Venous thromboembolism (VTE) as a
disease entity includes deep vein thrombosis
(DVT) and pulmonary embolism (PE).
• There are important differences between DVT and PE:
DVT occurs about 3 times more often than PE.
The major adverse outcome of DVT without PE is the development of postphlebitic
syndrome, occurring in more than 50% of DVT patients.
PE can be fatal or can cause chronic thromboembolic pulmonary hypertension.
• Most patients who succumb to pulmonary embolism do so within the first few hours of
the event. In patients who survive, recurrent embolism and death can be prevented with
prompt diagnosis and therapy.
• Unfortunately, the diagnosis is often missed because patients with pulmonary embolism
present with nonspecific clinical features.
• If left untreated, approximately one third of patients who survive an initial pulmonary
embolism die from a subsequent embolic episode.
Thrombus
• Is a solid mass formed in the circulation from constituents of the blood.
• Fragments of thrombi (emboli) may break off and block vessels downstream.
• Thrombus results from complex series of events involving coagulation factors, platelets,
red blood cells, and vessel walls.
Venous Thrombosis
• Often occurs in normal vessels
• Major causes are stasis and hypercoagulability of blood
• Majority of the venous thrombi occur in the deep veins of legs, originating around the
valves as red thrombi
• Red thrombi consist mainly of red blood cells and fibrin
• Propagating thrombus is formed of fibrin and platelets and is particularly liable to emboli
formation
Natural History of Venous Thrombosis
• Triad of factors that lead to venous thrombosis (Virchow triad)
Venous stasis
Injury to the intima
Enhanced coagulation properties of the blood
• Thrombosis usually originates as a platelet nidus on valves in the veins of the lower
extremities. Further growth occurs by aggregation of platelets and fibrin and progression
to red fibrin thrombus, which may either break off and embolize or result in total
occlusion of the vein.
• The endogenous thrombolytic system leads to partial dissolution then, the thrombus
becomes organized and is incorporated into the venous wall.
Natural History of Pulmonary Embolism
• Pulmonary emboli usually arise from the thrombi originating in the deep venous system
of the lower extremities.
• However, rarely they may originate in the pelvic, renal, or upper extremity veins or the
right heart chambers.
• After traveling to the lung, large thrombi can lodge at the bifurcation of the main
pulmonary artery or the lobar branches and cause hemodynamic compromise.
• Smaller thrombi typically travel more distally, occluding smaller vessels in the lung
periphery.
• These are more likely to produce pleuritic chest pain by initiating an inflammatory
response adjacent to the parietal pleura.
• Most pulmonary emboli are multiple, and the lower lobes are involved more commonly
then the upper lobes.
Epidemiology of Pulmonary Embolism
• Mortality/Morbidity
As a cause of sudden death, massive pulmonary embolism is second only to sudden
cardiac death.
Autopsy studies of patients who died unexpectedly in a hospital setting have shown
approximately 80% of these patients died from massive pulmonary embolism.
Anticoagulant treatment decreases the mortality rate to less than 5%.
• Race
The incidence of pulmonary embolism appears to be significantly higher in blacks
than in whites.
• Sex
period.
Analysis of national mortality data found that death rates from pulmonary embolism
were 20-30% higher among men than among women.
• Age
is the cause of death.
Etiology and Clinical Features of Pulmonary Embolism and Venous
Thrombosis
Pulmonary Embolism
Etiology of Pulmonary Embolism
• The causes for pulmonary embolism are multifactorial and are not readily apparent in
many cases.
• The following causes have been described in the literature
Hypercoagulable States
• Primary or acquired deficiencies in protein C, protein S, and antithrombin III are risk
factors.
• The deficiency of these natural anticoagulants are responsible for 10% of venous
thrombosis in younger people.
Immobilization/Venous Stasis
• Immobilization leads to local venous stasis by the accumulation of clotting factors and fibrin,
resulting in thrombus formation.
• The risk of pulmonary embolism increases with prolonged bed rest or immobilization of a
limb in a cast.
• Paralysis increases the risk.
Surgery and Trauma
• Both surgical and accidental trauma predisposes patients to venous thromboembolism by
activating clotting factors and causing immobility
• Fractures of the femur and tibia are associated with the highest risk, followed by pelvic,
spinal, and other fractures
• Severe burns carry a high risk of venous thrombosis or pulmonary embolism
• Pulmonary embolism may account for 15% of all postoperative deaths
Leg amputations and hip, pelvic, and spinal surgery are associated with the highest
risk
• Pregnancy
• The mechanism of venous thrombosis is venous stasis, decreasing fibrinolytic activity,
and increased procoagulant factors
Oral contraceptives and Estrogen Replacement
• Estrogen-containing birth control pills have increased the occurrence of venous
thromboembolism in healthy women.
Malignancy
• The neoplasms most commonly associated with pulmonary embolism, in descending
order of frequency, are pancreatic carcinoma; bronchogenic carcinoma; and carcinomas
of the genitourinary tract, colon, stomach, and breast.
Clinical Features
• History
The presentation of pulmonary embolism (PE) may vary from sudden catastrophic
hemodynamic collapse to gradually progressive dyspnea.
The diagnosis of pulmonary embolism should be sought actively in patients with
respiratory symptoms unexplained by an alternate diagnosis.
The symptoms of pulmonary embolism are nonspecific, therefore, a high index of
suspicion is required, particularly when a patient has risk factors for the condition.
The presentation of patients with pulmonary embolism can be categorized into 4
classes based on the acuity and severity of pulmonary arterial occlusion.
These categories are (1) massive pulmonary embolism, (2) acute pulmonary
infarction, (3) acute embolism without infarction, and (4) multiple pulmonary emboli.
