Continuing Education Activity

Phlegmasia alba dolens (PAD) and phlegmasia cerulea dolens (PCD) are uncommon conditions that result from acute, massive venous thromboembolism. These conditions are associated with deep vein thrombosis of the lower extremity and have high associated morbidity and mortality. Early diagnosis is critical for the reduction of overall morbidity and mortality and treatment needs to be in a timely manner. This activity outlines the clinical manifestations and management of PAD and PCD and highlights the importance of timely diagnosis by the interprofessional team in the care of patients with these conditions.

Objectives:

• Describe the pathophysiology of phlegmasia alba dolens and phlegmasia cerulea dolens.
• Outline the typical presentation and evaluation of phlegmasia alba dolens or phlegmasia cerulea dolens.
• Review the management considerations for patients with phlegmasia alba dolens or phlegmasia cerulea dolens.
• Summarize the importance of collaboration and communication amongst the interprofessional team to ensure early diagnosis and prompt therapeutic intervention to improve outcomes for patients affected by phlegmasia alba dolens and phlegmasia cerulea dolens.

Introduction

Understanding how to accurately and effectively diagnose acute venous thromboembolism (VTE) remains a primary focus in hospitalized patients as the sequela of VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE), are of the most common preventable causes of hospital deaths, and their complications are a source of substantial long-term morbidity.[1] Phlegmasia alba dolens (PAD) and phlegmasia cerulea dolens (PCD) are less frequently encountered complications along a spectrum of DVT with a high incidence of mortality and limb loss.[2]

Phlegmasia is a term that has been used to describe extreme cases of lower extremity DVT, which may progress to critical limb ischemia and potentially limb loss. This entity was first described by Fabricius Hildanius in the 16 century, and then in 1938, it was Gregoire who coined the term phlegmasia cerulea dolens translating to “painful blue inflammation,” differentiating it from the more commonly seen phlegmasia alba dolens or “painful white inflammation.”[3] PAD, also referred to as “milk leg,” references the early stages of this process due to compromise of arterial inflow secondary to extensive clot burden. PCD is a more advanced progression and is a precursor to venous gangrene.

Etiology

The underlying pathologic condition of phlegmasia dolens is acute extensive VTE occluding the venous outflow of an extremity. The lower extremities are more commonly affected than the upper extremities. In the lower extremities, almost always, the iliofemoral segment is involved and occluded. In 20%-40% of cases, phlegmasia has been associated with malignancy. However, other risk factors for VTE include hypercoagulable disorders, venous stasis or insufficiency, May Thurner syndrome (left iliac vein compression by the overlying right iliac artery), surgery, trauma, pregnancy, IVC filter placement, the use of hormonal therapy or oral contraceptives, prolonged immobilization, inflammatory bowel disease, heart failure, and central venous catheterization. In approximately 10% of cases, the etiology remains unknown.[3][4][5][6]

Epidemiology

PAD and PCD are a spectrum of disorders associated with acute massive VTE, with the exact incidence being difficult to predict due to the rarity of the disease process. The highest incidence of patients occurs in the fifth and sixth decades of life, but ischemic venous thrombosis has been reported as early as 6 months all the way into the 8th decade of life. It has a slightly higher predominance in males versus females.[2][7] 

The majority of cases involve the lower extremities, with the left limb more often affected than the right due to the anatomical relationship between the right iliac artery overlying the left iliac vein; however, it is not uncommon for both lower extremities to be involved. Given the involvement of the iliofemoral segment, PCD is associated with significant post-thrombotic morbidity and high recurrence rates if not treated adequately.[8][9] If symptoms progress to venous gangrene, the risk of amputation is between 20%-50% with a high rate of mortality at 20% to 40%.[10][11]

Pathophysiology

PAD is characterized by thrombosis of the deep venous system with patency of the collateral veins and the absence of limb ischemia. PCD is a progression of PAD in which there is near-total occlusion of the major deep venous system as well as most of the microvascular collateral veins of the extremity, causing severe venous congestion. The potential window for reversibility is what differentiates PCD from venous gangrene in which there is complete obstruction of venous outflow to the limb, including extensive, irreversible capillary involvement and often full-thickness necrosis.[3][6]

Increased venous hypertension due to venous outflow occlusion results in a change in the pressure differential between hydrostatic and oncotic pressure that leads to increasing interstitial edema and massive fluid sequestration into the limb. The increase in interstitial and compartment pressure ultimately leads to the collapse of the arterial system once the compartment pressure overcomes arterial wall tension. This leads to acute ischemia and venous gangrene. Because of fluid third spacing, hemodynamic instability and hypovolemia ensue, increasing patient morbidity and mortality.[3][10]

