133 Venous Thrombosis Flashcards
TRUE OR FALSE
Venous thrombosis of superficial veins is a relatively benign disorder unless extension into the deep venous system occurs.
TRUE
Venous thrombosis of superficial veins is a relatively benign disorder unless extension into the deep venous system occurs.
Confusingly, one of the major deep veins in the leg is called the superficial femoral vein.
Thrombosis involving the deep veins of the leg is divided into two prognostic categories:
- (a) Calf vein thrombosis: thrombi remain confined to the deep calf veins
- (b) Proximal vein thrombosis: thrombosis involves the popliteal, femoral, or iliac veins
Pulmonary emboli originate from thrombi in the deep veins of the leg in ___% or more of patients.
90%
Most clinically important PE arise from
Proximal deep venous thrombosis (DVT) of the leg
TRUE OR FALSE
The literature indicates a strong and consistent association of increasing incidence of VTE with increasing age.
TRUE
The literature indicates a strong and consistent association of increasing incidence of VTE with increasing age.
CLINICAL TRIAL
Extended thromboprophylaxis with betrixaban was safe and resulted in an important reduction in clinically important VTE from both an individual patient perspective and from a population health perspective
APEX study
Acute medically ill VTE prevention with extended duration betrixaban study
CLINICAL TRIAL
Study for the prevention of venous thromboembolism in hospitalized acutely ill medical patients comparing rivaroxaban with enoxaparin
MAGELLAN
The results of these clinical trials indicate that patients hospitalized with medical illness who are at increased risk of VTE should be considered for extended thromboprophylaxis for 35–45 days.
CLINICAL TRIAL
Study for the medically ill patient assessment of rivaroxaban versus placebo in reducing post-discharge venous thrombo-embolism risk
MARINER
The results of these clinical trials indicate that patients hospitalized with medical illness who are at increased risk of VTE should be considered for extended thromboprophylaxis for 35–45 days.
Patient characteristics that indicate an important increase in VTE risk
- Age older than 75 years
- A history of previous VTE
- Known thrombophilia
- Plasma D-dimer level of more than twice the upper limit of the normal range
Key patient features that indicate a high risk of bleeding and were used to exclude patients from extended thromboprophylaxis
- History of any bleeding or of GI ulcer disease in the prior 3 months
- Bronchiectasis or evidence of cavitary lung disease
- The need for dual antiplatelet drug therapy
- The presence of active cancer
Patients with cancer comprise ______% of the total disease burden of VTE.
20%
CLINICAL TRIAL
Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients
AVERT trial
CLINICAL TRIAL
Rivaroxaban for preventing venous thromboembolism in high-risk ambulatory patients with cancer
CASSINI trial
Clinical practice guidelines recommend offering such prophylaxis to patients with a Khorana score of _____
Khorana score of 2 or more
Thromboprophylaxis to patients with multiple myeloma receiving ________________-based regimens with chemotherapy and/or dexamethasone
Thalidomide- or lenalidomide-based regimens
LMWH is recommended for higher risk patients and either LMWH or aspirin for lower risk patients.
TRUE OR FALSE
Venous thrombi are composed mainly of platelets and leukocytes, with variable numbers of fibrin and red blood cells.
FALSE
Venous thrombi are composed mainly of fibrin and red blood cells, with variable numbers of platelets and leukocytes.
The thrombogenic stimuli first identified by Virchow in the 19th century are:
- (a) venous stasis
- (b) activation of blood coagulation
- (c) vascular damage
The protective mechanisms are
- (a) inactivation of activated coagulation factors by circulating inhibitors (eg, antithrombin and activated protein C)
- (b) clearance of activated coagulation factors and soluble fibrin polymer complexes by mononuclear phagocytes and the liver, and
- (c) lysis of fibrin by fibrinolytic enzymes derived from plasma and endothelial cells
PE occurs in at least ___% of patients with documented proximal vein thrombosis.
50%
- Many of these emboli are asymptomatic.
- The clinical importance of PE depends on the size of the embolus and the patient’s cardiorespiratory reserve.
- Usually only part of the thrombus embolizes, and 30% to 70% of patients with PE detected by angiography also have identifiable DVT of the legs.
