24 - VTE Flashcards
What is the Virchow triad in thrombosis?
- Endothelial injury (trauma to blood vessels)
- Abnormal blood flow (ex: sitting w/ legs crossed for long time)
- Hyper-coagulability (ex: genetics, infection, etc.)
Describe the intrinsic pathway
Injury -> exposure of collagen basement membrane (bloodstream should never see this protein matrix) (+contact activation) -> F12 -> F12a -> F11 -> F11a -> F9 -> F9a + F8C -> F10
Describe the extrinsic pathway
Injury -> tissue thromboplastins (tissue factor) -> 7 -> 7a -> catalyzes conversion of F10 -> F10a
Describe the common pathway
F10 -> F10a (+F5a) -> F-2 (prothrombin) -> F2a (thrombin) -> F1 (fibrinogen) + 13
F1 -> soluble fibrin (+13a) -> insoluble fibrin strands -> retracted fibrin thrombus “fibrin clot” -> soluble fibrin fragments
13 -> 13a (used to convert soluble fibrin to insoluble fibrin
Describe the platelet pathway
Injury -> vasoconstriction & endothelial adhesion (+stasis of blood flow) -> platelets (+adhesion) -> release reaction -> ADP + TxA2 + aggregation (this reaction produces all 3 but ADP -> TxA2 -> aggregation also) (+vWF) -> platelet thrombus -> retracted fibrin thrombus -> soluble fibrin fragments
Plasminogen -> plasmin -> retracted fibrin thrombus
What is important to note about thrombin?
- Will always form a clot
- Takes fibrinogen (floating in bloodstream) & catalyzes conversion to fibrin
- Also works in platelet pathway
What is important to note about insoluble fibrin?
Acts as protein layer that attaches itself to vessel wall (after a few days the clot will be digested)
What is vWF?
- Von Willebrand Factor
- Protein that binds to clump of platelets and collagen and then contracts and pulls platelets up against vessel wall
What is important to note about factor VIII (8)?
- Synthesized by vascular endothelial wall and released into bloodstream
- Factor 8C = coagulant material
- Binds to Factor-8vWF on blood vessel wall (F8C on blood side, F8vWF on tissue side)
- F8C pulls complex into bloodstream (“cleaves in the bloodstream”)
What are TxA2 and PGI? Where are each synthesized?
- TxA2 (thromboxane A2) = platelet aggregator and vasoconstrictor
- PGI (prostacyclin) = platelet anti-aggregator and vasodilator (prevents clotting)
- In the blood vessel wall – AA (arachidonic acid) -> PGI catalyzed by COX (cyclooxygenase)
- In platelets – AA -> TxA2 catalyzed by COX: TxA2 then exits platelets
Factors predisposing to bleeding
- Open vessel (ex: recent surgery)
- Platelet defects (ex: drugs – ASA, clopidogrel)
- Pro-clotting factor deficiencies (ex: excess of protein C or S; deficiency of inactivated forms of any clotting factors)
Describe the PT and INR tests
- Based on time for detection of clot formation in a test tube of px plasma after addition of thromboplastin and calcium
- Interpretation = > 12 sec is suggestive of defective extrinsic & common pathway; test is sensitive to reductions in factor 2, 7, & 10 (note: warfarin reduces synthesis of factors 2, 7, 9, & 10)
- Clinical notes = factor 7 is very sensitive to warfarin (b/c of its very short plasma t1/2), therefore PT (or INR) may rapidly become prolonged during warfarin therapy w/o adequate reduction of activated factors 2 or 10
- Thrombotic state may still be evident since both factors 2 & 10 may continue to be activated via intrinsic pathway
Does thrombocytopenia or defective platelets affect PT, INR, or aPTT?
None
Does ASA or other NSAIDs affect PT, INR, or aPTT?
None
Describe the aPTT (activated partial thromboplastin time) test
- Based on time for detection of clot formation in a test tube of px plasma after addition of activating agent and calcium
- Interpretation = 33 sec is suggestive of defective intrinsic & common pathway; test is sensitive to reductions in factors 2, 8, 9, 10, 11, & 12
- Clinical notes = heparin immediately accelerates binding & inactivation of activated forms of factors 2, 9, 10, 11, & 12 by antithrombin; PD action of heparin on PTT is immediate, but maximal effects are seen commonly after 6 h (4.5 half-lives of heparin)
Degradation rate of vit-K dependent clotting factors upon administration of warfarin
- Warfarin = vitamin-K antagonist, so inhibits production of these clotting factors (2, 7, 9, & 10)
- Factor 7 degrades in 4-7 h
- Factor 9 in 21-30 h
- Factor 10 in 27-48 h
- Factor 2 in 42-72 h
- Conclusion = can still form clot through intrinsic pathway in first 24-48 h after warfarin administration, but past that factors 2, 9, & 10 will diminish so no longer able to clot
Relationship between PT and INR
- INR = (PT/PTc)^ISI
- PT = px prothrombin time
- PTc = mean prothrombin time for lab control
- ISI = international sensitivity index
- Don’t really care about actual PT, only care about INR
Difference between red thrombi and white thrombi?
