Venous Thrombembolism Flashcards
What is the mortality rate for VTE?
Venous Thromboembolism is a major cause of morbidity and mortaliity (10% of hospital deaths due to pulmonary embolism)
More than death by breast cancer, HIV, and motor vehicle accidents
Is VTE treatment or prophylaxis the same as atrial fibrillation or secondary prevention of MI/Stroke?
No, they use different therapeutic agents
What are some characteristics of venous circulation?
- Return blood to heart for re-oxygenation
- Thinner walls vs arteries
- Elastic (variably widens as blood passes through)
- Lower shear rate than arteries
- One-way valves close to prevent backflow (damage can cause blood to pool)
What is the pathophysiology of venous thrombus (red clot)?
- Formed without damaging vessel wall
- Held together by mostly fibrin, less platelet
- Leads to VTE (DVT/PE)
What is the pathophysiology of arterial thrombus (white clot)?
- Formed from rupture of atherosclerotic plaque
- Held together by mostly platelet, less fibrin
- Leads to ACS, stroke, or peripheral arterial disease (PAD)
What is the definition of venous thromboembolism?
Results from clot formatrion within venous circulation
What causes venous thromboembolism to develop from a venous thrombus?
A venous thrombus (clot) may have the following:
- Lyse
- Obstruct venous circulation
- Embolize
- Combination
Where do thromboembolisms usually form?
Mainly in the lower extremities
Majority in calf veins, minority in arm, brain, GI tract, liver
What is the physiology of coagulation?
Generation of thrombin (factor 2a) is central to the coagulation cascade
Thrombin is made from prothrombin by factor 10a
Prothrombin –> Thrombin –> Fibrinogen –> Fibrin clot
What are the three main categories of risk factors for VTE?
- Stasis
- Vessel wall injury
- Hypercoagulability
What are some causes for circulatory stasis?
- Bed rest/immobility (often seen in hospitalization)
- Heart failure (Class III-IV)
- Varicose veins (maybe)
- Atrial fibrilation
What are some causes for vascular damage?
- Previous VTE
- Bacterial infection (sepsis)
- Prosthetic implants
- Peripheral vascular disease
- Trauma
- Surgery (especially following hip and knee replacements)
What are some causes of hypercoagulability?
- Medications
- Use of oral contraceptives
- Malignancy
- Inherited thrombophilias
- Advanced age (over 60)
- Obesity (BMI over 30)
- Protein C or S deficiency
- Smoking
What is the risk of getting VTE during pregnancy/post-partum?
Pregnancy (5-10x increase during pregnancy)
Early post-partum (15-35x increase)
What are some specific drug related increases in rates of VTE?
- Estrogen (2x risk vs. baseline)
- SERMS (Tamoxifen/raloxifen)
- Chemotherapy
- Older antipsychotics
- Erythropoietin
What are some signs and symptoms associated with VTE?
Often asymptomatic, and symptoms manifest as the clot get larger
Non-specific symptoms:
Leg pain (90%)
Tenderness (85%)
Ankle edema (76%)
Calf swelling (42%)
What are some signs and symptoms associated with pulmonary embolisms?
Symptoms of PE
- Sudden, unexplained SOB
- Tachypnea
- Tachycardia
- Cough
- Cyanosis
Are the recurrance rates associated with VTE low?
No, a large (as high as 7%) portion of people who have experienced a VTE will have a VTE more than once
What are some complications associated with VTE?
- Recurrent VTE
- Post-thrombotic syndroms
- Venous ulcers, chronic thromboembolism, pulmonary hypertension(CTEPH)
What is post-thrombotis syndrome (PTS)?
It develops in 10-50% of patients that have DVT and will develop within 3-6 months
What are some treatment options for post-thrombic syndrome?
Compression stockings (avoid if patient has lesions on legs)
30-45mgHg at ankle following DVT diagnosis
What causes skin ulcers following VTE?
They are caused by venous insufficiency, leading to pooling blood
Venous insufficiency is also a major cause of chronic wounds as they take longer to heal
What is chronic thromboembolic pulmonary hypertension (PTS)?