The dominant risk factor for VTE (population attributable risk >90%)
Aging
- Age older than 40
The most common hereditary abnormality predisposing to VTE
Activated protein C resistance
Factor V Leiden
Another common gene mutation: Prothrombin G20210A
- The defect results from substitution of glutamine for arginine at residue 506 in the factor V molecule, making factor Va resistant to proteolysis by activated protein C.
- The gene mutation is commonly designated factor V Leiden and follows autosomal dominant inheritance
The clinical features of DVT
- leg pain
- tenderness and swelling
- a palpable cord representing a thrombosed vessel
- discoloration
- venous distention
- prominence of the superficial veins
- cyanosis
The clinical diagnosis of DVT is highly nonspecific because each of the symptoms or signs can be caused by nonthrombotic disorders.
Occlusion of the whole venous circulation, extreme swelling of the leg, and compromised arterial flow
Massive iliofemoral thrombosis
Phlegmasia cerulea dolens
The clinical features of acute PE
- (a) transient dyspnea and tachypnea in the absence of other clinical features
- (b) pleuritic chest pain, cough, hemoptysis, pleural effusion, and pulmonary infiltrates noted on chest radiogram caused by pulmonary infarction or congestive atelectasis (also known as ischemic pneumonitis or incomplete infarction)
- (c) severe dyspnea and tachypnea and right-sided heart failure;
- (d) cardiovascular collapse with hypotension, syncope, and coma (usually associated with massive PE)
- (e) several less common and nonspecific clinical presentations, including unexplained tachycardia or arrhythmia, resistant cardiac failure, wheezing, cough, fever, anxiety or apprehension, and confusion
Syncope is common presenting feature of PE and not only massive PE.
Pretest probability scoring for DVT
Geneva score or Wells approach
TRUE OR FALSE
No laboratory changes can be used to establish the diagnosis of VTE or predict its development with high probability.
TRUE
No laboratory changes can be used to establish the diagnosis of VTE or predict its development with high probability.
A negative result of this marker is useful for excluding the diagnosis in many patients with suspected DVT or suspected PE
D-dimer
A positive result is highly nonspecific.
Among patients hospitalized for acute medical illness, a D-dimer level above ____________ is a useful marker of increased risk of developing VTE over the next 35–45 days for who extended thromboprophylaxis should be considered.
Twice the upper limit of the normal range
Preferred imaging test for most patients with DVT
Ultrasonography
Used for selected patients, such as those in whom ultrasonography is unavailable or inconclusive
Venography
Compression ultrasonography of the proximal veins performed at presentation (and, if normal, repeated once ______ days later) is a safe approach in symptomatic patients.
5–7 days
TRUE OR FALSE
Measurement of plasma D-dimer may be particularly useful as an exclusion test in patients with suspected acute recurrent DVT.
TRUE
Measurement of plasma D-dimer may be particularly useful as an exclusion test in patients with suspected acute recurrent DVT.
Compression ultrasonography may remain abnormal for 1 year in 50% of patients and for even longer in some patients because of persistent noncompressibility of the vein caused by fibrous organization of the original thrombus.
Venography is of limited value for excluding the diagnosis of recurrent DVT because of obliteration or recanalization of the previously affected venous segments or nonfilled venous segments.
Highly sensitive for large emboli (segmental or larger arteries) but is much less sensitive for emboli in subsegmental pulmonary arteries
Single-detector spiral CT
Imaging that has the advantage of providing clear results (positive or negative), with a low rate of nondiagnostic test results, good characterization of nonvascular structures for alternate or associated diagnoses, and the ability to simultaneously evaluate the deep venous system of the legs (computerized tomography venography [CTV])
Contrast-enhanced CTA
CLINICAL TRIAL
The accuracy and clinical utility of multidetector CTA and combined CTA-CTV
PIOPED II study
Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study
RADIONUCLIDE LUNG SCANNING
Example of a high-probability lung scan result
A normal perfusion lung scan excludes the diagnosis of clinically important PE.
Large perfusion defects with ventilation mismatch
The major limitation of lung scanning is that theresults are inconclusive in most patients, even when considered together with the pretest clinical probability.
CLINICAL TRIAL
Accuracy of magnetic resonance angiography (MRA) for diagnosing PE, with or without the addition of magnetic resonance venography (MRV)
PIOPED III study
Based on these findings, MRA has a very limited role in the diagnosis of PE.
