Venous and lymphatic

disease
Venous anatomy
• Veins are part of a dynamic and complex system that returns low-
nutrient deoxygenated blood to the heart. Venous blood flow is
dependent on multiple factors such as gravity, venous valves, the
cardiac and respiratory cycles, blood volume, and the calf muscle
pump. Alterations in the intricate balance of these factors can result
in venous pathology.
Structure vein
• Veins are thin-walled, highly distensible, and collapsible. Their
structure specifically supports the primary functions of veins to
transport blood toward the heart and serve as a reservoir to prevent
intravascular volume overload.
• The venous intima is composed of a nonthrombogenic endothelium
with an underlying basement membrane and anelastic lamina. The
endothelium produces endothelium-derived relaxing factors such as
nitric oxide and prostacyclin, which help maintain a nonthrombogenic
surface through inhibition of platelet aggregation and promotion of
platelet disaggregation.
• Circumferential rings of elastic tissue and smooth muscle located in
the media of the vein allow for changes in vein caliber with minimal
changes in venous pressure. The adventitia is most prominent in large
veins and consists of collagen, elastic fibers, and fibroblasts. When a
vein is maximally distended, its diameter may be several times greater
than that in the supine position.
• In the axial veins, unidirectional blood flow is achieved with multiple
venous valves. The inferior vena cava (IVC), common iliac veins, portal
venous system, and cranial sinuses are valveless. In the axial veins,
valves are more numerous distally in the extremities than proximally.
Each valve consists of two thin cusps of a fine connective tissue
skeleton covered by endothelium. Venous valves close in response to
cephaladto-caudal blood flow at a velocity of at least 30 cm/s.
Lower extremity vein
• Lower extremity veins are divided into superficial, deep, and perforating veins. The
superficial venous system lies above the uppermost fascial layer of the leg and thigh and
consists of the great saphenous vein (GSV) and small saphenous vein (SSV) and their
tributaries.
• The GSV originates from the dorsal pedal venous arch and courses cephalad, anterior to
the medial malleolus, entering the common femoral vein approximately 4 cm inferior
and lateral to the pubic tubercle. The saphenous nerve accompanies the GSV medially
from the ankle to the level of the knee and supplies cutaneous sensation to the medial
leg and ankle. The SSV originates laterally from the dorsal pedal venous arch and courses
cephalad in the posterior calf.
• Most often, it penetrates the popliteal fossa, between the medial and lateral heads of
the gastrocnemius muscle, to join the popliteal vein. The termination of the SSV may be
quite variable, however, with a proximal extension of the SSV (the vein of Giacomini)
frequently connecting with the deep femoral vein or GSV. The sural nerve accompanies
the SSV laterally along its course and supplies cutaneous sensation to the lateral
malleolarregion.
Upper extremity vein
• As in the lower extremity, there are deep and superficial veins in the upper
extremity. Deep veins of the upper extremity are paired and follow the
named arteries in the arm. Superficial veins of the upper extremity are the
cephalic and basilic veinsand their tributaries.
• The cephalic vein originates at the lateral wrist and courses over the
ventral surface of the forearm. In the upper arm, the cephalic vein
terminates in the infraclavicular fossa, piercing the clavipectoral fascia to
empty into the axillary vein.
• The basilic vein runs medially along the forearm and penetrates the deep
fascia as it courses past the elbow in the upper arm. It then joins with the
deep brachial veins to become the axillary vein. The median cubital vein
joins the cephalic and the basilic veins on the ventral surface of the elbow.
Evaluation of the venous system
• Evaluation of the venous system begins with a detailed history and
physical examination.
• Risk factors for acute and chronic venous disease are identified. They
include increased age, history of venous thromboembolism (VTE),
malignancy, trauma and spinal cord injury, hospitalization and
immobilization, obesity, nephrotic syndrome, pregnancy and the
recently postpartum state, oral contraceptive use or hormone
replacement therapy, varicose veins, and hypercoagulable states, as
well as the postoperative state.
• Venous pathology is often, but not always, associated with visible or
palpable signs that can be identified during the physical examination.
