Special Considerations in Vascular Anomalies: Hematologic Management
2010; Elsevier BV; Volume: 38; Issue: 1 Linguagem: Inglês
10.1016/j.cps.2010.08.002
ISSN1558-0504
Autores Tópico(s)Central Venous Catheters and Hemodialysis
ResumoProper care of the patient with a vascular anomaly requires the expertise of multiple specialists. Because of the need for an interdisciplinary approach, several vascular anomalies centers have now been developed across the world. A hematologist/oncologist provides clinical acumen in establishing a correct diagnosis and guiding the medical management of these patients. These patients can have complicated coagulopathies and need medical therapy. The hematologist/oncologist provides insights into the availability and suitability of enrollment into clinical trials or the use of novel experimental treatments for these complicated conditions. This article emphasizes the hematologic complications and management of these patients. The most common vascular tumor is the hemangioma of infancy that can be simple or complex and may be associated with other anomalies.1Mulliken J.B. Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics.Plast Reconstr Surg. 1982; 69: 412-422Crossref PubMed Scopus (2645) Google Scholar Infantile hemangiomas are not associated with a thrombocytopenic coagulopathy, and the patients with infantile hemangiomas do not have signs of active coagulopathy. Infants with hemangiomas may have a slightly elevated platelet count, with minor increase in dimerized plasmin fragment D (D-dimer) levels, and slightly decreased fibrinogen levels, all of which are within the normal range of measurement. Congenital hemangioma can be distinguished from infantile hemangioma because the former is fully developed at birth and can be diagnosed in utero. Congenital hemangioma has 2 subgroups: the rapidly involuting congenital hemangiomas (RICHs) and the noninvoluting congenital hemangiomas (NICHs).2Mulliken J.B. Enjoras O. Congenital hemangiomas and infantile hemangioma: missing links.J Am Acad Dermatol. 2004; 50: 875-882Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar The RICH lesions can appear violaceous at birth but rapidly regress during the first year of life. The NICH lesions are fully developed at birth and do not involute. There are distinguishing histochemical endothelial markers (such as Glut-1) that are present in infantile hemangiomas but not in the congenital hemangiomas.3North P.E. Waner M. Mizeracki A. et al.GLUT 1: a newly discovered immunohistochemical marker for juvenile hemangiomas.Hum Pathol. 2000; 31: 11-22Abstract Full Text PDF PubMed Scopus (643) Google Scholar Congenital hemangiomas can be associated with coagulopathy (thrombocytopenia, low fibrinogen levels, and increased levels of fibrin degradation products and D dimers). The coagulopathy usually occurs in RICH and is distinguished from Kasabach-Merritt phenomenon (KMP) because it is self-limited and is usually not associated with bleeding complications.4Baselga E. Cordisco M. Garzon M. et al.Congenital haemangioma associated with transient thrombocytopenia and coagulopathy: a case series.Br J Dermatol. 2008; 158: 1363Crossref PubMed Scopus (64) Google Scholar Hemangiomas and congenital hemangiomas should not be confused with the lesions known as kaposiform hemangioendotheliomas (KHEs) and tufted angiomas (TAs). KHEs and TAs were first described in 1940 by Kasabach and Merritt5Kasabach H. Merritt K. Capillary hemangioma with extensive purpura: report of a case.Am J Dis Child. 1940; 59: 1063-1070Crossref Google Scholar when they reported an infant with thrombocytopenic purpura caused by, what they thought was, a giant capillary hemangioma. Subsequently, the association of capillary hemangiomas with thrombocytopenia was referred to as Kasabach-Merritt Syndrome (KMS). In 1997, 2 groups of investigators demonstrated that these lesions were not true hemangiomas but distinct vascular tumors diagnosed histologically as KHE or TA.6Sarkar M. Mulliken J.B. Kozakewich H.P. et al.Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma.Plast Reconstr Surg. 1997; 100: 1377-1386Crossref PubMed Scopus (366) Google Scholar, 7Enjolras O. Wassef M. Mazoyer E. et al.Infants with Kasabach-Merritt syndrome do not have "true" hemangiomas.J Pediatr. 1997; 130: 631-640Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar KHEs and TAs have a different clinical profile than hemangiomas, with a predilection for the upper trunk, extremities, thigh, sacrum, or retroperitoneum. They are warm, firm, indurated, purpuric lesions. Magnetic resonance imaging shows that these lesions invade the skin and subcutaneous fat and muscle. The lesions are usually focal, but some reports have described their spread in lymph nodes as well. These tumors can be associated with what is now called KMP, which includes an enlarging vascular lesion, profound thrombocytopenia, microangiopathic hemolytic anemia, and a mild consumptive coagulopathy. KMP has been associated with a mortality rate as high as 20% to 30%. KHE and TA are not always associated with KMP,8Gruman A. Liang M.G. Mulliken J.B. et al.Kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon.J Am Acad Dermatol. 