Following a PE
Scarring in the lungs causes arteries to narrow in the lungs. This leads to a permanent increase in pulmonary blood pressure (may lead to right-sided heart failure)
Need to be anti-coagulated for life after treatment
How is VTE diagnosed?
Lab tests:
- D-dimer increase
- ESR and WBC count increase
Clinical prediction score:
- Wells criteria (DVT & PE)
Imaging:
- Compression ultrasonography
- CT scan
- Ventilation/perfusion scan
Does DVT have a higher mortality risk than PE?
No, Deep vein thrombosis have a low mortality is low if it is the only condition
PE shows a significant increase in mortality
What are some important lab values in treating VTE?
- Prothrombin time (PT)
- Partial thromboplastin time (PTT)
- Activated partial thromboplastin time (aPTT)
- Anti-Xa activity
- International normalized ratio (INR)
What are the goals of treatment for VTE?
- Prevent initial VTE
- Resolution of signs and symptoms of VTE (be specific to patient)
- Prevent extension of VTE (PE in patients with DVT)
- Prevent hemodynamic collapse and/or death
- Prevent VTE recurrance
What are some challenges presented by attempting to prevent and/or treat VTE?
- Precise dosing of anticoagulants
- Monitoring properly
- Balance bleed vs. clotting risk (especially in patients with liver disease or malignancy)
- Bleeding is the predominant adverse events (increases with intensity and duration of therapy)
- Drug interactions
- Drug/disease interactions
- Patient issues (compliance and administration)
- Clinical assessment and appropriate prophylaxis
What drugs are used in the treatment of VTE?
- Heparin
- Low molecular weight heparin
- Heparinoids (danaparoids)
- Fondaparinux
- Direct thrombin inhibitor (argatroban)
- Vitamin K antagonist (warfarin)
- Direct oral anticoagulants (DOACs)
What is the mechanism of action for heparin?
Catalyzes antithrombin, which inactivates factors 2a, 9a, 11a, and 12a (also binds to other plasma proteins)
Prolongs aPTT
Cannot bind to thrombin already in a clot
What is the onset of effect for heparin?
IV: Works immediately
Subcut: 30-60 min
What is the duration of effect for heparin?
half-life = 1-2 hours
IV: continous infusion to ensure level response
Subcut: 8 hours
What are some contraindications for heparin?
Most are not absolute contraindications, but risk factors for bleeds
- Hemorrhagic stroke
- Severe, uncontrolled HTN
- Active gastric/duodenal ulcer
- Blood clotting disorders
-Severe thrombocytopenia
Heparin-induced thrombocytopenia is an actual contraindication for heparin use
What is an approximate heparin dose for thromboprophylaxis?
5000 units SC every 8-12 hours
What is an approximate heparin dose for treatment of DVT/PE?
IV: LD 80 units/kg over 10 min, then 18 units/kg/hour
SC: 250 units/kg Q12h
Narrow therapuetic window + variable response rates (not preferred by nurses, because of frequent dose adjustments based on lab samples)
How long is heparin used for VTE treatment?
Usually, heparin will just be used for less than 7 days (if need to use anticoagulant for longer, HCPs will switch to something that is less monitoring intensive + more comfortable)
Heparin is simultaneously given with warfarin
Heparin is d/c when INR reaches target INR for 1-2 days
What are some common adverse effects associated with heparin?
- Minor bleeds
- Injection site reactions if subcut
- Transient, mild liver enzyme elevation
What are some concerning adverse effects associated with heparin?
- Heparin induced thrombocytopenia (HIT)
- Major bleeds
- Hyperkalemia
- Skin necrosis
- BMD decrease
What is the antidote used in reversing the anti-coagulation effect of heparin?
Protamine sulfate (most effective given closer to heparin dosing time)
What is heparin-induced thrombocytopenia (HIT?