There is variation among individuals in the prominence of superficial
veins when the person is standing (Fig. 24-1)
• The superficial veins of a lean athletic person, even when normal, will
appear large and easily visualized, but these veins will be far less
obvious in the obese individual. Possible signs of superficial venous
abnormalities are listed in Table 24-1. The deep veins cannot be
directly assessed clinically, and abnormalities within them can only be
inferred indirectly from changes found on clinical examination
• Chronic venous insufficiency (CVI) may lead to characteristic changes in the skin and
subcutaneous tissues in the affected limb. CVI results from incompetence of venous
valves, venous obstruction, or both. Most CVI involves venous reflux, and severe CVI
often reflects a combination of reflux and venous obstruction. It is important to
remember that although CVI originates with abnormalities of the veins, the target organ
of CVI is the skin, and the underlying physiologic and biochemical mechanisms leading to
the cutaneous abnormalities associated with CVI are poorly understood. A typical leg
affected by CVI will be edematous, with edema increasing over the course of the day. The
leg may also be indurated and pigmented with eczema and dermatitis.
• These changes are associated with excessive proteinaceous capillary exudate and
deposition of a pericapillary fibrin cuff that may limit nutritional exchange. In addition, an
increase in white blood cell trapping within the skin microcirculation in CVI patients may
lead to microvascular congestion and thrombosis. Subsequently, white blood cells may
migrate into the interstitium and release necrotizing lysosomal enzymes, potentially
leading to tissue destruction and eventual ulceration.
• Fibrosis can eventually develop from impaired nutrition, chronic
inflammation, and fat necrosis (lipodermatosclerosis). Hemosiderin
deposition due to the extravasation of red cells and subsequent lysis
in the skin contributes to the characteristic pigmentation of chronic
venous disease (Fig. 24-2). Ulceration can develop with longstanding
venous hypertension and is associated with alterations in
microcirculatory and cutaneous lymphatic anatomy and function. The
most common location of venous ulceration is approximately 3 cm
proximal to the medial malleolus (Fig. 24-3).
• Trendelenburg’s test is a clinical test, historically important but now
rarely used, that can help determine whether incompetent valves are
present and in which of the three venous systems (superficial, deep,
or perforator) the valves are abnormal. There are two components to
this test. First, with the patient supine, the leg is elevated 45° to
empty the veins, and the GSV is occluded with the examiner’s hand or
with a rubber tourniquet. With the GSV still occluded, the patient
stands and the superficial veins are observed for blood filling. The
compression on the GSV is released and the superficial veins are
observed for filling with blood. A negative result, indicating no
clinically relevant venous reflux, is the gradual filling of the veins from
arterial inflow.
• A positive result is the sudden filling of veins with standing while the
GSV remains occluded indicating incompetent perforator and deep
veins. The GSV valves are incompetent if the second component of
the test yields a positive result. Interpretation of the findings of
Trendelenburg’s test is subjective, and therefore, it has largely been
supplanted by the more objective noninvasive vascular laboratory
tests to localize sites of venous reflux.
Non invasive evaluation
• Before the development of vascular ultrasound, noninvasive
techniques to evaluate the venous system were based on
plethysmographic techniques. Although a variety of plethysmographic
techniques are used in the evaluation of both acute and chronic
venous disease, they are all based on the detection of volume
changes in the limb in response to blood flow.
• Duplex ultrasonography (DUS) augmented by color flow imaging is
now the most important noninvasive diagnostic method in the
evaluation of the venous system. DUS has become standard for the
detection of infrainguinal deep vein thrombosis (DVT), with near
100% sensitivity and specificity in symptomatic patients.
• It is also the preferred method of evaluation for upper extremity
venous thrombosis and is useful in the evaluation of CVI by
documenting the presence of valvular reflux and venous obstruction.
Overlying bowel gas and large body habitus make DUS less applicable
to evaluation of intra-abdominal veins. Magnetic resonance
venography (MRV) and computed tomography (CT) venography are
noninvasive techniques for evaluation of pelvic and intra-abdominal
veins.
Invasive evaluation
• Improved accuracy of noninvasive techniques for diagnostic purposes
has made the use of invasive procedures more selective. Both
venography and intravascular ultrasound (IVUS) are used as adjuncts
to percutaneous or open surgical treatment of venous disorders.
