Thrombosis

Question 1

Why anticoagulant medications are used?

Answer 1

To prevent and Treat Venous Thromboembolism with a precise dosing and monitoring.

Question 2

What is hemostasis?

Answer 2

The balance between bleeding and clotting. It is the cessation of blood loss from the damaged vessel & Dissolution of the clot when it no longer needed!

Question 3

In hemostasis, what are the 3 key players?

Answer 3

1) platelet function
2) Blood Coagulation
3) Fibrinolysis

Question 4

What are the characteristics of Hemostasis? Elaborate

Answer 4

1) Normal Clotting Response: TF and platelets –> activate Coagulation Cascade –> Fibrin rich clot
2) Normal Dissolution Response: Tissue plasminogen Activator –> binds to plasmin –> break fibrin clot –> Restore Normal Blood Flow

Question 5

What is Virchows Triad ? Elaborate

Answer 5

Risk Factors for thrombosis:
1) Blood stasis = immobility - paralysis
2) Vascular Injury = Surgery - Trauma - etc.
3) Hypercoagulation = inherited - Cancer - estrogen contraception etc.

Question 6

What are the duration and Risk factor of VTE which is Categorized as “ TRANSIENT”?

Answer 6

Duration: 3 months
Risk Factors (Example):
Major:
1) Surgery with general anesthesia for >or = 30min
2) Confined to bed in hospital for >or = 3 days with acute
illness (bathroom privilege only)
Minor:
A) Surgery with general anesthesia < 30min
B) Admission to the hospital < 3d with acute illness
C) Estrogen therapy
D) Pregnancy and puerperium
E) Confined to bed out of hospital for > or = 3 d with acute illness
F) Leg injury associated with decreased mobility for > or =
3days

Question 7

What are the duration and Risk factor of VTE which is Categorized as “Chronic / Persistant”?

Answer 7

Duration: persist after the development of VTE
Risk Factors (Example):
1) Active Cancer
2) Inflammatory bowel disease
3) Autoimmune disorders
4) Chronic infections
5) Chronic immobility (spinal cord injury)

Question 8

List the two different Types of VTE
List difference in Prognosis, Subjective, objective , Diagnosis

Answer 8

A) Deep Venous Thrombosis
1) Prognosis: prognose into PE (pulmonary Edema)
2) Subjective: leg swelling , pain , warmth
3) Objective: D Dimers
4) Diagnosis: Duplex ultrasonography ; Venography

B) Pulmonary Edema
1) Prognosis: It may lead to death
2) Subjective: Cough , palpitations; chest pain ; Dyspnea .. Massive ( cyanotic - hypotensive- lightheadedness)
3) Objective: increase in HR , RR + Hypoxic on ABG
D dimers
4) Diagnosis: V/Q scan + CTPA

Question 9

What are the goals of therapy for DVT prevention?
1) High risk
2) Low risk
3) High risk with bleeding

Answer 9

1) If high risk –> pharmacological
2) If lower risk –> no need or (non-pharmacological)
3) If high risk but patient is bleeding –> non-pharmacological until it’s safe to give pharmacologic

Giving anticoagulant in order to prevent VTE from developing

Question 10

What are the strategies for “ Non Pharmacological Prevention”

Answer 10

A- Elastic Compression sticking
B- Leg elevation
C- leg Exercise
D- Early ambulation
E- Intermittent pneumatic Compression (IPC) worn at least 18hrs/day

Question 11

What are the strategies for “Pharmacological Prevention”

Answer 11

A- Fixed low dose UFH: 5000 units SC every 8/12hrs

B- Low dose of LMWH
Enoxaparin 30mg SC BID
Enoxaparin 40mg SC once daily
Enoxaparin 30mg SC once daily (
CrCL< 30ml/min)

C- Fondaparinux: 2.5mg SC daily ( dont give CrCL < 30 ml/min or Weight =50kg)

D- Rivaroxaban 10mg po daily (inpatients total of 31-39 days) (dont use of CrCl < 30 ml/min)

E- NOACs - post operative
Apixaban 2.5mg PO BID
Dabigatran 220 mg po daily
Rivaroxaban 10mg po daily

Question 12

IN the hospitalized Medical patient: there are 10 Risk factors of PADUA ; list them and indicate each risk factor with its relative points

when is it high risk of developing DVT?

