Coagulation Flashcards
What are the 3 broad sides of Virchow’s Triad?
Endothelial Injury
Venous stasis
Hypercoagulable state
What is included in the common methods of “endothelial injury” in Virchow’s triad?
Surgery
Prior DVT
Venous access
Trauma
Sepsis
Vasculitis
What is included in the common methods of “venous stasis” in Virchow’s triad?
Advancing age
Immobilization (e.g. bed-ridden, long plane flights)
Stroke, cord injury
Anesthesia
Heart or lung failure
Hyperviscosity (e.g. in Sickle cell patients)
What is included in the common methods of developing a hypercoagulable state in Virchow’s triad?
Protein C, S or AT III deficiency
Activated protein C resistance (Leiden)
Hyperhomocysteinemia
Antiphospholipid antibody
Prothrombin 20210 mutation
Sickle Cell
Cancer
Estrogen
Pregnancy
HIT
MPN
What is the differential diagnosis of a painful, red, swollen leg?
Clot
Baker’s cyst (a buildup of synovial joint fluid) that forms a cyst behind the knee
Soft tissue infection (cellulitis)
What are some important risk factors for developing a clot?
- Prior hx of VTE
- Family hx of clot
- Surgical procedures
- Hospitalization
- Trauma
- Pregnancy
- Heart failure
- Immobility
- oral contraceptives or hormone replacement therapy
- obstetric history
- Cancer?
- Other illnesses
The best option for diagnosing a DVT is _____ for a patient with a moderate or high probability of having a first episode of a DVT.
What are other good options?
Duplex ultrasound
can also do a contrast venography, MRI venography, or impedance plethysmography
In a person with a low pretest probability, a NEGATIVE ____ test can rule OUT a clot, but a POSITIVE test is less helpful - why?
In a person with a low pretest probability, a NEGATIVE D-dimer test can rule OUT a clot, but a POSITIVE test is less helpful because there is a long list of things that could cause a positive result.
How does a D dimer test work?
A D dimer is a fragment of crosslinked fibrin clot that has undergone fibrinolysis.
Indicates a clot has formed somewhere.
Why do we treat DVTs?
- To prevent further clot extension
- To prevent acute pulmonary embolism - 50% of untreated proximal DVT will lead to PE.
- To reduce the risk of recurrent thrombosis
- To relieve the symptoms of massive iliofemoral thrombosis with acute lower limb ischemia and/or venous gangrene (ie, phlegmasia cerulea dolens)
- To limit the development of late complications, such as the post-thrombotic syndrome, chronic venous insufficiency, and chronic thromboembolic pulmonary hypertension.
How is a DVT treated?
- Everyone should have a CBC and PT/INR and aPTT drawn at baseline. Kidney and liver function tests help determine which drugs can be used most safely
- Everyone (almost) goes on an anticoagulant for at least three months
- At three months, we’ll evaluate for necessity of continuing anticoagulation therapy.
What types of clots aren’t treated with blood thinners? Why?
Superficial venous clots
Distal DVTs
Because these rarely embolize or cause long-term symptoms, and anticoagulants increase the risk of bleeding—so if the risks outweigh the benefits. . .don’t treat
Superficial Femoral Vein:
IS actually a deep vein and NOT a superficial vein. A clot in the SFV is a DVT and needs to be treated as a DVT.
Which arm veins are superficial and which are deep?
Superficial: radial, basilic, cephalic (clots here usually result from IVs and do NOT need anticoagulation)
Deep arm veins: brachial, axillary, subclavian
How do most patients get PEs?
From a clot (often DVT) that fragments and lodges in a pulmonary artery.
What symptoms are commonly associated with a clot that lodges in a major branch of the pulmonary artery?
Hypotension, right heart failure, syncope, and death (from lack of cardiac output)
If a PE lands in a more peripheral branch artery of the lungs, what symtoms are commonly found?
SOB, cough, and chest pain that is pleuritic (hurts more to breathe, especially deep breathing due to ischemia of outer portion of lobes and pleural lining)
What is included in a differential diagnosis for acute chest pain?
PE
Pneumonia
MI
Costochondritis
Muscle strain
Panic attack
Trauma
How is a PE diagnosed?
•CT angiography:
- CT scan with addition of contrast
- Can see the clot or sometimes another reason for the pulmonary symptoms
•V/Q scanning:
- A nuclear medicine study, looking at areas of ventilation and trying to match them with areas of perfusion
- A V/Q mismatch indicates a clot (something that’s ventilated but not perfused)
•Pulmonary angiography – the gold standard (but CT w/ angio is quickest, cheapest)
•Echocardiography:
- Can sometimes see the clot
- Can see the effect of the clot on the right side of the heart
What is indicated in this image?