History and Physical

PAD, historically known as “milk leg,” presents with the classic triad of edema, pain, and blanching without signs of cyanosis or tissue involvement. The onset of symptoms has proven to be unpredictable. They may be gradual over the course of days or fulminant with severe progression in a matter of hours. In 50% to 60% of patients, PAD will precede PCD.[3][6]

PCD presents similarly with pain and massive swelling due to fluid sequestration. Its most pathognomonic feature is the presence of cyanosis. As cyanosis and worsening venous congestion progress, patients will develop skin changes such as bullae and necrosis, and ultimately may experience paresthesia and motor weakness if edema causes severe arterial compromise and compartment syndrome. Cyanosis begins peripherally where it remains the most intense but may spread to involve the entire extremity. Gangrene will develop in about half of patients with PCD. In 10% to 20% of patients, this remains superficial with the preservation of arterial inflow. However, in more severe cases of venous gangrene, the deep musculature will be involved, and arterial pulses are absent.

Although much less common, upper extremity phlegmasia has been reported with the presence of ischemic venous thrombosis and gangrene. At least two of the following symptoms have been associated with upper extremity involvement: hemodynamic compromise secondary to impaired cardiac output, occlusion or thrombosis of central veins often associated with central venous catheterization, and occlusion of the peripheral veins.[3]

Pulmonary embolism is another clinical manifestation of phlegmasia as this disease process is highly emboligenic and has been shown to have increased incidence when tissue necrosis is present.[3][6] A high index of suspicion should be present for patients presenting with clinical symptoms of DVT and associated tachycardia or significant oxygen requirements.

Evaluation

A significant portion of the diagnosis of DVT and phlegmasia is made clinically with a focused history and physical exam, including details regarding onset and duration of symptoms, functional impairment related to the compromised limb, comorbidities, prior venous or arterial interventions, and personal or family history of thrombophilia or hypercoagulability. A thorough pulse exam of proximal and distal pulses in the extremities should be performed to assess arterial inflow. Often edema can make this challenging, and a doppler may be required to evaluate for intact signals. If blistering or skin necrosis, arterial or neural compromise, or venous gangrene are present at the presentation, this is considered emergent, and limb-threatening and immediate efforts to remove the thrombus and increase venous return should be performed.

Laboratory workup should include a complete blood count, standard coagulation profile (international normalized ratio, platelets, and partial thromboplastin time), and a basic metabolic panel to assess renal function and hydration status.

The gold standard for confirming the diagnosis of DVT is contrast venography; however, this is not clinically practical. Venous duplex ultrasonography has instead replaced contrast venography as the preferred imaging modality for diagnosis. Magnetic resonance venography (MRV) or computed tomography venogram (CTV) are alternative diagnostic studies particularly helpful in visualizing proximal thrombus in the iliac veins or IVC and identifying anatomical abnormality in the pelvis causing iliac vein compression. However, both imaging modalities have drawbacks. MRV is time-consuming compared to CT and can be limited by motion artifact in patients who present acutely with severe pain. CT inherently exposes the patient to radiation, but also poses the threat of nephrotoxicity with the use of iodinated contrast, particularly in a subset of patients who may be critically ill and in hypovolemic shock. Alternatively, patients who are candidates for catheter-based intervention may have venography performed at that time to further assess the extent and nature of the thrombus and to guide further management.

Ultrasound features suggestive of DVT on ultrasonography are the lack of compressibility, the absence of spontaneous flow through the vessel, enlarged vein diameter, and increased echogenicity present within the lumen of the vessel.

Treatment / Management

There has been variability regarding the management of acute DVT with associated phlegmasia or gangrene. The mainstays of treatment are to prevent the propagation of intravenous clotting and further stasis, reduce venous hypertension, avoidance of hypovolemic shock with fluid resuscitation, prevent progression to fulminant gangrene and preserve tissue viability, and treatment of the underlying condition.[3][6]

Supportive measures should be performed immediately and are considered first-line. The extremity should be elevated to an angle greater than 60 degrees above the level of the heart to prevent venous stasis and to increase venous return through remaining patent channels. Failure to achieve meaningful elevation may account for progression to venous gangrene. Elevation will also reduce edema and compression on the arterial system preventing circulatory collapse and hypovolemic shock. Historically, other supportive treatments, including hot packs, sympatholytics, antivasospastic drugs, and steroids have been advocated. However, these have proven little to no benefit and are not currently recommended.[3][6][7]

