Phlegmasia and venous gangrene

INTRODUCTION — Phlegmasia (phlegmasia cerulea dolens, phlegmasia alba dolens) is a rare and extreme manifestation of deep vein thrombosis (DVT) and is a potentially limb- and life-threatening condition. The incidence is higher for the lower extremity compared with the upper extremity.

The pathophysiology, clinical features, and management of phlegmasia and venous gangrene are reviewed.

The diagnosis and management of less severe manifestations of DVT are discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Overview of thoracic central venous obstruction".)

PATHOGENESIS AND DEFINITIONS — Phlegmasia is the result of large vessel venous thrombotic occlusion, more typically from iliocaval venous obstruction causing lower extremity manifestations, but thoracic central venous thrombotic occlusion can lead to upper extremity manifestations. Venous thrombosis is due to the combined effects of vascular stasis, vascular wall injury, and hypercoagulability. Thus, conditions that promote these in the major venous structures increase the risk.

Obstruction of the deep veins limits outflow from the superficial veins and thrombus can extend into the venous collaterals (eg, axial veins, tributary veins), leading to severe venous hypertension, fluid sequestration, and extremity edema. This can result in serious consequences regarding limb viability and possible limb loss. (See 'Complications and mortality' below.)

The severity of venous hypertension determines the clinical appearance [1-4]. (See 'Clinical features' below.)

Phlegmasia alba dolens — Phlegmasia alba dolens occurs when outflow through venous collaterals is sufficient to maintain flow in the subdermal and dermal venous plexuses and there is no overwhelming venous congestion. Cyanosis does not occur; focal compression blanches the skin. The clinical triad associated with phlegmasia alba dolens is pain, swelling, and white (alba) blanching skin.

Phlegmasia cerulea dolens — Phlegmasia cerulea dolens occurs when the venous collaterals thrombose and flow in the subdermal and dermal plexuses is severely reduced or absent, leading to cyanotic-appearing skin. The limb becomes very swollen and painful; the skin does not blanch to pressure. Massive limb swelling can occur from fluid sequestration into the tissues. The clinical triad associated with phlegmasia cerulea dolens is worsening pain, severe swelling, and dusky blue (cerulea) skin (nonblanching).

Venous gangrene — In a patient with phlegmasia cerulea dolens, ischemia occurs because the gradient for flow in the microcirculation is severely diminished or absent. In addition, venous hypertension drives fluid out of the vasculature resulting in severe fluid sequestration [5]. The type of arterial ischemia that develops begins primarily at the capillary level, with fluid sequestration and swelling within a tight fascial compartment, which leads to capillary thrombosis and subsequent thrombosis of the medium (tibial) vessels, then large vessel thrombosis (popliteal, superficial femoral, common femoral arteries).

EPIDEMIOLOGY AND RISK FACTORS — Phlegmasia is rare, and the true incidence is largely unknown. In one review of patients undergoing iliocaval venous intervention, 19 percent presented with phlegmasia (alba 3 percent, cerulea 16 percent) [6].

Paralleling the incidence of symptomatic deep vein thrombosis (DVT), the incidence of phlegmasia is higher for the lower extremity compared with the upper extremity. In the lower extremity, the incidence is higher in females (5:1) than in males for reasons that are unclear [7,8].

Data describing risk factors associated with phlegmasia are limited to case reports and small case series [9-12]. These support our experience that malignancy is the most common risk factor and is present in at least one-third of patients [9,13,14]. This can be related to compression of venous structures by tumors, causing venous outflow obstruction or malignancy-related hypercoagulability. Other masses including benign tumors and aneurysmal disease have also been reported to cause phlegmasia [15-18].

Other factors associated with phlegmasia include hypercoagulable states (eg, heparin-induced thrombocytopenia) [19-21], factor VII deficiency [22], antiphospholipid syndrome [14], congenital venous anomalies [23], trauma [24], cardiomyopathy [25], femoral venous catheterization, inferior vena cava filter placement [26-28], coronavirus disease 2019 (COVID-19) [29-33], surgery [34], hemodialysis [35], and pregnancy [10].