Clinical Features of Special Categories of Pulmonary
Embolism
Massive Pulmonary Embolism
• Large emboli compromise sufficient pulmonary circulation to produce circulatory
collapse and shock and the patient has
Hypotension
Appears weak
Pale
Sweaty
Oliguric
Develops impaired mentation
Acute Pulmonary Infarction
• Approximately 10% of patients have peripheral occlusion of a pulmonary artery causing
parenchymal infarction
• These patients present with acute onset of
Pleuritic chest pain
Breathlessness
Hemoptysis
• Although the chest pain maybe clinically indistinguishable from ischemic myocardial
pain, normal electrocardiogram findings, and no response to nitroglycerin rules it out.
Acute Embolism without Infarction
Patients have nonspecific symptoms of unexplained dyspnea and/or substernal discomfort
Multiple Pulmonary Emboli
• This group comprises 2 subsets of patients.
• The first subset has repeated documented episodes of pulmonary emboli over years,
eventually presenting with signs and symptoms of pulmonary hypertension and cor
pulmonale.
• The second subset has no previously documented pulmonary emboli but has widespread
obstruction of the pulmonary circulation with clot.
• They present with
Gradually progressive dyspnea
Intermittent exertional chest pain
Feature of pulmonary hypertension and cor pulmonale
Physical Examination
Physical examination findings are quite variable in pulmonary embolism
Massive Pulmonary Embolism
• These patients are in shock. They have systemic hypotension, poor perfusion of the
extremities, tachycardia, and tachypnea
• Signs of pulmonary hypertension
Acute Pulmonary Infarction
• These patients have decreased excursion of the involved hemithorax, palpable or audible
pleural friction rub, and even localized tenderness.
• Signs of pleural effusion, such as dullness to percussion and diminished breath sounds,
maybe present.
Acute Embolism without Infarction
• These patients have nonspecific physical signs that may easily be secondary to another
disease process
• Tachypnea and tachycardia frequently are detected, pleuritic pain sometimes maybe
present, crackles may be heard in the area of embolization, and local wheeze maybe
heard rarely.
Multiple Pulmonary Emboli or Thrombi
• Patients belonging to both the subsets in this category have physical signs of pulmonary
hypertension and cor pulmonale.
• Patients may have elevated jugular venous pressure, right ventricular heave, palpable
impulse in the left second intercostal space, right ventricular S3 gallop, systolic murmur
over the left sternal border that is louder during inspiration, hepatomegaly, ascites, and
dependent pitting edema.
The Most Common Symptoms of Pulmonary Embolism
• Dyspnea
• Pleuritic chest pain
• Cough
• Hemoptysis
• However, patients with pulmonary embolism may present with atypical symptoms
Seizures
Syncope
Abdominal pain
Fever
Productive cough
Wheezing
Flank pain
Decreasing level of consciousness
Delirium (in elderly patients)
Physical Examination
• Physical examination findings are quite variable in pulmonary embolism.
The Most Common Physical Signs
• Tachypnea (70%)
• Rales (51%)
• Tachycardia (30%)
• Fever of less than 39°C may be present in 14% of patients; however, temperature higher
than 39.5°C is not from pulmonary embolism.
Etiology of Venous Thrombosis
• The clinical evaluation of patients with suspected venous thrombosis is facilitated by an
assessment of risk factors.
• The following risk factors for venous thrombosis have been identified in many different
epidemiologic studies:
General
Age (more than 40 years)
Immobilization longer than 3 days
Pregnancy and the postpartum period
Major surgery in previous 4 weeks
Medical
Cancer
Previous venous thrombosis
Stroke
Acute myocardial infarction (AMI)
Congestive heart failure (CHF)
Sepsis
Nephrotic syndrome
Ulcerative colitis
Trauma
Multiple trauma
CNS/spinal cord injury
Burns
Lower extremity fractures
Hematologic
Polycythemia Rubra vera
Thrombocytosis
Inherited disorders of coagulation/fibrinolysis
Antithrombin III deficiency
Clinical Features of Deep Venous Thrombosis (DVT)
• The signs and symptoms of venous thrombosis is related to the degree of obstruction to
venous outflow and inflammation of the vessel wall.
• Many thrombi do not produce significant obstruction to venous flow; venous collaterals
may develop rapidly, and venous wall inflammation maybe minimal.
• Many patients are asymptomatic; however, the history may include the following.
Edema, principally unilateral, is the most specific symptom. Massive edema with
cyanosis and ischemia is rare.
Leg pain occurs in 50% of patients, but this is entirely nonspecific. Pain can occur on
dorsiflexion of the foot (Homans sign).
Tenderness occurs in 75% of patients but is also found in 50% of patients without
objectively confirmed venous thrombosis.
• Clinical signs and symptoms of PE as the primary manifestation occur in 10% of patients
with confirmed venous thrombosis.
• The pain and tenderness associated with venous thrombosis do not usually correlate
with the size, location, or extent of the thrombus.
• Warmth or erythema of skin can be present over the area of thrombosis.
• No single physical finding or combination of symptoms and signs is sufficiently accurate
to establish the diagnosis of venous thrombosis. The following is a list outlining the most
sensitive and specific physical findings in venous thrombosis.
Edema, principally unilateral
Tenderness, if present, is usually confined to the calf muscles or along the course
of the deep veins in the medial thigh.
Pain and/or tenderness away from these areas is not consistent with venous
thrombosis and usually indicates another diagnosis.
Homans sign
Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee
straight has been a time-honored sign of venous thrombosis. However, Homans
the sign is neither sensitive nor specific.
Venous distension and prominence of the subcutaneous veins
Superficial thrombophlebitis is characterized by the finding of a palpable,
indurated, cordlike, tender, subcutaneous venous segment.
Patients with superficial thrombophlebitis extending to the saphenofemoral
junction are also at higher risk for associated venous thrombosis.
Fever
Patients may7 have a fever, usually low grade. High fever is usually indicative of
an infectious process such as cellulitis or lymphangitis.
Phlegmasia cerulea dolens
Patients with venous thrombosis may have variable discoloration of the lower
extremity. The most common abnormal color is reddish-purple from venous
engorgement and obstruction.
In rare cases, the leg is cyanotic from massive iliofemoral venous obstruction.
