Kasabach-Merritt Syndrome 

Updated: Sep 05, 2018
Author: Alexandra C Cheerva, MD, MS; Chief Editor: Hassan M Yaish, MD 

Overview

Practice Essentials

The combination of giant hemangioma, thrombocytopenia, and consumption coagulopathy is termed Kasabach-Merritt syndrome (KMS). KMS is an infrequent but potentially fatal complication of rapidly growing vascular lesions in infants.[1, 2] See the image below.

Back of an arm showing the typical bruising associ Back of an arm showing the typical bruising associated with Kasabach-Merritt Syndrome.

Signs and symptoms

Signs and symptoms in KMS include the following:

  • Visible cutaneous giant hemangioma or multiple smaller hemangiomas, usually on the extremities

  • Enlarged abdomen

  • Hepatomegaly or jaundice

  • Petechiae, bruising, and frank bleeding

  • Painful lesions

  • Anemia

Physical findings may include the following:

  • Cutaneous hemangioma, often appearing as a large irregular bruise anywhere on the body and often circumscribed by widespread, overlying, shiny and dusky, purple skin

  • Kaposiform hemangioendothelioma (KHE) or tufted angioma (TA) - Blue or reddish-brown discoloration and skin induration

  • Petechiae and bruising

  • Painful, tender lesions

  • Bleeding from thrombocytopenia and coagulopathy (locally and, at times, distantly [disseminated intravascular coagulation (DIC)])

  • Tachycardia, feeding difficulty, and shock (signs of high-output cardiac failure)

  • Pallor (suggestive of anemia)

See Presentation for more detail.

Diagnosis

Any infant with unexplained thrombocytopenia, with or without evidence of DIC, should be evaluated for visceral or hidden vascular lesions (especially of the liver or spleen).

Laboratory studies that may be helpful include the following:

  • Complete blood count (CBC) count with differential, reticulocyte count, platelet count, and peripheral smear examination

  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) - These are prolonged in patients with significant DIC

  • Fibrinogen, fibrin degradation product (FDP), and D-dimer levels - The first are reduced in DIC, and the second and third are elevated

  • Blood culture (to exclude sepsis)

  • Chromosome tests (to exclude certain genetic syndromes)

Diagnostic imaging is obtained as appropriate and may include the following:

  • Radiography

  • Computed tomography (CT)

  • Magnetic resonance imaging (MRI)

  • Doppler flow studies

Radionuclide scanning

Although formal staging is not usually performed, documenting the extent of the invasion of the hemangioma into normal tissue is important for possible subsequent treatment with surgery or radiation. Hemangiomas do not metastasize.

See Workup for more detail.

Management

No single pharmacologic therapy has been proved most effective in patients with KMS. Agents that have been tried (most of them not specifically FDA-approved for this application), with varying success, include the following:

  • Corticosteroids (most commonly used)

  • Interferon alfa

  • Aminocaproic acid (to treat bleeding)

  • Aspirin

  • Dipyridamole

  • Ticlopidine

  • Pentoxifylline

  • Cryoprecipitate

  • Heparin

  • Vincristine (80% response reported)

  • Cyclophosphamide

  • Actinomycin D

  • Propranolol (unlike in infantile hemangioma, response is poor)

Nonpharmacologic treatment modalities include the following:

  • Surgical resection (when lesions are not too large or surgically inaccessible) - Wide local excision is recommended but may be difficult; amputation may be necessary for intractable lesions involving a limb

  • Interventional radiologic procedures (when surgical treatment is not feasible)

  • Intermittent pneumatic compression (most useful for a vascular lesion located on an extremity)

  • Radiation therapy (now largely abandoned because of long-term adverse effects)

See Treatment and Medication for more detail.