Phlegmasia can occur in the absence of these known risk factors, as 10 percent of cases are idiopathic [36].

CLINICAL FEATURES — The clinical features of phlegmasia occur along a clinical spectrum that can progress from phlegmasia alba dolens (early phase) to phlegmasia cerulea dolens (late phase) with or without venous gangrene (end stage) [1-4,24]. (See 'Pathogenesis and definitions' above.)

A detailed history should be obtained that includes onset and duration of symptoms, development of any sensory or functional abnormalities, medical conditions including any personal or family history of hypercoagulability, and any prior venous or arterial intervention or surgery.

Clinical manifestations may progress gradually over a variable period from days to weeks or can be fulminant progressing over hours. The early phase, phlegmasia alba dolens, may not be appreciated in up to half of patients because of rapid disease progression [2,3].

Symptoms — Lower extremity involvement is more common than upper extremity phlegmasia; while less common and estimated to occur in 5 percent of patients, upper extremity phlegmasia has been reported [19,32,35,37,38].

In the lower extremities, left-sided involvement is three to four times more common than right-sided involvement paralleling the incidence of May-Thurner syndrome (figure 1). However, bilateral phlegmasia has been reported [24,39]. (See "May-Thurner syndrome".)

Patients usually complain of sudden unilateral pain and swelling. The pain is constant and is often described as a severe, dull, aching pain. The pain usually starts proximally (eg, at the femoral triangle for the lower extremity) and progresses to involve the entire extremity. Pain is often out of proportion with the degree of limb swelling.

Patients may also present with clinical features of limb ischemia related to compartment syndrome [26]. (See "Acute compartment syndrome of the extremities", section on 'Clinical features'.)

Massive fluid sequestration into the limb can also lead to hypovolemia and possibly shock, which exacerbates limb ischemia.

Physical examination — On examination, the affected extremity is severely swollen and tender to touch. In the early phase of phlegmasia alba dolens, symptoms are associated with blanching (alba) of the skin. With progression to phlegmasia cerulea dolens, the affected extremity is cyanotic, a pathognomonic finding. Cyanosis progresses from the distal to the proximal extremity.

A complete pulse examination of proximal and distal pulses in the extremities should be performed. Severe edema may limit palpation of pulses. In most patients, we use a handheld Doppler to evaluate the strength of the arterial as well as venous signals. We also assess for the level of any sensory loss or muscle weakness.

Late in the course, the patient can show signs of venous gangrene with or without signs of sepsis. Patients with phlegmasia that progresses to venous gangrene present initially with diminished venous signals progressing to disappearance of venous signals, followed by the development of obstructive arterial signals (waterhammer), then complete loss of all signals. This is in contrast with acute limb ischemia from arterial obstruction, in which the venous signals are initially preserved, and subsequently lost with progression of ischemia.

As phlegmasia progresses, massive fluid sequestration may lead to bleb and bullae formation of the skin. Massive fluid sequestration increases tissue pressure, increasing the risk for extremity compartment syndrome. Fluid sequestration may be severe enough to cause signs of hypovolemia (tachycardia, hypotension, reduced urine output) and possibly shock.

DIAGNOSIS — The diagnosis of phlegmasia is based on ultrasound evidence of extensive deep vein thrombosis (DVT) with supportive clinical findings in the affected extremity including massive limb swelling, severe limb pain (particularly when disproportionate to the degree of swelling), and depending on severity, cyanosis or venous gangrene. (See 'Clinical features' above.)

Duplex ultrasound of the extremity is the imaging tool of choice and is highly sensitive for venous thrombosis. The deep veins and the superficial veins should be evaluated. Compression ultrasound in B-mode identifies the presence of thrombus (noncompressibility, increased echogenicity, increased diameter), and Doppler mode assesses venous flow. Arterial flow can also be evaluated to determine the severity of limb ischemia.