This ischemic form of venous occlusion was originally described as phlegmasia
cerulea dolens or painful blue inflammation. The leg is usually markedly
edematous, painful, and cyanotic. Petechiae are often present.
Phlegmasia alba dolens
Painful white inflammation was originally used to describe massive iliofemoral
venous thrombosis and associated arterial spasm. The affected extremity is often
pale with poor or even absent distal pulses.
The physical findings may suggest acute arterial occlusion, but the presence of
swelling, petechiae, and distended superficial veins point to this condition.
Differential Diagnosis and Investigation of Pulmonary Embolism and Deep
Venous Thrombosis
Differential Diagnoses of Pulmonary Embolism
• Myocardial infarction
• Angina Pectoris
• Pneumonia
• Shock
• Anaemia
• Cor- pulmonale pneumothorax
• Chronic obstructive pulmonary disease
Investigations for Pulmonary Embolism
• Most of the investigations for pulmonary embolism is done at the hospital level. Therefore,
patients suspected of having pulmonary embolism should be referred to hospitals for
proper investigations.
• The possible investigations may include;
Laboratory studies
Arterial blood gases: Arterial blood gas determinations characteristically reveal
hypoxemia, hypocapnia, and respiratory alkalosis; however, the predictive value of
hypoxemia is quite low.
Imaging studies
Chest radiography
The most appropriate study for ruling out other causes of chest pain in patients
with suspected pulmonary embolism.
Initially, the chest radiography findings are normal in most cases of pulmonary
embolism.
However, in later stages, radiographic signs may include a Westermark sign
(dilatation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural
effusion, and an elevated diaphragm.
Although chest radiography findings may indicate an alternate diagnosis, this
study alone is not sufficient to confirm the diagnosis of pulmonary embolism.
Pulmonary angiography
Pulmonary angiography remains the criterion standard for the diagnosis of
pulmonary embolism.
Angiography generally is a safe procedure. The mortality rate for patients
undergoing this procedure is less than 0.5% and the morbidity rate is less than
5%.
Negative pulmonary angiogram findings, even if false negative, exclude clinically
relevant pulmonary embolism.
Other imaging studies
Computed tomography
Magnetic resonance imaging
Differential Diagnosis of Deep Venous Thrombosis (DVT)
• many other conditions cause localized pain or edema in the lower
extremities and may be confused with venous thrombosis. These differential diagnoses
include
Ruptured popliteal synovial membrane or cyst (Baker’cyst)
Ruptured calf muscles or tendons
Severe muscle cramp
Cellulitis and lymphedema
Investigation of Deep Venous Thrombosis
• Investigations for venous thrombosis may be available in some of the hospitals and
therefore, patients should be referred for that. The possible investigations may include
Doppler ultrasound
A Doppler assessment is now the minimum level of investigation required before
treating somebody with venous disease. A Doppler flow probe can be used to
exclude arterial disease and to determine the patency of a vein, and a bidirectional
flow probe used to detect venous reflux.
Photoplethysmography and Other Plethysmographic Techniques
In this investigation, a probe is attached to the skin to assess venous filling of the
surface venules by measuring the light transmission of the skin. The filling of these
vessels reflect the pressure in the superficial veins of the leg.
Duplex Ultrasound Imaging
This technique involves the use of high-resolution B-mode ultrasound imaging
and Doppler ultrasound to obtain images of veins and simultaneously measure
flow in these vessels. It allows direct visualization of the veins and provides functional,
as well as anatomical, information
Venography
This investigation is the X-ray equivalent of duplex ultrasonography. Historically
it preceded ultrasonography and has been widely used in the past for the
assessment of patients with vein problems. An ascending venogram is performed
by canulating a vein in the foot in order to inject an X-ray contrast medium.
Treatment and Prevention of Venous Thrombosis and Pulmonary
Embolism
At Dispensary Level
• Refer the patient for investigations and treatments
At Hospital Level
• In case of Pulmonary embolism add
Oxygen therapy
In severe cases intravenous fluids and even inotropic agents to improve the pumping
the function of the heart.
Use of Anticoagulant
• Heparin-UFH, LMWH
• Oral anticoagulant-coumarins (warfarin) and indanedione
Medical Care
• Full Anticoagulation
Immediate full anticoagulation is mandatory for all patients suspected to have deep
vein thrombosis (venous thrombosis) or pulmonary embolism (PE).
Diagnostic investigations should not delay empirically anticoagulant therapy.
Current guidelines recommend starting unfractionated heparin (UFH) or low
molecular weight heparin (LMWH) in addition to an oral anticoagulant (warfarin) at
the time of diagnosis.
• Thrombolytic Therapy
Thrombolytic therapy should be considered for patients who are hemodynamically
unstable, patients who have right-sided heart strain, and high-risk patients with
underlying poor cardiopulmonary reserve.
Also, bed rest and analgesics
Further Management of Deep Venous and Pulmonary
Thrombosis
Treatment of Venous and Pulmonary Thrombosis
Low Molecular Weight Heparin
• Current guidelines for patients with acute non-massive pulmonary embolism recommend
LMWH over UFH.
• In patients with massive pulmonary embolism, if concerns regarding subcutaneous
absorption arises, severe renal failure exists, or if thrombolytic therapy is being
considered, intravenous UFH is the recommended form of initial anticoagulation.
• LMWHs have many advantages over UFH
Have a greater bioavailability
Can be administered by subcutaneous injections
Have a longer duration of the anticoagulant effect
• LMWH can be administered safely in an outpatient setting
Oral Anticoagulant Therapy
• The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–
dependent factors, which are II, VII, IX, and X.
• The peak effect does not occur until 36-72 hours after drug administration, and the
dosage is difficult to titrate
Duration of Anticoagulation
• A patient with a first thromboembolic event occurring in the setting of reversible risk
factors such as immobilization, surgery, or trauma, should receive warfarin therapy for at
least 3 months.
• Among patients with idiopathic (or unprovoked) first events, the current recommendation
is anticoagulation for at least 3 months in these patients, and the need for extending the
duration of anticoagulation should be re-evaluated at that time.
