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Flashcards in 38 Venous Thromboembolism Deck (20)
1

Epidemiology

  • Venous thromboembolism (VTE) consists of two interrelated conditions 
  • Both of these...
  • Incidence

  • Venous thromboembolism (VTE) consists of two interrelated conditions
    • Deep vein thrombosis (DVT)
    • Pulmonary embolism (PE)
  • Both of these...
    • Frequently occur in the absence of any symptoms or signs
  • Incidence
    • Unknown
    • ~5 million episodes of DVT occur annually in the US
    • > 10 % (500,000) lead to PE
    • > 10 % of (50,000) die each year

2

Risk factors

  • Most conditions that predispose to VTE can be linked to at least one of three basic factors
  • The risk of VTE increases with...

  • Most conditions that predispose to VTE can be linked to at least one of three basic factors: "Virchow's triad"
    • Hypercoagulability
    • Stasis of blood flow
    • Vessel injury
  • The risk of VTE increases with...
    • The number of predisposing factors

3

Risk factors:
Hypercoagulable states

  • Disorders that predispose to blood coagulation may be due either to...
  • Primary disorders
  • Frequency of primary disorders 

  • Disorders that predispose to blood coagulation may be due either to...
    • Inborn abnormalities of the coagulation or fibrinolytic systems (primary)
    • Acquired (secondary) conditions
  • Primary disorders
    • Protein C deficiency
    • Protein S deficiency
    • Antithrombin III deficiency
    • Hyperhomocystinemia
    • Plasminogen deficiency
  • Frequency of primary disorders 
    • Occur in a very small percentage of patients with VTE

4

Risk factors:
Hypercoagulable states:
Most common primary disorders

  • Most common
    • General
    • Defect
    • Factor V Leiden
      • General
      • Prevalence
      • Risk of VTE
  • Second most common
    • General
    • Defect

  • Most common
    • Inability of activated protein C (APC) to cleave and inactivate the activated form of factor V
    • The molecular defect responsible for APC resistance
      • A single point mutation in the factor V gene
      • Causes glutamine to be substituted for argenine, rendering the factor V
        molecule resistant to cleavage by APC
    • Factor V Leiden
      • The most common primary hypercoagulable disorder
      • Prevalence of the factor V Leiden mutation
        • Varies among ethnic group
          • ~3-5% of caucasians are carriers of the mutation
          • Much less common in noncaucasians
        • Found in ~20% of patients with DVT
      • The risk of VTE is increased by 5-10 fold in heterozygous carriers of the factor V Leiden mutation and by up to 80 times in homozygotes
  • Second most common
    • A genetic variant that increases the plasma prothrombin concentration
    • This defect: prothrombin 20210A mutation
      • Present in 5-6% of patients with DVT
      • Heterozygotes have a 2-5 fold increased risk of developing VTE

5

Risk factors:
Hypercoagulable states:
Conditions that produce an acquired or secondary hypercoagulable state that predisposes to VTE

  • Malignancy 
  • Estrogens 
  • Pregnancy 
  • Anti-phospholipid antibodies 

  • Malignancy
    • Hypercoagulability is believed to result from procoagulant material released by malignant cells
    • The risk of VTE is greatest in patients with adenocarcinomas and appears to increase with tumor burden
  • Estrogens
    • The risk of VTE increases with estrogen dose
    • Patients receiving high-dose estrogens (e.g. for prostate cancer) have the greatest risk
  • Pregnancy
    • The risk of VTE is increased throughout pregnancy, but is actually greater in the post-partum period
  • Anti-phospholipid antibodies
    • Includes the “lupus anticoagulant” and anticardiolipin antibodies associated with a variety of disorders

6

Risk factors:
Venous stasis:
Most important conditions leading to stasis of blood in the venous system that predispose to VTE

  • Surgery 
  • Lower extremity paralysis 
  • Immobilization 

  • Surgery
    • Orthopedic procedures on the legs, especially those involving the knee and hip, are accompanied by a very high risk of VTE
    • In the absence of prophylactic therapy, the incidence of DVT and PE is approximately 50% and 5%, respectively
    • Other major surgical procedures including abdominal, pelvic, thoracic, and neurosurgery also carry a significant risk of VTE
  • Lower extremity paralysis
    • Any disorder leading to paralysis of the legs significantly increases the risk of VTE
    • Patients with acute spinal cord injury are at particularly high risk, especially in the first 2-4 weeks following injury
  • Immobilization
    • This category includes any condition that decreases the use of the legs, such as bed rest, fracture of the pelvis or femur, and immobilization in a cast
    • The risk of VTE increases with the degree and duration of immobility

7

Risk factors:
Vessel injury

  • Risk factors in this category include orthopedic and vascular surgery as well as non-surgical vessel trauma
  • These factors also obviously predispose to venous stasis

8

Risk factors​:
Miscellaneous factors

  • Prior thromboembolism 
  • Age 

  • Prior thromboembolism
    • Patients with previous VTE are much more likely to develop recurrent disease, especially when other risk factors are present
  • Age
    • The risk of VTE increases exponentially with increasing age above 40 years
    • That is, the risk of VTE approximately doubles with each decade after age 40

9

Pulmonary embolism

  • Occurs when...
  • The consequences of PE depend primarily on...
  • The morbidity and mortality associated with PE result from...