May be useful for patients in whom CTA or lung scanning is contraindicated
MRA and MRV
TRUE OR FALSE
Pulmonary angiography using selective catheterization of the pulmonary arteries is a relatively safe technique for patients who have pulmonary hypertension or cardiac failure
FALSE
Pulmonary angiography using selective catheterization of the pulmonary arteries is a relatively safe technique for patients who do not have pulmonary hypertension or cardiac failure
Pulmonary angiography should be used when other approaches are inconclusive and when definitive knowledge about the presence or absence of PE is required because the risk of angiography in properly selected patients is less than the risk of unnecessary anticoagulant therapy
TRUE OR FALSE
Detection of proximal vein thrombosis by objective testing provides is not a sufficent indication for anticoagulant treatment.
FALSE
Detection of proximal vein thrombosis by objective testing provides an indication for anticoagulant treatment
Regardless of the presence or absence of PE, and prevents the need for further testing
TRUE OR FALSE
A negative result by objective testing for DVT does not exclude the presence of PE
TRUE
A negative result by objective testing for DVT does not exclude the presence of PE
To whom should selective pulmonary angiography be done
Patients with features suggesting a possible alternate source of embolism to proximal DVT of the leg (eg, upper-extremity thrombosis, renal vein thrombosis, pelvic vein thrombosis, or right-heart thrombus).
The key prognostic marker for recurrent VTE
Presence of proximal vein thrombosis
Untreated proximal vein thrombosis is associated with a 10% rate of fatal PE.
Inadequately treated proximal vein thrombosis results in a 20% to 50% risk of recurrent VTE events.
Risk of clinically important PE in calf vein thrombosis
≤1%
Options for documented calf vein thrombosis
- Receive anticoagulant treatment to prevent extension or
- Undergo monitoring for proximal extension using serial ultrasonography
Symptoms of postthrombotic syndrome
Pain, heaviness, swelling, cramps, and itching or tingling of the affected leg; ulceration
The symptoms usually are aggravated by standing or walking and improve with rest and elevation of the leg.
The strongest independent risk factors for Chronic Thromboembolic Pulmonary Hypertension:
- History of PE (odds ratio [OR], 19)
- Idiopathic PE at presentation (OR, 5.7)
The objectives of treatment in patients with established VTE
- (a) Prevent death from PE and
- (b) Prevent morbidity from recurrent DVT or PE, especially the postthrombotic syndrome and chronic pulmonary hypertension
Indicated to prevent death from PE in patients in whom anticoagulant treatment is absolutely contraindicated
IVC filter
Anticoagulant therapy for at least ___ months is required to prevent a high frequency (15–25%) of symptomatic extension of thrombosis and recurrent venous thromboembolic events.
3 months
Absolute contraindications to anticoagulant treatment
- Intracranial bleeding
- Severe active bleeding
- Recent brain, eye, or spinal cord surgery
- Malignant hypertension
Relative contraindications to anticoagulant treatment
- Recent major surgery
- Recent cerebrovascular accident
- Active GI tract bleeding
- Severe hypertension
- Severe renal or hepatic failure
- Severe thrombocytopenia (platelets <50 × 109/L)
Preferred anticoagulant for the initial treatment of most patients with either DVT or PE
LMWH given subcutaneously once or twice daily
Initial anticoagulant therapy in patients with severe renal failure
IV UFH
Initial treatment with LMWH or UFH should be continued for at least ___ days
5 days
Treatment of Venous Thromboembolism
Example of Low-Molecular-Weight Heparin
- Enoxaparin: 1.0 mg/kg BID
- Dalteparin: 200 IU/kg once daily
- Tinzaparin: 175 IU/kg once daily
- Nadroparin
- Reviparin
Treatment of Venous Thromboembolism
Example of INDIRECT FACTOR Xa INHIBITOR
Fondaparinux
- 7.5 mg once daily if patient weighs 50–100 kg
- 5.0 mg once daily if patient weighs < 50 kg
- 10.0 mg once daily if patient weighs >100 kg
Treatment of Venous Thromboembolism
Example of DIRECT ORAL ANTICOAGULANTS
- Dabigatran: 150 mg BID after 5 days of parenteral LMWH or heparin
- Rivaroxaban: 15 mg BID for 21 days; then 20 mg once daily Taken with food
- Apixaban: 10 mg BID for 7 days; then 5 mg BID After 6 months, 2.5 mg BID for extended therapy
- Edoxaban: 60 mg once daily after 5 days of parenteral LMWH or heparin
An alternative
to an oral vitamin K antagonist for long-term treatment
Dalteparin
Tinzaparin
If UFH is used for initial therapy, it is important to achieve an adequate anticoagulant effect, defined as
Activated partial thromboplastin time (aPTT) above the lower limit of therapeutic range within the first 24 hours
Treatment with a VKA is started with initial heparin or LMWH therapy and overlapped for _____ days.