• Warfarin treatment for longer than 6 months is indicated in patients with recurrent venous
thromboembolism or in those in whom a continuing risk factor for venous
thromboembolism exists, including malignancy, immobilization, or morbid obesity.
• Patients who have pulmonary embolism and pre-existing irreversible risk factors, such as
deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence
of antiphospholipid antibodies, should be placed on long-term anticoagulation.
• Compression stockings: For patients who have had a proximal venous thrombosis, elastic
compression stockings with a pressure of 30-40 mm Hg at the ankle for 2 years following
the diagnosis is recommended to reduce the risk of postphlebitic syndrome.
Activity
Activity is recommended as tolerated. Early ambulation is recommended over bed rest when
feasible.
Thrombolytics
• Thrombolytic regimens currently in use for pulmonary embolism include two forms of
recombinant tissue-plasminogen activators.
Urokinase
• Loading dose: 250,000 U IV over 30 min
• Maintenance dose: Infuse 100,000 U/h IV for 12-72 h
Streptokinase: By IV infusion
• Loading dose: 4400IU/kg over 10 minutes, then
• Maintenance: 4400IU/kg per hour
The safety and efficacy of different thrombolytic agents is comparable.
• Streptokinase may cause anaphylaxis, hypotension, and other adverse reactions, leading
to the cessation of therapy in many cases.
Low Molecular Weight Heparin (LMWHs)
• Loading dose: 5000Units (10,000 Units in severe PE) follow by
• Continuous IV infusion of 12-25 Units/Kg/hour adjusted daily according to laboratory
test results.
Or
• By IV infusion, 5000 – 10,000 units every 4 hours.
• Prophylaxis of DVT, by SC injection, 5000 units 2 hours until the patient is ambulant; in
pregnancy 10,000 units every 2 hours.
• Treatment of DVT, by Sc injection, initially 10,000 – 20,000 units every 12 hours.
Warfarin (Coumadin)
• Interferes with hepatic synthesis of vitamin K–dependent coagulation factors
• Dose: Initially 10 – 15mg PO daily for 3 days. Maintenance dose: 3 – 4mg PO taken at
the same time daily
Prevention
• Heparin Prophylaxis
The incidence of deep venous thrombosis, pulmonary embolism (PE), and death can
be significantly reduced by embracing a prophylactic strategy in high-risk patients
Prevention of deep vein thrombosis (venous thrombosis) in the lower extremities
inevitably reduces the frequency of pulmonary embolism; therefore, populations at
risk must be identified, and safe and efficacious prophylactic modalities should be
used.
• Sequential Compression Devices
Compression stockings provide compression of 30-40 mm Hg gradient and are a
safe and effective therapy to prevent venous thromboembolism in patients who are at
high risk when heparin therapy is not desirable or is contraindicated.
These devices provide a gradient of compression that is highest at the toes and
gradually decreases to the level of the thigh.
Complications and Prognosis Pulmonary Embolism
• Sudden cardiac death
• Obstructive shock
• Pulseless electrical activity
• Atrial or ventricular arrhythmias
• Secondary pulmonary arterial hypertension
• Cor pulmonale
• Severe hypoxemia
• Right-to-left intracardiac shunt
• Lung infarction
• Pleural effusion
• Paradoxical embolism
Complications of Deep Vein Thrombosis
• Development of Postphlebitic Syndrome:
It is a late complication of DVT, caused by permanent damage to the venous valves of
the leg which becomes incompetent and permits abnormal exudation of interstitial fluid
from the venous system.
Patients present with chronic ankle swelling, calf swelling and aching especially after
prolonged standing.
If severe, it causes skin ulceration, especially in the medial malleolus of the leg.
Prognosis
• The prognosis of patients with pulmonary embolism depends on 2 factors, namely (1) the
underlying disease state and (2) appropriate diagnosis and treatment.
• Patients who develop PE after an operation has tthe he lowest recurrence rate; in other
groups, recurrence rates may be as high as 9% per year.
• Most patients treated with anticoagulants do not develop long-term sequelae upon followup
evaluation.
• The mortality rate in patients with undiagnosed pulmonary embolism is 30%.
• The deaths occur due to cardiac disease, recurrent pulmonary embolism, infection, and
cancer.
• The risk of recurrent pulmonary embolism is due to the recurrence of proximal venous
thrombosis; approximately 17% of patients with recurrent pulmonary embolism was
found to have proximal venous thrombosis
• In a small proportion of patients, pulmonary embolism does not resolve; hence, chronic
thromboembolic pulmonary arterial hypertension results.
• Persistent pulmonary hypertension and right ventricular dysfunction 6 weeks after PE
identify high-risk patients with an increased likelihood of developing overt right
ventricular failure over the next 5 years.
Special Concerns
• Pregnancy
The risk of venous thromboembolism is increased during pregnancy and the
postpartum period.
Pregnant women who are in a hypercoagulable state or have had previous venous
thromboembolism should receive prophylactic anticoagulation during pregnancy.
Pulmonary embolism is the leading cause of death in pregnancy.
Pregnant patients diagnosed with venous thrombosis or pulmonary embolism are
treated with unfractionated heparin or LMWH throughout their pregnancy.
Warfarin is contraindicated because it crosses the placental barrier and can cause fetal
malformations.
Therefore, either subcutaneous unfractionated heparin or LMWH at full
anticoagulation doses should be continued until delivery.
Women experiencing a thromboembolic event during pregnancy should receive
therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with
anticoagulation continuing for 4-6 weeks postpartum, and for a total of at least 6
months.
REFERENCES;
Braunwald & Fauci (2001). Harrison’s principles of internal medicine 15th Ed. Oxford: McGraw Hill
Davidson, S (2006). Principles and practice of medicine 20th Ed. Churchill: Livingstone.
Kumar & Clark (2003) Textbook of clinical medicine. Churchill: Livingstone.
