Norman Vryne Cadua

Internal Medicine

Deep Venous Thrombosis and Pulmonary

Thromboembolism
VENOUS THROMBOEMBOLISM
● Encompasses both deep venous thrombosis (DVT) and pulmonary embolism (PE)
● Long-term complications include:
o Chronic thromboembolic pulmonary hypertension which causes breathlessness,
especially with exertion
o Post thrombotic syndrome (chronic venous insufficiency) damages the venous valves of
the leg and worsens the quality of life by causing ankle or calf swelling and leg aching,
especially in standing. In its most severe form, it may also cause skin ulcerations.

EPIDEMIOLOGY
● Causes cardiovascular death and disability as well as psychological illness and emotional distress
● Most common preventable cause of death among hospitalized patients (100, 000 – 180, 000
annual deaths in the US).

PATHOPHYSIOLOGY
INFLAMMATION AND PLATELET ACTIVATIONINFLAMMATION AND PLATELET ACTIVATION

PROTHROMBOTIC STATES
● Two most common autosomal dominant genetic mutations:
o Factor V Leiden – cause resistance to endogenous anticoagulant, activated C protein
(inactivates factor V and VIII)
o Prothrombin gene mutation – increases plasma prothrombin concentration
● Deficiencies with naturally occurring coagulation inhibitors (antithrombin, protein C, and protein
S) are associated with VTE, but is rare
● Common predisposing factors:
o Cancer
o Obesity
 o Cigarette smoking
o Systemic arterial hypertension
o Chronic obstructive pulmonary disease
o Chronic kidney disease
o Blood transfusion
o Long-haul air-travel
o Air pollution
o Estrogen-containing contraceptives
o Pregnancy
o Postmenopausal hormone replacement
o Surgery
o Trauma
o Inflammatory states
o Sedentary lifestyle

EMBOLIZATION
● Detachment of venous thrombi from site of formation and lodging into a different blood vessel
o Lodging of thrombi into the pulmonary arterial circulation can cause pulmonary
embolism

PHYSIOLOGY
● Most common gas exchange abnormalities:
o Arterial hypoxemia
o Increased alveolar-arterial O2 tension gradient – represents inefficiency of O2 transfer
across the lungs
● Anatomic dead space – breathed gas does not enter gas exchange units of the lung
● Physiologic dead space – ventilation exceed blood flow through the pulmonary capilliaries
● Other abnormalities:
o Increased pulmonary vascular resistance – vascular obstruction or platelet secretion of
vasoconstricting neurohumoral agents such as serotonin produce a ventilation-perfusion
mismatch at sites remote to the thrombus causing the discordance in a small PE, but
large alveolar-arterial O2 gradient
o Impaired gas exchange – may be due to:
▪ Increased alveolar dead space from vascular obstruction
▪ Hypoxemia from alveolar hypoventilation relative to perfusion in the
non-obstructed lung (increased physiologic dead space)
▪ Right-to-left-shunting
▪ Impaired carbon monoxide transfer due to loss of gas exchange surface (i.e.
pulmonary fibrosis)
o Alveolar hypoventilation – reflex stimulation of irritant receptors
o Increased airway resistance – due to constriction of airways distal to the bronchi
o Decreased pulmonary compliance – due to lung edema, lung hemorrhage, or loss of
surfactant
PULMONARY HYPERTENSION, RIGHT VENTRICULAR DYSFUNCTION, AND RV MICROINFARCTION

CLASSIFICATION OF PULMONARY EMBOLISM AND DEEP VENOUS THROMBOSIS

PULMONARY EMBOLISM
● Massive PE – characterized by extensive thrombosis affecting at least half of the pulmonary
vasculature
o 5-10% of cases
o Hallmarks:
▪ Dyspnea
▪ Syncope
▪ Hypotension
▪ Cyanosis
o May present with cardiogenic shock and can die of multisystem organ failure
● Submassive PE – characterized by RV dysfunction despite normal arterial pressure
o 20-25% of cases
o High risk for clinical deterioration if the RV dysfunction is combined with release of
cardiac biomarker
● Low-risk PE – has excellent prognosis
o 65-75% of cases

DEEP VENOUS THROMBOSIS

● Low extremity DVT – begins in the calf and propagates proximally to the popliteal vein, femoral
vein, and iliac veins
o 10 times more common than upper extremity DVT
● Upper extremity DVT – precipitated by placement of pacemakers, internal cardiac defibrillators,
or indwelling central venous catheters
o Likelihood of occurrence is directly proportional to the catheter diameter size and
number of lumens
 ● Superficial venous thrombosis – presents with erythema, and a “palpable cord”
o Poses a risk for extension of the thrombosis into the deep-venous system, resulting to
DVT

DIAGNOSIS
CLINICAL EVALUATION
● PE is known as “the Great Masquerader” due to non-specific symptoms and signs, making
diagnosis difficult
o Most common symptom is breathlessness
o If with occult presentation combined with overt congestive heart failure or pneumonia,
the patient has poor prognosis
● DVT’s most common symptom is a cramp or “charley horse” in the lower calf that persists and
intensifies over several days

● Patients with low-moderate likelihood of VTE should undergo a d-dimer test without imaging while
patients with high-likelihood should have immediate imaging, skipping the d-dimer test
CLINICAL PEARLS

