Phlegmasia Alba and Cerulea Dolens

Phlegmasia stems from a Greek term (phlegma) meaning inflammation. It has been used in the medical literature in reference to extreme cases of lower-extremity deep venous thrombosis (DVT) that cause critical limb ischemia and possible limb loss. Phlegmasia alba dolens (PAD) describes the patient with swollen and white leg because of early compromise of arterial flow secondary to extensive DVT. This condition is also known as “milk leg,” especially as it affects women in the third trimester of pregnancy or post partum.

Phlegmasia cerulea dolens (PCD) is more advanced and considered a precursor of frank venous gangrene.[1] It is characterized by severe swelling and cyanosis and blue discoloration of the extremity. It was first described by Hildanus in the 16th century.[2] Later, the term PCD was first used by Gregoire in 1938.[3] Its rarity notwithstanding, phlegmasia is a life-threatening condition. It is crucial for nonvascular specialists to be able to recognize this condition promptly and accurately; treatment is time-sensitive.

In PAD, the thrombosis involves only major deep venous channels of the extremity, thus sparing collateral veins. The venous drainage is decreased but still present; the lack of cyanosis differentiates this entity from PCD. In PCD, the thrombosis extends to collateral veins, resulting in severe venous congestion with massive fluid sequestration and more significant edema. Without established gangrene, these phases are reversible if proper measures are taken.

Of PCD cases, 40-60% also have capillary involvement, which results in irreversible venous gangrene that involves the skin, subcutaneous tissue, or muscle.[4] Under these conditions, the hydrostatic pressure in arterial and venous capillaries exceeds the oncotic pressure, causing fluid sequestration in the interstitium. Venous pressure may increase rapidly, as much as 16- to 17-fold within 6 hours.[5, 6]

Fluid sequestration may reach 6-10 L in the affected extremity within days. Circulatory shock, which is present in about one third of patients, and arterial insufficiency may ensue. The exact mechanism for the compromised arterial circulation is debatable but may involve shock, increased venous outflow resistance, and collapse of arterioles due to increased interstitial pressure.

DVT affects as many as 2 million Americans every year. The majority of patients are treated medically, with anticoagulation being the mainstay of therapy to promote thrombus resolution and prevent propagation and embolization. Because phlegmasia is a rare condition, its incidence is unknown. The best estimate is derived from case series of patients treated for extensive DVT. In more recent series, 10-20% of patients undergoing thrombolysis with possible stenting for extensive DVT presented with phlegmasia.[7, 8, 9]

The prevalence is thought to be slightly higher in men than in women, with a male-to-female ratio of 1.5:1.[10]

Despite all the therapeutic modalities currently available (see Treatment), PCD and venous gangrene remain life-threatening and limb-threatening conditions, with overall mortality in the range of 20-40%. Pulmonary embolism (PE) is responsible for 30% of the deaths reported from PCD. Overall, amputation rates of 12-50% have been reported among survivors. The postphlebitic sequelae are apparent in 60-94% of survivors. Strict adherence to the use of long-term compression stockings helps control chronic edema.[10, 4]

Phlegmasia alba dolens (PAD) and phlegmasia cerulea dolens (PCD) predominantly affect the lower extremities, with fewer than 5% of cases believed to involve the upper extremities. In the lower extremities, left-side involvement is three to four times more common. PAD is known by the triad of edema, pain, and blanching (alba) without cyanosis.

The onset of symptoms may be gradual or fulminant. PAD precedes PCD in 50-60% of cases. With increasing cyanosis and progression, patients develop bullae, paresthesia, and motor weakness. Compartment syndrome may be precipitated by venous congestion. Venous gangrene and shock are the ultimate killers, and it is vital that patients be treated before reaching that stage.

Malignancy is the most common triggering factor and is present in approximately 20-40% of patients with PCD.[10] The presence of malignancy is also associated with higher mortality. Other associated risk factors include the following:

• Hypercoagulable syndrome
• Surgery
• Trauma, ulcerative colitis
• Inferior vena cava filter insertion
• May-Thurner syndrome (compression of the left iliac vein by the right iliac artery)

Pregnancy has often been associated with PAD, especially during the third trimester, when the uterus is large enough to compress the left common iliac vein against the pelvic rim (ie, milk leg syndrome). Finally, 10% of patients with phlegmasia have no apparent risk factors.