This is a CT angio that shows a bilobed PE called a “saddle PE”
What does this image indicate?
This is a V/Q mismatch test, which shows the difference in ventilation vs. perfusion of an area. In this photo, the patient has a PE in the R lobe.
How is a PE treated?
- Mainstay is anticoagulation for at least three months
- Can sometimes consider giving thrombolytic therapy for massive PE with right heart collapse
- Supportive care (oxygen, blood pressure support)
What are IVC filters used for?
- Interrupt the IVC (inferior vena cava) to “catch” clots arising from the lower extremities—preventing further PEs
- Indicated in patients who are unable to safely use anticoagulation, such as someone who just had neurosurgery 12 hours ago with a new DVT or in someone with recurrent PEs despite therapeutic anticoagulation
What problems are associated with IVC filters?
They only work for a year, then they get clotted off and lead to worsening lower extremity symptoms
They can migrate and perforate
What are the consequences of an unprevented VTE?
- Symptomatic DVT or PE
- Fatal PE
- Increased spending for investigating symptomatic patients
- Increased risk of recurrence
- Chronic post-thrombotic syndrome
What are the two categories of VTE prophylaxis?
-Mechanical:
- Graduated Compression Stockings (GCS)
- Intermittent Pneumatic Compression Devices (IPC)
-Pharmacologic (drugs given at lower doses than full “treatment” doses)
Thrombophilias are inherited states that predispose patients to _____.
blood clotting
Thrombophilias typically lead to ___ clots rather than ___ clots
Thrombophilias typically lead to venous clots rather than arterial clots
Describe the Protein C system:
Thrombin can act as both a pro and anti coagulant. When bound to thrombomodulin on an in-tact endothelial surface, thrombin acts as an anti-coagulant.
Here, it doesn’t activate platelets or fibrinogen or Factors 5 and 9 like it does when it is pro-coagulating in the serum. Instead, it activates Protein C. Activated protein C has a cofactor called protein S. These two inactivate Factor VIIIa and Va.
This turns off the coagulation cascade.
How is the aPTT changed when Activated protein C is added to a normal patient’s serum?
The aPTT gets longer, because it slows the coagulation cascade.
Factor V Leiden (FVL) is a mutation in the factor V molecule, rendering it resistant to cleavage by ______. Factor V remains a procoagulant and thus predisposes the carrier to ____ formation.
Factor V Leiden (FVL) is a mutation in the factor V molecule, rendering it resistant to cleavage by activated protein C. Factor V remains a procoagulant and thus predisposes the carrier to clot formation.
What is the mutation responsible for Factor V Leiden? What populations is this disease prevalent in?
Mutation: FV R506Q
Found in 5% of Caucasians
What are the symptoms associated with Factor V Leiden and why?
The deficiency in this disorder is due to a mutation in the factor V molecule, which makes it resistant to cleavage by Activated Protein C. As a result, the coagulation cascade can’t be properly turned off.
Patients thus experience an increased risk for their first episode of a DVT 5 fold.
HOWEVER, has no effect on VTE recurrence.
Many proteases cleave at ___ (amino acid). Why is this important in Factor V Leiden?
Cleave at arginines
Mutation in FV is R506Q, changing an arginine to a glutamate, thus abolishing the major cleavage site by APC.
The prothrombin G20210 mutation is a ____ mutation in the 3’ untranslated region of the ___ gene.
The prothrombin G20210 mutation is a gain of function mutation in the 3’ untranslated region of the Factor II gene.
Patients with the Prothrombin G20210 mutation have higher ___ levels, resulting in ____.
Patients with the Prothrombin G20210 mutation have higher Factor II levels, resulting in mild thrombophilia.
(increased risk for DVT 4 fold, no effect on VTE recurrence)
**factor II is prothrombin
What inherited thrombophilias are gain of function vs loss of function?
Gain of function:
- Prothrombin G20210
Loss of function:
- Factor V Leiden
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
Among patients with thrombosis, what is the most common genetic disorder found?
Factor V Leiden
What is Antiphospholipid Syndrome and how is it characterized?
A clinico-pathologic diagnosis characterized by the presence of antibodies that can lead to an increased risk for clotting.