Clinical Clues for differential diagnosis of DVT and PE:

● Ruptured Baker’s cyst – sudden, severe calf discomfort
● Cellulitis – fever and chills with mild leg discomfort (if present)
● May-Thurner Syndrome – recurrent left thigh edema, especially in young women, with right
proximal iliac artery compression of the left proximal iliac vein
● Acute exacerbation of chronic venous insufficiency – diffusely edematous leg
● Upper extremity venous thrombosis – asymmetry in the supraclavicular fossa or the
circumference of the upper arms
● Pulmonary infarction – small PE; painful due to the thrombus lodging peripherally, near the
innervation of the pleural nerves
● Non-thrombotic PE – embolism of fat (pelvic or long bone fracture), tumor, bone marrow, or air,
cement or bony fragment embolism (total hip or knee replacement), hair, talc, cotton (IV drug
users), or amniotic fluid (fetal membrane leakage in a tear in the placental margin) instead of
thrombus
NON-IMAGING DIAGNOSTIC MODALITY
● Blood tests: Plasma D-dimer enzyme-linked immunosorbent assay (ELISA)
o Detects the breakdown of fibrin by plasmin
o Indicates endogenous, although often clinically ineffective thrombolysis
o More useful to “rule out” diseases since it is non-specific
o False positives include: patients with MI, pneumonia, sepsis, cancer, post-operative
state, and those in second or thord trimester of pregnancy
● Elevated cardiac biomarkers
o RV microinfarction may cause increase in serum troponin and plasma heart-type fatty
acid binding protein levels
o Myocardial stretch may release brain natriuretic peptide or NT-pro-brain natriuretic
enzyme
● Electrocardiogram (ECG/EKG)
o Most frequent abnormalities seen
▪ Sinus tachycardia
▪ S1Q3T3 sign: S wave at lead I, Q wave and inverted T wave in lead III – specific,
but not sensitive; due to RV strain and ischemia

NON-INVASIVE IMAGING MODALITIES

● Venous ultrasonography – relies on the loss of vein compressibility as the primary diagnostic
criterion for DVT. Normal veins will compress, giving the illusion of a “wink”
o Loss of compressibility is due to the presence of thrombus in the vein
o Visualization of the thrombus, homogenous and low echogenic mass, makes the
diagnosis of DVT more secure
● Chest roentgenography – usually normal or nearly normal. Abnormalities seen may include:
o Westermark’s sign – focal oligemia
o Hampton’s Hump – peripheral wedge-shaped density located at the pleural base
o Palla’s sign – enlarged descending pulmonary artery
● Chest CT with contrast – principal imaging test for diagnosis of PE
o May help establish differentials in the absence of PE such as pneumonia, emphysema,
pulmonary fibrosis, pulmonary mass, and aortic pathology
o Lung scanning – second-line diagnostic test for PE, mostly for patients who cannot
tolerate contrast
▪ Small particulate aggregated of albumin labeled with a gamma-emitting
radionuclide is injected IV, and trapped in the pulmonary capillary bed
▪ Detects the absence or decrease in blood flow possibly due to PE
▪ Ventilation scans, with the use of radiolabeled inhaled gas such as xenon or
krypton, improve specificity of the perfusion scan
o Magnetic resonance imaging (MRI) with contrast – can help detect DVT and large
proximal PE (MR angiography), but not reliable for smaller segmental and subsegmental
PE
▪ Used when ultrasound is equivocal
▪ Uses gadolinium contrast
o Echocardiography – not reliable for acute PE; more useful in detecting conditions
mimicking PE, such as acute MI, pericardial tamponade, and aortic dissection
▪ McConnell’s sign – best known indirect sign of PE; hypokinesis of RV free wall
with normal or hyperkinetic motion of the RV apex

INVASIVE IMAGING MODALITIES

● Pulmonary angiography – reserved for patients with technically unsatisfactory chest CTs and for
those whom interventional procedure such as catheter-directed thrombolysis is planned
o Definitive diagnosis of PE is seen when there is an intraluminal filling defect in more than
one direction
 o Secondary signs of PE include abrupt occlusion of vessels, segmental oligemia, and
prolonged arterial phase with slow filling, and tortuous, tapering peripheral vessels
● Contrast phlebography

TREATMENT
DEEP VENOUS THROMBOSIS
● Primary Therapy – clot dissolution using pharmacomechanical therapy, usually including
low-dose catheter-directed thrombolysis
● Secondary Prevention
o Anticoagulation
o Placement of inferior vena cava (IVC) filter
o Compression stockings, graduated, 30-40 mmHg (only for patients with diagnosed acute
DVT)

PULMONARY EMBOLISM
● Risk Stratification
o High-risk of adverse clinical outcome despite use of anticoagulation therapy:
▪ Hemodynamic instability
▪ RV dysfunction on echocardiography
▪ RV enlargement on chest CT
▪ Elevation of troponin level
 ● Anticoagulation: Three major strategies:
o Classical but waning strategy of parenteral anticoagulation with unfractionated heparin
(UFH), low molecular weight heparin (LMWH), or fondaparinux “bridged” to warfarin
o Parenteral therapy switched after 5 days to novel oral anticoagulant such as dabigatran
(direct thrombin inhibitor), or edoxaban (anti-Xa agent)
o Oral anticoagulation monotherapy with rivaroxaban or apixaban (noth are anti-Xa
agents) with a 3-week or 1-week loading dose, respectively followed by maintenance
dose without parenteral anticoagulation
● Argatroban and bivalidurin – parenteral direct thrombin inhibitors for patients with VTE in the
setting of suspected or proven heparin-induced thrombocytopenia