Background

The Kasabach-Merritt syndrome (KMS) was first described in 1940 in a male infant with a large, rapidly enlarging, discolored lesion on his thigh that was associated with consumption coagulopathy and thrombocytopenia. The lesion in this original case was a kaposiform hemangioendothelioma, not a classic infantile hemangioma. The combination of enlarging vascular lesion (either a kaposiform hemangioendothelioma or a tufted angioma), profound thrombocytopenia, microangiopathic hemolytic anemia, and consumption coagulopathy is termed KMS or Kasabach-Merritt phenomenon (KMP).[3, 4, 1, 2]

The vascular lesion may be an obvious superficial lesion or a lesion within a visceral organ or even within the brain. Thrombocytopenia is often severe (ie, platelet count < 50,000/µL). Thrombocytopenia and consumption coagulopathy are not complications of all vascular lesions, and size alone does not determine which vascular lesions are associated with thrombocytopenia and coagulopathies. KMS is infrequent but has a potentially fatal outcome (reported at 40% in one report) and is characterized by rapid growth of the vascular lesions in infants.[5]  Infantile hemangiomas, the most common tumors of infancy, typically undergo rapid postnatal growth for several months, followed by a prolonged phase of involution.

Pathophysiology and Etiology

The thrombocytopenia associated with vascular lesions is caused by a localized consumption coagulopathy. The vascular lesion triggers an intravascular coagulation with platelet trapping, consequent thrombocytopenia, and fibrinogen consumption and degradation, as well as activation and consumption of coagulation factors, resulting in disseminated intravascular coagulation (DIC).[6]  Activation of platelets also promotes further growth of vascular tissue. 

KMS is associated with the two following rare vascular lesions::

  • Kaposiform hemangioendothelioma (KHE)[7, 8]

  • Tufted angioma (TA)[9]

The phenomenon may be associated with trauma in the area of the vascular lesion.

In a study by Ji et al, multivariate analysis indicated that in patients with kaposiform hemangioendothelioma, risk factors for the presence of Kasabach-Merritt syndrome (KMS) include patient age under 6 months, a lesion size of over 5.0 cm, and the existence of a mixed lesion.[10]

Epidemiology

United States and international statistics

Hemangiomas are common vascular tumors that occur in as many as 2.5% of neonates in the United States. Most are benign, and 70-80% regress by the age of 7 years. Some hemangiomas are life-threatening; 1 hemangioma in 300 is associated with coagulopathy.[11] Worldwide, reports of KMS are rare.

Age-, sex-, and race-related demographics

KMS typically occurs in early infancy (< 1 year) or childhood, though prenatal cases (diagnosed with the aid of ultrasonography), newborn presentations, and rare cases in older children and adults have been reported. KMS should be included in the differential diagnosis of unexplained chronic thrombocytopenia at any age.

Boys and men are affected slightly more often than girls and women are. In this respect, KMS differs notably from hemangioma of infancy (infantile hemangioma), which affects girls much more often than it does boys. No racial predilection has been identified.

Prognosis

When KMS is promptly recognized and properly treated, the prognosis is usually excellent because the DIC resolves as the vascular lesion recedes and because KMS does not recur. Therefore, most children do well if they reach age 2 years. When KMS goes untreated, mortality is 10-37%, primarily due to bleeding secondary to the consumption coagulopathy.[11] Even after failed treatment, however, the hematologic abnormalities may spontaneously resolve over a few months.

Mortality and morbidity are influenced by the anatomic location, depth, and extent of the vascular lesion. Besides bleeding, other conditions associated with morbidity and mortality are as follows:

  • Visceral involvement (particularly in the retroperitoneal area and mediastinum)

  • Profound thrombocytopenia

  • DIC

  • Severe infection

  • Iatrogenic complications (eg, from procedures such as arterial ligation, arterial embolization, or surgical excision)

Hemolytic anemia resulting from physical damage to the red blood cells (RBCs) may be mild, moderate, or severe. The results of the direct antibody test (DAT) or the Coombs test is negative in patients with anemia, and anemia is secondary to microangiopathic destruction of the RBCs,[12]  manifested by the presence of schistocytes on peripheral blood smear examination (a helpful tool in suggesting the presence of viseral hemangiomas).

Heart failure often occurs in affected infants as a result of the large volume of blood flowing through the giant hemangioma.[13]

An association of KMS with trisomy 21 mosaicism is uncommon; however, 43% of children with Down syndrome have cutaneous vascular lesions. One child with Down syndrome and KMS has been reported.[14]

 

Presentation

History

Visible cutaneous blue, violaceous, or reddish-brown lesions are often the presenting features in patients with Kasabach-Merritt syndrome (KMS).[6] Most lesions are located on the extremities. Some infants and older children with visceral lesions present with an enlarged abdomen. Those with hepatic kaposiform hemangioendotheliomas also may present with hepatomegaly or jaundice. These vascular lesions may continue to enlarge during the first 18 months of life.