Definitive management involves anticoagulation, catheter-directed thrombolysis, thrombectomy, or any combination of the three depending on the severity of the presentation. The majority of patients will respond to treatment with fluid resuscitation, aggressive elevation, and anticoagulation. Unfractionated intravenous heparin should be given immediately as a bolus dose of 10-15 units/kg and then continued as an intravenous infusion being titrated to a therapeutic active partial thromboplastin time (aPTT) of 1.5 to 2 times the laboratory control value. Patients who present with advanced PCD or venous gangrene or those with refractory venous thrombosis on anticoagulation may be considered for catheter-directed thrombolysis (CDT), percutaneous mechanical thrombectomy, or open surgical thrombectomy. Other indications for aggressive intervention will depend on the institution and interventionalists but include the following: extensive thrombus burden, symptoms in a young functional individual, thrombus in the IVC, floating thrombus, propagation of DVT while on systemic anticoagulation, or structural abnormality.[7][12][13]

Prior to the advent of endovascular intervention, open surgical thrombectomy was the treatment of choice regarding emergent intervention. This is associated with high rates of recurrence and vessel-related complications such as denudation of the endothelium, rupture, intimal hyperplasia, and poor clinical durability. CDT, on the other hand, allows less mechanical trauma to the vessel and has become preferred over open surgical thrombectomy in patients who are candidates for lysis. Additionally, it allows for potential recanalization and clearing of thrombus from smaller venules that open surgery cannot access. Using this technique, thrombolytic agents are directly infused into the venous system through a multi-side-hole infusion catheter allowing the dissolution of a thrombus in the small distal and collateral vessels not accessible to a balloon embolectomy catheter. Heparin is infused simultaneously at a subtherapeutic rate (300 to 500 IU/hour) to prevent catheter thrombosis, and fibrinolytic is infused into the target area for a maximum period of 48 hours. The most common agent used with CDT is tissue plasminogen activator (tPA), and the usual dose is 0.5 mg to 1 mg/hour. The degree of swelling, as well as pulses, should be assessed routinely, and clotting factors should be monitored with serial lab draws to ensure close monitoring given the increased risk of bleeding. Repeat venography is subsequently performed to determine if the resolution of clot is achieved or adjunctive therapy is warranted, such as mechanical thrombectomy, or balloon angioplasty, and stenting in the setting of structural complications (i.e., May-Thurnher syndrome).

The clinical efficacy of CDT has been proven in several studies demonstrating that patients with symptomatic iliofemoral DVT had significant clinical improvement with a rapid reduction in thrombus burden, restoration of luminal patency, and a decreased risk of valvular dysfunction and post-thrombotic syndrome.[12][14][15][16] Like any fibrinolytic treatment, it carries a risk of hemorrhagic complications, with the most severe being intracranial hemorrhage. Additionally, it is less successful in patients with subacute or chronic symptoms with a duration of symptoms for greater than 10 to 14 days.

Contraindications to lysis therapy include:[17]

• Absolute contraindications
  • Active bleeding or bleeding diathesis (excluding menses)
  • Closed head/facial trauma or cerebrovascular accident within 3 months
  • Recent neurologic surgery
  • Coagulopathy
  • Intracranial vascular or malignant lesion or recent spinal surgery
  • Prior intracranial hemorrhage
• Relative contraindications
  • Surgery within the previous 10 days
  • Severe uncontrolled hypertension on presentation
  • Recent trauma or gastrointestinal hemorrhage or active peptic ulcer
  • Severe liver or kidney disease
  • Traumatic or prolonged CPR
  • Current use of anticoagulant with INR > 1.7 or PT >15s
  • Pregnancy 

Percutaneous mechanical thrombectomy (PMT) has also proven to be an effective alternate or adjunctive therapy to CDT using a mechanical thrombectomy catheter that aspirates or macerates the thrombus. There are multiple catheter-directed techniques for mechanical thrombectomy and manual extraction of thrombus, including rheolytic, rotational, aspiration, and angioplasty.  Comparing PMT to CDT, P.H. Lin et al. reported advantages of PMT being less thrombolytic infusion time compared to CDT alone and a lower risk of bleeding. Additionally, they found there were significantly shorter ICU stays as well as shorter hospital length of stay and the need for fewer venograms.[12]

In addition to bleeding complications, in patients who are undergoing CDT or PMT, there is also a risk for pulmonary embolus. Lysis can cause clot fragmentation, and manipulating wires within the veins may dislodge thrombus. Given this concern, consideration should be made for the placement of an IVC filter in select patients with extensive burden that extends into the IVC. Recently, a randomized controlled trial FILTER-PEVI (Filter Implantation To Lower Thromboembolic Risk in Percutaneous Endovascular Intervention) demonstrated an eightfold increase in symptomatic iatrogenic PE in patients who did not receive a filter prior to intervention. However, mortality was no different in those without a filter compared to subjects who had a filter placed.[18]