Answer 12

ARAR EHAA OO
1. Acute cancer (3)
2. Reduced mobility >3d (3)
3. Known Thrombophilia condition (3)
4. Trauma / Surgery less than 1 month (2)
5. Elderly age >70 yr (1)
6. Heart/ respiratory failure (1)
7. Acute myocardial Infarction or ischemic stroke (1)
8. Acute infection and/or rheumatologic disorder (1)
9. Obesity (BMI> 30) (1)
10.Ongoing hormonal treatment (1)

> or = 4 points –> high risk of developing DVT –> pharmacological prevention

Question 13

Surgical Patients: list the two types of thrombosis , and there respective type of surgery ( with the list of examples if possible)

Answer 13

1. High risk thrombosis
   a. Orthopedic surgery and open abdominal surgery:

i. Total Hip Arthroplasty (THA), Total Knee Arthroplasty (TKA): Duration for a minimum of 10 to 14 days, we can consider extending up to 35 days from the day of surgery.
Agents: heparin, LMWH, fondaparinux , NOACs are also options!

ii. Hip Fracture Surgery (HFS): Duration for a minimum of 10 to 14 days, we can consider extending up to 35 days from the day of surgery
Agents: heparin, LMWH, fondaparinux , NOACs NOT an option (studies are lacking)

2. Low risk thrombosis
   a. Laproscopic surgeries

Question 14

What are the goals of treating thrombosis?

Answer 14

1. Prevent thrombus extension and embolization
2. Reduce recurrence risk
3. Prevent long-term complications such as the post-thrombotic syndrome
4. Carefully use anticoagulant drugs to reduce the risk of bleeding associated with these agents

Question 15

what are the types of VTE treatment? and duration of each?

Answer 15

1) Primary treatment:
Duration: 3-6months
Start Immediately
2) Secondary Treatment:
Duration: Lifelong
Always Assess (at least annually)

Question 16

what are the guidelines for Venous thromboembolism

Answer 16

1st line = NOACs : dabigatran, apixaban, edoxaban or rivaroxaban
2nd line= Conventional treatment (VKA = Sintrom or warfarin) + paranteral anticoagulation

Question 16

what are the steps regarding primary treatment?

Answer 16

1) Directly oral anticoagulants (NOACs) - Rivaroxaban 15mg PO BID for 21 days, followed by 20mg PO daily
Apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily

2) switching (NOACs): start parenteral anticoagulant for 7 days then either switch to Dabigatran 150mg PO BID or to Edoxaban 60mg daily (if CrCl 30-50ml/min & weight <60kg or taking pgp i –> 30mg PO daily)

3) Bridging: Conventional therapy : parenteral anticoagulant + bridge to oral therapy VKA both PO and IV @ the same time after 5 days -> remove AC , when VKA reach therapeutic range –> KEEP only PO VKA

Question 16

what are the steps of secondary prevention ?

Answer 16

1) VKA+ INR 2-3

2)Direct AC PO :
Rivaroxaban 10mg PO daily (after 6m of full dose)
Rivaroxaban 20mg PO daily
Apixaban 2.5 mg po BID (after 6m of full dose)
Apixaban 5 mg po BID

Refusal –> give instead Aspirin

Question 17

who are candidate for secondary prevention?

Answer 17

1) Provoked VTE by a transient risk factor: no need
2) Provoked VTE by a chronic risk factor: indefinite (considered if no risk of bleeding)
3) Unprovoked VTE: complete initial 3 months, then indefinite (considered if no risk of bleeding)

Question 18

What are the 3 VTE treatment strategies?
Duration of each

Answer 18

A- Acute phase
Duration: 0-7 d

B- Early maintenance
Duration: 8-90 d

C- Extended
Duration: >91 d

Question 19

What are different methods/ Strategies for treating VTE

Answer 19

ALL ORAL:

1) Apixaban 10mg PO BID for 7 days (acute) ——–> Apixaban 5mg PO BID (early maintenance and first days of extended phase) ——–> Optional: apixaban 2.5 mg PO BID after first 6m