It is an immune-mediated platelet aggregation reaction
- Causes platelets to activate and stick together
- Increased thrombotic and bleed risk
Onset typically occurs 5-10 dats after heparin initiation
What is being measured by the 4T scale?
It measures the probability of heparin-induced thrombocytopenia (HIT)
The following conditions are associated with HIT risk:
1. Thrombocytopenia
2. Timing of the decrease in platelet count
3. Thrombosis or other sequelae
4. Other causes of thrombocytosis
Decreases in platelet count are represented by the following scores:
1. less than 30% fall (0 points)
2. 30-50% fall (1 point)
3. More than 50% fall (2 points)
Review slide 57 for 4T scale (know for exam)
How is heparin-induced thrombocytopenia treated?
d/c all sources of heparin
Begin alternate anticoagulation (warfarin is initially unsuitable, but can use argatroban, fondaparinux, danaparoid, bivalirudin)
DOACs (rivaroxaban) can be used in stable patients (rivaroxaban 15mg PO BID until platelets restored)
Transition to warfarin once platelets restored
Why is warfarin initially unsuitable for VTE and HIT?
Warfarin initially reduces protein C and S, which increases thrombotic risk
What are some drug interactions associated with heparin?
- ACEi/ARBs (increases risk of hyperkalemia)
- Antiplatelets (Increased anti-coagulation)
- Aspirin/NSAIDs (increased anti-coagulation)
- Estrogens/progestins (pro-thrombotic)
- Herbs (194 herbs have anti-coagulant properties)
- Potassium salts/ potassium diuretics
How is heparin therapy for VTE treatment monitored?
Must monitor aPTT In VTE treatment for efficacy (exact normal aPPT values vary between labs)
Platelet count, HgB and hematocrit, and potassium (only if at risk of hyperkalemia)
What are some examples of LMWH?
- Enoxaparin (used in ACS)
- Tinzaparin (most commonly used LMWH in SHA)
- Dalteparin
- Nadroparin
All appear to be equally clinically in safety and efficacy (Not interchangeable)
What is the mechanism of action for LMWH?
Same as heparin, but higher affinity for factor 10a
Can affect aPTT levels
Cannot bind to thrombin already in a clot
LMWHs have more predictable PK parameters vs heparin (allows fixed doses of LMWH with less dose adjustment)
What are some contraindications for LMWH?
Same as heparin
Heparin-induced thrombocytopenia is an actual contraindication for heparin use
Caution:
- Hemorrhagic stroke
- Severe, uncontrolled HTN
- Active gastric/duodenal ulcer
- Blood clotting disorders
-Severe thrombocytopenia
How are LMWHs dosed broadly?
Depends on the condition and patient factors:
- Prophylaxis vs. treatment
- What type of LMWH is being used
- Renal function
- Obesity
- Indication
LMWH is only subcutaneous admin (no IV or oral dosage forms)
How is tinzaparin dosed?
Tinzaparin 75 units/kg for VTE prophylaxis (some references use Tinza 4500u across the board regardless of weight)
TInzaparin 175units/kg for VTE treatment
Tinzaparin 2500 units subcut for dialysis line patency
Are tinzaparin doses adjusted for impaired renal function?
No, but normal tinzaparin doses can be used in prophylaxis and treatment in patients with CrCl of 20mL/min and 30mL/min respectively
If patient’s renal function falls below these limits, they cannot take tinzaparin
How is tinzaparin dosed in patients with obesity (BMI over 30)?
Continue using body weight to determine tinza dose (Doses of 30,000 units and above subcut can be used safely as long as weight is also high)
How is tinzaparin dosed in pregnant women?
The metabolism of LMWH is altered during the course of pregancy, especially in the third trimester
Opinion differs
- Use weight at begining and do not adjust
- Weigh every trimester and adjust dose
- Switch to heparin at 36 weeks
What is the onset of effect seen with LMWH?
Starts in 1 hour following administration and peak anti-coagulant response is 3-5 hours after administration
What is the duration of effect for LMWH?
Anti-Xa activity persists for 12-24 hours with subcut dose
Half-life is only 3-6 hours
What are some common side effects associated with LMWH?
