133 Venous Thrombosis

Question 1

TRUE OR FALSE

Venous thrombosis of superficial veins is a relatively benign disorder unless extension into the deep venous system occurs.

Answer 1

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.

Question 2

Thrombosis involving the deep veins of the leg is divided into two prognostic categories:

Answer 2

• (a) Calf vein thrombosis: thrombi remain confined to the deep calf veins
• (b) Proximal vein thrombosis: thrombosis involves the popliteal, femoral, or iliac veins

Question 3

Pulmonary emboli originate from thrombi in the deep veins of the leg in ___% or more of patients.

Answer 3

90%

Question 4

Most clinically important PE arise from

Answer 4

Proximal deep venous thrombosis (DVT) of the leg

Question 5

TRUE OR FALSE

The literature indicates a strong and consistent association of increasing incidence of VTE with increasing age.

Answer 5

TRUE

The literature indicates a strong and consistent association of increasing incidence of VTE with increasing age.

Question 6

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

Answer 6

APEX study

Acute medically ill VTE prevention with extended duration betrixaban study

Question 7

CLINICAL TRIAL

Study for the prevention of venous thromboembolism in hospitalized acutely ill medical patients comparing rivaroxaban with enoxaparin

Answer 7

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.

Question 8

CLINICAL TRIAL

Study for the medically ill patient assessment of rivaroxaban versus placebo in reducing post-discharge venous thrombo-embolism risk

Answer 8

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.

Question 9

Patient characteristics that indicate an important increase in VTE risk

Answer 9

• 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

Question 10

Key patient features that indicate a high risk of bleeding and were used to exclude patients from extended thromboprophylaxis

Answer 10

• 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

Question 11

Patients with cancer comprise ______% of the total disease burden of VTE.

Answer 11

20%

Question 12

CLINICAL TRIAL

Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients

Answer 12

AVERT trial

Question 13

CLINICAL TRIAL

Rivaroxaban for preventing venous thromboembolism in high-risk ambulatory patients with cancer

Answer 13

CASSINI trial

Question 14

Clinical practice guidelines recommend offering such prophylaxis to patients with a Khorana score of _____

Answer 14

Khorana score of 2 or more

Question 15

Thromboprophylaxis to patients with multiple myeloma receiving ________________-based regimens with chemotherapy and/or dexamethasone

Answer 15

Thalidomide- or lenalidomide-based regimens

LMWH is recommended for higher risk patients and either LMWH or aspirin for lower risk patients.

Question 16

TRUE OR FALSE

Venous thrombi are composed mainly of platelets and leukocytes, with variable numbers of fibrin and red blood cells.

Answer 16

FALSE

Venous thrombi are composed mainly of fibrin and red blood cells, with variable numbers of platelets and leukocytes.

Question 17

The thrombogenic stimuli first identified by Virchow in the 19th century are:

Answer 17

• (a) venous stasis
• (b) activation of blood coagulation
• (c) vascular damage

Question 18

The protective mechanisms are

Answer 18

• (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

Question 19

PE occurs in at least ___% of patients with documented proximal vein thrombosis.

Answer 19

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.

Question 20

The dominant risk factor for VTE (population attributable risk >90%)

Answer 20

Aging

• Age older than 40

Question 21

The most common hereditary abnormality predisposing to VTE

Answer 21

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

Question 22

The clinical features of DVT

Answer 22

• 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.

Question 23

Occlusion of the whole venous circulation, extreme swelling of the leg, and compromised arterial flow

Massive iliofemoral thrombosis

Answer 23

Phlegmasia cerulea dolens

Question 24

The clinical features of acute PE

Answer 24

• (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.

Question 25

Pretest probability scoring for DVT

Answer 25

Geneva score or Wells approach

Question 26

TRUE OR FALSE

No laboratory changes can be used to establish the diagnosis of VTE or predict its development with high probability.

Answer 26

TRUE

No laboratory changes can be used to establish the diagnosis of VTE or predict its development with high probability.

Question 27

A negative result of this marker is useful for excluding the diagnosis in many patients with suspected DVT or suspected PE

Answer 27

D-dimer

A positive result is highly nonspecific.

Question 28

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.

Answer 28

Twice the upper limit of the normal range

Question 29

Preferred imaging test for most patients with DVT

Answer 29

Ultrasonography

Question 30

Used for selected patients, such as those in whom ultrasonography is unavailable or inconclusive

Answer 30

Venography

Question 31

Compression ultrasonography of the proximal veins performed at presentation (and, if normal, repeated once ______ days later) is a safe approach in symptomatic patients.

Answer 31

5–7 days

Question 32

TRUE OR FALSE

Measurement of plasma D-dimer may be particularly useful as an exclusion test in patients with suspected acute recurrent DVT.

Answer 32

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.