Requires BOTH clinical symptoms AND lab abnormalities
Clinical findings:
- Thrombosis – venous or arterial
- Recurrent pregnancy loss
Lab abnormalities—antiphospholipid antibodies:
- Lupus anticoagulant or/and
- Anticardiolipin antibodies
- Beta-2- glycoprotein I antibodies
Mechanism of clots–unclear
How is Antiphospholipid Syndrome diagnosed?
These antibodies can occur as a reaction to a clot OR they can be the reason behind the clot.
We make sure that the antibodies are present at least twice—antibodies measured at least 12 weeks apart.
What are common environmental risk factors for a VTE?
- Estrogens - pregnancy, combined OCP, HRT
- Surgery - abdomen/pelvis, orthopedic to back, pelvis, lower extremities
- Trauma - back, pelvis, lower extremities
- Prolonged immobilization - 3+ days bed rest, stroke
- Long distance airline travel (6+ hours)
- Indwelling venous catheters
- Cancer (“Trousseau’s syndrome”)
Why screen for a thrombophilia?
- Because it might impact the length of anticoagulation
- Because patients want to know why they had a clot
- Because it may have impact on other family members in terms of OCPs, etc.
Why NOT screen for a thrombophilia?
- Because it’s expensive
- Because at the time of a clot, some of the measurements of proteins can be abnormally low due to consumption
- Because in a provoked event, it won’t change management
- Because some of the mild thrombophilias may never produce symptoms,
- Asymptomatic family members with the thrombophilia may not be able to get life/disability insurance
What events might prompt a clinicial to consider screening for thrombophilia
NOT with a provoked VTE
Maybe if:
age <50
Clot in a weird place
Family history of clot
Recurrent clots
How is Thrombophilia managed?
In asymptomatic carriers, consider prophylaxis in high risk situations
After a patient’s first clot, use standard 3-6 mo anticoagulation
Consider indefinite anticoagulation under the following circumstances:
- Cancer
- Antiphospholipid antibodies
- Compound thrombophilias
- Recurrent unprovoked VTE
At low doses, aspirin produces an antithrombotic effect by irreversibly acetylating ___, thus inhibiting platelet generation of ______. Higher doses also inhibit _____.
At low doses, aspirin produces an antithrombotic effect by irreversibly acetylating COX-1, thus inhibiting platelet generation of thromboxane A2. Higher doses also inhibit COX-2.
____ is used for both primary and secondary prevention of arterial blockages (MI, stroke, PVD)
aspirin
List important adverse effects associated with aspirin use:
•GI upset
•GI bleeding—inflammation and peptic ulcer disease
•Can provoke asthma in atopic patients
•Contra-indicated in children and teenagers with chickenpox or flu symptoms (Risk of Reyes syndrome)
•Kidney damage by renal papillary necrosis
•At high doses, salicylate toxicity and tinnitus
What is the mechanism of action of warfarin?
Warfarin is a vitamin K antagonist (interferes with the vitamin K cycle)
Warfarin interacts with the Vitamin K epoxide reductase enzyme so that oxidized Vitamin K cannot be recycled back to normal, functional reduced vitamin K (KH2), which is used to gamma-carboxylate the vitamin K-dependent factors.
This leads to a depletion of vitamin KH2, thereby limiting the γ- carboxylation of the coagulation factors (II, VII, IX, X, Protein C and S).
Factors like prothrombin are thus not gamma-carboxylated, and cannot effectively bind to phospholipid membranes. Thus blood coagulation is limited.
Warfarin acts to block ___ synthesis of the vitamin K-dependent factors. Why is this important?
Warfarin acts to block NEW synthesis of the vitamin K-dependent factors.
SO there are still some pre-formed factors left, and thus Warfarin’s anticoagulant effect isn’t immediate.
For the first three days of “warfarinization,” the levels of _____ drop faster than ______
For the first three days of “warfarinization,” the levels of protein C and S (anticoagulation factors) drop faster than procoagulation proteins (Factor II, VII, IX, X)
What are bridging anticoagulant therapies and why are they used?
These are anticoagulant therapies that act quickly, such as heparin, that are used to reverse the temporary hypercoagulable state characteristic of the first 3 days of “warfarinization.” The hypercoagulable state is worse in patients with Protein C or underlying vitamin K deficiency. Additionally, patients are not fully anticoagulated until levels of factor II drop to 20% or so.
What vitamin K-dependent clotting factor has the shortest half-life?
Factor VII
What is warfarin used for?
•Treatment of VTE
•Prevention of thrombosis on mechanical heart valves and artificial hearts
•Prevention of embolic stroke in patients with atrial fibrillation
How do we measure the effect of warfarin?
Measure the effect on the INR - in most cases, we want this value between 2-3
What needs to happen when a patient begins warfarin?