● Unfractionated heparin (UFH) – prevents additional thrombus formation by binding to, and
accelerating the activity of antithrombin
o Dose should be enough to achieve activated partial thromboplastin time (aPTT) of 60-80s
o Advantage is its short half-life
o Has pleiotropic effects that may decrease systemic and local inflammation
● Low molecular weight heparin (LMWH) – has less binding to plasma proteins and endothelial cells,
resulting to having a greater bioavailability, a more predictable dose response, and longer half-life
than UFH
o Fragments of UFH
o No need for monitoring unless patient is markedly obese or has chronic kidney disease
● Fondaparinux – anti-Xa penta-saccharide that is administered as a weight-based once-daily
subcutaneous injection in a pre-filled syringe
o No monitoring is required as it does not cause heparin-induced thrombocytopenia
o Must be adjusted downward for patients with renal dysfunction
● Warfarin – vitamin K antagonist that prevents the carboxylation activation of coagulation factors II,
VII, IX, and X
o Required up to 5 days to have the full effect
o If initiated as a monotherapy during an acute thrombotic illness, may cause paradoxical
exacerbation of hypercoagulability and increase likelihood of thrombosis, therefore a need
for UFH, LMWH, fondaparinux, or parenteral direct thrombin inhibitor is needed for the first
5 days to nullify the early pro-coagulating effect of warfarin
▪ Very prone to drug-drug and drug-food interaction that affects it metabolism.
Increase in age ang presence of systemic illness reduce the required dose of warfarin
▪ Initial doe is 5 mg, titrated until the goal of 2.5 international normalized ratio (INR),
with a range of 2.0-3.0.
 ▪ Adverse effects include: major hemorrhage (especially intracranial, even when INR is
at target range), alopecia, arterial vascular calcification, and in some patients, feeling
cold or fatigued
o Novel oral anticoagulants (NOACs) - administered in a fixed dose, establish effective
anticoagulation within hours of ingestion, require no laboratory coagulation monitoring, and
have few of the drug-drug or drug-food interaction
▪ Betrixaban – direct factor Xa inhibitor for VTE prophylaxis in acutely ill medical
patients during hospitalization and continuing for a total of 5-6 weeks.
▪ Rivaroxaban and apixaban – direct factor Xa inhibitors as monotherapy for acute and
extended treatment of DVT and PE without a parenteral “bridging” anticoagulant
▪ For treatment of VTE after an initial 5-day course of parenteral anticoagulation
● Dabigatran – direct thrombin inhibitor
● Edoxaban – factor Xa inhibitor

COMPLICATION OF ANTICOAGULANTS
● Hemorrhage – most serious complication

APPROACH TO COMPLICATIONS OF ANTICOAGULANTS

● Protamine sulfate – treatment for life threatening or intracranial hemorrhage due to UFH or
LMWH
● There is no specific reversal agent for bleeding caused by fondaparinux of Xa inhibitors
● Idarucizumab – dabigatran antibody; rapidly-acting antidote for adverse effect of dabigatran
● Andexanet – still for review; possible universal anti-Xa antidote for betrixaban, rivaroxaban,
apixaban, and edoxaban
● Prothrombin complex concentrate – treatment for major bleeding due to warfarin
● Fresh-frozen plasma and IV vitamin K – treatment of less serious bleeding due to warfarin
● Oral vitamin K – for managing minor bleeding or excessively high INR in the absence of
bleeding

DURATION OF ANTICOAGULATION
● 3 months therapy – DVT isolated to an upper extremity or calf provoked by surgery, trauma,
estrogen, or indwelling venous central catheter or pacemaker
● 3-6 months therapy – for initial episode of provoked DVT
● For patients with cancer and VTE – LMWH monotherapy (without warfarin) and continue
anticoagulation indefinitely until the patient is cancer-free
● Idiopathic, unprovoked VTE – recurrence rate is high after cessation of anticoagulation; may
cause an exacerbation of underlying inflammatory state
o Anticoagulation for indefinite duration with target INR between 2 and 3
o Reduce intensity of anticoagulation after 6 months of therapy, lowering the target INR to
between 1.5 and 2.
o Consider low-dose aspirin after completing the initial period of standard anticoagulation
● For patients with antiphospholipid antibody syndrome – indefinite duration of anticoagulation,
even if the initial VTE was provoked by trauma or surgery
● There is no increase in risk of recurrent VTE in patients with heterozygous factor V Leiden and