Question 33

Highly sensitive for large emboli (segmental or larger arteries) but is much less sensitive for emboli in subsegmental pulmonary arteries

Answer 33

Single-detector spiral CT

Question 34

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])

Answer 34

Contrast-enhanced CTA

Question 35

CLINICAL TRIAL

The accuracy and clinical utility of multidetector CTA and combined CTA-CTV

Answer 35

PIOPED II study

Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study

Question 36

RADIONUCLIDE LUNG SCANNING

Example of a high-probability lung scan result

A normal perfusion lung scan excludes the diagnosis of clinically important PE.

Answer 36

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.

Question 37

CLINICAL TRIAL

Accuracy of magnetic resonance angiography (MRA) for diagnosing PE, with or without the addition of magnetic resonance venography (MRV)

Answer 37

PIOPED III study

Based on these findings, MRA has a very limited role in the diagnosis of PE.

Question 38

May be useful for patients in whom CTA or lung scanning is contraindicated

Answer 38

MRA and MRV

Question 39

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

Answer 39

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

Question 40

TRUE OR FALSE

Detection of proximal vein thrombosis by objective testing provides is not a sufficent indication for anticoagulant treatment.

Answer 40

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

Question 41

TRUE OR FALSE

A negative result by objective testing for DVT does not exclude the presence of PE

Answer 41

TRUE

A negative result by objective testing for DVT does not exclude the presence of PE

Question 42

To whom should selective pulmonary angiography be done

Answer 42

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).

Question 43

The key prognostic marker for recurrent VTE

Answer 43

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.

Question 44

Risk of clinically important PE in calf vein thrombosis

Answer 44

≤1%

Question 45

Options for documented calf vein thrombosis

Answer 45

• Receive anticoagulant treatment to prevent extension or
• Undergo monitoring for proximal extension using serial ultrasonography

Question 46

Symptoms of postthrombotic syndrome

Answer 46

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.

Question 47

The strongest independent risk factors for Chronic Thromboembolic Pulmonary Hypertension:

Answer 47

• History of PE (odds ratio [OR], 19)
• Idiopathic PE at presentation (OR, 5.7)

Question 48

The objectives of treatment in patients with established VTE

Answer 48

• (a) Prevent death from PE and
• (b) Prevent morbidity from recurrent DVT or PE, especially the postthrombotic syndrome and chronic pulmonary hypertension

Question 49

Indicated to prevent death from PE in patients in whom anticoagulant treatment is absolutely contraindicated

Answer 49

IVC filter

Question 50

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.

Answer 50

3 months

Question 51

Absolute contraindications to anticoagulant treatment

Answer 51

• Intracranial bleeding
• Severe active bleeding
• Recent brain, eye, or spinal cord surgery
• Malignant hypertension

Question 52

Relative contraindications to anticoagulant treatment

Answer 52

• Recent major surgery
• Recent cerebrovascular accident
• Active GI tract bleeding
• Severe hypertension
• Severe renal or hepatic failure
• Severe thrombocytopenia (platelets <50 × 109/L)

Question 53

Preferred anticoagulant for the initial treatment of most patients with either DVT or PE

Answer 53

LMWH given subcutaneously once or twice daily

Question 54

Initial anticoagulant therapy in patients with severe renal failure

Answer 54

IV UFH

Question 55

Initial treatment with LMWH or UFH should be continued for at least ___ days

Answer 55

5 days

Question 56

Treatment of Venous Thromboembolism

Example of Low-Molecular-Weight Heparin

Answer 56

• Enoxaparin: 1.0 mg/kg BID
• Dalteparin: 200 IU/kg once daily
• Tinzaparin: 175 IU/kg once daily
• Nadroparin
• Reviparin

Question 57

Treatment of Venous Thromboembolism

Example of INDIRECT FACTOR Xa INHIBITOR

Answer 57

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

Question 58

Treatment of Venous Thromboembolism

Example of DIRECT ORAL ANTICOAGULANTS

Answer 58

• 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

Question 59

An alternative
to an oral vitamin K antagonist for long-term treatment

Answer 59

Dalteparin
Tinzaparin

Question 60

If UFH is used for initial therapy, it is important to achieve an adequate anticoagulant effect, defined as

Answer 60

Activated partial thromboplastin time (aPTT) above the lower limit of therapeutic range within the first 24 hours

Question 61

Treatment with a VKA is started with initial heparin or LMWH therapy and overlapped for _____ days.

Answer 61

4–5 days

Question 62

The dose of VKA should be adjusted to maintain the international normalized ratio (INR) between

Answer 62

2.0 and 3.0

Question 63

TRUE OR FALSE

High-intensity VKA treatment (INR, 3.0–4.0) should be used in patients with the antiphospholipid syndrome and recurrent thrombosis.

Answer 63

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.