Douglas Model (2006): Making sense of Clinical Examination of the Adult patient. 1st Ed. Hodder Arnold
Longmore, M., Wilkinson, I., Baldwin, A., & Wallin, E. (2014). Oxford handbook of clinical medicine. Oxford
Macleod, J. (2009). Macleod's clinical examination. G. Douglas, E. F. Nicol, & C. E. Robertson (Eds.). Elsevier Health Sciences.
Nicholson N., (1999), Medicine of Non-communicable diseases in adults. AMREF
Stuart and Saunders (2004): Mental health Nursing principles and practice. 1st Ed. Mosby
Swash, M., & Glynn, M. (2011). Hutchison's clinical methods: An integrated approach to clinical practice.
(DVT) and pulmonary embolism (PE).
• There are important differences between DVT and PE:
DVT occurs about 3 times more often than PE.
The major adverse outcome of DVT without PE is the development of postphlebitic
syndrome, occurring in more than 50% of DVT patients.
PE can be fatal or can cause chronic thromboembolic pulmonary hypertension.
• Most patients who succumb to pulmonary embolism do so within the first few hours of
the event. In patients who survive, recurrent embolism and death can be prevented with
prompt diagnosis and therapy.
• Unfortunately, the diagnosis is often missed because patients with pulmonary embolism
present with nonspecific clinical features.
• If left untreated, approximately one third of patients who survive an initial pulmonary
embolism die from a subsequent embolic episode.
Thrombus
• Is a solid mass formed in the circulation from constituents of the blood.
• Fragments of thrombi (emboli) may break off and block vessels downstream.
• Thrombus results from complex series of events involving coagulation factors, platelets,
red blood cells, and vessel walls.
Venous Thrombosis
• Often occurs in normal vessels
• Major causes are stasis and hypercoagulability of blood
• Majority of the venous thrombi occur in the deep veins of legs, originating around the
valves as red thrombi
• Red thrombi consist mainly of red blood cells and fibrin
• Propagating thrombus is formed of fibrin and platelets and is particularly liable to emboli
formation
Natural History of Venous Thrombosis
• Triad of factors that lead to venous thrombosis (Virchow triad)
Venous stasis
Injury to the intima
Enhanced coagulation properties of the blood
• Thrombosis usually originates as a platelet nidus on valves in the veins of the lower
extremities. Further growth occurs by aggregation of platelets and fibrin and progression
to red fibrin thrombus, which may either break off and embolize or result in total
occlusion of the vein.
• The endogenous thrombolytic system leads to partial dissolution then, the thrombus
becomes organized and is incorporated into the venous wall.
Natural History of Pulmonary Embolism
• Pulmonary emboli usually arise from the thrombi originating in the deep venous system
of the lower extremities.
• However, rarely they may originate in the pelvic, renal, or upper extremity veins or the
right heart chambers.
• After traveling to the lung, large thrombi can lodge at the bifurcation of the main
pulmonary artery or the lobar branches and cause hemodynamic compromise.
• Smaller thrombi typically travel more distally, occluding smaller vessels in the lung
periphery.
• These are more likely to produce pleuritic chest pain by initiating an inflammatory
response adjacent to the parietal pleura.
• Most pulmonary emboli are multiple, and the lower lobes are involved more commonly
then the upper lobes.
Epidemiology of Pulmonary Embolism
• Mortality/Morbidity
As a cause of sudden death, massive pulmonary embolism is second only to sudden
cardiac death.
Autopsy studies of patients who died unexpectedly in a hospital setting have shown
approximately 80% of these patients died from massive pulmonary embolism.
Anticoagulant treatment decreases the mortality rate to less than 5%.
• Race
The incidence of pulmonary embolism appears to be significantly higher in blacks
than in whites.
• Sex
period.
Analysis of national mortality data found that death rates from pulmonary embolism
were 20-30% higher among men than among women.
• Age
is the cause of death.
Etiology and Clinical Features of Pulmonary Embolism and Venous
Thrombosis
Pulmonary Embolism
Etiology of Pulmonary Embolism
• The causes for pulmonary embolism are multifactorial and are not readily apparent in
many cases.
• The following causes have been described in the literature
Hypercoagulable States
• Primary or acquired deficiencies in protein C, protein S, and antithrombin III are risk
factors.
• The deficiency of these natural anticoagulants are responsible for 10% of venous
thrombosis in younger people.
Immobilization/Venous Stasis
• Immobilization leads to local venous stasis by the accumulation of clotting factors and fibrin,
resulting in thrombus formation.
• The risk of pulmonary embolism increases with prolonged bed rest or immobilization of a
limb in a cast.
• Paralysis increases the risk.
Surgery and Trauma
• Both surgical and accidental trauma predisposes patients to venous thromboembolism by
activating clotting factors and causing immobility
• Fractures of the femur and tibia are associated with the highest risk, followed by pelvic,
spinal, and other fractures
• Severe burns carry a high risk of venous thrombosis or pulmonary embolism
• Pulmonary embolism may account for 15% of all postoperative deaths
Leg amputations and hip, pelvic, and spinal surgery are associated with the highest
risk
• Pregnancy
• The mechanism of venous thrombosis is venous stasis, decreasing fibrinolytic activity,
and increased procoagulant factors
Oral contraceptives and Estrogen Replacement
• Estrogen-containing birth control pills have increased the occurrence of venous
thromboembolism in healthy women.
Malignancy
• The neoplasms most commonly associated with pulmonary embolism, in descending
order of frequency, are pancreatic carcinoma; bronchogenic carcinoma; and carcinomas
of the genitourinary tract, colon, stomach, and breast.
Clinical Features
• History
The presentation of pulmonary embolism (PE) may vary from sudden catastrophic
hemodynamic collapse to gradually progressive dyspnea.
The diagnosis of pulmonary embolism should be sought actively in patients with
respiratory symptoms unexplained by an alternate diagnosis.
The symptoms of pulmonary embolism are nonspecific, therefore, a high index of
suspicion is required, particularly when a patient has risk factors for the condition.
The presentation of patients with pulmonary embolism can be categorized into 4
classes based on the acuity and severity of pulmonary arterial occlusion.