4–5 days
The dose of VKA should be adjusted to maintain the international normalized ratio (INR) between
2.0 and 3.0
TRUE OR FALSE
High-intensity VKA treatment (INR, 3.0–4.0) should be used in patients with the antiphospholipid syndrome and recurrent thrombosis.
FALSE
High-intensity VKA treatment (INR, 3.0–4.0) should not be used because it has not improved effectiveness in patients with the antiphospholipid syndrome and recurrent thrombosis
Low-intensity therapy (INR, 1.5–1.9) is not recommended because it is less effective than standard-intensity treatment (INR, 2.0–3.0) and does not reduce bleeding complications.
Indicated for select patients in whom VKAs are contraindicated (eg, pregnant women) and in patients with concurrent cancer
LMWH
The advantages of DOACs
- (a) they can be administered orally once or twice daily without the need for anticoagulant monitoring and dose titration;
- (b) they have fewer clinically relevant drug interactions;
- (c) because of a fast onset of anticoagulant action, similar to that of LMW heparin, they can simplify treatment for many patients by replacing the standard approach of a parenteral drug (heparin, LMWH, or fondaparinux) followed by an oral VKA with a single drug given for both initial and long-term therapy
- (d) they result in less clinically important bleeding than the approach of LMWH combined with a VKA
Clinical Trials of Direct Oral Anticoagulants for Treatment of Venous Th
Edoxaban:
Apixaban:
Rivaroxaban:
Dabigatran:
Edoxaban: Hokusai-VTE
Apixaban: AMPLIFY
Rivaroxaban: EINSTEIN-DVT, EINSTEIN-PE
Dabigatran: RE-COVER II, RE-COVER I
Each of these trials met the prespecified criteria for noninferiority of the efficacy of the DOAC for preventing recurrent VTE.
Exceptions in the use of DOACs
- (a) patients with severe renal impairment (creatinine clearance < 30 mL/min) because they were not included in the clinical trials
- (b) patients who have a mechanical heart valve because treatment with a DOAC was associated with higher risks of thrombosis, bleeding and death
- (c) patients with the antiphospholipid syndrome because of an excess risk of recurrent arterial thromboembolic events
DOACs preceded by at least 5 days of heparin or LMWH treatment
Dabigatran and edoxaban
Duration of treatment for provoked DVT
3 months or until the risk factor is reversed
Duration of treatment for unprovoked DVT
Indefinite
Factors associated with an increased incidence of recurrent thromboembolism
- Residual DVT assessed by compression ultrasonography
- Elevated levels of plasma D-dimer after discontinuing anticoagulant treatment
- Male gender
Indefinite anticoagulant treatment should be considered in patients with a first episode of VTE and
- Antiphospholipid antibodies
- Presence of one or a combination of the more potent thrombophilias (deficiency of antithrombin, protein C or protein S, homozygous factor V Leiden, or prothrombin 20210A gene mutation, or one of these with a family history of VTE)
Clinical Trial
The relative efficacy and safety of the DOAC rivaroxaban compared with aspirin for the extended treatment of VTE
EINSTEIN CHOICE trial
Aspirin should now have a very limited, if any, role for extended treatment of VTE
DOACs that can be reduced by 50% without loss of efficacy for preventing recurrent VTE after an initial 6–12 months of anticoagulant treatment
Apixaban or rivaroxaban
Anticoagulant Therapy of Venous Thromboembolism in Patients with Cancer
LMWH for the first 3–6 months of long-term treatment or indefinitely or until the cancer resolves
The regimens of LMWH that are established as effective for long-term treatment
- Dalteparin 200 U/kg once daily for 1 month, followed by 150 U/kg daily thereafter
- Tinzaparin 175 U/kg once daily
DOACs as appropriate options for treatment in patients with cancer with VTE
Edoxaban and rivaroxaban
Caution is recommended for patients with GI cancer
A humanized monoclonal antibody fragment that, when given intravenously, rapidly reverses the anticoagulant effect of dabigatran
Idarucizumab
Dose of Idarucizumab
5 g administered as two 50-mL bolus infusions, each containing 2.5 mg of idarucizumab, no more than 15 minutes apart
Helpful for reversing the anticoagulant effect of dabigatran in patients with significant renal impairment if idarucizumab is unavailable
Hemodialysis
Dabigatran is removed by hemodialysis, with up to 60% cleared during a 4- to 6-hour dialysis session
A recombinant variant of FXa that binds and sequesters FXa inhibitors, including DOACs and LMW heparin
Andexanet-α
Dose of Andexanet-α
IV bolus over 15–30 minutes (target rate, 30 mg/min) followed by a 2-hour infusion
Apixaban and for rivaroxaban given more than 7 hours: 400 mg is given over approximately 15 minutes, and the infusion dose is 480 mg (4 mg/min)
Edoxaban, enoxaparin, and for a dose of rivaroxaban given less than 7 hours: 800 mg given over approximately 30 minutes, and the infusion dose is 960 mg (8 mg/min)
Options for anticoagulant therapy of pregnant patients with VTE
LMWH and adjusted-dose subcutaneous heparin
The DOACs have not been evaluated in pregnant patients.