The thrombocytopenia and consumption coagulopathy associated with KMS may not initially be severe. However, symptoms may worsen as the lesion enlarges and the infant grows. Affected infants may present soon after birth or may not come to medical attention for several months. Affected individuals rarely present as late as the second or third decade of life.

Petechiae, bruising, and frank bleeding may be the initial symptoms prompting medical treatment. The lesions may be painful.

The large volume of blood circulating through the lesion may cause high-output congestive heart failure in infants.[15] Cardiovascular compromise or collapse, petechiae, and bleeding may resemble acute overwhelming sepsis. When no cutaneous lesion is present, the physician must search for vascular lesions located in a visceral organ (eg, the spleen, liver,[16] or brain).

Some patients with diffuse cavernous kaposiform hemangioendothelioma (KHE) of a visceral organ may present with anemia, thrombocytopenia, coagulopathy, and bleeding, which may be misdiagnosed as immune thrombocytopenic purpura.[17]

The natural history of KHE is that of slow regression, with the lesion leaving a reddish-brown discoloration that often does not resolve completely. It is unknown what percentage of KHE lesions develop into KMS.

Physical Examination

A cutaneous vascular lesion is usually obvious, often appearing as a large irregular bruise (see the first image below). These lesions may occur anywhere on the body and may grow through the first 12-18 months of life, often circumscribed by widespread, overlying, shiny and dusky, purple skin.[18] Lesions of KHE (see the second image below), tufted angioma (TA), or a mixture of both present with a blue or reddish-brown discoloration and skin induration. When thrombocytopenia increases, a large violaceous, ecchymotic indurated mass forms.

Back of an arm showing the typical bruising associ Back of an arm showing the typical bruising associated with Kasabach-Merritt Syndrome.
Leg with a Kaposiform hemangioendothelioma, lesion Leg with a Kaposiform hemangioendothelioma, lesion associated with Kasabach-Merritt Syndrome.

Affected infants may exhibit petechiae, bruising, and bleeding. Bruising and ecchymoses may occur at distant sites. Internal lesions may present with only bruising and ecchymoses on the skin. The lesions are usually painful and tender. Aggressive infiltration with ulceration and infection is rare but can occur. Bleeding from thrombocytopenia and coagulopathy is observed both locally and, at times, distantly (ie, disseminated intravascular coagulation [DIC]).

Physical signs of high-output cardiac failure include tachycardia, feeding difficulty, and shock. Pallor may be evident in patients with significant anemia.

Complications

The clinical course of KMS is unpredictable, and effective treatment depends on control of the invasive tumor before secondary complications occur.

Various complications of KMS relate to the site of the vascular lesion. For example, hemangiomas of the chest that invade the thorax can compromise lung expansion and cause respiratory insufficiency.

Other complications that may be seen include the following:

  • Severe thrombocytopenia (platelet count < 5 X 109/L (< 5000/µL)

  • Ulceration and bleeding into the vascular lesion

  • Bleeding secondary to DIC and unresponsive to platelet transfusions (potentially fatal)

  • Toxicity from the agents used to treat KMS (eg, secondary malignancy from radiation therapy)

  • High-output cardiac failure (potentially fatal)

  • Infections from skin breakdown with sepsis

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Classic capillary hemangioma of infancy (a common infantile vascular anomaly but not associated with Kasabach-Merritt syndrome [KMS]; it affects girls more than boys and usually regresses spontaneously with age)

  • Congenital hemangiopericytoma

  • Cystic teratoma

  • Diffuse neonatal hemangiomatosis (DNH)

  • Encephalocele

  • Epithelioid hemangioendothelioma

  • Hereditary hemorrhagic telangiectasia

  • Infantile fibrosarcoma

  • Infantile myofibromatosis

  • Kaposiform hemangioendothelioma of infancy and childhood

  • Lumbar lipomyelomeningocele

  • Lymphatic malformation

  • Port-wine stain

  • Tufted angioma or angioblastoma

  • Thrombocytopenia

  • Venous malformation

Once the diagnosis of KMS is confirmed, it is important to inform parents regarding the signs of congestive heart failure and thrombocytopenia in infants (eg, difficulty feeding, petechiae, bruising, hematuria, and bloody stools).