In the author's practice, once a diagnosis of ipsilateral acute DVT has been established, we also perform iliac venous duplex to evaluate for more proximal venous outflow obstruction. Although direct ultrasound imaging above the ilioinguinal ligament may be suboptimal in some clinical circumstances, finding a lack of respiratory variation in the venous waveform at the level of the common femoral vein is suspicious for more proximal obstruction.

Positive ultrasound findings along with the clinical presentation are usually sufficient to proceed with treatment. Obtaining cross-sectional studies is not usually necessary, as it will not change the course of the disease and will not alter the approach to intervention.

The imaging diagnosis of iliocaval and thoracic central venous thrombosis is discussed in more detail separately. (See "Overview of iliocaval venous obstruction" and "Clinical features, diagnosis, and classification of thoracic central venous obstruction", section on 'Vascular imaging'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of phlegmasia includes conditions that cause limb swelling, those that cause extremity cyanosis and those that cause acute limb ischemia.

●Extremity swelling – Other conditions that can cause lower extremity swelling include:

•Limited venous thrombosis without vascular compromise, which can cause a variable degree of swelling. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'Differential diagnosis'.)

•Lymphedema, which is not associated with cyanosis. (See "Clinical features and diagnosis of peripheral lymphedema".)

•Acute cellulitis, which is associated with an erythematous appearance. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

•Compartment syndrome from etiologies other than venous thrombosis. (See "Pathophysiology, classification, and causes of acute extremity compartment syndrome".)

●Acute limb ischemia – Conditions that lead to acute limb ischemia from arterial obstruction include arterial thrombosis, embolism, and dissection, among others. The acutely ischemic limb due to arterial occlusion is pale with diminished capillary filling and delayed venous filling, and therefore without swelling or cyanosis. Reduced perfusion associated with phlegmasia can cause a level of pain that is like that experienced in those with acute arterial occlusion. Phlegmasia can also be associated with neurologic dysfunction (sensory loss, motor dysfunction). (See "Clinical features and diagnosis of acute lower extremity ischemia".)

●Peripheral cyanosis – Conditions that lead to a peripheral cyanosis are more likely to be symmetric and bilateral and include cardiopulmonary conditions and some hematologic conditions that reduce oxygen saturation and cause central cyanosis with or without peripheral cyanosis. (See "Methemoglobinemia" and "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis".)

Other conditions can cause acrocyanosis with a variable distribution. (See "Erythromelalgia" and "Pernio (chilblains)" and "Cold agglutinin disease" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Purpura fulminans'.)

TREATMENT

Treatment overview — Treatment of phlegmasia aims to limit propagation of thrombus, reduce venous hypertension to minimize tissue loss, prevent hypovolemia and shock, and identify and treat any inciting conditions. The aggressiveness of treatment depends on the severity of the presentation (algorithm 1). There are no formal criteria by which to classify the severity of phlegmasia, but since phlegmasia represents a form of acute limb ischemia, some experts have adopted the Rutherford classification criteria (table 1) [40]. (See "Classification of acute and chronic lower extremity ischemia".)

We broadly classify severity as early versus late phlegmasia.

●Early phlegmasia – We define early phlegmasia as symptoms and signs of severe venous outflow obstruction, but arterial Doppler signals remain present (corresponds to Rutherford I [viable limb]). Patients with early phlegmasia may respond quickly to anticoagulation (see 'Anticoagulation' below) and limb elevation; however, if progress is not satisfactory within 12 hours of conservative management, venous intervention should be offered. (See 'Early phlegmasia: Viable limb' below.)

●Late phlegmasia – We define late phlegmasia as symptoms and signs of severe venous outflow obstruction without arterial Doppler signals with or without neurologic dysfunction (corresponds to Rutherford II [threatened limb]). Patients presenting in the late phase (arterial Doppler pulses absent) require venous intervention. Treatment is required as quickly as possible to re-establish venous outflow and improve limb perfusion. Delays in treatment increase the risk for limb loss and death [9]. (See 'Late phlegmasia: Threatened limb' below.)