MANAGEMENT OF MASSIVE PE
● For patients with massive PE and hypotension – replete volume with 500 mL normal saline
o Extreme caution should be exercised in fluid resuscitation since it might exacerbate RV
wall stress, cause more profound RV ischemia, worsen LV compliance and filling, causing
a intraventricular septal shift to the left
● For treatment of PE-related shock – dopamine and dobutamine
o “Trial and error” approach with low-threshold use of dopamine and dobutamine
o Other agents that may also be effective: norepinephrine, vasopressin, or phenylephrine
FIBRINOLYSIS
● If successful, reverses right heart failure, lowering rate of death and recurrence of PE by:
o Dissolving as much of the anatomically obstructing pulmonary arterial thrombus
o Preventing the continued release of serotonin and other neurohumoral factors that
exacerbate pulmonary hypertension
o Lysing much of the source thrombus in the pelvic or deep leg veins, decreasing the
likelihood of recurrent PE
● Preferred systematically administered fibrinolytic regimen – 100 mg of recombinant tissue
plasminogen activator (tPA) as continuous IV infusion over 2 hours.
o Can be used for at least 14 days after the PE occurred
o Should be done as soon as possible for better effectivity
● Off-label regimen – 50 mg tPA administered over 2 hours
o Associated with fewer bleeding complication
● Contraindications:
o Intracranial disease
o Recent surgery
o Trauma
● Use of fibrinolysis agents in patients with submassive PE is still controversial

PHARMACOMECHANICAL CATHETER-DIRECTED THERAPY

● Combines physical fragmentation or pulverization of thrombus with catheter directed low-dose
thrombolysis
● Mechanical techniques include:
o Catheter maceration and intentional embolization of clot more distally
o Suction thrombectomy
o Rheolytic hydrolysis
o Low-energy ultrasound-facilitated thrombolysis
● Alteplase dose is usually 20-25 mg

PULMONARY EMBOLECTOMY
● Surgical removal of the embolism
● Considered due to risk of major hemorrhage with systemically administered fibrinolysis

PULMONARY THROMBOENDARTERECTOMY
● Indicated for patients with chronic thromboembolic pulmonary hypertension, especially those
complaining of dyspnea
● Surgical removal of blood clots from the arteries in the lung
● The operation requires median sternotomy, cardiopulmonary bypass, deep hypothermia, and
periods of hypothermic circulatory arrest.