Differentials

Angiosarcoma

Arterial Vascular Malformations Including Hemangiomas and Lymphangiomas

Arteriovenous Malformations

Consumption Coagulopathy

Hemangioblastoma

Hepatic Hemangiomas

Immune Thrombocytopenic Purpura

Infantile Hemangioma

Klippel-Trenaunay-Weber Syndrome

Teratomas and Other Germ Cell Tumors

Neuroblastoma

Subcutaneous Fat Necrosis of the Newborn

 

Workup

Approach Considerations

Any infant with unexplained thrombocytopenia, with or without evidence of disseminated intravascular coagulation (DIC), should be evaluated for visceral or hidden vascular lesions (especially of the spleen). Without prompt and appropriate attention, these forms of Kasabach-Merritt syndrome (KMS) are associated with a high mortality. Patients should also be evaluated for malignancy because malignant lesions may resemble the lesions seen in patients with KMS.

Clinicians must monitor blood work, with special emphasis on the platelet count. Additional tests are ordered as necessary for clinical evaluation. For example, blood cultures may be appropriate for excluding the possibility of sepsis, and chromosome tests may be needed to exclude certain genetic syndromes.

Diagnostic imaging is obtained as appropriate. No procedures are required initially. If a complete excision is not feasible, a biopsy should not be performed, because it may lead to uncontrolled bleeding at the site.

Although formal staging is not usually performed, documenting the extent of the invasion of the vascular lesion into normal tissue is important for possible subsequent treatment with surgery or radiation. Metastasis does not occur.

Laboratory Studies

A complete blood count (CBC) count with differential, reticulocyte count, platelet count, and peripheral smear is obtained to evaluate for microangiopathic hemolytic anemia and thrombocytopenia in KMS. Platelets may be larger than normal when they are released early from the bone marrow. Burr cells and schistocytes may be present in patients with microangiopathic hemolytic anemia.

The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged in patients with significant DIC.

Fibrinogen levels are low in patients with significant DIC. levels of fibrin degradation products (FDPs) and D-dimer are elevated in patients with DIC. A D-dimer test is usually more sensitive than a test for FDPs. Low-grade chronic DIC may be present.

Radiography, CT, MRI, and Ultrasonography

Radiography, computed tomography (CT), and magnetic resonance imaging (MRI) of areas involved with known vascular lesions should be performed as appropriate. These studies are advisable even when all vascular lesions are cutaneous. Scans are important to determine the extent of the visible vascular lesions and to evaluate the patient for possible visceral vascular lesions.

MRI or CT commonly reveals a vascular enhancing mass that is difficult to differentiate from a vascular malformation, solid tumor, or proliferative vascular lesion. If KMS is suspected in patients who have no visible vascular lesions, CT scans or MRIs of the head, chest, abdomen, and pelvis should be obtained to identify any visceral lesions.

Doppler flow studies may help differentiate a solid mass from a vascular lesion.

Radionuclide Scanning

Radionuclide imaging may be indicated. Scans that use chromium isotope 51, indium In 111 oxine–labeled platelets, or iodine I 131–labeled fibrinogen probably are more sensitive than CT scans or MRIs for delineating the size and number of vascular lesions.[19] Radionuclide scans are infrequently used because the diagnosis is usually made clinically. In certain centers, they may not be readily available. Scintigraphic studies should be strongly considered when the etiology of the thrombocytopenia remains uncertain.

Histologic Findings

Enjolras et al characterized the histology of kaposiform hemangioendothelioma (KHE) and tufted angioma (TA), the vascular lesions associated with KMS.[9] The original case report described lobules of fine capillaries separated by cellular intercapillary tissue consisting of spindle-shaped cells.

The histologic picture of KHE consists of lobules or sheets of tightly packed spindle cells or rounded endothelial cells and pericytes. The cellular areas have an infiltrative pattern in the dermis, subcutaneous fat, and muscles and generally contain few obvious vascular lumina. TAs are composed of small tufts or lobules of rounded capillaries with small lumina. The tufts are discrete and evenly distributed in a cannonball pattern and are characterized by peripheral, crescentic, slitlike vessels and an associated fibrosis.