In addition to anticoagulation and venous intervention, when indicated, care of patients with phlegmasia includes absolute bed rest, elevation of the affected extremity to as high as is tolerated (ideally >30 degrees), pain control, judicious fluid resuscitation, and monitoring for rhabdomyolysis (serial electrolytes, creatine kinase, myoglobinuria) and compartment syndrome. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Acute compartment syndrome of the extremities".)

Crystalloid solutions are administered for signs of hypovolemia (eg, tachycardia, hypotension, reduced urine output). Severe hypovolemia leading to shock occurs in approximately one-third of patients, particularly those with rapid progression. Fluid sequestration into the affected extremity may be as much as 10 L. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Nonhemorrhagic shock'.)

Unless the patient has already been admitted to vascular services, subspecialty consultation is necessary to assess of the severity of ischemia, determine the optimal approach to intervention, and assess the medical suitability of the patient. Subspecialty consultation is also necessary to obtain compartment pressures and perform extremity compartment decompression, as needed, or for those with an unsalvageable limb, amputation. If appropriate vascular or other surgical services are not available, the patient should be transferred to a facility with clinicians experienced in these interventions.

Anticoagulation — For patients with phlegmasia, anticoagulation is required, provided there are no contraindications [41]. While awaiting confirmation on venous duplex ultrasound, we immediately anticoagulate all patients in whom phlegmasia is strongly suspected based on clinical features. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Unfractionated heparin (UFH) is used as the initial anticoagulant (or an alternative intravenous agent for those with heparin allergy) regardless of severity to minimize progression in those with less severe disease and to minimize tissue loss in more severe disease. UFH is used rather than other anticoagulants in anticipation of intervention. Due to its short half-life, UFH is ideal since it can be adjusted quickly. Other anticoagulants such as low-molecular-weight heparin or direct oral anticoagulants have a role in subsequent management once the patient is clinically stable and there is no further concern for intervention. Data are lacking to support these agents during the acute phase of management in this population.

Some patients with early phlegmasia may respond adequately to anticoagulation such that subsequent intervention may not be needed. In one early series, 4 of 12 patients improved with anticoagulation alone [42-44]. However, there are no validated criteria by which to select patients, and thus, venous intervention is considered mandatory unless the limb is not salvageable or the patient refuses intervention. Patients who cannot be anticoagulated can still be treated with nonpharmacologic mechanical thrombectomy or surgical thrombectomy [45]. (See 'Vascular intervention' below.)

Importantly, venous intervention does not prohibit administration of systemic anticoagulation with UFH. Anticoagulation is maintained during endovenous intervention; however, before surgical intervention UFH may be held to reduce the risk of procedure-related bleeding. Protocols for UFH administration (table 2) and monitoring are reviewed separately. (See "Venous thromboembolism: Initiation of anticoagulation", section on 'Unfractionated heparin'.)

Once the limb threat is resolved, patients are treated with anticoagulant therapy for a minimum of three months [46,47]. Agent selection and duration of therapy are like that in the general population. (See "Venous thromboembolism: Anticoagulation after initial management" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Vascular intervention

Options for intervention — One or a combination of endovascular techniques can be used to reduce thrombus burden. Available options include endovenous mechanical thrombectomy (MT), endovenous thrombolysis, and open surgical thrombectomy.

●Endovenous mechanical thrombectomy – MT uses a variety of endovascular devices to break up and physically remove thrombus using suction without or with administration of supplemental pharmacologic thrombolysis. (See "Endovenous intervention for iliocaval venous obstruction", section on 'Percutaneous mechanical thrombectomy'.)