EMOTIONAL SUPPORT
● Usual concerns needed to be addressed:
o Not being able to adapt to new limitations imposed by anticoagulation
o Health of the family and genetic implications of the illness
o Feeling of vulnerability to VTE recurrence when anticoagulation is discontinued
 Arterial Diseases of the
Extremities
PERIPHERAL ARTERIAL DISEASE
● Is a clinical disorder in which there is a stenosis or occlusion in the aorta or the arteries of the
limbs
● Atherosclerosis is the leading cause in patients >40 years. Other causes include thrombosis,
embolism, vasculitis, fibromuscular dysplasia, entrapment, cystic adventitial disease, and
trauma.
● Highest prevalence in 6th -7th decade
● Increased risk with use of cigarette smoking, in persons with Diabetes, hypercholesterolemia,
hypertension or renal insufficiency
Pathology
● Segmental lesions that cause stenosis or occlusion are usually localized to large and medium-size
vessels.
● Pathology of lesion includes: atherosclerotic plaques with calcium deposition, thinning of the
media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic
lamina, and thrombi composed of platelets and fibrin
● Primary sites involved
o abdominal aorta and iliac A. (30%)
o Femoral and popliteal A. (80-90%)
o Tibial and peroneal A. (40-50%)
● Atherosclerotic plaques occur preferentially in arterial branch points. Involvement of distal
vasculature is common in patients with diabetes
Clinical evaluation
● <50% of patients are symptomatic, although many present with slow or impaired gut
● Most common symptom: intermittent claudication (pain, ache, cramp, numbness, or a sense of
fatigue in the muscles that occurs during exercise and is relieved by rest.
● Site of claudication: distal to the location of the occlusive lesion
● Symptoms are more common in lower than upper extremities due to higher incidence of
obstructive lesions in upper extremities
● In patients with severe PAD, critical limb ischemia may develop
● Patients will complain of rest pain or a feeling of cold or numbness in the foot and toes especially
at night.
● Physical finding: decreased or absent pulses distal to the obstruction, presence of bruits over the
narrowed artery & muscle atrophy
● In severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature,
and pallor or cyanosis are common physical signs while inpatients with critical ischemia, ulcers
and gangrene may form
 ● In other cases, patients with severe ischemia may develop peripheral edema due to keeping
their legs in dependent position most of the time. Ischemic neuropathy may result in numbness
and hyporeflexia
Noninvasive Testing
● Sphygmomanometric cuffs at the ankles and the use of a Doppler device are used in recording
arterial pressures in the legs
● Ankle- Brachial Index (ABI): it compares pressures in your ankle with the blood pressure in one’s
arm. In normal situation, SBP in legs and arms is similar. In presence of hemodynamically
significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the
ankle and brachial artery pressures (termed the ankle: brachial index, or ABI) is 1.00–1.40 in
normal individuals. ABI values of 0.91–0.99 are “borderline,” and 1.40 indicate noncompressible
arteries secondary to vascular calcification.
● Other tests include: segmental pressure measurements, segmental pulse volume recordings,
duplex ultrasonography (which combines B-mode imaging and Doppler flow velocity waveform
analysis), transcutaneous oximetry, and stress testing.
● Duplex ultrasonography is used to image and detect stenotic lesions in native arteries and
bypass grafts
● Treadmill testing allows assessment of functional limitations objectively. Decline of the ABI
immediately after exercise provides further support diagnosis of PAD in patients with equivocal
symptoms and findings on examination
● Each test is useful in defining the anatomy to assist planning for endovascular and surgical
revascularization procedures.
Prognosis
● Approximately 1/3 to ½ of patients with PAD have evidence of CAD
● Patients have 15–25% 5-year mortality rate and a two- to sixfold increased risk of death from
coronary heart disease
● Higher mortality in those with severe disease
● Likelihood of symptomatic progression of PAD is lower than the chance of succumbing to CAD
● Approximately 75–80% of nondiabetic patients who present with mild to moderate claudication
remain symptomatically stable
● Approximately 25–30% of patients with critical limb ischemia undergo amputation within 1 year
● Prognosis is worse in those who smoke as well as those with Diabetes
Treatment
● Patients should receive therapies to reduce risk of associated cardiovascular events, improve
limb symptoms, prevent progression to critical limb ischemia and preserve limb viability.
● Antiplatelet therapy should be initiated
● Cigarette smoking should be discouraged
● ACE and ARBs may be given to reduce risk of cardiovascular events in symptomatic patients. In
patients with coexistent CAD. β-Adrenergic blockers may be used to treat hypertension.
● Statins are given in patients to reduce the risk of myocardial infarction, stroke, and death in
patients with hypercholesterolemia
● Platelet inhibitors; aspirin & clopidogrel, reduce the risk of adverse cardiovascular events in
patients with atherosclerosis. These are also recommended for patients with symptomatic PAD,
 including those with intermittent claudication or critical limb ischemia or prior lower extremity
revascularization
● Combination of antiplatelet and vorapaxar, a protease activated receptor-1 antagonist decreases
the risk of adverse cardiovascular events in patients with atherosclerosis, reduces the risk of
acute limb ischemia and peripheral revascularization. Side effects is increased risk of moderate
bleeding
● Combination of low dose of the oral factor Xa inhibitor, rivaroxaban, and aspirin improves
cardiovascular outcomes in patients with established atherosclerosis, including PAD, though is
associated with increased risk of bleeding
● Therapies include: supportive measures, medications, exercise training, endovascular
interventions, and surgery
● Supportive measures include meticulous care of feet, wearing well fitted and protective shoes
and avoidance of elastic support hose.
● Patients are advised to exercise (30-45 min session 3-5x/ week) regularly and at progressively
more strenuous levels
● Pharmacologic
o Cilostazol, a phosphodiesterase inhibitor with vasodilator and antiplatelet properties,
increases claudication distance by 40–60% and improves measures of quality of life
o Pentoxifylline, a substituted xanthine derivative, increases blood flow to the
microcirculation and enhances tissue oxygenation.
Revascularization
● Procedures including catheter-based and surgical interventions, are indicated for patients with
disabling, progressive, or severe symptoms of intermittent claudication despite medical therapy
so as to improve walking distance and functional capacity
● MRA, CTA, or conventional angiography should be performed to assess vascular anatomy in
patients who are being considered for revascularization
● Endovascular interventions include percutaneous transluminal balloon angioplasty (PTA), stent
placement, stent grafts, and atherectomy
● PTA and stenting of the iliac artery have higher success rates than those of femoral and popliteal
arteries.
● Endovascular interventions of the infrapoplital, tibial, and peroneal arteries and treatment of
more proximal lesions can be used to treat critical limb ischemia and prevent limb loss
● Operative procedures for aortoiliac disease include; aortobifemoral bypass, axillofemoral bypass,
femoro-femoral bypass, and aortoiliac endarterectomy
● Operative therapy for femoral-popliteal artery disease includes; in situ and reverse autogenous
saphenous vein bypass grafts, placement of polytetrafluoroethylene (PTFE) or other synthetic
grafts, and thromboendarterectomy
● Preoperative cardiac risk assessment, stress testing, radionuclide myocardial perfusion imaging,
or echocardiography are used in assessing risk stratification
● Cardiac catheterization should be considered in patients with unstable angina, angina refractory
to medical therapy as well as those suspected of having left main or three-vessel CAD.

FIBROMUSCULAR DYSPLASIA
● Is a hyperplastic disorder that affects medium-size and small arteries
 ● Occurs predominantly in females
● Involves renal and carotid arteries but can affect extremity vessels e.g., iliac and subclavian
arteries.
● Histological classification; Intimal fibroplasia (or focal), medial dysplasia (multifocal), and
adventitial hyperplasia.
● Medial dysplasia is further subdivided into medial fibroplasia, perimedial fibroplasia, and medial
hyperplasia
● Medial fibroplasia is the most common type and is characterized by alternating areas of thinned
media and fibromuscular ridges
● In fibromuscular dysplasia, iliac arteries are most commonly affected. This is identified by “string
of beads “appearance caused by thickened fibromuscular ridges contiguous with thin,
less-involved portions of the arterial wall seen in angiography
● Clinical manifestations are similar to atherosclerosis in cases where limb vessels are involved
● PTA and surgical reconstruction are beneficial