These categories are (1) massive pulmonary embolism, (2) acute pulmonary
infarction, (3) acute embolism without infarction, and (4) multiple pulmonary emboli.
Clinical Features of Special Categories of Pulmonary
Embolism
Massive Pulmonary Embolism
• Large emboli compromise sufficient pulmonary circulation to produce circulatory
collapse and shock and the patient has
Hypotension
Appears weak
Pale
Sweaty
Oliguric
Develops impaired mentation
Acute Pulmonary Infarction
• Approximately 10% of patients have peripheral occlusion of a pulmonary artery causing
parenchymal infarction
• These patients present with acute onset of
Pleuritic chest pain
Breathlessness
Hemoptysis
• Although the chest pain maybe clinically indistinguishable from ischemic myocardial
pain, normal electrocardiogram findings, and no response to nitroglycerin rules it out.
Acute Embolism without Infarction
Patients have nonspecific symptoms of unexplained dyspnea and/or substernal discomfort
Multiple Pulmonary Emboli
• This group comprises 2 subsets of patients.
• The first subset has repeated documented episodes of pulmonary emboli over years,
eventually presenting with signs and symptoms of pulmonary hypertension and cor
pulmonale.
• The second subset has no previously documented pulmonary emboli but has widespread
obstruction of the pulmonary circulation with clot.
• They present with
Gradually progressive dyspnea
Intermittent exertional chest pain
Feature of pulmonary hypertension and cor pulmonale
Physical Examination
Physical examination findings are quite variable in pulmonary embolism
Massive Pulmonary Embolism
• These patients are in shock. They have systemic hypotension, poor perfusion of the
extremities, tachycardia, and tachypnea
• Signs of pulmonary hypertension
Acute Pulmonary Infarction
• These patients have decreased excursion of the involved hemithorax, palpable or audible
pleural friction rub, and even localized tenderness.
• Signs of pleural effusion, such as dullness to percussion and diminished breath sounds,
maybe present.
Acute Embolism without Infarction
• These patients have nonspecific physical signs that may easily be secondary to another
disease process
• Tachypnea and tachycardia frequently are detected, pleuritic pain sometimes maybe
present, crackles may be heard in the area of embolization, and local wheeze maybe
heard rarely.
Multiple Pulmonary Emboli or Thrombi
• Patients belonging to both the subsets in this category have physical signs of pulmonary
hypertension and cor pulmonale.
• Patients may have elevated jugular venous pressure, right ventricular heave, palpable
impulse in the left second intercostal space, right ventricular S3 gallop, systolic murmur
over the left sternal border that is louder during inspiration, hepatomegaly, ascites, and
dependent pitting edema.
The Most Common Symptoms of Pulmonary Embolism
• Dyspnea
• Pleuritic chest pain
• Cough
• Hemoptysis
• However, patients with pulmonary embolism may present with atypical symptoms
Seizures
Syncope
Abdominal pain
Fever
Productive cough
Wheezing
Flank pain
Decreasing level of consciousness
Delirium (in elderly patients)
Physical Examination
• Physical examination findings are quite variable in pulmonary embolism.
The Most Common Physical Signs
• Tachypnea (70%)
• Rales (51%)
• Tachycardia (30%)
• Fever of less than 39°C may be present in 14% of patients; however, temperature higher
than 39.5°C is not from pulmonary embolism.
Etiology of Venous Thrombosis
• The clinical evaluation of patients with suspected venous thrombosis is facilitated by an
assessment of risk factors.
• The following risk factors for venous thrombosis have been identified in many different
epidemiologic studies:
General
Age (more than 40 years)
Immobilization longer than 3 days
Pregnancy and the postpartum period
Major surgery in previous 4 weeks
Medical
Cancer
Previous venous thrombosis
Stroke
Acute myocardial infarction (AMI)
Congestive heart failure (CHF)
Sepsis
Nephrotic syndrome
Ulcerative colitis
Trauma
Multiple trauma
CNS/spinal cord injury
Burns
Lower extremity fractures
Hematologic
Polycythemia Rubra vera
Thrombocytosis
Inherited disorders of coagulation/fibrinolysis
Antithrombin III deficiency
Clinical Features of Deep Venous Thrombosis (DVT)
• The signs and symptoms of venous thrombosis is related to the degree of obstruction to
venous outflow and inflammation of the vessel wall.
• Many thrombi do not produce significant obstruction to venous flow; venous collaterals
may develop rapidly, and venous wall inflammation maybe minimal.
• Many patients are asymptomatic; however, the history may include the following.
Edema, principally unilateral, is the most specific symptom. Massive edema with
cyanosis and ischemia is rare.
Leg pain occurs in 50% of patients, but this is entirely nonspecific. Pain can occur on
dorsiflexion of the foot (Homans sign).
Tenderness occurs in 75% of patients but is also found in 50% of patients without
objectively confirmed venous thrombosis.
• Clinical signs and symptoms of PE as the primary manifestation occur in 10% of patients
with confirmed venous thrombosis.
• The pain and tenderness associated with venous thrombosis do not usually correlate
with the size, location, or extent of the thrombus.
• Warmth or erythema of skin can be present over the area of thrombosis.
• No single physical finding or combination of symptoms and signs is sufficiently accurate
to establish the diagnosis of venous thrombosis. The following is a list outlining the most
sensitive and specific physical findings in venous thrombosis.
Edema, principally unilateral
Tenderness, if present, is usually confined to the calf muscles or along the course
of the deep veins in the medial thigh.
Pain and/or tenderness away from these areas is not consistent with venous
thrombosis and usually indicates another diagnosis.
Homans sign
Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee
straight has been a time-honored sign of venous thrombosis. However, Homans
the sign is neither sensitive nor specific.
Venous distension and prominence of the subcutaneous veins
Superficial thrombophlebitis is characterized by the finding of a palpable,
indurated, cordlike, tender, subcutaneous venous segment.
Patients with superficial thrombophlebitis extending to the saphenofemoral
junction are also at higher risk for associated venous thrombosis.