●Endovenous thrombolysis – Thrombolysis administers a thrombolytic agent (eg, tissue plasminogen activator, urokinase, streptokinase) using specialty catheters that distribute the agent throughout the thrombus (ie, catheter-directed thrombolysis). Some devices administer the thrombolytic agent with additional energy designed to break up the thrombus to increase the surface area upon which the thrombolytic agent can act (ie, pharmacomechanical thrombolysis). Contraindications to thrombolysis are provided in the table (table 3). (See "Endovenous intervention for iliocaval venous obstruction", section on 'Combined treatment: Pharmacomechanical thrombolysis'.)

●Open surgical thrombectomy – Open surgical involves exposing typically the common femoral vein and passing thrombectomy catheters proximally and distally to remove thrombus. Gentle pressure on the extremity from distal to proximal can facilitate moving thrombus toward the groin. More distal or more proximal access can also be used to facilitate passage of the balloon catheters or perform direct thrombectomy. The veins are typically irrigated with saline or can be flushed with a heparin solution to facilitate thrombus removal.

Following restoration of venous outflow, significant venous stenotic lesions are treated to prevent recurrent thrombosis. For patients who undergo stenting to maintain venous patency, antiplatelet therapy is initiated. (See "Endovenous intervention for iliocaval venous obstruction", section on 'Angioplasty/stenting' and "Endovenous intervention for iliocaval venous obstruction", section on 'Antithrombotic therapy'.)

If persistent venous outflow obstruction remains, surgical venous bypass may be needed [48]. (See "Techniques used for open iliocaval venous reconstruction".)

Approach to intervention — The approach to venous intervention in patients with phlegmasia is individualized and depends upon the duration and severity of limb ischemia, patient comorbidities, and local expertise (algorithm 1). Patients presenting in the late phase (arterial Doppler signals absent), and those with early phlegmasia without satisfactory improvement within 12 hours of conservative management require venous intervention. Suitable candidates for intervention include those with symptoms present for less than 14 days, a life expectancy of more than one year, and good functional status [35].

Early phlegmasia: Viable limb — For early phlegmasia, either MT or thrombolysis can be used depending on local resources and expertise. We suggest using MT as the initial approach to venous intervention rather than thrombolysis alone. The rationale is based on the faster timeframe to restore venous outflow, which is more immediate for MT compared with thrombolysis alone, where the effect is often not apparent for least 24 to 48 hours [49,50]. In a review of 93 patients undergoing venous intervention, compared with thrombolysis alone, MT with or without thrombolysis reduced the length of intensive care unit stay (0.6 versus 2.4 days) and hospital stay (4.6 versus 8.4 days) [49]. Although at one year, follow-up primary patency rates were similar. Bleeding was increased when thrombolytic therapy is concurrently used.

After the bulk of thrombus has been removed, anticoagulation is continued, and the limb is carefully monitored. With expedient MT, ongoing anticoagulation, and limb elevation, most patients improve quickly within first couple of hours. Swelling and pain are reduced, and the calves become soft. While uncommon with early phlegmasia, we monitor all patients for extremity compartment syndrome, and perform fasciotomy as indicated [22,31]. Thrombolysis can be initiated for those who do not demonstrate adequate improvement provided there are no contraindications (table 3). (See "Catheter-directed thrombolytic therapy in deep venous thrombosis of the lower extremity: Patient selection and administration", section on 'Patients who fail thrombolysis'.)

Alternatively, if resources are not available to perform MT, thrombolysis can be used but requires vigilant monitoring of the extremity, most often in the intensive care unit.

Late phlegmasia: Threatened limb — For patients with late phlegmasia (arterial Doppler signals absent), rapid thrombus removal is necessary to improve venous outflow very quickly either using endovenous mechanical thrombectomy or open surgical thrombectomy [51-54]. Choosing between MT or open surgical thrombectomy depends on local availability and expertise and surgical candidacy of the patient.

●For most patients, if resources are available, we suggest MT. Following debulking with MT, thrombolysis can be initiated, as needed, provided there are no contraindications (table 3). If MT is not available, surgical thrombectomy is an alternative.