THROMBOANGIITIS OBLITERANS (Buerger’s disease

● Is an inflammatory occlusive vascular disorder involving small and medium-size arteries and
veins in the distal upper and lower extremities
● More in men<40 years
● Prevalence: higher in Asians, East European descent
● Definite relationship with smoking
● Initial stages: PMN infiltrate walls of small & medium sized arteries and veins with lamina being
preserved and cellular inflammatory thrombus develops in vascular lumen
● As disease progresses, mononuclear cells, fibroblasts, and giant cells replace the neutrophils.
● Later stages are characterized by perivascular fibrosis, organized thrombus, and recanalization
● Clinical features (Triad of claudication): Raynaud’s phenomenon, and migratory superficial vein
thrombophlebitis.
● Primarily affects distal vessels
● Presence of severe digital ischemia: trophic nail changes, painful ulcerations, and gangrene may
develop
● Physical exam: normal brachial & popliteal pulses, reduced or absent radial, ulnar, and/or tibial
pulses
● Diagnosis made using MRA, CTA, and conventional arteriography showing smooth, tapering
segmental lesions in the distal vessels. Excisional biopsy and pathologic vessel examination
confirms diagnosis
● Patients are advised to abstain from tobacco
● Arterial bypass of the larger vessels may be used as well as local debridement, depending on the
symptoms & severity of ischemia
● Antibiotics may be useful
● Amputation is done in case other management fail.

VASCULITIS
Vasculitides e.g., Takayasu’s arteritis and giant cell (temporal) arteritis may affect the arteries that supply
the upper and lower extremities

ACUTE LIMB ISCHEMIA

● Occurs when arterial occlusion results in the sudden cessation of blood flow to an extremity
● Severity and variability of extremity depends on location and extent of the occlusion and the
presence and subsequent development of collateral blood vessels
● Principal causes: embolism, thrombus in situ, arterial dissection, and trauma
● Most common sources: heart, aorta, and large arteries
● Emboli to the distal vessels may also originate from proximal sites of atherosclerosis and
aneurysms of the aorta and large vessels.
● Trauma to an artery may disrupt continuity of blood flow and cause acute limb ischemia via
formation of an acute arterial thrombus or by disruption of an artery’s integrity and
extravasation of blood.
● Arterial occlusion may be associated with thoracic compression outlet syndrome,
hypercoagulable disorders and polycythemia veraClinical features
● Symptoms of an acute arterial occlusion depend on the location, duration, and severity of the
obstruction.
● Often severe pain, paresthesia, numbness, and coldness develop in the involved extremity within
● Paralysis may occur with severe and persistent ischemia
● Physical findings: loss of pulses distal to the occlusion, cyanosis or pallor, mottling, decreased
skin temperature, muscle stiffening, loss of sensation, weakness, and/or absent deep tendon
reflexes
● Clinical evaluation includes: Doppler assessment of peripheral blood flow
● MRA, CTA, or catheter-based arteriography is used to confirm the diagnosis and demonstrate the
location and extent of arterial occlusion.
Treatment
● Catheter-directed thrombolysis/ thrombectomy, surgical thromboembolectomy, and arterial
bypass procedures are used to restore blood flow to the ischemic extremity promptly,
particularly when a large proximal vessel is occluded.
● In cases of recent acute arterial occlusion, intraarterial thrombolytic therapy with recombinant
tissue plasminogen activator, reteplase, or tenecteplase is most effective
● Percutaneous mechanical thrombectomy for thrombus removal
● Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to
prevent limb loss or when symptoms of occlusion have been present for >2 weeks.
● In case a limb is not viable, amputation is performed (characterized by loss of sensation,
paralysis, and the absence of Doppler-detected blood flow in both arteries and veins)
● In cases where acute limb ischemia is caused by cardiac thromboembolism, long term
anticoagulation is indicated
● Emboli resulting from infective endocarditis, the presence of prosthetic heart valves, or atrial
myxoma often require surgical intervention to remove the cause.
ATHEROEMBOLISM
● In this condition, multiple small deposits of fibrin, platelets, and cholesterol debris embolize
from proximal atherosclerotic lesions or aneurysmal sites.
● Distal pulses remain palpable
● Patients complain of tenderness at site of embolization
● Digital vascular occlusion may cause ischemia and the “blue toe” syndrome; digital necrosis and
gangrene
● Cholesterol deposits may be seen in skin or muscle biopsy
● Necrotic areas are treated with amputation, analgesics are given to relieve pain
● Antiplatelet drugs and statins improve cardiovascular outcome
● Surgical intervention to remove or bypass the atherosclerotic vessel or aneurysm may be
necessary.
THORACIC OUTLET COMPRESSION SYNDROME
● Is a symptom resulting from compression of the neurovascular bundle (artery, vein, or nerves) at
the thoracic outlet as it courses through the neck and shoulder.
● Divided into arterial, venous, and neurogenic compression.
●
Approach to patient with Thoracic Outlet Compression Syndrome
o Generally, distal pulses are decreased or absent, digital cyanosis and ischemia may be evident
o Several maneuvers may be done
1. abduction and external rotation test (affected arm is abducted by 90° and the shoulder is
externally rotated)
2. Scalene maneuver (extension of the neck and rotation of the head to the side of the
symptoms)
3. costoclavicular maneuver (posterior rotation of shoulders)
4. hyperabduction maneuver (raising the arm 180°)
o Chest X-ray will indicate presence of cervical ribs
o Duplex ultrasonography, MRA, and contrast angiography can be performed during provocative
maneuvers to demonstrate thoracic outlet compression of the subclavian artery
o Neurophysiologic tests such as the electromyogram, nerve conduction studies, and
somatosensory evoked potentials may be abnormal if the brachial plexus is involved
o Management: mostly conservatively, patients are advised to avoid positions that cause
symptoms
o Many patients benefit from shoulder girdle exercises
o Surgical: removal of the first rib and resection of the scalenus anticus muscle are necessary
occasionally for relief of symptoms or treatment of ischemia.
POPLITEAL ARTERY ENTRAPMENT
● Affects: young athletic men and women
● Happens when gastrocnemius or popliteus muscle compresses the popliteal artery causing
intermittent claudication
o Thrombosis, embolism, or popliteal artery aneurysm may occur.
o Diagnosis: duplex ultrasound, CTA, MRA, or conventional angiography
o Treatment: surgical release of the popliteal artery or vascular reconstruction.
POPLITEAL ARTERY ANEURYSM
● Most common peripheral artery aneurysms
● Approximately 50% are bilateral.
● Patients have other aneurysms especially of aorta
● Most clinical presentation: limb ischemia secondary to thrombosis or embolism, rupture rarely
seen
● Other complications: compression of the adjacent popliteal vein or peroneal nerve
● Palpation detects, duplex ultrasonography confirms diagnosis
● Repair: if diameter of aneurysm >2-3cm due to risk of thrombosis, embolism, or rupture