Another condition that might present with limb ischemia in the setting of patent arterial supply is symmetric peripheral gangrene, a condition in which microvascular occlusion of venules and capillaries occurs in the setting of severe systemic infection and widespread inflammation.[11] In this condition, patients have systemic tissue ischemia and coagulopathy, resulting in autoamputation of distal digits in combination with disseminated intravascular coagulation (DIC). There is cyanotic discoloration of the tips of all four limbs (ie, acral cyanosis), as well as patches of cyanosis throughout the body (ie, nonacral cyanosis or purpura fulminans).

Contrast venography is still considered the gold standard for the diagnosis of deep venous thrombosis (DVT), though at present, it is rarely used (only for diagnostic purposes). Duplex ultrasonography has replaced venography as the preferred imaging modality, with an accuracy exceeding 90%. Features suggestive of DVT on duplex ultrasonography are as follows:

• Lack of compressibility of the vein
• Lack of spontaneous flow
• Increased vein diameter
• Increased echogenicity within the lumen

The advantages of ultrasonography lie in its availability, portability, and noninvasive nature (which also avoids the need for radiation).

Computed tomography (CT) venography, and magnetic resonance (MR) venography are seldom used but can help determine the proximal and distal extents of the thrombus. They can also determine any anatomic abnormalities in the pelvis that may be compressing the iliac veins and precipitating thrombosis.

The diagnosis of phlegmasia alba dolens (PAD) or phlegmasia cerulaea dolens (PCD) is made on clinical grounds in patients who have extensive DVT on imaging.

Treatment of phlegmasia alba dolens (PAD) or phlegmasia cerulea dolens (PCD) should be initiated as soon as the diagnosis is suspected. The patient is started on anticoagulation, and the involved extremity is elevated. Intravenous (IV) resuscitation is administered if there is significant fluid sequestration and the patient appears to have intravascular fluid depletion, as manifested by tachycardia, hypotension, and decreased urine output.

Heparin administration is initiated with an IV bolus of 80-100 U/kg, followed by continuous infusion at a rate of of 15-18 U/kg/hr.  The activated partial thromboplastin time (aPTT) should be monitored, with a goal in the range of 2.0-2.5 times the laboratory reference range. Platelet counts should be monitored to allow early detection of heparin-induced thrombocytopenia. Heparin drip is preferred because it has a shorter half-life and can be rapidly titrated in the event of bleeding or need for surgical intervention. The goal of early anticoagulation is to halt thrombus propagation and prevent pulmonary embolism (PE).

Low-molecular-weight heparins (LMWHs) have been found to be safe, effective, and convenient for use in PCD and result in shorter hospital stays because they can be used on an outpatient basis.[12, 13]

The oral factor Xa inhibitors rivaroxaban and apixaban are approved for treatment of deep venous thrombosis (DVT) and can potentially be used for treatment of phlegmasia. Alternative anticoagulation agents are longer-acting than heparin and should be started when patient is clinically stable and there is no concern for additional interventions.

If patients improve with elevation and anticoagulation and do not progress to critical limb ischemia, compression therapy with stockings or elastic bandages can help decrease edema and swelling and may be used as tolerated. Many physicians have the patient fitted for a prescription stocking while the limb is still severely edematous. This is inadvisable; instead, the patient may use nonprescription stockings or an elastic bandage, in combination with elevation, to minimize edema before being fitted for a prescription stocking.

Patients are treated with anticoagulation for at least 6 months.

Endovascular intervention

Catheter-directed thrombolytic therapy is the mainstay of therapy for the extensive DVT that is usually associated with phlegmasia. It is minimally invasive, effective, and safe, as shown in a 2012 systematic review of the literature.[14]

The patient is kept on heparin drip and brought to an angiography suite or a hybrid operating room. Under ultrasonographic guidance, the popliteal vein or a tibial vein is accessed and a 6-French sheath placed. The thrombus is crossed with a 0.035-in. wire, a multihole infusion catheter is placed in the vein, and an infusion of alteplase is started.