Fever
Patients may7 have a fever, usually low grade. High fever is usually indicative of
an infectious process such as cellulitis or lymphangitis.
Phlegmasia cerulea dolens
Patients with venous thrombosis may have variable discoloration of the lower
extremity. The most common abnormal color is reddish-purple from venous
engorgement and obstruction.
In rare cases, the leg is cyanotic from massive iliofemoral venous obstruction.
This ischemic form of venous occlusion was originally described as phlegmasia
cerulea dolens or painful blue inflammation. The leg is usually markedly
edematous, painful, and cyanotic. Petechiae are often present.
Phlegmasia alba dolens
Painful white inflammation was originally used to describe massive iliofemoral
venous thrombosis and associated arterial spasm. The affected extremity is often
pale with poor or even absent distal pulses.
The physical findings may suggest acute arterial occlusion, but the presence of
swelling, petechiae, and distended superficial veins point to this condition.
Differential Diagnosis and Investigation of Pulmonary Embolism and Deep
Venous Thrombosis
Differential Diagnoses of Pulmonary Embolism
• Myocardial infarction
• Angina Pectoris
• Pneumonia
• Shock
• Anaemia
• Cor- pulmonale pneumothorax
• Chronic obstructive pulmonary disease
Investigations for Pulmonary Embolism
• Most of the investigations for pulmonary embolism is done at the hospital level. Therefore,
patients suspected of having pulmonary embolism should be referred to hospitals for
proper investigations.
• The possible investigations may include;
Laboratory studies
Arterial blood gases: Arterial blood gas determinations characteristically reveal
hypoxemia, hypocapnia, and respiratory alkalosis; however, the predictive value of
hypoxemia is quite low.
Imaging studies
Chest radiography
The most appropriate study for ruling out other causes of chest pain in patients
with suspected pulmonary embolism.
Initially, the chest radiography findings are normal in most cases of pulmonary
embolism.
However, in later stages, radiographic signs may include a Westermark sign
(dilatation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural
effusion, and an elevated diaphragm.
Although chest radiography findings may indicate an alternate diagnosis, this
study alone is not sufficient to confirm the diagnosis of pulmonary embolism.
Pulmonary angiography
Pulmonary angiography remains the criterion standard for the diagnosis of
pulmonary embolism.
Angiography generally is a safe procedure. The mortality rate for patients
undergoing this procedure is less than 0.5% and the morbidity rate is less than
5%.
Negative pulmonary angiogram findings, even if false negative, exclude clinically
relevant pulmonary embolism.
Other imaging studies
Computed tomography
Magnetic resonance imaging
Differential Diagnosis of Deep Venous Thrombosis (DVT)
• many other conditions cause localized pain or edema in the lower
extremities and may be confused with venous thrombosis. These differential diagnoses
include
Ruptured popliteal synovial membrane or cyst (Baker’cyst)
Ruptured calf muscles or tendons
Severe muscle cramp
Cellulitis and lymphedema
Investigation of Deep Venous Thrombosis
• Investigations for venous thrombosis may be available in some of the hospitals and
therefore, patients should be referred for that. The possible investigations may include
Doppler ultrasound
A Doppler assessment is now the minimum level of investigation required before
treating somebody with venous disease. A Doppler flow probe can be used to
exclude arterial disease and to determine the patency of a vein, and a bidirectional
flow probe used to detect venous reflux.
Photoplethysmography and Other Plethysmographic Techniques
In this investigation, a probe is attached to the skin to assess venous filling of the
surface venules by measuring the light transmission of the skin. The filling of these
vessels reflect the pressure in the superficial veins of the leg.
Duplex Ultrasound Imaging
This technique involves the use of high-resolution B-mode ultrasound imaging
and Doppler ultrasound to obtain images of veins and simultaneously measure
flow in these vessels. It allows direct visualization of the veins and provides functional,
as well as anatomical, information
Venography
This investigation is the X-ray equivalent of duplex ultrasonography. Historically
it preceded ultrasonography and has been widely used in the past for the
assessment of patients with vein problems. An ascending venogram is performed
by canulating a vein in the foot in order to inject an X-ray contrast medium.
Treatment and Prevention of Venous Thrombosis and Pulmonary
Embolism
At Dispensary Level
• Refer the patient for investigations and treatments
At Hospital Level
• In case of Pulmonary embolism add
Oxygen therapy
In severe cases intravenous fluids and even inotropic agents to improve the pumping
the function of the heart.
Use of Anticoagulant
• Heparin-UFH, LMWH
• Oral anticoagulant-coumarins (warfarin) and indanedione
Medical Care
• Full Anticoagulation
Immediate full anticoagulation is mandatory for all patients suspected to have deep
vein thrombosis (venous thrombosis) or pulmonary embolism (PE).
Diagnostic investigations should not delay empirically anticoagulant therapy.
Current guidelines recommend starting unfractionated heparin (UFH) or low
molecular weight heparin (LMWH) in addition to an oral anticoagulant (warfarin) at
the time of diagnosis.
• Thrombolytic Therapy
Thrombolytic therapy should be considered for patients who are hemodynamically
unstable, patients who have right-sided heart strain, and high-risk patients with
underlying poor cardiopulmonary reserve.
Also, bed rest and analgesics
Further Management of Deep Venous and Pulmonary
Thrombosis
Treatment of Venous and Pulmonary Thrombosis
Low Molecular Weight Heparin
• Current guidelines for patients with acute non-massive pulmonary embolism recommend
LMWH over UFH.
• In patients with massive pulmonary embolism, if concerns regarding subcutaneous
absorption arises, severe renal failure exists, or if thrombolytic therapy is being
considered, intravenous UFH is the recommended form of initial anticoagulation.
• LMWHs have many advantages over UFH
Have a greater bioavailability
Can be administered by subcutaneous injections
Have a longer duration of the anticoagulant effect
• LMWH can be administered safely in an outpatient setting
Oral Anticoagulant Therapy
• The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–
dependent factors, which are II, VII, IX, and X.