Same as heparin, but lower incidence (for both common and serious adverse effects)
Common:
- Minor bleeds
- Injection site reactions if subcut
- Transient, mild liver enzyme elevation
Serious:
- Heparin induced thrombocytopenia (HIT) (an order of magnitude lower vs. heparin)
- Major bleeds
- Hyperkalemia
- Skin necrosis
- BMD decrease
How are LMWHs monitored for efficacy?
- Cannot use aPTT
- Anti-Xa testing 10h after dose is indicated only in some populations:
a. Obese
b. Pregnant
c. Renal insufficiency (measure anti-Xa, 4 hours post-dose)
How are LMWHs monitored for safety?
- Platelet count (get baseline and compare everyday)
- HgB and hematocrit (every 3 days and used to track occult blood loss)
- Potassium (only if high risk of hyperkalemia)
- Renal function
Review slides 80 & 81 for differences between heparin and LMWH
What anticoagulants are used in patients with heparin-induced thrombocytopenia (HIT)?
Factor Xa inhibitors:
- Heparinoids (Danaparoid)
- Glycosaminoglycan (fondaparinux)
Thrombin (factor IIa) inhibitor:
- Direct thrombin inhibitor (Argatroban)
What are the official indications for Danaparoid?
Prevention of DVT after surgery, or use in HIT
What are the official indications for Fondaparinux?
Same as LMWH, plus use in HIT
What are the official indications for Argatroban?
Anticoagulation in patients with HIT
Note: can affect INR, so concurrent titration of warfarin is weird
Review slide 85 for fondaparinux vs. danaparoid & argatroban
What is the mechanism of action for Warfarin?
It is a Vitamin K antagonist that interferes with the production of clotting factors dependent on Vitamin K
Factors X, IX, VII, and II (inhibition results in increased bleeding)
Protein C & S (inhibition results in clotting)
This is why warfarin is not started initially
Canada vs. Soviets in 1972
What is the onset of effect for Warfarin?
Not immediate, must clear vitamin K clotting factors from circulation
Can take 2-7 days to fully clear old clotting factors
ANy changes in dose also have a delayed response
What conditions are contraindications for warfarin?
Pregnancy (high risk of bleed when benedit of anticoagulation is less than risk of bleeding)
Active bleeds
Recent CNS or eye surgery
Previous skin reaction to warfarin
How is warfarin initiated?
Multiple approaches exist
ex. Start at 5mg and adjusting dose to acheive INR of 2-3
Be mindful of other factors that can impact INR (DOACs, heparin, liver disease, argatroban, etc.)
How does liver disease impact INR?
The liver produces clotting factors, so some liver disease may cause reduced clotting factor production
How is warfarin dosed?
Step 1: Determine indication and target INR; any symptoms of high or low INR?
Step 2: If no issues above; is the patient at risk of having those issues develop?
Step 3: Determine if sub/supra-therapeutic INR is permanent or transient cause
What are the max warfarindose changes in a day?
Increase or decrease by 10-20% daily if dose change is needed
What is bridging in Warfarin therapy?
Due to the pro-thrombotic activity of Warfarin initially, LMWH or heparin are initiated to counteract those effects and produce a net anti-thrombic effect
LMWH or heparin dose is reduced as warfarin activity becomes more anti-thrombic
How is warfarin therapy stopped?
It has a delayed offset, and it can take a couple of days for new clotting factors with adequate Vitamin K to form.
This is often done prior to surgery. After stopping warfarin, it can take multiple days before INR drops to below 1.5
Resume warfarin therapy 24 hours after surgery
What are some common side effects associated with warfarin use?
- Minor bleeds (10%)
- Abdominal cramps
- Diarrhea
- Nausea
- Skin reactions (hives)
What are some serious side effects associated with warfarin?
- Major bleeds ex. GI bleeds(1.3-3% per year)
- Purple toe syndroms (cholesterol emboli into toe blocks circulation)
- Skin necrosis (microclots form near the extremities)
Is warfarin known to have minimal drug interactions?