●For patients with progressive symptoms despite attempts at MT or contraindications to thrombolysis, surgical thrombectomy is the only option [55,56]. Surgical thrombectomy may relieve acute symptoms in up to half of patients but may be less effective overall compared with methods that include thrombolysis [8,57].

Thrombectomy alone does not directly address thrombus in the collateral outflow veins (eg, axial veins, tributaries) involved in the progression to phlegmasia and venous gangrene, and additional thrombolysis is generally needed [7,11,58,59]. In a review of 22 patients, a multimodality approach was required in 45 percent [7]. In the above review of 93 patients, the addition of MT reduced the amount of thrombolytic agent required [49].

Patients with late phlegmasia are at risk for reperfusion injury after venous intervention including the potential sequelae of myoglobinuria and hyperkalemia. Reperfusion also exacerbates already elevated tissue pressures. Prophylactic fasciotomy should be strongly considered. For patients with limited venous gangrene, timely fasciotomy can also reduce the extent of tissue loss. Aggressive debridement of necrotic tissue along with objective assessment of arterial blood flow are imperative to salvage as much of the limb as possible. Techniques for fasciotomy and patient management following fasciotomy are discussed separately. (See "Lower extremity fasciotomy techniques" and "Upper extremity fasciotomy techniques" and "Patient management following extremity fasciotomy".) [26]

Nonviable limb — For patients with phlegmasia who have a nonviable extremity, amputation is required. The timing and manner of amputation (primary versus staged) depends upon the medical condition of the patient and presence of infection. The level of amputation is determined by the viability of tissues at the time of surgery. We preserve as much length as possible to improve the likelihood for successful rehabilitation. Further details regarding amputation are provided separately. (See "Lower extremity amputation" and "Techniques for lower extremity amputation" and "Upper extremity amputation".)

COMPLICATIONS AND MORTALITY — Case series report mortality rates ranging from 20 to 66 percent [7,9,11]. In one study of 22 patients with phlegmasia, death occurred in two-thirds of patients who underwent percutaneous thrombectomy alone and half of those who underwent pharmacomechanical thrombolysis alone [7]. Death is related to pulmonary embolism in approximately 30 percent of patients [9,60].

●Amputation – When venous gangrene is not established, phlegmasia is generally considered reversible. Patients with a viable extremity who undergo successful venous intervention can generally expect a full recovery. However, approximately 40 to 60 percent of patients with phlegmasia have irreversible ischemia [4]. Case series report amputation rates among survivors ranging from 12 to 50 percent [4,7,9,11]. Major amputation is needed in up to 25 percent of survivors [43].

●Thrombosis – Patients with phlegmasia, like other patients with deep vein thrombosis, are at risk for pulmonary embolism, recurrent thrombosis, and postphlebitic syndrome. Whether patients with phlegmasia are at increased risk of these complications compared with patients who have DVT without the clinical features of phlegmasia is unknown. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'Suspected recurrent DVT' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

●Venous valvular incompetence – Despite prompt treatment, many patients will develop venous valvular incompetence. In one review, deep venous insufficiency was present in 20 and 44 percent of patients at 5 and 10 years, respectively, following treatment [59]. (See "Post-thrombotic (postphlebitic) syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Deep vein thrombosis (blood clot in the leg) (The Basics)")

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Phlegmasia – Phlegmasia is a rare and extreme manifestation of deep vein thrombosis (DVT) and is a potentially limb-threatening and life-threatening. Phlegmasia occurs in the lower extremity more often than the upper extremity. Malignancy (obstructing tumor, hypercoagulability) is the most common risk factor and is present in at least one-third of patients. Other conditions include benign masses causing venous obstruction, hypercoagulable states, trauma, congenital venous anomalies, venous instrumentation, and pregnancy, among others. (See 'Epidemiology and risk factors' above.)

●Clinical features – The clinical features of phlegmasia occur along a clinical spectrum that can progress from phlegmasia alba dolens (early phase) to phlegmasia cerulea dolens (late phase) with or without venous gangrene (end stage). Progression can occur over days to weeks or can be fulminant, progressing over hours. (See 'Pathogenesis and definitions' above and 'Clinical features' above.)