2) Rivaroxaban 15mg PO BID for 1st 21 days ( acute phase + some days of early maintenance ) ——–> rivaroxaban 20mg PO daily (early maintenance + some days extended phase) ——–> Optional: Rovaroxaban 10mg PO daily after 6m

Switching:
1) UFH , LMWH , Fondaparinux SC 1st 5 days ( acute) ——–> Dabigatran 150mg PO BID / Edoxaban 60mg PO daily (2 last days of acute phase + till the end of treatment = early maintenance and extended)

Overlap:
1) UFH , LMWH , Fondaparinux SC (acute phase) + warfarin PO daily overlapped with AC IV for @ least 5 days & INR > or = 2 —> dose adjust to target INR = 2.5 (2-3)

Question 20

What is the treatment of Recurrent VTE?
Provoked / Unprovoked / while on treatment?

Answer 20

• The old and recurrent VTE are both provoked due to transient risk Factor ——> No need for lifelong AC
• Recurrent unprovoked VTE ——> extend therapy for 3m
• Recurrent VTE while on warfarin treatment/NOAC - compliant ——> switch to LMWH temporarily @ least 1m
• Recurrent VTE while on long term LMWH - compliant ——> increase LMWH dose about 1/4 - 1/3

Question 21

how to treat Cancer associated with VTE ?

Answer 21

1) LMWH alone (less rate of recurrent VTE + keep on therapeutic range + compliance + withhold / adjust + can be used in thrombocytopenia or when invasive interventions are required

2) NOACs (Edoxaban, Apixaban and Rivaroxaban) ———> with caution in GI cancer

Question 22

what are the risk factors for bleeding while on AC? and how assess (Moderate/High)

Answer 22

• Age> 75 yo and frail
• Previous bleeding
• Renal or liver failure
• Thrombocytopenia( ~ 100,000)
• Concurrent antiplatelet use
• Previous stroke
• Poor anticoagulant control or non-compliance
• Frequent falls or alcohol abuse
• Presence of structural lesions that can bleed (tumor, recent surgery)

Moderate 1-2
High > or = 3

Question 23

What is the treatment for Unstable PE?

Answer 23

Acute PE + Hypotension + no risk of bleeding --------> fibrinolytics: Alteplase rt-PA 100mg infusion over 2h -------> institute or resume AC IV near end or immediately following it (when aPTTT returns to normal/almost normal)

Question 24

What to do with Patients who cant take AC (absolute Contraindicated) ? and how to differentiate them?

Answer 24

Given Inferior Vena Cava (IVC) filters Absolute Contraindications: 1) Active bleeding 2) Hemophilia or other hemorrhagic tendencies 3) Severe thrombocytopenia (platelet count <20,000) 4) Inability to meticulously supervise and monitor treatment (really difficult patient to deal with)

Question 25

what are the list of AC IV? and their properties (dosing/CI/ monitoring)?

Answer 25

1) UFC (unfractionated heparin) IV -------> can be used during pregnancy half life 1hr + not renally excreted Dosing: 80 units/kg IV bolus , followed by a continuous IV infusion, starting dose of 18units/kg/hr {No max dose} Weight used in the calculation: actual body weight --------> if obese --> adjusted body weight SC -------> 333 units/kg, followed by 250 units/kg every 12 hours ------> not used much -------> no need to monitor aPTT Monitoring: Efficacy: check aPTT q 4-6hr (1.5-2.5 times the control - sec) Safety: signs of bleeding Hb, Hct, Platelets (thrombocytopenia) For special population: Anti Xa SE: High incidence of thrombocytopenia + Osteoporosis 2) LMWH ( low molecular weight heparin) SC -------> 1st line in pregnancy Renally excreted ; half life 4 hr A- Enoxaparin (lovenox) SC Dosing: if CrCl > 30 mL/min --> 1mg/kg BID or 1.5 mg/kg daily if CrCl<30 mL/min --> 1 mg/Kg daily B- Tinzaparin (innohep) SC Monitoring: monitor special population; routinely for others not required -LMWH anti Xa levels ( renal impairement ; Pregnancy; obesity ; prolonged therapy more than 2 w ; weight less than 50kg) Counseling: under skin not into muscles + wash hands and area + syringe clear + don't push any air or drug out + lie down and pinch a fold of skin + don't rub the site + use different area of your body SE: less incidence of thrombocytopenia 3) Fondaparinux SC: half life 17-21 hr ; prolonged with renal impairment renally excreted Dosing: if weight <50kg ----> 5mg daily if weight 50 -100kg ----> 7.5 mg daily if weight >100 kg ----> 10 mg daily CI: if CrCl <30min/L Monitoring: SrCr special population: Anti Xa levels