  • Occurs when...
    • Thrombi in the deep venous system dislodge, flow through the central veins, and impact in the pulmonary arterial circulation
  • The consequences of PE depend primarily on...
    • The size of the embolus (i.e. on the degree to which the pulmonary vascular bed is obstructed)
    • The extent of underlying pulmonary disease
  • The morbidity and mortality associated with PE result from...
    • Disturbances in both gas exchange and hemodynamics

10

Pulmonary embolism:
Altered gas exchange

  • Pulmonary emboli...
  • High V/Q regions...
  • Low V/Q regions...
  • Intra-pulmonary shunting...

  • Pulmonary emboli...
    • Occlude a portion of the pulmonary vascular bed
    • This prevents blood from reaching some ventilated alveoli and at the same time increases blood flow to normally ventilated areas
    • Pulmonary embolism, therefore, produces both abnormally high and low ventilation-perfusion ratios
  • High V/Q regions...
    • Increase alveolar dead space and the amount of ventilation required to maintain a normal PaCO2
  • Low V/Q regions...
    • Lead to arterial hypoxemia and to an increase in PA-aO2
  • Intra-pulmonary shunting...
    • Does not occur, although acute right ventricular failure may cause a right to left intracardiac shunt through a patent foramen ovale

11

Pulmonary embolism:
Altered hemodynamics

  • By reducing the cross-sectional area of the pulmonary vascular bed, PE causes...
  • If excessive, this leads to...
  • RV dysfunction may reduce left ventricular output by two mechanisms
  • Significant decreases in cardiac output can lead to...

  • By reducing the cross-sectional area of the pulmonary vascular bed, PE causes...
    • An increase in pulmonary vascular resistance, which, in turn, increases right ventricular (RV) afterload
  • If excessive, this abrupt increase in afterload leads to...
    • RV dysfunction, both directly and by inducing RV ischemia
  • RV dysfunction may reduce left ventricular output by two mechanisms
    • (1) Impaired RV systolic function decreases the amount of blood pumped to the left ventricle
    • (2) As the RV fails, it dilates, and the intraventricular septum shifts toward the LV
      • This decreases the size and compliance of the LV and further reduces LV preload and cardiac output
  • Significant decreases in cardiac output can lead to...
    • Systemic hypotension and shock, which may further impair coronary perfusion and right and left ventricular function

12

Pulmonary embolism:
Source of pulmonary emboli

  • The majority of clinically significant PEs arise from...
  • Other potential sources of emboli 

  • The majority of clinically significant PEs arise from...
    • The proximal deep veins of the legs (i.e. the popliteal and femoral veins)
  • Other potential sources of emboli
    • The pelvic veins
    • Calf veins
    • The internal jugular and subclavian veins (especially in the presence of a central venous catheter)

13

Pulmonary embolism:
Clinical presentation

  • Symptomatic patients with PE most commonly present with...
  • The relationship between clinical suspicion and the likelihood of PE
  • Although most patients present with acute symptoms and signs, an unknown (but presumably small) percentage of patients with PE develop...

  • Symptomatic patients with PE most commonly present with...
    • The acute onset of dyspnea and tachypnea
      • Common features of most pulmonary diseases
    • For this reason, clinical assessment alone is unreliable in distinguishing patients with and without PE
  • The relationship between clinical suspicion and the likelihood of PE
    • High – 68%
    • Intermediate – 30%
    • Low – 9%
  • Although most patients present with acute symptoms and signs, an unknown (but presumably small) percentage of patients with PE develop...
    • Chronic, progressive dyspnea due to pulmonary hypertension
    • This is believed to result from progressive occlusion of the pulmonary vascular bed from recurrent, often asymptomatic pulmonary emboli that for unknown reasons are not cleared by endogenous fibrinolysis

14

Pulmonary embolism:
Diagnostic studies:
D-dimer

  • During clot formation,...
  • During endogenous fibrinolysis,...
  • D-dimers
  • D-dimer assays 

  • During clot formation,...
    • Thrombin cleaves fibrinogen to form fibrin molecules, which cross-link in a region referred to as the “D-domain”
  • During endogenous fibrinolysis,...
    • Plasmin degrades cross-linked fibrin to yield covalently bonded D-Page domains from two adjacent fibrin molecules
    • These fragments are referred to as D-dimers
  • D-dimers
    • Unlike other fibrin or fibrinogen degradation products, D-dimers are specific for the lysis of cross-linked fibrin and are increased by any condition in which coagulation and fibrinolysis occur
  • D-dimer assays
    • A means of diagnosing and excluding VTE
    • Have a very high negative predictive value (i.e. very few patients with a negative test have PE)
      • A negative result can effectively rule out VTE
    • A positive result, on the other hand, is not helpful in making the diagnosis because of a very low positive predictive value

15

Pulmonary embolism:
Diagnostic studies:
CT angiography

  • Modern CT scanning is performed by...
  • This technique allows...
  • Pulmonary emboli appear as...