ARTERIOVENOUS FISTULA
● Abnormal communications between an artery and a vein, bypassing the capillary bed
● May be congenital or acquired
● Clinical features: palpable pulsatile mass, thrill & bruit over fistula lasting throughout systole and
diastole
● Longstanding cases: chronic venous insufficiency, stasis pigmentation, ischemia, high skin
temperature, increased cardiac output with consequently cardiomegaly and heart failure may be
seen.
● Diagnosis: physical exam shows slow heart rate, presence of AVF on duplex sonography, size and
site of AVF on CTA & conventional angiography
● Management: surgery, radiotherapy or embolization. autogenous or synthetic grafting may also
be necessary
Congenital form
● Result from persistent embryonic vessels that fail to differentiate into arteries and vein
● May be associated with birthmarks
● Can be located in any organ of the body, frequently the extremities.
● Treated using elastic support
Acquired form
● Created to provide vascular access for hemodialysis, may occur as a result of a penetrating injury
or as complications of arterial catheterization or surgical dissection
● Amenable to surgery

RAYNAUD’S PHENOMENON
● Characterized by episodic digital ischemia
● Manifested clinically by the sequential development of digital blanching, cyanosis, and rubor of
the fingers or toes after cold exposure and subsequent rewarming
● May be precipitated by emotional stress
● Color changes are well demarcated and confined to fingers and toes
● Typically, one or more digits will appear white when the patient is exposed to a cold
environment or touches a cold object
● Blanching, or pallor resulting from vasospasm of digital arteries represents ischemic phase of the
phenomenon. During this phase, deoxygenated blood is present in capillaries and venules
causing them to dilate and then cyanosis.
 ● Phases of pallor and cyanosis are accompanied by sensation of cold, numbness or paresthesia of
the digits
● Rewarming resolves vasospasms and increases blood flow into the dilated arterioles and
capillaries imparting a bright red color to digits
“reactive hyperemia”
● Patients also experience throbbing, painful sensation during the hyperemic phase
● Raynaud’s phenomenon separated into two: idiopathic or primary & secondary Raynaud’s
phenomeno

Primary Raynaud’s phenomenon

● Over 50% have this form
● Women affected 5x more than men
● Age of presentation: between 20-40 years
● Involvement: fingers>toes
● Initial episodes may involve only one or two fingertips, but subsequent attacks may involve the
entire finger
● Rarely involves: earlobes, the tip of the nose, tongue, nipple, or penis
● Occurs mostly in patients with migraine headaches or variant angina
● Radial, ulnar, and pedal pulses are usually normal on examination
● Fingers and toes may be cool, nailfold capillaroscopy reveals normal superficial capillaries, which
appear as regularly spaced hairpin loops
● Thickening and tightening of the digital subcutaneous tissue (sclerodactyly) develop in 10% of
patients
● Generally, these patients have milder manifestations, <1% will lose a part of a digit, e disease
improves spontaneously in ~15% of patients and progresses in about 30%.
Secondary Raynaud’s phenomenon
● Occurs in 80–90% of patients with systemic sclerosis (scleroderma), 20% in patients with SLE,
30% in patients with dermatomyositis or polymyositis as well as in Rheumatoid arthritis.
● In men aged>50 years, atherosclerosis of extremities is a common cause
● Thromboangiitis obliterans though an uncommon cause, should be considered in young men,
particularly cigarette smokers
● Occasionally, it may follow acute occlusion of large and medium-sized arteries by a thrombus or
embolus.
● May also be seen in patients with thoracic outlet compression syndrome due to diminished
intravascular pressure, stimulation of sympathetic fibers in the brachial plexus, or a combination
of both
● May also occur in patients with hypertension, variety of blood dyscrasias and hyper viscosity
syndromes
● It occurs often in those who use vibrating hand tools, pianists and keyboard operators
● Drugs implicated include: ergot preparations, methysergide, β-adrenergic receptor antagonists,
and the chemotherapeutic agents bleomycin, vinblastine, cisplatin, and gemcitabine.
Treatment
● Supportive: reassurance, dress warmly, avoid cold, no tobacco use
 ● Pharmacotherapy (severe cases): Dihydropyridine calcium channel antagonists such as
nifedipine, isradipine, felodipine, and amlodipine
● Others: postsynaptic α1 -adrenergic antagonist, phosphodiesterase 5 inhibitors
● Injection of botulinum toxin into the perivascular tissue of the wrist or palm in severe cases