Question 26

what are the list of DTI (DIRECT THROMBIN INHIBITORS) ? what are they used to? how to monitor?

Answer 26

IV DTI: 1) Argatroban 2) Bivalirudin 3) Lepirudin USED: bridging VKA in heparin induced thrombocytopenia HIT will work on factor X and II Monitoring: SrCr, LFTs , aPTT

Question 27

what are the list of AC PO ? what are the main clotting factor's half life? and their properties (dosing/CI/ monitoring)?

Answer 27

VKA are the only AC PO Factor X 70 hr Factor II 60 hr Factor VII 4-6 hr Warfarin (hydroxycoumarol): 20-60 hours --> takes time to reach steady state (add DTI for this reason) half life 20-60hr full effect: 5-7 d Dosing: - Starting 2.5-10mg Lower Dosing: age > or = 60 and frail / poor nutritional status (hypoalbuminemia) / liver disease / CHF Higher dosing: enzyme inducers + resistant to effects of warfarin - Maintenance: Gradual increase in dose and avoid big jumps of INR Monitoring: INR (not on AC and normal liver ---> INR = 1; GOAL in DVT and PE 2-3) and PT High INR -----> increase risk of bleeding low INR -----> increase risk of clotting SE: anaphylactic shock ; hypersensitivity, skin necrosis, gangrene, “purple toes” syndrome + Osteoporosis (long usage) + Bleeding CI: Pregnancy except for women with mechanical heart valves (hi risk of Thromboembolism) Sintrom (acenocoumarol ): 8 to 11 hours full effect: 5 d ----> INR will change faster but doesnt mean full effect is reached half life 8-11 hr

Question 28

What affects VKA dose/response to therapy?

Answer 28

1) Dietary Vitamin K intake: Food rich in vitamin K: green leafy vegetables, beef liver, green tea, herbal products ( more vitK -----> decrease in INR -----> increase in clots) 2) Disease states: CHF, Fluid congestion, fever, cirrhosis 3) Drug interactions A- Bile acid sequestrants (cholestyramine) --> decrease warfarin absorption B- Disruption of the gut flora --> less clotting factors --> increase INR C- CYP inducers (such as phenobarbital, phenytoin,rifampin and carbamazepine ) ---> increase metabolism of warfarin ----> decrease INR D- CYP inhibitors (such as amiodarone, acute ethanol ingestion, cimetidine, miconazole, quinolone antibiotics, sulfonamide antibiotics ) ----> decrease metabolism of Warfarin --> increase INR E- Highly bound proteins --> compete with warfarin (highly bound to proteins) F- Antiplatelets , anticoagulants , NSAIDs ---> increase risk of bleeding

Question 29

what are the list of NOACs ? and their properties (dosing/CI/ monitoring)?

Answer 29

SHOULD ONLY BE GIVEN IF CrCl < 30 ml /min (all except Apixaban ------> < 25 mL/min) NO monitoring or adjusting the dose depending on INR // aPTT // PT Monitor: Hb, Hct, Plt count, signs of bleed , SrCR or CrCl A- Dabigatran: In switching: start AC IV for 7 d ------> switch to Dabigatran 150mg BID mostly renally excreted DONT CRUSH OR CHEW Monitoring: No routine test + aPTT or thrombin time for dose adjustment + SrCr ---- half life 12-17hr ---- B- Rivaroxaban: 15mg BID for 21d -------> 20mg daily Can be crushed TAKE with MEALS for bioavailability Monitoring: No routine test , but PT or anti Xa for dose adjustment + SrCr ---- half life 7-11 hr ---- C- Apixaban : 10 mg BID for 7 days -------> 5 mg BID least renally excreted Can be crushed Take with/without meals Monitoring: No routine test , but PT or anti Xa for dose adjustment + SrCr ---- half life 9-14 hr ---- D- Edoxaban: In switching: start AC IV for 7 d ------> switch to Edoxaban 60mg once daily --- if CrCrl 30-50ml/min, weight<60kg or taking potent pgp inhibitors) 30mg once daily --- ---- half life 10-14 hr ---- NOT FOUND IN LEBANON

Question 30

Who shouldn't receive NOACs?