  • Modern CT scanning is performed by...
    • Scanning continuously as the patient is rapidly advanced through the machine (spiral or helical CT)
  • This technique allows...
    • The pulmonary arteries to be well-visualized when intravenous contrast is rapidly injected during the scan
  • Pulmonary emboli appear as...
    • Filling defects in the opacified pulmonary arteries

16

Pulmonary embolism:
Diagnostic studies:
Venous ultrasonography

  • What venous ultrasound detects
  • The major criterion for diagnosing DVT with ultrasound 
  • Normally, when imaged by ultrasound, the lumen of a deep vein...
  • When a thrombus is present in the vein,...

  • What venous ultrasound detects
    • Since most clinically significant PE originate from thrombi in the proximal deep veins of the legs, finding or excluding a DVT would aid in the diagnosis of PE
  • The major criterion for diagnosing DVT with ultrasound
    • The loss of compressibility of the vein
  • Normally, when imaged by ultrasound, the lumen of a deep vein...
    • Will completely disappear when pressure is applied by the ultrasound probe
  • When a thrombus is present in the vein,...
    • This does not occur

17

Pulmonary embolism:
Diagnostic studies:
Venous ultrasonography

  • Accuracy
  • Why the usefulness of ultrasound in the evaluation of patients with suspected PE is limited
  • The absence of DVT...
  • A positive venous ultrasound...

  • Accuracy
    • Ultrasound is very accurate at detecting DVT in symptomatic patients
    • Sensitivity and specificity exceed 90%
  • Why the usefulness of ultrasound in the evaluation of patients with suspected PE is limited
    • ~50% of patients with PE have no evidence of leg DVT by venous ultrasound
    • The majority of patients with DVT do not have PE
  • The absence of DVT...
    • Does not exclude a PE
  • A positive venous ultrasound...
    • Is helpful though, not because it confirms the presence of PE, but because the therapy of DVT and PE are identical in most cases

18

Pulmonary embolism:
Therapy:
Anticoagulation

  • Anticoagulation
  • Heparin
    • Acts by...
    • Discontinued only after...
  • Warfarin
    • Acts...
    • Given...

  • Anticoagulation
    • The standard therapy for VTE
    • Heparin and warfarin sodium (Coumadin)
  • Heparin
    • Acts by enhancing the effect of antithrombin III so that it more efficiently combines with and inactivates a number of clotting factors, most notably factor II (thrombin), factor X, and factor IX
    • Discontinued only after therapeutic anticoagulation has been achieved with warfarin
  • Warfarin
    • Acts in the liver by inhibiting the synthesis of the vitamin K-dependent clotting factors II, VII, IX, and X
    • Given orally once a day, and is started simultaneously with heparin
  • Unless a contraindication to anticoagulation exists, therapy is initiated with...
    • An intravenous bolus of heparin followed by a continuous intravenous infusion

19

Pulmonary embolism:
Therapy:
Thrombolytic therapy

  • As opposed to anticoagulants, which...
  • ...thrombolytic agents...
  • Three thrombolytic agents are currently approved by the FDA for use in patients with VTE
  • Thrombolytic therapy should be used...

  • As opposed to anticoagulants, which...
    • Merely prevent thrombus propagation
  • ...thrombolytic agents...
    • Dissolve thrombi by converting the plasma proenzyme plasminogen to the active enzyme plasmin, which degrades cross-linked fibrin.
  • Three thrombolytic agents are currently approved by the FDA for use in patients with VTE
    • Streptokinase (SK)
    • Urokinase (UK)
    • Tissue plasminogen activator (t-PA)
      • Used almost exclusively
  • Thrombolytic therapy should be used...
    • Only in patients with massive pulmonary embolism accompanied by hemodynamic compromise

20

Pulmonary embolism:
Therapy:
Inferior vena cava filters

  • Several types of wire mesh screens can be...
  • The three major indications for filter placement 

  • Several types of wire mesh screens can be...
    • Placed percutaneously into the inferior vena cava to prevent venous thrombi in the legs and pelvis from embolizing to the lungs
  • The three major indications for filter placement
    • Recurrent PE despite adequate anticoagulant therapy
    • Unability to use anticoagulant therapy (e.g. bleeding)
    • High risk from recurrent PE

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