- White thrombi = arterial thrombi; primarily made of platelets but also fibrin & WBC’s (ex: coronary artery thrombosis, cerebral circulation thrombi)
- Red thrombi = venous thrombi; primarily fibrin & RBC’s and a small platelet plug (ex: DVT, pulmonary emboli, ischemic limbs)
- ASA plays no role in tx or prevention of venous thrombi
What are some examples of procoagulants and anticoagulants?
- Clotting (procoagulants) – tissue thromboplastins, exposed collagen, activated factors, TxA2, vWF, factor-8 coagulant material
- Bleeding (anticoagulants) – protein C, protein S, factor deficiencies, antithrombin (AT), prostacyclin, heparin, tPA, plasmin
Common causes of hypercoagulable disorders?
- DVT
- MI
- Prosthetic devices in contact w/ blood
- Atrial fibrillation
Pathophysiology of less common hypercoagulable disorders
- Factor 5 Leiden & prothrombin gene mutations are relatively common inherited thrombophilic abnormalities in Caucasian population conferring the individual w/ small increase risk for venous thrombosis
- Antithrombin, protein C, & protein S deficiency are less common that confer a significantly higher risk for venous thrombosis
- Development of phospholipid antibodies is an autoimmune condition that predisposes an individual to arterial thrombosis, venous thrombosis, and/or pregnancy loss
- Cancer is common cause of thrombophilia
- Long-term anticoagulation often considered in these px; tx should be individualized, balancing risk of thrombosis vs. risk of bleeding w/ anticoagulants
What are some risk factors for thrombogenesis?
- Obesity
- Age > 40 y/o
- Malignancy
- Immobilization
- Major surgery
Characteristics of deep vein thrombosis
- Unilateral, warm, swollen, painful leg
- Usually starts in calf (distal DVT)
- May progress, moving up the thigh (proximal DVT)
- Diagnosis based on symptomatology alone is correct in less than 50% of the time
Characteristics of pulmonary embolism
- Most common clinical presentation = tachypnea, chest pain, dyspnea, tachycardia (very acute onset)
- Commonly found in px w/ recent history of DVT
- Not an easy diagnosis; requires objective methods to establish
Atrial fibrillation increases risk of ____ embolization
Cerebral
What is important to note about px w/ prosthetic heart valves?
- Px w/ prosthetic heart valves are at increased risk of developing valvular thromboembolism (most common clinical manifestation = cerebral embolism)
- Embolization greater w/ mechanical than bioprosthetic valves
Describe the difference between tx for mechanical and bioprosthetic valves
- Mechanical valves – warfarin ING target 2.5 recommended for valves in aortic position w/ no risk factors for TE; if risk factors present then target 3; target 3 recommended for valve in mitral position
- Bioprosthetic valves – generally lower risk for systemic embolization; ASA 75-100 mg reasonable in all px w/ bioprosthetic valves; for first 3-6 months after bioprosthetic valve surgery target warfarin INR 2.5
What are the goals and monitoring parameters for UFH and warfarin?
- Goals – maintain aPTT w/in the labs specific therapeutic range (ex: 59-99 sec)
- Heparin provides immediate anticoagulant effect, so check aPTT’s q6h initially and adjust heparin infusion to maintain aPTT w/in desired range as early as possible (ie: w/in first 24 h)
- Check platelet count daily
- Start warfarin on day 1 at 5 mg po & adjust subsequent daily dose according to INR goal (individualized to thromboembolic disorder)
- Stop heparin after at least 5 days of combined therapy & when INR is greater than target for at least 2 consecutive days
- Exceptions – px w/ major pulmonary embolism or iliofemoral vein thrombosis – run heparin for up to 10 days & start warfarin after a delay of 4 days
- Possible indications – pulmonary embolism w/ shock; massive DVT w/ limb gangrene
Parameters to monitor therapy for UFH, LMWH, or warfarin
- aPTT, INR, Hgb, PLTS, & clinical signs of bleeding
- Clinical signs of bleeding (melena (black tarry stools), hematuria, ecchymosis, hematemesis, hemoptysis, epistaxis) monitor at least daily
What are the drugs and duration recommendations for DVT and PE?
- UFH or LMWH and start on warfarin at the same time
- UFH or LMWH usually d/c after 5 days provided that INR has been in therapeutic range (> 2) for at least 24 h
- Heparin should be continued longer (ie: 10 days) in those w/ massive pulmonary embolism or iliofemoral vein thrombosis
- For provoked VTE, continue warfarin for 3 months maintaining INR target 2.5
- For idiopathic or unprovoked VTE, therapy recommended for 3 or more months (up to 2.5 years)
- Continue warfarin indefinitely if pt has risk factors (ex; malignancy, AT deficiency)
- If pt has thrombotic/embolic recurrence despite anticoagulation, continue warfarin indefinitely, but increase INR target to 3
Which DOAC has the longest t1/2?