Both KHE and TA contain aggregates of rounded, dilated capillaries lined by attenuated endothelial cells with small, dark nuclei and filled with RBCs. Microthrombi and hemosiderin deposits are often present. Lymphlike vessels are often part of the lesion. Findings of both KHE and TA often appear in the same patient; the 2 conditions may be variations of each another.

The histology of classic hemangioma of infancy, which is the most common benign vascular neoplasm in children, is distinct from these proliferations and is not associated with KMS.

 

Treatment

Approach Considerations

Management of Kasabach-Merritt syndrome (KMS) involves hastening vascular lesion regression, interfering with platelet trapping within the lesion, and supporting the patient with transfusions.[20]

Patients with KMS are admitted to the hospital with profound thrombocytopenia and evidence of coagulopathy. They are commonly treated with drug therapy initially[21, 22, 23, 24, 25, 26, 27, 28, 29] and with surgical or interventional radiologic measures either simultaneously or subsequently.[18, 30, 31, 32, 33]

Selected patients who have KMS with absent or mild thrombocytopenia and coagulopathy may be evaluated on an outpatient basis. However, as vascular lesions grow, these infants often require inpatient evaluation and treatment because most develop significant thrombocytopenia and disseminated intravascular coagulation (DIC).

Pharmacologic Therapy

No single therapy has been proved most effective in patients with KMS. Multiple treatments have been used in many infants. Success rates have varied. Treatments that are effective in some patients have no benefit for others. Many of these medications have serious adverse effects, especially in patients with thrombocytopenia and DIC, and should be administered only by physicians with expertise in this area. Most of them are not specifically approved by the US Food and Drug Administration (FDA) for treatment of KMS.

Corticosteroids are the drugs most commonly used and have been successful in many cases, though they do not always yield satisfactory results.[34, 32] In addition to high-dose oral steroids, pulsed or intravenous (IV) steroids have also been used.

Some success with interferon alfa-2a (3 million U/m2/day or 3 times weekly) has been reported, though the failure rate is high.[35, 36, 37] The subcutaneous injection may result in nausea, fever, or neutropenia. Interferon alfa has been associated with neurologic problems in certain patients[38, 39] ; some infants have developed spastic diplegia after receiving this agent.

Other medications, including ε-aminocaproic acid, aspirin, dipyridamole,[24] ticlopidine, pentoxifylline,[39] cryoprecipitate, and heparin, have also been used to treat KMS, with varying degrees of efficacy.

Chemotherapy, including vincristine, cyclophosphamide, and actinomycin D, has been successfully employed in some patients.[40, 23, 41, 42, 43] In particular, vincristine is increasingly often being given to treat KMS.[25, 26, 27, 29, 44, 45, 46] Nevertheless, there have been treatment failures.

In 2008, Leaute-Labreze et al reported using propranolol in 2 infants with severe hemangiomas.[47] Potential explanations of the therapeutic effect included vasoconstriction, decreased expression of VEGF and bFGF genes, and the triggering of apoptosis of capillary endothelial cells.

A study by Su et al found that transcatheter arterial embolization with polyvinyl alcohol particles combined with drug therapy achieved good results in six infants with KMS. The patients, with lesions in the temporal region, parotid region, or submandibular region and neck, experienced shrinkage and/or lightening of the hemangioma, while the mean platelet count reached over 80,000/L in five patients; one patient achieved a platelet count of 102,000/L. Neither hemangioma rebound growth nor platelet count reduction were found at 12- to 18-month follow-up.[48]

Surgical and Endovascular Interventions

Surgical management often is not feasible in KMS, because the lesions are too large. When the lesions are sufficiently small, surgery has resulted in a rapid normalization of the platelet count and other blood abnormalities. Complete surgical resection, when possible, is the most effective treatment of vascular lesions complicated by KMS.[49] Thrombocytopenia and DIC resolve after the lesion has been resected.[50]

Depending on the location of the tumor, general surgery, thoracic surgery, or neurosurgery may be needed for excision or ligation of the vessels feeding the vascular lesion. Wide local excision is recommended but may be difficult. The large size and infiltrative growth pattern of the vascular lesion may cause complications (eg, hemorrhage, obstruction, and respiratory compromise). Amputation may be necessary for intractable lesions involving a limb.

