Thrombosis Flashcards
Why anticoagulant medications are used?
To prevent and Treat Venous Thromboembolism with a precise dosing and monitoring.
What is hemostasis?
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!
In hemostasis, what are the 3 key players?
1) platelet function
2) Blood Coagulation
3) Fibrinolysis
What are the characteristics of Hemostasis? Elaborate
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
What is Virchows Triad ? Elaborate
Risk Factors for thrombosis:
1) Blood stasis = immobility - paralysis
2) Vascular Injury = Surgery - Trauma - etc.
3) Hypercoagulation = inherited - Cancer - estrogen contraception etc.
What are the duration and Risk factor of VTE which is Categorized as “ TRANSIENT”?
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
What are the duration and Risk factor of VTE which is Categorized as “Chronic / Persistant”?
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)
List the two different Types of VTE
List difference in Prognosis, Subjective, objective , Diagnosis
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
What are the goals of therapy for DVT prevention?
1) High risk
2) Low risk
3) High risk with bleeding
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
What are the strategies for “ Non Pharmacological Prevention”
A- Elastic Compression sticking
B- Leg elevation
C- leg Exercise
D- Early ambulation
E- Intermittent pneumatic Compression (IPC) worn at least 18hrs/day
What are the strategies for “Pharmacological Prevention”
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
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?
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
Surgical Patients: list the two types of thrombosis , and there respective type of surgery ( with the list of examples if possible)
- 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)
- Low risk thrombosis
a. Laproscopic surgeries
What are the goals of treating thrombosis?
- Prevent thrombus extension and embolization
- Reduce recurrence risk
- Prevent long-term complications such as the post-thrombotic syndrome
- Carefully use anticoagulant drugs to reduce the risk of bleeding associated with these agents
what are the types of VTE treatment? and duration of each?
1) Primary treatment:
Duration: 3-6months
Start Immediately
2) Secondary Treatment:
Duration: Lifelong
Always Assess (at least annually)
what are the guidelines for Venous thromboembolism
1st line = NOACs : dabigatran, apixaban, edoxaban or rivaroxaban
2nd line= Conventional treatment (VKA = Sintrom or warfarin) + paranteral anticoagulation
what are the steps regarding primary treatment?
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
what are the steps of secondary prevention ?
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
who are candidate for secondary prevention?
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)
What are the 3 VTE treatment strategies?
Duration of each
A- Acute phase
Duration: 0-7 d
B- Early maintenance
Duration: 8-90 d
C- Extended
Duration: >91 d
What are different methods/ Strategies for treating VTE
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)
What is the treatment of Recurrent VTE?
Provoked / Unprovoked / while on treatment?
- 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
how to treat Cancer associated with VTE ?
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
what are the risk factors for bleeding while on AC? and how assess (Moderate/High)
- 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
What is the treatment for Unstable PE?
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)
What to do with Patients who cant take AC (absolute Contraindicated) ? and how to differentiate them?
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)
what are the list of AC IV? and their properties (dosing/CI/ monitoring)?
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
what are the list of DTI (DIRECT THROMBIN INHIBITORS) ? what are they used to? how to monitor?
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
what are the list of AC PO ? what are the main clotting factor’s half life? and their properties (dosing/CI/ monitoring)?
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
What affects VKA dose/response to therapy?
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
what are the list of NOACs ? and their properties (dosing/CI/ monitoring)?
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
Who shouldn’t receive NOACs?
- 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
If Patient prefers to avoid injections which NOACs should be given?
Apixaban or Rivaroxaban
If Patient presents with Dyspepsia or Gerd which NOACs should be given?
Rivaroxaban, apixaban, edoxaban
If Patient had a GI bleed before which NOACs should be given?
Apixaban, Edoxaban
If Patient poor compliance with BID which NOACs should be given?
Rivaroxaban or edoxaban
what is the antidote of Heparin?
1mg Protamine Sulfate IV for each 100 units of heparin
Maximum dose : 50mg
what is the antidote of LMWH
1mg of protamine for earch 1mg of enoxaparin
neutralized around 60-70%
what should be done in a life threatening bleed?
Give 10mg IV phytonadione (Vit K)
Also give blood derivatives:
– Fresh frozen plasma
– Prothrombin Complex concentrate
– Recombinant activated factor VII
what should be done for a bleeding patient?
- Interrupt a VKA dose
- Give medium dose ~ 5mg of Vit K PO/IV (IV faster reversal than PO)
What should be done if INR of a patient is > 3 and <20 {with no bleed}
- Interrupt VKA dose (skip a dose)
- Give Low doses oral vit K : between 1-2.5mg Vitk
What should be done if patient had elective invasive procedure?
Interruption of VKAs may be sufficient (omit 1-2 doses)
what are the low doses of VitK to reduce the INR at 24hr
IV 1mg ; PO 5mg to have similar effect
what is the onset of action of VitK? to increase the coagulation factors
PO: 6-10hr
IV:1-2 hr
what is the peak level of VitK? for the INR value to return to normal
PO: 24-48 hr
IV: 12-14 hr
What is the main SE of VitK? and how to manage it?
SE: anaphylactoid Reactions
To minimize: VitK mixed with minimum of 50mL of IV fluid and administered using an infusion pump for minimum of 20min
what is the antidote of Dabigatran?
Idarucizumab IV
what is the antidote of Apixaban?
Andexanet Alfa IV
what is the antidote of Rivaroxaban ?
Andexanet Alfa IV
what is the antidote of Edoxaban ?
Andexanet Alfa IV
What it is HIT and HITThrombosis?
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
what is HAT
A mild / transient drop of 10-30%
Onset 1-3 d
Nadir platelets 100,000
non immune
sequence BENIGN
How is the pre - test scoring system? and what does each score tell us? how about the management done?
- 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
which drugs induces Thrombocytopenia?
abciximab
cephalosporins
diltiazem
eptifibatide
quinine
tirofiban
vancomycin
what are the 4 factors of 4T score?
1) thrombocytopenia
2)Timing of platelet count fall
3) thrombosis or other sequelae
4) other causes of thrombocytopenia
what are the diseases that might cause thrombocytopenia ?
Bone marrow disease
cardiac surgery
vitamin B12 deficiency
folic acid deficiency
idiopathic thrombocytopenia
thrombotic thrombocytopenic purpura
post transfusion purpura
During surgery , what should be taken into consideration regarding AC?
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)
what are example of Minor bleeding risk surgery?
Endoscopy with biopsy; electrophysiological study or simple
radiofrequency catheter ablation; angiography
what are example of Major bleeding risk surgery
spinal or epidural anaesthesia; lumbar diagnostic puncture; thoracic
surgery; abdominal surgery; major orthopaedic surgery; liver biopsy;
transurethral prostate resection; kidney biopsy.
how to manage Periprocedural (surgeries) using VKA?
Specify the management also for WARFARIN & LMWH
what is the dose of LMWH
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
What is the appropriate timing to withhold DOACs Perioperatively? - Interruption
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)
What is the appropriate timing to withhold DOACs Perioperatively? - Resumption
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)