Advantage of LMWH than UFH among pregnant
- Less thrombocytopenia and probably less osteoporosis
- Effective when given once daily, whereas UFH requires twice-daily injection
Most common side effect of anticoagulant therapy
Bleeding
Bleeding can be classified as major or clinically relevant nonmajor
Major bleeding is defined as clinically overt bleeding resulting in
- Decline of hemoglobin of at least 2 g/dL
- Transfusion of at least 2 U of packed red cells
- Bleeding that is retroperitoneal or intracranial or occurs into other critical spaces
Patients at increased risk of major bleeding during anticoagulant therapy
- Those who have undergone surgery or experienced trauma within the previous 14 days
- Those with a history of GI or intracranial bleeding, peptic ulcer disease, or genitourinary bleeding
- Those with miscellaneous conditions predisposing to bleeding, such as thrombocytopenia, liver disease, and multiple invasive lines
The earliest clinical manifestation of heparin-associated osteoporosis
Nonspecific low back pain primarily involving the vertebrae or the ribs
Up to one-third of patients treated with long-term heparin may have subclinical reduction in bone density.
Indicated for patients with PE who present with hypotension or shock and for select patients with PE who have evidence of right ventricular dysfunction and are at high risk of hemodynamic collapse
Thrombolytic therapy
Thrombolytic therapy regimens
- 100 mg of recombinant tissue plasminogen activator by IV infusion over 2 hours (50 mg/hr)
- 30–50 mg (depending on body weight) of tenecteplase given as a single bolus injection
Heparin then is given by continuous infusion when the thrombin time or aPTT is less than twice the control value.
The starting infusion dose is 1000 U/hr.
Clinical Trial
Evaluated the effectiveness and safety of thrombolysis with tenecteplase followed by anticoagulant therapy compared with anticoagulant therapy alone
PEITHO trial
Thrombolytic therapy may be indicated in patients with DVT
The role of thrombolytic therapy in patients with DVT is limited.
- Acute massive proximal vein thrombosis (phlegmasia cerulea dolens with impending venous gangrene)
- Occasional patients with extensive iliofemoral vein thrombosis who have severe symptoms because of venous outflow obstruction
Effective for reducing the incidence or severity of the postthrombotic syndrome
Catheter-directed thrombolysis (CDT)
Clinical Trial
Use of PCDT in addition to standard therapy (anticoagulation and compression) with standard therapy alone
ATTRACT Study
PCDT should have a limited role in the care of patients with DVT, such as the occasional patient with iliofemoral DVT and persistent venous outflow obstruction in whom limb viability is threatened or in whom leg symptoms persist or worsen.
Indications for insertion of an IVC filter
- Acute VTE and an absolute contraindication to anticoagulant therapy
- Patients who have objectively documented recurrent VTE during adequate anticoagulant therapy
TRUE OR FALSE
If the indication for filter placement is transient,a permanent vena cava filter should be used.
FALSE
If the indication for filter placement is transient,a retrievable vena cava filter should be used.
A retrievable filter can then be removed in the several weeks to months later when the filter is no longer required.
If a permanent filter is placed, longterm anticoagulant treatment should be given as soon as safely possible to prevent morbidity from recurrent DVT.