Some lesions are surgically inaccessible and thus call for nonsurgical treatment modalities. Interventional radiologic procedures use polyvinyl alcohol or absolute ethanol to embolize or sclerose the vessels of the vascular lesion.[33, 51] Another technique involves injecting polyvinyl beads to stop the feeder blood supply. Endovascular treatment (eg, transfemoral arterial embolization) has yielded good results in a number of cases.[52, 53, 54, 34, 55]

Treatment with the tunable dye laser (TDL) may help patients with diffuse cutaneous vascular lesions.[56]

Pneumatic Compression

Treatment with intermittent pneumatic compression, either alone or in combination with other therapies, has helped some patients.[57] This modality is most useful when the vascular lesion is located on an extremity.

Encircle the lesion with a blood pressure cuff, and gradually increase the pressure to midway between the systolic and diastolic blood pressures. Inflate the cuff intermittently (eg, 90 seconds of compression, then 30 seconds of rest). A cuff may be used for an extended period. Compression with surgical hose stockings may help. It is often worthwhile to attempt pneumatic compression to see if it helps before attempting other potentially more toxic treatments.

Radiation Therapy

Radiation therapy has been used in patients with severe disease.[18, 58] It has also been combined with interferon alfa therapy, with some success.[59] Although low radiation doses have been reported to offer benefit in some cases, the long-term adverse effects of radiotherapy must be carefully weighed against the problems caused by the vascular lesion—especially in very young children, who are at risk for malignancy or decreased bone growth in the radiated field with this treatment.

Currently, because of the long-term adverse effects of radiation therapy in survivors, this mode of therapy is no longer favored for KMS, and many practitioners have abandoned it.

Consultations

A pediatric hematology consultation is required for management of the complex hemostatic problems of KMS patients and for administration and management of many of the medications needed for the most fulminant cases. Additional consultations that may be advisable are as follows:

  • Dermatologist

  • Surgeon

  • Pediatrician

  • Interventional radiologist

Consultations with neonatal or pediatric intensive care specialists may be required, depending on the age of the patient.

 

Medication

Medication Summary

No single therapy has been proved most effective in patients with Kasabach-Merritt syndrome (KMS). Multiple treatments have been used in many infants. Treatments that are effective in some patients have no benefit for others. Many of these medications have serious adverse effects, especially in patients with thrombocytopenia and disseminated intravascular coagulation (DIC), and should be administered only by physicians with expertise in this area.

The medications listed below are among the most frequently used, though other medications in these and other categories may also have been used to treat KMS. Most of these medications are not approved by the US Food and Drug Administration (FDA) for treatment of KMS.

Corticosteroids

Class Summary

Systemic corticosteroids are synthetic chemicals that stabilize blood vessels and reduce fibrinolysis. They have been successfully used to treat proliferative vascular lesions; treatment of KMS is usually not as successful. High-dose oral prednisone (2-4 mg/kg/day) can rapidly increase the platelet count.

Prednisone (Rayos)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It may increase the sensitivity of arterioles and precapillaries to vasoconstriction and may competitively inhibit other hormonal agents.

Prednisolone (Pediapred, Prelone, Orapred, Millipred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It may increase the sensitivity of arterioles and precapillaries to vasoconstriction and may competitively inhibit other hormonal agents.

Triamcinolone (Amcort)

Triamcinolone is used for inflammation responsive to steroids. It decreases inflammation by suppressing migration of PMNs and reversing capillary permeability.

Methylprednisolone (Solu-Medrol, Depo-Medrol, A-Methapred)

Methylprednisolone is used for inflammation responsive to steroids. It decreases inflammation by suppressing migration of polymorphonuclear leukocyte (PMN) activity and reversing capillary permeability.

Immunomodulators

Class Summary

Antiangiogenic agents are naturally produced proteins that have antiviral, antitumoral, and immunomodulatory actions. Interferon alfa, beta, and gamma may be administered topically, systemically, or intralesionally. Antiangiogenic agents have a direct antiproliferative effect against vascular tumors. Agents in development include thalidomide, vascular endothelial growth factor (VEGF), receptor inhibitors (SU 5416), and anti-VEGF antibodies.

Interferon alfa-2b (Intron A)

Interferon alfa-2b is a protein product manufactured by means of recombinant DNA technology. The mechanism of its antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Interferon alfa is a protein product manufactured by means of recombinant DNA technology. It appears to produce its antiangiogenic effect by down-regulating the expression of basic fibroblast growth factor (bFGF) in the rapidly proliferating vascular lesion. The proliferative phase of growth is characterized by high bFGF expression, which then falls during involution of the lesion.