- Start dose (usually 5 mg)—check INR in 2 days
- Lower dose in those with underlying Vit K deficiency
- Bridge!!—and don’t stop the bridge for at least 5 days
What is important for maintaining warfarin treatment?
- Drug-food interactions - maintain steady amount of Vit-K containing foods
- Drug-Drug interactions:
- Drugs that interfere with CYP enzymes
- Antibiotics - kill gut bacteria that make vitamin K
•Constant INR monitoring – weekly to start, then at least monthly
What lab values do we test/expect to see while monitoring warfarin patients?
- At therapeutic levels, we follow the PT/INR
- At toxic levels, the aPTT will also be prolonged.
- No effect on the PFA-100
Possible side effects of warfarin:
- Alopecia
- Osteoporosis
- Bleeding
•Warfarin Skin Necrosis
- When warfarin is started in someone who is vitamin K deficient or who has protein C deficiency without bridging
- Microvascular thrombosis
- Fatty tissues
Discuss warfarin use during pregnancy:
- Warfarin is a teratogen (5-30% risk of birth defects)
- Warfarin embryopathy
- 1st trimester, especially between weeks 6-12
- Bone/cartilage abnormalities
- stippled epiphyses and nasal and limb hypoplasia
•Other—CNS abnormalities reported with warfarin use throughout pregnancy.
•OK for lactating women, since it’s not excreted into breast milk
How is warfarin reversed?
-Vitamin K
-Plasman (not super helpful because you have to give a lot and it takes a while to thaw)
-Prothrombin complex concentrates (PCC)
- Pharmacologic concentrate, plasma derived, virally inactivated
- KCentra is a Mixture of Factor II, VII, IX, X
- Fast, effective, and only a small amount needed to reverse effects.
Heparin is a ________ containing variable amounts of a disaccharide-repeating unit of either iduronic acid or glucuronic acid residues linked to a glucosamine residue.
polysaccharide
Heparin is composed of variable amounts of either iduronic acid or glucuronic acid residues, each of which is _______
variably sulfated
Both the variation in polysaccharide sequence and length and the variation in the degree of sulfation results in a(n) ____ population of molecules that collectively is called heparin
heterogenous
All of heparin’s effects require binding to ____. The resulting complex will then inactivate __, __, and __.
All of heparin’s effects require binding to antithrombin. The resulting complex will then inactivate Xa, IXa, and XIa.
Full length heparin (at least ___ long) will form a ternary complex with ____ and ___, which accelerates the action of antithrombin to inactivate thrombin by 10,000 fold.
Full length heparin (at least 18 sugars long) will form a ternary complex with thrombin and antithrombin, which accelerates the action of antithrombin to inactivate thrombin by 10,000 fold.
Unfractionated heparin:
- Must be given intravenously (for treatment) or subcutaneously (for prophylaxis)
- UFH has variable binding to plasma proteins, endothelium, and macrophages, So there is not a fixed dose for therapeutic anticoagulation.
•Must be monitored and administered in the hospital (generally)
What is heparin used for?
- VTE
- Both treatment and prophylaxis (different doses)
- Arterial occlusions—acutely
- MI, stroke, peripheral arterial disease
- Angioplasty
- Vascular and cardiac surgery
- Hemodialysis
- Flushes to keep IV catheters patent
How is heparin monitored?
- Follow the aPTT (prolonged)
- Follow the anti-Xa level (prolonged) (either directly measured or derived from the aPTT). Xa activity is measured by the rate of conversion of a substrate into a colored byproduct.
- The TCT will be prolonged
- The PT will be prolonged with very large doses of heparin, but normal otherwise
- Why?? Because the PT reagent mix also contains heparinase to degrade any stray amounts of heparin around
How is the anti-Xa level measured?
- The lab activates FX to FXa using a snake venom.
- Xa activity is measured by the rate of conversion of a substrate into a colored byproduct.
- We then add the patient’s plasma to the reagent mix and see if it slow the conversion of colorless solution into a colored solution.
- The decrease in rate is the Anti-Xa level
Heparin side effects:
- Bleeding
- Osteoporosis with long-term use
- Some patients can develop hyperkalemia
- Development of HIT
- 5% of patients treated with UFH
- Can paradoxically lead to thrombosis
What is the antidote to heparin?
Protamine sulfate
(positively charged—neutralizes the negatively charged heparin)
Low Molecular Weight Heparin:
- Made from UFH by further chemical or enzymatic processing.
