Week 2 - C2

Platelets are fragments of

megakaryocytes

What molecules creation is stimulated by cytokines and thrombopoietin (TPO)?

Platelets

What is the term for platelet activation?

Degranulation

What cell is the principle initiator of blood coagulation?

Tissue-factor bearing cells

Which factors are dependent on vitamin K?

II

VII

IX

X

C and S

What are the antithrombotic factors?

C and S

Antithrombin inactivates which molecules?

Serine proteases IIa, IXa, XIa, XIIa

Explain the process of primary hemostasis?

Vasoconstriction

Platelet adhesion and activation

Collagen and thrombin activate platelets

what does adhere mean in the role of platelets?

Adhere to collagen in the vascular subendothelial

Exposed collagen releases von Willebrand factor

What does activate (Degranulation) mean in the role of platelets?

Granules release ADP, Ca and thromboxane A2 to activate further platelets

GP IIb/IIIa receptors are exposed on the platelet

What does aggregate mean in the role of platelets?

Changes shape from discoid to spherical with extensions and then a flat shape to cover the injury

Forms a platelet plug

What is initiation in secondary hemostasis?

Release of TF activates VII which activates IX and X 

IX and X catalyzes conversion of factor II to IIa 

IIa cleaves fibrinogen to fibrin 

What does amplification mean in secondary hemostasis?

Thrombin generated in initiation activates platelets and coagulation factors V, VIII, XI

Factor VIII is activated by releasing it from Von Willebrand factor

Factor XIa catalyzes activation of IX to IXa

What is propagation in secondary hemostasis?

Tenase and Prothrombinase are formed

Thrombin activates enough fibrin to stabilize platelet plug

Thrombin activates factor XIIIa which soldifies the fibrin polymer

What is fibrinolysis?

Process of breaking down fibrin into degradation products

What breaks down the clot in fibrinolysis?

Plasmin - serum protease that cleaves fibrin 

What catalyzes the formation of plasmin?

Thrombin - functions as its own negative feedback loop

Why does a clot form to begin with?

Hypercoagulable state

Circulatory state

Vascular injury

What is a hypercoagulable state?

Malignancy

Pregnancy

Inflammatory state

Factor V Leiden

Protein C/S deficiency

Oral contraceptives

What are examples of circulatory stasis?

Hospitalization

surgery

Obesity

Long distance travel

What are examples of vascular injury?

Orthopedic surgery

trauma

Venous catheters

Smoking

What are some other risk factors for clots

History of VTE

Age

Metabolic syndrome

Inflammatory disorders: Chrons, UC, RA, infections

What characterizes a DVT?

Usually occurs in a lower extremity

Due to blockage

RARELY FATAL

What is characteristic of a PE?

Occurs in the lung

Usually due to dislodged blockage 

Can be fatal 

What is an arterial clot rich in?

Platelets

What is a venous clot rich in?

Fibrin

What are the s/s of DVT?

Unilateral leg pain, redness swelling and/or warmth

Positive hosmans sign

Elevated D-dimer

What is proximal DVT?

70-80% of DVTs are proximal, most commonly the popliteal and superficial femoral vein

What is a distal DVT?

20-30% of DVTs are isolated in veins of the calf: the anterior tibial peroneal and posterior tibial veins

Which type of DVT is unlikely to lead to PE?

Distal

How do we test for DVT?

Duplex ultrasound with doppler flow

• allows viewing of BF

What are the s/s of PE?

Classic triad: dyspnea, pleuritic chest pain and hemoptysis

Cough

Tachypnea

Tachycardia

Elevated D-dimer 

What is dead space ventilation?

Oxygen in the area but there is no perfusion

Limits ability to eliminate carbon dioxide

What is the bodies reaction to dead space ventilation?

Overcompensates for this by increasing minute ventilation → blows off extra CO₂ → respiratory alkalosis

What does testing for PE include?

Ventilation/perfusion scan

CT pulmonary angiography

What is severity of PE dependent on?