The patient is transferred to an intensive care unit (ICU) and typically receives alteplase infusion over a period of 2-4 days. A low-dose heparin drip is given at constant rate through the access sheath to prevent thrombosis around the sheath. The patient goes back for angiographic checks on a daily basis.

A combination of pharmacomechanical thrombolysis using devices that macerate and aspirate the clot (eg, AngioJet [Boston Scientific, Marlborough, MA] or Trellis [Covidien, Minneapolis, MN]) or balloon angioplasty to break down the thrombus is performed. Venous occlusive lesions or areas of stenosis can be treated with stenting after dissolution of the acute thrombus.

In patients with tissue compromise because of extensive thrombosis, a more aggressive approach using pharmacomechanical thrombolysis[9] or aspiration thrombectomy[5, 15] during the first angiogram can provide enough outflow to avoid progression of ischemia. Placement of an inferior vena cava (IVC) filter decreases the risk of iatrogenic PE during thrombolysis but has not been shown to affect survival.[16]

Catheter-directed thrombolysis is contraindicated in certain patients.[17] Absolute contraindications include the folowing:

• Active bleeding
• Recent neurologic surgery (cranial or spinal)
• Trauma or cerebrovascular accident less than 2 months previously
• Brain tumor
• Severe hypertension
• Coagulopathy
• Allergy to thrombolytic agents

Relative contraindications include the following:

• Surgery less than 10 days previously
• Recent trauma or gastrointestinal hemorrhage
• Subacute bacterial endocarditis
• Severe liver or kidney disease
• Pancreatitis
• Pregnancy
• Any other scenario in which there seems to be a risk of hemorrhage that might be either excessive or difficult to control

In a study that included 692 patients with acute proximal DVT, Vedantham et al compared anticoagulation plus pharmacomechanical thrombolysis with anticoagulation alone, the primary outcome being development of the postthrombotic syndrome between 6 and 24 months of follow-up.[18] They found that the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the postthrombotic syndrome but did result in a higher risk of major bleeding.

Endovascular iliocaval reconstruction has been described for the treatment of iliocaval thrombosis.[19]

Open surgery

Open surgical thrombectomy[20] is an alternative treatment for patients who cannot undergo thrombolysis and who require thrombus removal.

The patient is taken to the operating room. Placement of an IVC filter can protect the lungs from embolization during thrombectomy and should be done at the beginning of the procedure. An intraoperative Trendelenburg position may be used to decrease the risk of PE as well.

A longitudinal incision is made in the groin area to explore the femoral vein. A venotomy is performed to decompress the vein and allow passage of a Fogarty balloon catheter antegrade and retrograde in the vein to remove thrombus. Open access of the popliteal or tibial veins is sometimes needed to permit a more extensive thrombectomy and to facilitate pasage of the Fogarty balloons against the valves in the veins. A tourniquet can also be applied on the lower extremities with gradual compression to try to squeeze or “milk” thrombus out of the femoral venotomy.[21]

Transabdominal cavotomy and thrombectomy can also be performed. This approach permits better control of the cava above the thrombus and thus provides protection against PE, but it carries a higher morbidity.

Procedures that have been performed in an effort to decrease the rethrombosis rate include cross-pubic vein-to-vein reconstruction with polytetrafluoroethylene (PTFE) or the great saphenous vein (GSV) in conjunction with an arteriovenous fistula between the femoral artery and the GSV. These adjuvant procedures may be especially beneficial in cases that involve proximal iliofemoral vein constriction, damage, or external compression.

Surgical thrombectomy cannot open the small venules that are affected in venous gangrene and is therefore thought to be less effective than thrombolysis in clearance of acute thrombus.

For patients with acute compartment syndrome,[22] a four-compartment fasciotomy and decompression are required to prevent muscle necrosis. Finally, if all efforts fail, an amputation is required. It is best to delay the procedure as long as possible so as to reduce edema, allow venous channels to recanalize, and allow necrotic tissue to demarcate.