No, Warfarin interacts with so mant drugs, it is safer to assume Warfarin will interact with any drug with unknown interaction status
ex. Antibiotics, Antidepressants, Antiplatelets, Anti-inflammatory agents, Acetaminophen (commonly used in large sections of population)
What antibiotics in particular interact with warfarin?
Metronidazole
TMP/SMX
These antibiotics can significantly affect Warfarin
How are Warfarin drug interactions managed?
In some cases, empiric dose adjustment to warfarin can be riskier and unpredictable vs. the DI itself
Must balance the risk of bleet or clot with benefit of therapy
What are some clinical tips for managing Warfarin drug interactions?
If a DI is due to a regularly dosed drug, warfarin dose can be adjusted to accomodate such a difference in PK
Main takeaway: Do not change anything drastic about drug and diet withour consulting pharmacists and/or physicians
What is an antidote for Warfarin?
Use in case of bleed or extremely elevated INR (over 10)
Vitamin K IV or oral is given
What is a common procedure in a serious bleed for a patient on Warfarin??
- Hold warfarin
- Give Vitamin K 5-10mg IV every 12 hours
- Give factor IV (prothrombin complex or FFP)
What are some examples of DOACs?
Rivaroxaban
Apixaban
Dabigatran
Edoxaban
What are the mechanisms of action for DOACs?
Inhibition of Factor Xa:
- RIvaroxaban
- Apixaban
- Edoxaban
Direct inhibition of thrombin:
- Dabigatran
What is the onset of effect for DOACs?
All acheive peak ant-coagulation in about 2 hours
How long do the effects of DOACs last?
Usually for an average of 10 hours
What are some drug-interactions associated with DOACs?
- Agents with antiplatelet properties (NSAIDs, ASA, antidepressants)
- Strong 3A4 and P-gp inducers (Carbemazepine, phenytoin, rifampin, St. John’s Wort)
- Strong 3A4 inhibitors and P-gp inhibitors (Ketoconazole, clarithromycin, flucanazole)
- Strong 3A4 inhibitors (HIV protease inhibitors)
What two DOACs are not impacted by CYP interactions?
Dabigatran and edoxaban
Dabigatran is affected by drugs/conditions that raise pH
Review slide 117 for DOAC use in VTE treatment
How are DOAC doses adjusted for obesity?
For BMI below 40 (standard rivaroxaban and apixaban doses)
For BMI over 40, can use DOACs but patient must understand potential unknown risks
Avoid dabigatran and edoxaban
What are some common side effects seen with DOACs?
-Minor bleeding
- GI upset and dyspepsia (same as warfarin)
- Diarrhea or constipation
- Itch
What is a serious side effect seen with DOACs?
Bleeding, but mostly better or same as Warfarin
What is the role of thrombolytics in DVT?
Alteplase and Tenectaplase are more rapid and complete in their breakdown of DVT
Only indicated in VTE for high risk pulmonary embolisms
What are the risks associated with thrombolytics in DVT treatment?
More major bleeding
How long should anticoagulants be used for?
Depends on whether VTE is provoked vs. unprovoked and the number of VTE episoded experienced
If switching from heparin to a DOAC besides edoxaban, what is the protocol?
Stop heparin infusion and start apixaban, dabigatran, or rivaroxaban at the same time
If switching between heparin to edoxaban, what is the protocol?
Stop heparin infusion, and start edoxaban 4 hours later
If switching between heparin and LMWH, what is the protocol?
Stop heparin infusion, and start LMWH at the same time
Can also take a more conservative approach (start LMWH 2h after heparin infusion is stopped)
If switching between LMWH and Dabigatran or Rivaroxaban, what is the protocol?
Start dabigatran or rivaroxaban about 0-2 hours before the next dose of LMWH
If switching between LMWH and Apixaban or Edoxaban, what is the protocol?
Start apixaban or edoxaban at the same time as the ned scheduled dose of LMWH
If switching from Apixaban to heparin or LMWH, what is the protocol?