Clot burden

Neurohormonal reflexes

Pre-existing cardiopulmonary disease

In pts WITHOUT a cardiopulmonary disease can accommodate an occlusion up to

~1/3 of their pulmonary circulation

Adapts to diverted blood flow through the recruitment and dilation of compliant pulmonary arterial vessels

In pts WITH cardiopulmonary disease the size of emboli does not correlate with ?

level of hemodynamic compromise

What classifies intermediate risk for PE?

Right ventricular strain:

On ECHO

(+) Troponin

(+) BNP

What characterizes high risk for PE?

Systolic BP <90 mmHg or decrease of 40 mmHg from baseline 

Requiring vasopressors

Pulseless

What are the indications for anticoagulants?

Prevention (prophylaxis) (low doses)

Tx: A. Fib

VTE (full doses)

Some valvular disease

Some hypercoagulable states

What are the parenteral anticoagulants?

Heparin

LMWH

Fondaparinux

Bivalirudin

Argatroban

What are the oral anticoagulants?

Warfarin

Apixaban

Rivaroxaban

Edoxaban

Dabigatran 

Which drugs are DOACs (Direct acting Oral AntiCoagulants)?

Apixaban

Rivaroxaban

Edoxaban

Dabigatran

When is warfarin indicated?

A. Fib with history of moderate/severe rheumatic mitral stenosis

Mechanical heart valves

Some hypercoagulable states

Heparin MOA?

Potentiates antithrombin

Decreased transformation from prothrombin to thrombin

What increases heparin activity?

Binding to AT - increases by 1000-fold 

If heparin is administered via SQ, what is its use?

Prophylaxis

If heparin is administered via IV, what is its use?

Tx

What are the efficacy levels of heparin?

Anti-Xa levels or aPTT (1.5-2.5x baseline)

GOAL: Anti-Xa 0.3-0.7 unit/ml (aPTT will be dependent on lab)

What does LMWHs MOA include that Heparins does not?

Inactivates factor Xa

What is the dosing of LWMH?

1mg/kg q12h

What are the renal considerations for LWMH?

CrCl <30 mL/min

When do we need to adjust dosing in obesity with LMWH?

BMI >40 kg/m²

What efficacy monitoring does LWMH need?

Anti-Xa monitoring in obese pts, renal dysfunction, and pregnancy

LMWH has a shorter chain fraction of heparin leading to

Less effect on thrombin

Increases effect on factor X

Warfarin MOA?

Reduction in hepatic synthesis of factors II, VII, IX, and X as well as protein C and S by blocking carboxylation

What are the common DDIs with warfarin?

CYP2C9

CYP3A4

(amiodarone, marcolide antibiotics, azoles, sulfas, rifampin)

Warfarin decreases synthesis of 

new clotting factors

Natural anticoagulants protein C and S

For warfarin to work currently active clotting factors need to be

Washed out

Why do we need to overlap warfarin with a parenteral anticogaulant?

Protein C quickly depletes = transient PROTHROBOTIC STATE

Factor II takes multiple days to wash out

What is the initial dosing for warfarin in a outpatient setting (STARTING on warfarin)?

5 mg daily for 3 days

More sensitive = 2.5 mg daily for 3 days

What is the dosing for warfarin in a outpatient setting after day 4 and INR is <1.5?

7.5-10 mg daily for 2-3 days 

More sensitive 5-7.5 mg daily for 2-3 days 

What is the dosing for warfarin in a outpatient setting after day 4 and INR is 1.5-1.9?

5 mg daily for 2-3 days

More sens: 2.5 mg daily for 2-3 days

What is the dosing for warfarin in a outpatient setting after day 4 and INR is 2-3?

2.5 mg daily for 2-3 days

More sens: 1.25 mg daily 2-3

What is the dosing for warfarin in a outpatient setting after day 4 and INR is 3.1-4?