When planning endovascular or open surgical treatment, venography
may be used to identify areas of obstruction in infrainguinal, intra-
abdominal, and upper extremity veins as well as reflux in intra-
abdominal and infrainguinal veins. IVUS, with access generally via the
common femoral vein, is used primarily to assess for occlusive lesions
of the iliac veins and appears more sensitive than venography in
detecting iliac vein obstruction.
• Complications of venography include pain, thrombosis, or hematoma
at the puncture site.
• Systemic effects of iodinated contrast media include allergic reaction
and risk of renal failure.
• Complications of IVUS are primarily related to the access site
Venous Thromboembolism
• The incidence of VTE is approximately 100 per 100,000 people per
year in the general population, with 20% of the diagnoses made
within 3 months of a surgical procedure
• The estimated number of cases of VTE may well be over 600,000 per
year in the United States, making it a major U.S. health problem
• DVT and 12% of PE cases within 1 month of diagnosis.5 Not only does
VTE pose a veritable threat to life, but it also places patients at higher
risk for recurrence and post-VTE sequelae such as pulmonary
hypertension and postthrombotic syndrome, with 4% and up to 30%
incidence, respectively
Risk factors
• Three conditions, first described by Rudolf Virchow in 1862,
contribute to VTE formation: stasis of blood flow, endothelial damage,
and hypercoagulability
• hypercoagulability appears most important in most cases of
spontaneous VTE, or so-called idiopathic VTE
Diagnosis
• Early in the course of a DVT, there may be no or few clinical findings
such as pain or swelling.
• Clinical symptoms may worsen as DVT propagates and involves the
major proximal deep veins. Extensive DVT of the major axial deep
venous channels of the lower extremity with relative sparing of
collateral veins causes a condition called phlegmasia cerulea dolens
• This condition is characterized by pain and pitting edema with
associated cyanosis. When the thrombosis extends to the collateral
veins, massive fluid sequestration and more significant edema ensue,
resulting in a condition known as phlegmasia alba dolens.
Vascular lab and radiologic evaluation
• Duplex Ultrasound DUS is now the most commonly performed test
for the detection of infrainguinal DVT, both above and below the
knee, and has a sensitivity and specificity of >95% in symptomatic
patients.
• The examination begins at the ankle and continues proximally to the
groin. Each vein is visualized, and the flow signal is assessed with
distal and proximal compression.
• Lower extremity DVT can be diagnosed by any of the following DUS
findings: lack of spontaneous flow (Fig. 24-6), inability to compress
the vein (Fig. 24-7), absence of color filling of the lumen by color flow
DUS, loss of respiratory flow variation, and venous distention
Impedance pletysmography
• Impedance plethysmography (IPG) was the primary noninvasive
method of diagnosing DVTbefore the widespread use of DUS but is
infrequently used today.Changes in electrical resistance resulting from
lower extremity blood volume changes are quantified. IPG is less
accurate than DUS for the detection of proximal DVT, with 83%
sensitivity in symptomatic patients. It is a poor detector of calf vein
DVT.
Iodine-125 Fibrinogen Uptake
• Iodine-125 fibrinogen uptake (FUT) is a seldom used technique that
involves IV administration of radioactive fibrinogen and monitoring
for increased uptake in fibrin clots.
• An increase of 20% or more in one area of a limb indicates an area of
thrombus
• In a prospective study, FUT had a sensitivity of 73% and specificity of
71% for identification of DVT in a group of symptomatic and
asymptomatic patients
Venography
• Venography is the gold standard to which other diagnostic modalities
are compared. A small catheter is placed in a dorsal foot vein with
injection of a radiopaque contrast agent. Radiographs are obtained in
at least two projections.
• A positive study result is failure to fill the deep system with passage of
the contrast medium into the superficial system or demonstration of
discrete filling defects
Treatment
• Once the diagnosis of VTE has been made, antithrombotic therapy
should be initiated promptly
• Once the diagnosis of VTE has been made, antithrombotic therapy
should be initiated promptly
• Treatment regimens may include antithrombotic therapy, temporary
or permanent vena cava filter placement, catheter-directed or
systemic thrombolytic therapy, and operative thrombectomy.