Heparin and LMWH (Stop apixaban and start heparin infusuin at the same time as the next dose of apixaban is due)
If switching from Dabigatran to heparin or LWMH, what is the protocol?
Depends on renal clearance
For both heparin and LMWH:
-CrCl is 30mL/min or greater: Wait 12 hours after last dose of dabigatran before starting heparin or LMWH infusion\
-CrCl is below 30mL/min, wai 24 hours after last dose before starting heparin
If switching from Edoxaban to heparin or LWMH, what is the protocol?
Heparin & LMWH:
- d/c edoxaban and start heparin/LMWH at the time of next schedules edoxaban dose
If switching from Rivaroxaban to heparin or LMWH, what is the protcol?
Heparin & LMWH:
- Stop rivaroxaban and start heparin/LMWH at the time of next dose of rivaroxaban
How is a patient switched from warfarin to a DOAC?
To rivaroxaban: Stop warfarin, wait until INR is less than 2.5
To dabigatran, apixaban, and edoxaban: Stop warfarin, wait until INR is less than 2.0
How are patients switched from DOACs to warfarin?
From rivaroxaban/apixaban:
Use both concurrently. Test INR on day 3, then each day prior to dose. Once INR is above 2.0, d/c DOAC
From dabigatran/edoxaban:
- If CrCl is more than 50, start warfarin 3 days before d/c
- If CrCl is between 30-50mL/min, start warfarin 2 days before d/c
What is the purpose of VTE prophylaxis in hospital?
PE remains the leading cause of preventable in-hospital death
The risk of venous thrombosis in patients admitted to the hospital depends on medical versus surgical admission and, among surgical patients, type of surgery
What situations are grounds for opt-out for Tinzaparin use in hospitalized patients?
- On therapeutic anticoagulation already
- Fully mobile and expected length of stay less than 48 hours
- Palliative/compassionate terminal care
- No acute medical conditiond and awaiting placement in long-term care
- Psychiatric admission with no known VTE risk factors
What are some mechanical options for VTE prophylaxis?
Compression stockings
Intermittent pneumatic compression device
What is VTE risk during air travel?
For flights of over 24 hours (1.5-10% of people get VTE)
These patients all had many risk factors for VTE
What can be done to manage increased VTE risk during air travel?
Compression stockings
Frequent ambulation
Flexion of ankles and knees
Hydration
Pharmacologic prophylaxis not needed in these situations
When is VTE risk the highest in pregnant or recently pregnant women?
60x risk increase in the 3 months post-partum (highest in the first 6 weeks)
What VTE treatment options can be used in pregnancy?
Heparin
LMWH
Danaparoid
Potentially fondparinux
Do not use Warfarin or DOACs
When should pregnant patients with elevated VTE risk be started on a anticoagulant?
Initiate treatment as soon as pregnancy occurs
If already on anti-coagulants (switch to something safer ex. heparin or LMWH)
What is the VTE prophylactic tinzaparin dose in pregnant women?
Tinza 75 units/kg subcut
OR
Tinza 4500 units subcut
What is the intermediate Tinzaparin dosing for pregnant women?
Tinza 10,000 units subcut daily
What is the therapeutic tinzaparin dosing for pregnant women?
Tinza 175 units/kg subcut once daily
What are some complications associated with VTE treatment in pregnant women?
Bleeds
HIT (heparin-induced thrombocytopenia)
Bone loss
If a patient has cancer, are they most likely bleedy or clotty?
Depends on the type of cancer and is progression. In general, cancers make blood both more bleedy and clotty
What are some causes of increasing bleeding risk in cancer?
- Chemotherapy-induced thrombocytopenia
- Disseminated intravascular coagulation
- Direct invasion of cancer
- Increased fibrinolytic factors
- Radiation-induced tissue damage
What is the drug of choice in cancer associated thrombosis?
LMWH has been used historically
Evidence for DOAC usage (Not reccomended in Gi/GU malignancy)