• The peak effect does not occur until 36-72 hours after drug administration, and the
dosage is difficult to titrate
Duration of Anticoagulation
• A patient with a first thromboembolic event occurring in the setting of reversible risk
factors such as immobilization, surgery, or trauma, should receive warfarin therapy for at
least 3 months.
• Among patients with idiopathic (or unprovoked) first events, the current recommendation
is anticoagulation for at least 3 months in these patients, and the need for extending the
duration of anticoagulation should be re-evaluated at that time.
• Warfarin treatment for longer than 6 months is indicated in patients with recurrent venous
thromboembolism or in those in whom a continuing risk factor for venous
thromboembolism exists, including malignancy, immobilization, or morbid obesity.
• Patients who have pulmonary embolism and pre-existing irreversible risk factors, such as
deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence
of antiphospholipid antibodies, should be placed on long-term anticoagulation.
• Compression stockings: For patients who have had a proximal venous thrombosis, elastic
compression stockings with a pressure of 30-40 mm Hg at the ankle for 2 years following
the diagnosis is recommended to reduce the risk of postphlebitic syndrome.
Activity
Activity is recommended as tolerated. Early ambulation is recommended over bed rest when
feasible.
Thrombolytics
• Thrombolytic regimens currently in use for pulmonary embolism include two forms of
recombinant tissue-plasminogen activators.
Urokinase
• Loading dose: 250,000 U IV over 30 min
• Maintenance dose: Infuse 100,000 U/h IV for 12-72 h
Streptokinase: By IV infusion
• Loading dose: 4400IU/kg over 10 minutes, then
• Maintenance: 4400IU/kg per hour
The safety and efficacy of different thrombolytic agents is comparable.
• Streptokinase may cause anaphylaxis, hypotension, and other adverse reactions, leading
to the cessation of therapy in many cases.
Low Molecular Weight Heparin (LMWHs)
• Loading dose: 5000Units (10,000 Units in severe PE) follow by
• Continuous IV infusion of 12-25 Units/Kg/hour adjusted daily according to laboratory
test results.
Or
• By IV infusion, 5000 – 10,000 units every 4 hours.
• Prophylaxis of DVT, by SC injection, 5000 units 2 hours until the patient is ambulant; in
pregnancy 10,000 units every 2 hours.
• Treatment of DVT, by Sc injection, initially 10,000 – 20,000 units every 12 hours.
Warfarin (Coumadin)
• Interferes with hepatic synthesis of vitamin K–dependent coagulation factors
• Dose: Initially 10 – 15mg PO daily for 3 days. Maintenance dose: 3 – 4mg PO taken at
the same time daily
Prevention
• Heparin Prophylaxis
The incidence of deep venous thrombosis, pulmonary embolism (PE), and death can
be significantly reduced by embracing a prophylactic strategy in high-risk patients
Prevention of deep vein thrombosis (venous thrombosis) in the lower extremities
inevitably reduces the frequency of pulmonary embolism; therefore, populations at
risk must be identified, and safe and efficacious prophylactic modalities should be
used.
• Sequential Compression Devices
Compression stockings provide compression of 30-40 mm Hg gradient and are a
safe and effective therapy to prevent venous thromboembolism in patients who are at
high risk when heparin therapy is not desirable or is contraindicated.
These devices provide a gradient of compression that is highest at the toes and
gradually decreases to the level of the thigh.
Complications and Prognosis Pulmonary Embolism
• Sudden cardiac death
• Obstructive shock
• Pulseless electrical activity
• Atrial or ventricular arrhythmias
• Secondary pulmonary arterial hypertension
• Cor pulmonale
• Severe hypoxemia
• Right-to-left intracardiac shunt
• Lung infarction
• Pleural effusion
• Paradoxical embolism
Complications of Deep Vein Thrombosis
• Development of Postphlebitic Syndrome:
It is a late complication of DVT, caused by permanent damage to the venous valves of
the leg which becomes incompetent and permits abnormal exudation of interstitial fluid
from the venous system.
Patients present with chronic ankle swelling, calf swelling and aching especially after
prolonged standing.
If severe, it causes skin ulceration, especially in the medial malleolus of the leg.
Prognosis
• The prognosis of patients with pulmonary embolism depends on 2 factors, namely (1) the
underlying disease state and (2) appropriate diagnosis and treatment.
• Patients who develop PE after an operation has tthe he lowest recurrence rate; in other
groups, recurrence rates may be as high as 9% per year.
• Most patients treated with anticoagulants do not develop long-term sequelae upon followup
evaluation.
• The mortality rate in patients with undiagnosed pulmonary embolism is 30%.
• The deaths occur due to cardiac disease, recurrent pulmonary embolism, infection, and
cancer.
• The risk of recurrent pulmonary embolism is due to the recurrence of proximal venous
thrombosis; approximately 17% of patients with recurrent pulmonary embolism was
found to have proximal venous thrombosis
• In a small proportion of patients, pulmonary embolism does not resolve; hence, chronic
thromboembolic pulmonary arterial hypertension results.
• Persistent pulmonary hypertension and right ventricular dysfunction 6 weeks after PE
identify high-risk patients with an increased likelihood of developing overt right
ventricular failure over the next 5 years.
Special Concerns
• Pregnancy
The risk of venous thromboembolism is increased during pregnancy and the
postpartum period.
Pregnant women who are in a hypercoagulable state or have had previous venous
thromboembolism should receive prophylactic anticoagulation during pregnancy.
Pulmonary embolism is the leading cause of death in pregnancy.
Pregnant patients diagnosed with venous thrombosis or pulmonary embolism are
treated with unfractionated heparin or LMWH throughout their pregnancy.
Warfarin is contraindicated because it crosses the placental barrier and can cause fetal
malformations.
Therefore, either subcutaneous unfractionated heparin or LMWH at full
anticoagulation doses should be continued until delivery.
Women experiencing a thromboembolic event during pregnancy should receive
therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with
anticoagulation continuing for 4-6 weeks postpartum, and for a total of at least 6
months.
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