Answer 30

- Severe renal impairment - Liver disease (Child-Pugh B/C) - Pregnancy and lactation - Patients with antiphospholipid antibody syndrome - Compliance is a concern - Extreme body weight (caution avoid when weight > 120 kg or BMI> 40 kg/m2) - who is taking: Antimicrobials (antifungals, antibiotics, antiretrovirals) / Antiepileptics (Carbamazepine) / Immunosuppressants / Verapamil / Amiodarone

Question 31

If Patient prefers to avoid injections which NOACs should be given?

Answer 31

Apixaban or Rivaroxaban

Question 32

If Patient presents with Dyspepsia or Gerd which NOACs should be given?

Answer 32

Rivaroxaban, apixaban, edoxaban

Question 33

If Patient had a GI bleed before which NOACs should be given?

Answer 33

Apixaban, Edoxaban

Question 34

If Patient poor compliance with BID which NOACs should be given?

Answer 34

Rivaroxaban or edoxaban

Question 35

what is the antidote of Heparin?

Answer 35

1mg Protamine Sulfate IV for each 100 units of heparin Maximum dose : 50mg

Question 36

what is the antidote of LMWH

Answer 36

1mg of protamine for earch 1mg of enoxaparin neutralized around 60-70%

Question 37

what should be done in a life threatening bleed?

Answer 37

Give 10mg IV phytonadione (Vit K) Also give blood derivatives: -- Fresh frozen plasma -- Prothrombin Complex concentrate -- Recombinant activated factor VII

Question 38

what should be done for a bleeding patient?

Answer 38

1. Interrupt a VKA dose 2. Give medium dose ~ 5mg of Vit K PO/IV (IV faster reversal than PO)

Question 39

What should be done if INR of a patient is > 3 and <20 {with no bleed}

Answer 39

1. Interrupt VKA dose (skip a dose) 2. Give Low doses oral vit K : between 1-2.5mg Vitk

Question 40

What should be done if patient had elective invasive procedure?

Answer 40

Interruption of VKAs may be sufficient (omit 1-2 doses)

Question 41

what are the low doses of VitK to reduce the INR at 24hr

Answer 41

IV 1mg ; PO 5mg to have similar effect

Question 42

what is the onset of action of VitK? to increase the coagulation factors

Answer 42

PO: 6-10hr IV:1-2 hr

Question 43

what is the peak level of VitK? for the INR value to return to normal

Answer 43

PO: 24-48 hr IV: 12-14 hr

Question 44

What is the main SE of VitK? and how to manage it?

Answer 44

SE: anaphylactoid Reactions To minimize: VitK mixed with minimum of 50mL of IV fluid and administered using an infusion pump for minimum of 20min

Question 45

what is the antidote of Dabigatran?

Answer 45

Idarucizumab IV

Question 46

what is the antidote of Apixaban?

Answer 46

Andexanet Alfa IV

Question 47

what is the antidote of Rivaroxaban ?

Answer 47

Andexanet Alfa IV

Question 48

what is the antidote of Edoxaban ?

Answer 48

Andexanet Alfa IV

Question 49

What it is HIT and HITThrombosis?

Answer 49

HIT: heparin induced thrombocytopenia = immune mediated adverse effect - IgG when platelets count drop of >or = 50% Onset: 5-14 d Nadir platelets 30,000 - 50,000 If not thrombosis ---> HIT If thrombosis develops ---> HITThrombosis

Question 50

what is HAT

Answer 50

A mild / transient drop of 10-30% Onset 1-3 d Nadir platelets 100,000 non immune sequence BENIGN

Question 51

How is the pre - test scoring system? and what does each score tell us? how about the management done?