Vascular proliferative lesions vary in response to treatment with interferon. Most patients have been treated with interferon alfa-2a; however, some lesions have been treated with good results with interferon alfa-2b. Their similar clinical and in vitro effects on angiogenesis suggest that the 2 agents may have similar efficacy in these vascular lesions. Not all lesions respond to interferon alfa therapy.

Pegylated interferon alfa-2a (Pegasys)

PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. PEG-IFN has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing and significantly improves quality of life for patients.

Hemorheologic Agents

Class Summary

Blood viscosity−improving agents improve blood flow through hemangiomas and decrease microthrombus formation.

Pentoxifylline

Pentoxifylline may alter the rheology of red blood cells (RBCs), thereby reducing blood viscosity.

Anticoagulants, Hematologic

Class Summary

Anticoagulants decrease microthrombus formation in hemangiomas.

Heparin

Heparin augments the activity of antithrombin III (ATIII) and prevents conversion of fibrinogen to fibrin. It does not actively lyse but inhibits further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Enoxaparin (Lovenox)

Enoxaparin is a low-molecular-weight heparin (LMWH) produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). It binds to ATIII, enhancing its therapeutic effect. The heparin-ATIII complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). LMWH differs from UFH in that it has a higher ratio of antifactor Xa to antifactor IIa.

Enoxaparin does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis. Advantages include intermittent dosing and a decreased requirement for monitoring. Heparin antifactor Xa levels may be obtained if necessary to establish adequate dosing.

Enoxaparin prevents deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in surgical patients at risk for thromboembolic complications. It is used for prevention in hip replacement surgery, knee replacement surgery, or abdominal surgery in those at risk for thromboembolic complications, as well as in nonsurgical patients at risk for thromboembolic complications secondary to severely restricted mobility. It is used with warfarin to treat acute DVT with or without PE (inpatient) or acute DVT without PE (outpatient).

There is no use in checking the activated partial thromboplastin time (aPTT); the drug has a wide therapeutic window, and the aPTT does not correlate with the anticoagulant effect. The average duration of treatment is 7-14 days.

Antiplatelet Drugs

Class Summary

Antiplatelet agents decrease microthrombus formation.

Ticlopidine

Ticlopidine

Ticlopidine is a second-line antiplatelet therapy for patients who cannot tolerate aspirin therapy or in whom aspirin therapy fails.

Dipyridamole (Persantine)

Dipyridamole is used to complement the usual warfarin therapy. It is a platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine (itself an inhibitor of platelet reactivity). In addition, dipyridamole may inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2. It may enhance the effects of aspirin.

Antifibrinolytic Agents

Class Summary

Antifibrinolytic agents inhibit thrombus breakdown, thus interfering with DIC. They are often administered with cryoprecipitate in patients with KMS.

Aminocaproic acid (Amicar)

Aminocaproic acid is a lysine analogue that inhibits fibrinolysis through inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It is widely distributed, with a half-life of 1-2 hours. Peak effect occurs within 2 hours, and hepatic metabolism is minimal. Aminocaproic acid may be administered either orally or intravenously (IV).

Tranexamic acid (Cyklokapron, Lysteda)

Tranexamic acid is an alternative to aminocaproic acid; it inhibits fibrinolysis by displacing plasminogen from fibrin.

Antineoplastic Agents

Class Summary

Antineoplastic agents inhibit tumor cell growth and proliferation. The standard dosage is 1-1.5 mg/m2 or 0.05-0.065 mg/kg once weekly.

Vincristine (Vincasar PFS)

The mechanism by which vincristine acts is uncertain; it may involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms fully explains this agent's effect in patients with thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS).

Cyclophosphamide

Cyclophosphamide is a cyclic polypeptide that suppresses some humoral activity. In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.

Chemically related to nitrogen mustards, cyclophosphamide is biotransformed by cytochrome P-450 in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As alkylating agents, active metabolites may act through cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. In autoimmune diseases, the mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

Dactinomycin (Cosmegen)

Dactinomycin intercalates between guanine and cytosine base pairs, inhibiting protein synthesis and DNA and RNA synthesis. It is administered in a free-flowing vein or central catheter.