•Phlegmasia alba dolens – Phlegmasia alba dolens occurs when outflow through venous collaterals is sufficient and there is no overwhelming venous congestion. The clinical triad associated with phlegmasia alba dolens is pain, swelling, and white (alba) blanching skin.

•Phlegmasia cerulea dolens – Phlegmasia cerulea dolens occurs when the venous collaterals thrombose leading to severe venous hypertension. The clinical triad associated with phlegmasia cerulea dolens is worsening pain, swelling, and dusky blue (cerulea) skin (nonblanching). Severe venous hypertension can lead massive fluid sequestration into the extremity, severe hypovolemia, and shock. The development of extremity compartment syndrome further worsens limb ischemia.

•Venous gangrene – Venous gangrene is due to capillary thrombosis that progresses to involve larger vessels. Venous gangrene can develop without or with signs of septic shock.

●Diagnosis – The diagnosis of phlegmasia is based on ultrasound evidence of extensive DVT along with supportive clinical findings including severe limb swelling and pain (particularly when disproportionate to the degree of swelling), and depending on severity, cyanosis or venous gangrene. The differential diagnosis includes other conditions that cause a limb swelling, those that cause extremity cyanosis, and those that cause acute limb ischemia. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Initial treatment – Initial care of all patients with phlegmasia alba dolens or phlegmasia cerulea dolens includes absolute bed rest, elevation of the affected extremity as high as is tolerated (ideally >30 degrees), pain control, and judicious fluid resuscitation using crystalloid solutions. All patients are immediately anticoagulated while awaiting confirmation on venous duplex ultrasound. We suggest intravenous unfractionated heparin (UFH) as the initial anticoagulant, regardless of disease severity, based on clinical experience and in anticipation of venous intervention.

●Approach to intervention – The approach to venous intervention in patients with phlegmasia is individualized and depends upon the duration and severity of limb ischemia, patient comorbidities, and local expertise (algorithm 1). Patients in the early phase (arterial doppler signals present) may respond to conservative management (anticoagulation, limb elevation) alone. Patients presenting in the late phase (arterial Doppler signals absent) and those who do not have satisfactory progress after 12 hours of conservative management require venous intervention. Suitable candidates for intervention include those with symptoms present for less than 14 days, a life expectancy of more than one year, and good functional status.

•Early phlegmasia: Viable limb – For patients with early phlegmasia, we suggest mechanical thrombectomy (MT) as the initial approach to intervention, rather than thrombolysis alone (Grade 2C). After the bulk of thrombus has been removed, anticoagulation is continued, and the limb is carefully monitored. For patients who do not demonstrate adequate improvement, thrombolysis can be initiated if there are no contraindications (table 3).

•Late phlegmasia: Threatened limb – For patients with late phlegmasia, rapid thrombus removal is necessary to improve venous outflow.

-For most patients, we suggest MT (Grade 2C). Following debulking with MT, thrombolysis can be initiated, as needed, provided there are no contraindications (table 3). If MT is not available, surgical thrombectomy is an alternative.

-For patients with progressive symptoms despite attempts at MT or contraindications to thrombolysis, surgical thrombectomy is the only option. Surgical thrombectomy may relieve acute symptoms in up to half of patients but may be less effective overall compared with methods that include thrombolysis.

-Patients with late phlegmasia are at risk for reperfusion injury, which also exacerbates already elevated tissue pressures. Prophylactic fasciotomy should be strongly considered.

•Nonviable limb – For patients with phlegmasia who have a nonviable extremity, amputation is required. The timing and manner of amputation depends upon the medical condition of the patient and presence of infection.

●Outcomes – For patients with phlegmasia, morbidity and mortality are high. Mortality rates range from 20 to 66 percent. Death is often related to pulmonary embolism. Among survivors, major amputation occurs in up to 25 percent.