1.25 mg daily for 2-3 days

More sens: 0.5 mg daily for 2-3 daily

What is the dosing for warfarin in a outpatient setting after day 4 and INR is >4?

HOLD until INR <3

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is <1.5, what do we do?

Increase weekly maintenance dose by 10% to 20%

Consider a one time supplemental dose 1.5-2 times the daily dose

If pt is already on warfarin and needs maintenance adjustment for warfarin, and their INR is 1.5-1.7, what do we do?

Increase weekly maintenance dose by 5-15%

Consider one time supplemental dose: 1.5-2 times the daily dose

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is 1.8-1.9, what do we do?

No dose adjustment may be necessary if the last 2 INRs were in range 

If needed increase weekly maintenance dose by 5-10% 

Consider a one time supplemental dose : 1.5-2 times the daily dose

If the factor causing subtherapeutic INR is transient (missed dose, temporary DDI) consider what as first option?

Resumption of maintenance dose following a one time supplemental dose

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is 3.1-3.2, what do we do?

No dose adjustment needed if last 2 INR readings were in range

If dosage adjustment needed, decrease weekly maintenance dose by 5-10%

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is 3.3-3.4, what do we do?

Decrease weekly maintenance by 5-10%

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is 3.5-3.9, what do we do?

Consider holding 1 dose

Decrease weekly maintenance dose by 5-15%

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is >4 but <10 and no bleeding, what do we do?

Hold until INR below upper limit of therapeutic range

Decrease weekly maintenance dose by 5% to 20%

If pt considered to be at significant risk for bleeding consider oral vitamin K

If pt is already on warfarin and needs maintenance adjustment for warfarin and their INR is >10 and no bleeding what do we do?

Hold until INR below upper limit of therapeutic range

Administer K orally

Decrease weekly maintenance dose by 5-20%

What is the dosing of apixaban (eliquis) in Afib?

5 mg BID

What is the dosing of apixaban in VTE?

10 mg BUD x 1 wk

THEN, 5mg BID

What are the renal dose adjustments for apixaban?

Adjust dose to 2.5 mg twice daily if 2 of 3 criteria are met

1. SCr >1m5

2. Weight <60 kg

   1. Age >80

Apixaban is a major substrate of 

CYP3A4 and PgP

What is the best DOAC in pts with poor renal function/ESRD dialysis?

Apixaban

What is the dosing of rivaroxaban (xarelto) in Afib?

20 mg daily

What is the dosing of rivaroxaban in VTE?

15 mg BID x 21 days and then 20 mg daily

What are the renal adjustments for rivaroxaban in CrCl 15-50?

15 mg daily

When do we avoid use of rivaroxaban?

CrCl <15 mL/min

What should we do for >10mg doses of rivaroxaban?

Give with food

What is the dosing of edoxaban (savaysa) in Afib?

60 mg daily

What is the dosing of edoxaban (Savaysa) in VTE?

>60 kg - 60 mg 

</= 60 kg - 30 mg daily

We only use edoxaban when?

CrCl 15-95 mL/min

What are the dosing adjustments for a pt taking edoxaban and has CrCl 15-50 ?

30 mg

Which two DOACs are preferred when a pt is obese?

Rivaroxaban

Apixaban

When do we avoid ise of fondaparinux?

CrCl <30 mL/min

<50 kg

Which anticoagulant is okay to use in pts wishing to avoid pork?

Fondaparinux (arixtra)

What is the dosing of dabigatran in Afib?

150 mg BID

What is the dosing of dabigatran in VTE?

150 mg BID

If a pt has Afib and a CrCl 15-29 what is the dosing for dabigatran?

75 mg BID 

When do we avoid use of dabigatran?

VTE

CrCl <30

>120

BMI >40

Why is dabigatran rarely used?

Increased risk of GI bleeds compared to warfarin

What are the two parenteral DTIs?

Argatroban

Bivalirudin

Which parenteral DTI is dialyzable?

Bivalirudin