Phlegmasia Alba and Cerulea Dolens

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. The iliofemoral segment is almost always involved and occluded in the lower extremities. 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 into the 8th decade of life. It has a slightly higher predominance in males versus females.[2][7] 

Most 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 and 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 changes the pressure differential between hydrostatic and oncotic pressure, 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 days or fulminant with severe progression in a matter of hours. In 50% to 60% of patients, PAD precedes 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 develop skin changes such as bullae and necrosis. They 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 develops 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 is involved, and arterial pulses are absent.

Although much less common, upper extremity phlegmasia has been reported with ischemic venous thrombosis and gangrene. At least 2 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 the 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 skin necrosis, arterial or neural compromise, or venous gangrene is 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 or computed tomography venogram are alternative diagnostic studies that are 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. Magnetic resonance venography 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 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, spontaneous flow through the vessel, the enlarged vein diameter, and increased echogenicity within the vessel's lumen.

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, avoid hypovolemic shock with fluid resuscitation, prevent progression to fulminant gangrene, preserve tissue viability, and treat 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 also reduces 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 are not recommended and have little to no benefit.[3][6][7](B2)

Definitive management involves anticoagulation, catheter-directed thrombolysis, thrombectomy, or any combination of the 3, depending on the severity of the presentation. The majority of patients 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 titrated to a therapeutic active partial thromboplastin time 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 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](B2)

Before the advent of endovascular intervention, open surgical thrombectomy was the treatment of choice regarding emergent intervention. This is associated with high recurrence rates 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 48 hours. The most common agent used with CDT is a tissue plasminogen activator, and the usual dose is 0.5 mg to 1 mg/hour. Swelling and 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 the clot is achieved or adjunctive therapy is warranted, such as mechanical thrombectomy, balloon angioplasty, and stenting in the setting of structural complications (ie, 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 greater than 10 to 14 days.(B2)

Contraindications to lysis therapy include:[17](A1)

• 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, 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 >15 seconds
  • 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 thrombus extraction, including rheolytic, rotational, aspiration, and angioplasty. Comparing PMT to CDT, P.H. Lin et al reported the advantages of PMT, which include less thrombolytic infusion time than CDT alone and a lower risk of bleeding. Additionally, they found significantly shorter ICU stays, shorter hospital lengths, and the need for fewer venograms.[12](B2)

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 the thrombus. Given this concern, consideration should be made for placing 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 pulmonary embolism in patients who did not receive a filter before intervention. However, mortality was no different in those without a filter compared to subjects who had a filter placed.[18](B2)

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 before the advent of endovascular and 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

The differential diagnoses for phlegmasia alba and cerulea dolens are as follows:

• 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 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

The complications that can manifest with phlegmasia alba and cerulea dolens are as follows:

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