, 1A2, or 3A4 inhibitor? What about an inducer?

o CYP inhibitor --> less warfarin metabolized/cleared --> more warfarin active --> more anticoagulation —> high INR

o CYP inducer --> more warfarin metabolized/cleared --> less warfarin active --> less anticoagulation —> low INR

What value is used to therapeutically monitor warfarin? What's the target value? What are the risks if the value is too high? Too low?

INR. A higher INR means more anticoagulation

• For most indications, the target is 2.5 (2.0 - 3.0)

• If INR is too high (>3), there is significantly increased bleeding risk

• If INR is too low (<2), there is significantly increased risk of thrombosis

What's the typical starting dose for warfarin?

5 mg, then adjust from there based on INR

How long does it take for a warfarin dose initiation/change to be reflected in the INR? Why does it take so long to kick in?

o It can take up to 5-7 days for the dose to take effect

o This is because factor 2 has a very long half-life. Giving warfarin prevents the activation of additional factor 2, but there are still already-activated molecules in circulation. The dose change won't fully be reflected until those activated molecules are cleared

How do pharmacogenomics impact warfarin dosing?

o 2 main genes to consider: VKORC1 (the gene that codes for VKOR, which warfarin inhibits) and 2C9 (the CYP that metabolizes the S isomer of warfarin)

o Patients may have mutations in one or both genes, leading to very different warfarin sensitivity and metabolism

o Pts with mutations may need very different doses compared to pts with the wildtype