Question 64

Indicated for select patients in whom VKAs are contraindicated (eg, pregnant women) and in patients with concurrent cancer

Answer 64

LMWH

Question 65

The advantages of DOACs

Answer 65

• (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

Question 66

Clinical Trials of Direct Oral Anticoagulants for Treatment of Venous Th

Edoxaban:
Apixaban:
Rivaroxaban:
Dabigatran:

Answer 66

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.

Question 67

Exceptions in the use of DOACs

Answer 67

• (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

Question 68

DOACs preceded by at least 5 days of heparin or LMWH treatment

Answer 68

Dabigatran and edoxaban

Question 69

Duration of treatment for provoked DVT

Answer 69

3 months or until the risk factor is reversed

Question 70

Duration of treatment for unprovoked DVT

Answer 70

Indefinite

Question 71

Factors associated with an increased incidence of recurrent thromboembolism

Answer 71

• Residual DVT assessed by compression ultrasonography
• Elevated levels of plasma D-dimer after discontinuing anticoagulant treatment
• Male gender

Question 72

Indefinite anticoagulant treatment should be considered in patients with a first episode of VTE and

Answer 72

• 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)

Question 73

Clinical Trial

The relative efficacy and safety of the DOAC rivaroxaban compared with aspirin for the extended treatment of VTE

Answer 73

EINSTEIN CHOICE trial

Aspirin should now have a very limited, if any, role for extended treatment of VTE

Question 74

DOACs that can be reduced by 50% without loss of efficacy for preventing recurrent VTE after an initial 6–12 months of anticoagulant treatment

Answer 74

Apixaban or rivaroxaban

Question 75

Anticoagulant Therapy of Venous Thromboembolism in Patients with Cancer

Answer 75

LMWH for the first 3–6 months of long-term treatment or indefinitely or until the cancer resolves

Question 76

The regimens of LMWH that are established as effective for long-term treatment

Answer 76

• Dalteparin 200 U/kg once daily for 1 month, followed by 150 U/kg daily thereafter
• Tinzaparin 175 U/kg once daily

Question 77

DOACs as appropriate options for treatment in patients with cancer with VTE

Answer 77

Edoxaban and rivaroxaban

Caution is recommended for patients with GI cancer

Question 78

A humanized monoclonal antibody fragment that, when given intravenously, rapidly reverses the anticoagulant effect of dabigatran

Answer 78

Idarucizumab

Question 79

Dose of Idarucizumab

Answer 79

5 g administered as two 50-mL bolus infusions, each containing 2.5 mg of idarucizumab, no more than 15 minutes apart

Question 80

Helpful for reversing the anticoagulant effect of dabigatran in patients with significant renal impairment if idarucizumab is unavailable

Answer 80

Hemodialysis

Dabigatran is removed by hemodialysis, with up to 60% cleared during a 4- to 6-hour dialysis session

Question 81

A recombinant variant of FXa that binds and sequesters FXa inhibitors, including DOACs and LMW heparin

Answer 81

Andexanet-α

Question 82

Dose of Andexanet-α

Answer 82

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)

Question 83

Options for anticoagulant therapy of pregnant patients with VTE

Answer 83

LMWH and adjusted-dose subcutaneous heparin

The DOACs have not been evaluated in pregnant patients.

Question 84

Advantage of LMWH than UFH among pregnant

Answer 84

• Less thrombocytopenia and probably less osteoporosis
• Effective when given once daily, whereas UFH requires twice-daily injection

Question 85

Most common side effect of anticoagulant therapy

Answer 85

Bleeding

Bleeding can be classified as major or clinically relevant nonmajor

Question 86

Major bleeding is defined as clinically overt bleeding resulting in

Answer 86

• 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

Question 87

Patients at increased risk of major bleeding during anticoagulant therapy

Answer 87

• 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

Question 88

The earliest clinical manifestation of heparin-associated osteoporosis

Answer 88

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.

Question 89

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

Answer 89

Thrombolytic therapy

Question 90

Thrombolytic therapy regimens

Answer 90

• 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.

Question 91

Clinical Trial

Evaluated the effectiveness and safety of thrombolysis with tenecteplase followed by anticoagulant therapy compared with anticoagulant therapy alone

Answer 91

PEITHO trial

Question 92

Thrombolytic therapy may be indicated in patients with DVT

The role of thrombolytic therapy in patients with DVT is limited.

Answer 92

• 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

Question 93

Effective for reducing the incidence or severity of the postthrombotic syndrome

Answer 93

Catheter-directed thrombolysis (CDT)

Question 94

Clinical Trial

Use of PCDT in addition to standard therapy (anticoagulation and compression) with standard therapy alone

Answer 94

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.

Question 95

Indications for insertion of an IVC filter

Answer 95

• Acute VTE and an absolute contraindication to anticoagulant therapy
• Patients who have objectively documented recurrent VTE during adequate anticoagulant therapy

Question 96

TRUE OR FALSE

If the indication for filter placement is transient,a permanent vena cava filter should be used.

Answer 96

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.