ACROCYANOSIS
● In this condition, there is arterial vasoconstriction and secondary dilation of the capillaries and
venules with resulting persistent cyanosis of the hands and, less frequently, the feet after
exposure to cold environment
● Categorized into: primary and secondary
Primary forms
● Affectation: Women> men
● Age of onset <30 years
● Patients are asymptomatic though common complaint is discoloration
● Prognosis: favorable
● Pain, ulcer and gangrene do not occur
● In comparison to Raynaud’s phenomenon, it is persistent and not episodic, discoloration extends
proximally from the digits, and blanching does not occur.
● Patients also have normal pulses excluding ischemia due to arterial occlusive disease
● No presence of central cyanosis or decreased arterial O2 saturation
● No intervention needed, patients are reassured, advised to dress warmly and avoid cold
Secondary forms
● Results from hypoxemia, vasopressor medications, connective tissue diseases, atheroembolism,
antiphospholipid antibodies, cold agglutinins, or cryoglobulins
● Associated with anorexia nervosa and postural orthostatic tachycardia syndrome.
● Treat underlying disorder

LIVEDO RETICULARIS
● This condition involves; development of mottled or rete (netlike) appearance of reddish to blue
discoloration in localized areas of the extremities which is prominent after cold exposure
● Divided into primary and secondary forms
Primary form
● Either benign or with ulcer associations
● Affectation: women> men
● common in 3rd decade
● Patients are asymptomatic
● no drug treatment is required except they are advised to avoid cold exposure
● If with ulceration, it is called atrophie blanche en plaque
Secondary forms
● Rarely develop ulcers
● Can occur with atheroembolism, SLE and other vasculitides, APAS, hyper viscosity,
cryoglobulinemia, and Sneddon’s syndrome (ischemic stroke and livedo reticularis)
PERNIO (CHILBIANS)
● A vascular disorder associated with exposure to cold
● Raised erythematous lesions develop on the lower part of the legs and feet in cold weather and
are associated with pruritus, burning sensation and may rupture or ulcerate
● Pathologic exam: angiitis characterized by intimal proliferation and perivascular infiltration of
mononuclear and polymorphonuclear leukocytes. In cases of subcutaneous tissue, giant cell may
be present
● Supportive treatment: avoid exposure to cold, keep ulcer clean and protected with dressing
● Pharmacotherapy: sympatholytic drugs and dihydropyridine calcium channel antagonists may be
effective

ERYTHROMELALGIA
● Disorder characterized by burning pain and erythema of the extremities
● Affectation: Feet>hands
● Males>females
● Most commonly affects middle age
● Characterized into primary and secondary.
Primary/ Inherited
● In inherited forms, mutations in SCN9A gene which encode Nav1.7 voltage-gated sodium
channel expressed in sensory and sympathetic nerves have been found
Secondary form
● Most common causes are myeloproliferative disorders e.g., polycythemia vera and essential
thrombocytosis. Other causes include; drugs, such as calcium channel blockers, bromocriptine,
and pergolide; neuropathies; connective tissue diseases such as SLE; and paraneoplastic
syndromes.
● Patient’s experience burning relieved by exposing the affected area to cool air or water or by
elevation
● In comparison to Ischemia due to PAD, peripheral pulses are present in erythromelalgia
● No specific treatment. However, aspirin may produce relief in some cases

FROSTBITE
● Tissue damage results from severe environmental cold exposure or from direct contact with a
very cold object
● Injury results from both freezing and vasoconstriction
● Frostbite mostly affects distal aspects of the extremities or exposed parts of the face, such as the
ears, nose, chin, and cheeks. Superficial frostbite involves skin and subcutaneous tissue
● Patients experience pain or paresthesia, and the skin appears white and waxy.
● After rewarming, there is cyanosis and erythema, wheal-and-flare formation, edema, and
superficial blisters
● Deep frostbite involves muscle, nerves, and deeper blood vessels and may result in edema of the
hand or foot, vesicles and bullae, tissue necrosis, and gangrene
● Initial treatment is rewarming and is accomplished by immersion of the affected part in a water
bath at temperatures of 40°–44°C (104°–111°F)
● Injured areas should be cleansed with soap or antiseptic, and sterile dressings should be applied
and analgesics may be required