Dabigatran
What factors do LMWH, dabigatran, rivaroxaban, and apixaban target?
- LMWH = factors 2a and 10a
- Dabigatran = factor 2a
- Rivaroxaban and apixaban = factor 10a
Should LMWH, dabigatran, rivaroxaban, and apixaban be avoided in CrCl < 30?
- Yes
- Avoid apixaban if CrCl < 25
Drug interactions for LMWH, dabigatran, rivaroxaban, and apixaban?
- LMWH = none known
- Dabigatran = P-gP inhibitors/ inducers
- Rivaroxaban and apixaban = CYP 3A4 and P-gP inhibitors/ inducers
Which DOAC has the overall lowest risk of bleeding?
Apixaban
Reversal agents for anticoagulant related bleeding
- *Effectiveness if anticoagulant specific
- Protamine (IV)
- Vit K (PO, SC, IV)
- FFP (fresh frozen plasma)
- fRVIIA (recombinant factor VIIa 7a)
- 4-PCC (4 factor prothrombin complex concentrates)
- Idarucizumab (monoclonal Ab fragment specifically targeted at dabigatran)
Warfarin - indication, onset, monitoring, reversal options
- Tx of major thrombosis
- Causes clotting factor depletion (factors 2, 7, 9, 10)
- Oral only
- Slow onset (days); full effects > 1 week
- INR for monitoring
- Stop 1 week prior to planned surgeries
- Use w/ any degree of renal function
- Reversal = vit K, FFp, rFVIIa, 4-PCC; dialysis not effective in overdose
Dabigatran - indication, onset, monitoring, reversal options
- For prevention of stroke w/ A fib
- Binds to & inhibits thrombin (2a)
- Oral only
- Fast onset (1 h); full effects in 3 days
- Increases aPTT test (but not recommended for monitoring according to manufacturer)
- Stop 1-2 days prior to planned surgeries
- Use CI if ClCr < 30
- Reversal = hemodialysis, rFVIIa; no role for FFP b/c dabigatran provides anticoagulation by inhibition not by clotting factor depletion; 4-PCC not effective
Rivaroxaban/ apixaban - indication, onset, monitoring, reversal options
- For prevention of stroke w/ A fib
- Binds to & inhibits factor 10a
- Oral only
- Fast onset (3-4 h), full effects in 2 days
- Increases INR test (but not recommended for monitoring according to manufacturer)
- Stop 1-2 days prior to planned surgeries
- Use CI if ClCr < 30
- Reversal = 4-PCC (octaplex); hemodialysis removal not effective; no role for FPP b/c these agents provide anticoagulation by inhibition, not be clotting factor depletion
Describe the Greenfield filter. What are some indications?
- Mechanical device placed in inferior vena cava to “filter” emboli origination from lower extremities
- Possible indications – CI to anticoagulant therapy (ex: bleeding PUD – peptic ulcer), recurrent PE despite adequate anticoagulation
Counselling issues for px on LMWH, warfarin, or DOAC’s
- Inform all HCP’s of anticoagulant use
- Avoid ASA and other NSAIDs, and some dietary supplements as may exacerbate bleeding
- Discuss w/ pharmacist before taking any new medication (Rx or OTC) b/c lots of drug interactions
- Maintain usual diet; we will dose warfarin to your diet (can be affected by diets high in vitamin K); avoid changes in diet
- Recommend medic-alert bracelet identifying anticoagulant use
- For warfarin, instruct pt they will be undergoing weekly or biweekly monitoring of blood INR values
- Inform Dr. immediately if experience any of the following
- Bleeding after cuts that don’t stop reasonably quickly
- Black or blue spots or bruises on skin
- Bleeding from nose or mouth
- Red or dark brown urine
- Red or black appearing stools
Describe hemophilia
- Result is the same despite the type (can’t catalyze 10 -> 10a)
- Type A = deficiency of Factor 8C w/ normal factor 8-vWF; referred to as “classical hemophilia”
- Type B = deficiency of factor 9; referred to as “Christmas disease”
What is von Willebrand’s disease?
Diminished factor 8-vWF, but normal factor 8C
What is disseminated intravascular coagulation?
Simultaneous clotting and bleeding; commonly seen w/ severe sepsis
What is thrombocytopenia?
- Platelet count < 100,000
- Decreased platelet count from either decrease in bone marrow production or due to increased peripheral (ie: circulating blood) destruction (give platelet infusion if < 30,000 b/c could have spontaneous bleed in brain)
What effect does severe liver disease have on clotting/bleeding?
- Bleeding secondary to factor deficiencies
- Decreased hepatic synthesis of factors 1-13, except factor 8
- Also, have decreased synthesis of AT, plasminogen, and alpha 2-antiplasmin
- DIC may also occur