As mentioned previously, open surgical therapy is performed relatively infrequently. Venous thrombectomy in the form of open exposure followed by passing a Fogarty balloon catheter proximal and distal was historically performed. Other more involved procedures have also been described, such as transabdominal cavotomy and thrombectomy, but this was also more often performed prior to the advent of endovascular, percutaneous therapy and no longer has a role in the treatment of PCD and venous gangrene. Overall, they have been shown to decrease the risk of fatal and non-fatal pulmonary embolus; however, the procedure itself is very morbid.

Although not often encountered in patients who present with phlegmasia and venous gangrene, compartment syndrome should always be considered. If there is a question following the restoration of arterial inflow and venous outflow to the limb, a four-compartment fasciotomy to prevent muscle necrosis should be performed. If amputation is ultimately required because early efforts with fasciotomy have failed, it is recommended this be delayed if possible to give the limb time to demarcate and for edema to improve.

Differential Diagnosis

• Arterial embolism
• Deep vein thrombosis
• Cellulitis
• Lymphedema
• Venous valvular insufficiency
• Superficial thrombophlebitis

Prognosis

The overall prognosis remains relatively poor and worsens with the progression of symptoms. Overall mortality ranges from 20%-40%, particularly if gangrene is present.[3][4][5]

Despite prompt treatment in patients who develop acute DVT or phlegmasia, a significant percentage of patients will develop venous valvular insufficiency and post-thrombotic syndrome. Valvular incompetence has been reported as high as 20% and 44% at 5 and 10 years respectively.[13]

Complications

• Venous gangrene
• Limb loss
• Pulmonary embolus
• Compartment syndrome
• Post-thrombotic syndrome
• Death

Deterrence and Patient Education

Awareness of risk factors for developing DVT is important for early recognition and prevention of the progression of symptoms. The following are risk factors: previous diagnosis of DVT or PE, a family history of DVT or PE, hypercoagulable disorders, a diagnosis of venous stasis or insufficiency, May Thurner syndrome (left iliac vein compression by the overlying right iliac artery), recent major surgery, trauma, pregnancy, obesity, the use of hormonal replacement therapy or oral contraceptives, prolonged immobilization, inflammatory bowel disease, heart failure, and central venous catheterization.

If patients experience pain, limb swelling, skin changes or discoloration, or motor and/or sensory loss in the setting of the above-mentioned risk factors, they should seek a prompt medical evaluation with concern for deep venous thrombosis.

Enhancing Healthcare Team Outcomes

The presence of acute iliofemoral DVT with the symptoms of a painful, edematous, and cyanotic extremity is consistent with the diagnosis of phlegmasia alba dolens or cerulea dolens. Given its ability to rapidly progress to tissue necrosis and venous gangrene, this is an emergency. It is generally managed by an interprofessional team of healthcare professionals, including a vascular surgeon, a hospitalist, a hematologist if the DVT is unprovoked, and depending on severity, a critical care specialist. Clinically, this is an easily recognized entity, and the diagnosis can be confirmed with venous duplex ultrasound imaging. If diagnosed early, DVT can often be managed conservatively. However, patients who present with signs of phlegmasia cerulea dolens frequently require more invasive surgical intervention. If there is progression to venous gangrene, this can ultimately lead to limb loss and even death. Given this risk, early diagnosis is vital, and patient and provider awareness and recognition are critical. Once the diagnosis is confirmed, the patient should promptly be placed on bed rest, fluid resuscitation should be undertaken, the affected extremity should be elevated, and intravenous heparin bolus followed by infusion should be initiated.[7]

Institutional resources and specialist expertise should be a consideration when determining the management of PCD and venous gangrene. Ideally, vascular surgery or interventional radiology consultation should be obtained to assess and evaluate the extremity to determine if further intervention is required. The use of systemic thrombolytic therapy was initially trialed but is not recommended for the treatment of DVT and its sequela due to an increased risk of major bleeding. [Level 1] In the appropriate patients, catheter-based thrombolytic therapy or mechanical thrombectomy in combination with systemic anticoagulation has proven to improve treatment outcomes for patients who have failed to respond to systemic anticoagulation therapy alone.[11][12][13] 

In patients with progressive venous gangrene, open surgical thrombectomy may be considered as a first-line intervention to allow rapid removal of thrombus and restoration of peripheral circulation, particularly if they are not a candidate for lysis or endovascular intervention. [Level 3][2][3]