Answer 51

* High probability (6-8 points) ----> HIT or HITT --> discontinue heparin like agents + stop AC + dont start warfarin until platelets back to normal ( 150 x 10 ^9) / bridge VKA + non heparin AC for 5 d ----> continue treatment for 3 m Intravenous DTI: argatroban or Subcutaneous Pentasaccharides: Fondaparinux NOACs HITT : rivaroxaban 15 mg twice daily for 21 days, then 20 mg once daily for a duration of 3-6 months * Intermediate probability (4-5 points) ----> apply clinical judgment or diagnosis for treatment * Low probability (≤ 3 points) ----> HAT -----> keep patient on Heparin or LMWH and expect platelet to resolve alone

Question 52

which drugs induces Thrombocytopenia?

Answer 52

abciximab cephalosporins diltiazem eptifibatide quinine tirofiban vancomycin

Question 53

what are the 4 factors of 4T score?

Answer 53

1) thrombocytopenia 2)Timing of platelet count fall 3) thrombosis or other sequelae 4) other causes of thrombocytopenia

Question 54

what are the diseases that might cause thrombocytopenia ?

Answer 54

Bone marrow disease cardiac surgery vitamin B12 deficiency folic acid deficiency idiopathic thrombocytopenia thrombotic thrombocytopenic purpura post transfusion purpura

Question 55

During surgery , what should be taken into consideration regarding AC?

Answer 55

avoid risk of bleeding --> evaluate need to discontinue AC Due to high clotting risk --> AC should be given --> short acting IV (UFH,LMWH as a bridge)

Question 56

what are example of Minor bleeding risk surgery?

Answer 56

Endoscopy with biopsy; electrophysiological study or simple radiofrequency catheter ablation; angiography

Question 57

what are example of Major bleeding risk surgery

Answer 57

spinal or epidural anaesthesia; lumbar diagnostic puncture; thoracic surgery; abdominal surgery; major orthopaedic surgery; liver biopsy; transurethral prostate resection; kidney biopsy.

Question 58

how to manage Periprocedural (surgeries) using VKA? Specify the management also for WARFARIN & LMWH what is the dose of LMWH

Answer 58

1) Discontinue warfarin 4 d before surgery 2) Clear of VKA --> short acting IV (UFH,LMWH at prophylactic or treatment doses) 3) prior to surgery discontinue IV AC (UFH 6 hr before ; LMWH before 24hr) 4)Resume IV AC after surgery overlap with Warfarin if high blood risk: Warfarin: discontinue before 5 days , and re-take it after the surgery LMWH: discontinue before 1 day and take it after 1-2 days after surgery If low to moderate risk: warfarin same as high LMWH: discontinue before 1 day and take it after 1 day of surgery If minimal bleed risk: warfarin (no need to stop) LMWH: full dose: enoxaparin 1mg/kg BID or 1.5mg/kg Daily / Dalteparin 100IU/kg BID or 200 IU/kg daily low dose: 40mg daily Enoxaparin / Dalteparin 5000 IU daily

Question 59

What is the appropriate timing to withhold DOACs Perioperatively? - Interruption

Answer 59

High Bleeding risk: ---> before 3 days: Apixaban + Dabigatran ( CrCl>or= 50) + Edoxaban + Rivaroxaban ---> before 5 days: Dabigatran ( CrCl <50) Low/Mod Bleeding risk: ---> before 1 day: Apixaban + Dabigatran ( CrCl>or= 50) + edoxaban + Rivaroxaban ---> Before 2 days: Dabigatran ( CrCl <50)

Question 60

What is the appropriate timing to withhold DOACs Perioperatively? - Resumption

Answer 60

Directly after Procedure/surgery: All low /Mod bleeding risk with Any of the medication: Apixaban + Dabigatran ( CrCl>or= 50) + Edoxaban + Rivaroxaban +Dabigatran ( CrCl <50) After 2-3 days: All high bleeding risk with any of the medications:Apixaban + Dabigatran ( CrCl>or= 50) + Edoxaban + Rivaroxaban +Dabigatran ( CrCl <50)