- Smaller—about 1/3 the size of UFH lengths
- Multiple formulations, all a little different
- Enoxaparin = Lovenox
- Dalteparin
- Tinzaparin
How/when is LMWH administered and monitored?
- Given Subcutaneously – best if given twice daily (bid)
- Immediately bioavailable
- Can use to bridge warfarin
- Weight based dosing—very reliable anticoagulation
- Cleared by the kidneys
- No need to follow levels except in:
- Children
- Very obese
- Renal insufficiency
- Pregnant
What is the mechanism of action of low molecular weight heparin?
Remember enoXaparin is the drug
- Binds to AT using the pentasaccharide sugar motif
- But the LMWH-AT complex cannot inactivate thrombin
•It ONLY inactivates Xa
What levels are measured during LMWH monitoring?
•NO effect on the PT or aPTT
•I know—it doesn’t make sense—since it’s blocking FXa—which is needed to make a normal PT and aPTT. But trust me—it doesn’t prolong these tests. And no one I know can explain why.
•Need to follow Anti–Xa levels (order this as a LMWH level)
NO ANTIDOTE
What is LMWH used for?
•VTE:
-
Treatment
- Can be done at home if patients are taught to give themselves SQ injections
- Especially in pregnant women
- prophylaxis
•VTE associated with Cancer:
- This should NOT be treated with warfarin
- LMWH has been shown to be better
- Treat indefinitely
•Acute coronary syndromes
Side effects of LMWH:
- Bleeding
- Pain at injection site
•Renally cleared, so may not use in dialysis or ESRD
•Can cause HIT (but less commonly than UFH)
- If HIT occurs, then CANNOT use LMWH
- Cost - one month’s supply about $1000
What is Fondaparinux composed of/generated from?
- Chemically synthesized
- made from JUST the pentasaccharide part of heparin
What is the mechanism of action of Fondaparinux?
- Contains the pentasaccharide part of heparin
- Binds to antithrombin and inactivates Xa
- Does not cause HIT, but may potentiate HIT once it has occurred
Can Fondaparinux be used in patients with renal failure?
No - cleared renally
How is fondaparinux administered?
SQ administration
Once daily dosing
What is the antidote for Fondaparinux?
Tricked ya
there’s not one
What is Fondaparinux used for?
Used for treatment and prophylaxis of VTE
What is Dabigatran and what is its mechanism of action?
•The first US approved DOAC (direct oral anticoagulant)
•Directly binds and inactivates IIa (thrombin)
•No need for antithrombin as a mediator
What is Dabigatran used for?
- Use for prevention of stroke in Atrial Fibrillation and also for treatment of VTE
- May NOT use for heart valves
Important considerations for Dabigatran use:
Renally cleared
Variable dose effect
prolongs the thrombin time
Side effects of dabigatran:
Bleeding
GI upset (1/3 need to stop drug)
Renal clearance - so increased bleed risk in patients with renal impairment
What is the antidote for Dabigatran?
Idarucizumab
- Trade name is Prax-bind (trade name for dabigatran is Pradaxa)
- Humanized monoclonal antibody fragment (Fab)
- Specifically binds to dabigatran and its metabolites and reverses their anticoagulant effect immediately after administration
What is Argatroban?
- An intravenous direct thrombin inhibitor
- Currently, only used in hospital for patients with HIT
How is argatroban metabolized?
hepatically
What will coagulation time tests look like with argatroban use?
•Prolongs the aPTT, the PT/INR, and the TCT
•Monitor using the aPTT
What is the mechanism of action of Rivaroxaban, apixaban, and endoxaban?
Bind and inactivate Factor Xa
How are Rivaroxaban, apixaban, and endoxaban cleared by the body?
cleared by both the kidney and by chemical degradation
What are Rivaroxaban, apixaban, and endoxaban indicated for use for?
VTE treatment and prophylaxis
Stroke prevention in A fib
What is the antidote to Xa inhibitors (rivaroxaban, apixaban, and endoxaban)?
Andexanet
- Synthetic analog of Xa
- Binds the Xa inhibitor competitievely with Xa
- GLA domain removed to prevent anticoagulant effect
- Catalytic domain mutated to prevent thrombin generation
- Currently limited in distribution
- Cost is at least $27000 per dose
Why use a DOAC instead of warfarin?
More convenient to administer
Fewer intracranial bleeds
What are the disadvantages of using DOACs instead of warfarin?
•NOT effective in preventing stroke in patients with mechanical heart valves
- Dabigatran-treated patients had slightly more MIs than warfarin-treated patients
- Dabigatran and Rivaroxaban caused more GI bleeds in the elderly