Antithrombotic theraphy
• Most often, antithrombotic therapy for VTE is initiated with IV or
subcutaneous (SC) unfractionated heparin or SC low molecular weight
heparin. Fondaparinux, a synthetic pentasaccharide, is sometimes also
used as an alternative to heparin to initiate therapy.
• An oral vitamin K antagonist, usually sodium warfarin, is begun shortly
after initiation of IV or SC therapy. Either SC or IV therapy is continued until
effective oral anticoagulation with warfarin is achieved as indicated by an
international normalized ratio (INR) ≥2 for 24 hours minimum of 5 days of
heparin or fondaparinux therapy is recommended.
• 27 Recently, the U.S. Food and Drug Administration (FDA) has also
approved alternative oral anticoagulants for both treatment and
prophylaxis for VTE
• Unfractionated heparin (UFH) binds to antithrombin via a specific 18-
saccharide sequence. This increases antithrombin activity over 1000-
fold. The antithrombin-heparin complex primarily inhibits factor IIa
(thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and
XIIa of the coagulation cascade. In addition, UFH also binds to tissue
factor pathway inhibitor, which inhibits the conversion of factor X to
Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of
thrombin by heparin cofactor II via a mechanism independent of
antithrombin.
• UFH therapy is most commonly administered with an initial IV bolus
of 80 units/kg. Weight-based UFH dosages have been shown to be
more effective than standard fixed boluses in rapidly achieving
therapeutic levels
• The initial bolus is followed by a continuous IV drip at 18 units/kg per
hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose
dependent
• The level of antithrombotic therapy should be monitored every 6
hours using the activated partial thromboplastin time (aPTT), with the
goal range of 1.5 to 2.5 times control values. This should correspond
with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL
• Initial anticoagulation with UFH may also be administered SC,
although this route is less commonly used. Adjusted-dose therapeutic
SC UFH is initiated with 17,500 units, followed by 250 units/kg twice
daily, and dosing is adjusted to an aPTT goal range similar to that for
IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333
units/kg, followed by 250 units/kg twice daily
• Hemorrhage is the primary complication of UFH therapy. The rate of
major hemorrhage (fatal, intracranial, retroperitoneal, or requiring
transfusion of >2 units of packed red blood cells) is approximately 5%
in hospitalized patients undergoing UFH therapy (1% in medical
patients and 8% in surgical patients).
• Heparin-induced thrombocytopenia (HIT) results from heparin-
associated antiplatelet antibodies (HAAbs) directed against platelet
factor 4 complexed with heparin.30 HIT occurs in 1% to 5% of patients
being treated with heparin.
• HIT is diagnosed based on previous exposure to heparin, platelet
count less than 100,000, and/or platelet count decline of 50%
following exposure. All heparin must be stopped and alternative
anticoagulation initiated immediately to avoid thrombotic
complications, which may approach 50% over the subsequent 30 days
in affected individuals
• Low molecular weight heparins (LMWHs) are derived from the
depolymerization of porcine UFH. Like UFH, LMWHs bind to
antithrombin via a specific pentasaccharide sequence to expose an
active site for the neutralization of factor Xa.
• Most patients treated with weight-based once- or twicedaily SC
LMWH injections do not require laboratory monitoring for
anticoagulant effect, a distinct advantage over continuous IV infusions
of UFH.
• Patients who do require monitoring include those with significant
renal insufficiency, pediatric patients, obese patients greater than 120
kg, and pregnant patients. Monitoring may be performed using anti-
Xa activity assays.
• A major benefit of LMWHs is that it allows outpatient treatment of
VTE.
• Fondaparinux currently is a synthetic pentasaccharide that has been
approved by the FDA for the initial treatment of DVT and PE. Its five-
polysaccharide sequence binds and activates antithrombin, causing specific
inhibition of factor Xa. In two large noninferiority trials, fondaparinux was
compared with the LMWH enoxaparin for the initial treatment of DVT and
with IV UFH for the initial treatment of PE.41,42 The rates of recurrent VTE
ranged from 3.8% to 5%, with rates of major bleeding of 2% to 2.6%, for all
treatment arms.
• The drug is administered SC once daily with a weight-based dosing
protocol: 5 mg, 7.5 mg, or 10 mg for patients weighing <50 kg, 50 to 100
kg, or >100 kg, respectively. The half-life of fondaparinux is approximately
17 hours in patients with normal renal function. There are rare case reports
of fondaparinux-induced thrombocytopenia.43
• Direct thrombin inhibitors (DTIs) include recombinant hirudin,
argatroban, and bivalirudin. These antithrombotic agents bind to
thrombin, inhibiting the conversion of fibrinogen to fibrin as well as
thrombin-induced platelet activation. Thes actions are independent
of antithrombin. The DTIs should be reserved for (a) patients in whom
there is a high clinical suspicion or confirmation of HIT, and (b)
patients who have a history of HIT or test positive for heparin-
associated antibodies. In patients with established HIT, DTIs should be
administered for at least 7 days, or until the platelet count
normalizes. Warfarin may then be introduced slowly, overlapping
therapy with a DTI for at least 5 days
• Vitamin K antagonists, which include warfarin and other coumarin
derivatives, are the mainstay of long-term antithrombotic therapy in
patients with VTE. Warfarin inhibits the γ-carboxylation of vitamin K–
dependent procoagulants (factors II, VII, IX, and X) and anticoagulants
(proteins C and S), resulting in formation of less functional proteins
• Warfarin usually requires several days to achieve full effect because
normal circulating coagulation proteins must first undergo their
normal degradation. Factors X and II have the longest half-lives, in the
range of 36 and 72 hours, respectively. A steady-state concentration
of warfarin is usually not reached for 4 to 5 days.
Systemic and catheter directed thrombolysis
• Patients with extensive proximal, iliofemoral DVT may benefit from
systemic thrombolysis or catheter-directed thrombolysis (CDT). CDT
appears to be more effective (see later in chapter) and potentially
reduces acute congestive lower extremity symptoms more rapidly
than anticoagulation alone and decreases the development of PTS.
• Several thrombolytic agents are available, including streptokinase,
urokinase, alteplase (recombinant tissue plasminogen activator),
reteplase, and tenecteplase.
• Streptokinase is purified from β-hemolytic Streptococcus and is
approved for the treatment of acute myocardial infarction, PE, DVT,
arterial thromboembolism, and occluded central lines and
arteriovenous shunts. It is not specific for fibrin-bound plasminogen,
however, and its use is limited by its significant rates of antigenicity.
Fevers and shivering occur in 1% to 4% of patients.
• Urokinase is derived from human neonatal kidney cells grown in
tissue culture. Currently, it is only approved for lysis of massive PE or
PE associated with unstable hemodynamics.
• Alteplase, reteplase, and tenecteplase all are recombinant variants of
tissue plasminogen activator. Alteplase is indicated for the treatment
of acute myocardial infarction, acute ischemic stroke, and acute
massive PE. However, it often is used for CDT of DVT. Reteplase and
tenecteplase are indicated only for the treatment of acute myocardial
infarction.
Inferior vena cava filters
• Early filters were placed surgically through the femoral vein.
Currently, less invasive techniques allow percutaneous filter
placement through a femoral vein, internal jugular vein, or small
peripheral vein under fluoroscopic or ultrasound guidance.
• Placement of an IVC filter is indicated for patients who have
manifestations of lower extremity VTE and absolute contraindications
to anticoagulation, those that have a bleeding complication from
anticoagulation therapy of acute VTE, or those who develop recurrent
DVT or PE despite adequate anticoagulation therapy and for patients
with severe pulmonary hypertension
Operative Venous Thrombectomy
• In patients with acute iliofemoral DVT, surgical therapy is generally
reserved for patients who worsen with anticoagulation therapy and
those with phlegmasia cerulea dolens and impending venous
gangrene.
• If the patient has phlegmasia cerulea dolens, a fasciotomy of the calf
compartments is first performed. In iliofemoral DVT, a longitudinal
venotomy is made in the common femoral vein and a venous balloon
embolectomy catheter is passed throughthe thrombus into the IVC
and pulled back several times until no further thrombus can be
extracted.