2005; 52: 616-622Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar but the coagulopathy seen in KMP causes morbidity and mortality in patients with these lesions. The resulting profound thrombocytopenia and hypofibrinogenemia cause the most serious hemorrhagic complications. The primary cause of this coagulopathic abnormality is profound thrombocytopenia. Several theories have been proposed to explain this particular coagulopathy, such as trapping or consumption of platelets in the tumor, increased peripheral destruction of platelets outside the tumor, and decreased production of platelets in the bone marrow.9Inceman S. Tangun Y. Chronic defibrination syndrome due to a giant hemangioma associated with microangiopathic hemolytic anemia.Am J Med. 1969; 46: 997Abstract Full Text PDF PubMed Scopus (61) Google Scholar, 10Staub P.W. Kessler S. Schreiber A. et al.Chronic intravascular coagulation in the Kasabach-Merritt syndrome: preferential accumulation of fibrinogen 131 I in a giant hemangioma.Arch Intern Med. 1972; 129: 475Crossref PubMed Scopus (42) Google Scholar Several therapies have been reported for the treatment of these lesions, but none has been uniformly effective. Therapies include the systemic use of corticosteroids, interferon, antifibrinolytic agents, and chemotherapy including the use of vincristine, cyclophosphamide, and actinomycin.11Haisley-Royster C. Enjolras O. Frieden I.J. et al.Kasabach-Merritt phenomenon: a retrospective study of treatment with vincristine.J Pediatr Hematol Oncol. 2002; 24: 459-462Crossref PubMed Scopus (186) Google Scholar, 12Mulliken J.B. Anupindi S. Ezekowitz R.A. et al.Case 13-2004: a newborn girl with a large cutaneous lesion, thrombocytopenia, and anemia.N Engl J Med. 2004; 350: 1764-1775Crossref PubMed Scopus (73) Google Scholar, 13Hauer J. Graubner U. Konstantopoulos N. et al.Effective treatment of kaposiform hemangioendotheliomas associated with Kasabach-Merritt phenomenon using four-drug regimen.Pediatr Blood Cancer. 2007; 49: 852-854Crossref PubMed Scopus (57) Google Scholar These lesions are challenging to manage because their clinical presentation and response to therapy can vary greatly. Platelet infusions should be limited because they can stimulate proliferation of the lesions, secondary to proangiogenic factors in platelet granules. Fibrinogen levels should thus be kept high (>100 mg/Dl). Clinical response can be subtle and may take months to occur. Some lesions can remain for years after resolution of the KMP, leading to other morbidities such as orthopedic anomalies and chronic pain. Cincinnati Children's Hospital Medical Center presently has a clinical registry open to prospectively investigate the clinical course of these lesions (http://www.cincinnatichildrens.org/svc/alpha/h/vascular). Coagulopathic abnormalities in vascular malformations (venous malformation [VM], lymphatic malformation, lymphaticovenous malformation [LVM], capillary-lymphaticovenous malformation [CLVM]) are likely caused by different mechanisms and should not be labeled as KMP (Table 1).Table 1Abnormal coagulation in vascular anomaliesData from Mulliken JB, Anupindi S, Ezekowitz RA. Case 13-2004: a newborn girl with a large cutaneous lesion, thrombocytopenia and anemia. N Engl J Med 2004; 350:1764.FeaturesKHE/TAVM/LM/LVM/CLVMHematologic Features PlateletsVery lowLow FibrinogenSignificantly decreasedDecreased PT/aPTTNormal or increasedIncreased D dimer↑↑↑PathogenesisPlatelet trappingFibrinogen consumptionStasis and thrombin activation on abnormal vasculatureManagementPharmacologic treatmentAvoid plateletsNo heparinSclerotherapyResectionLMWHCompressionAbbreviations: aPTT, activated partial prothrombin time; LM, lymphatic malformation; LMWH, low-molecular-weight heparin; PT, prothrombin time. Open table in a new tab Abbreviations: aPTT, activated partial prothrombin time; LM, lymphatic malformation; LMWH, low-molecular-weight heparin; PT, prothrombin time. Another distinct vascular disorder cutaneovisceral angiomatosis with thrombocytopenia is a rare disorder presenting at birth with cutaneous and visceral lesions (in gastrointestinal tract, lung, spleen, bone, muscle). This disorder has a proliferative potential and thus can be classified as having elements of a malformation and tumor.14Prasad V. Fishman S.J. Mulliken J.B. et al.Cutaneovisceral angiomatosis with thrombocytopenia.Pediatr Dev Pathol. 2005; 8: 407Crossref PubMed Scopus (51) Google Scholar This condition has also been called multifocal lymphangioendotheliomatosis with thrombocytopenia because it was identified lymphatic histomorphologic features.15North P.E. Kahn T. Cordsco M.R. et al.Multifocal lymphangioendotheliomatosis with thrombocytopenia: a newly recognized clinicopathological entity.Arch Dermatol. 2004; 140: 599Crossref PubMed Scopus (90) Google Scholar The associated thrombocytopenia is in the range of 10,000 to 70,000 cells/mm3. The cause of the thrombocytopenia is unclear but perhaps is related to endothelial hyperplasia. Gastrointestinal tract bleeding with associated congenital, multifocal, discrete red/brown/blue macules and papules is the typical presentation. These patients have been treated with medical management such as corticosteroid, interferon, and thalidomide, with mixed results. Hematologists play a key role in the management of vascular malformations because the lesions can result in severe coagulopathies. Coagulopathic abnormalities can occur in almost all malformations but are most significant in diffuse and multifocal VMs, LVMs, and CLVMs. The coagulopathy is referred to as localized intravascular coagulopathy (LIC) and is characterized by low levels of plasma fibrinogen, factor V, factor VIII, factor XIII (prekallikrein), and antithrombin.16Mulliken J.B. Young A.E. Vascular birthmarks: hemangiomas and malformations. WB Saunders, Philadelphia1988: 320Google Scholar The levels of D dimers and fibrin split products are also elevated in LIC. Minor to moderate thrombocytopenia may also be observed. With surgical resection, sclerotherapy, embolization, trauma, infection, or drugs, LIC can sometimes progress to disseminated intravascular coagulation (DIC) that can be life threatening. Furthermore, this chronic consumptive coagulopathy can cause the formation of microthrombi, which calcify (forming phleboliths) and cause pain. The pathogenesis of the coagulopathy in vascular malformations is probably multifactorial and best understood in relation to Virchow triad of abnormalities of the blood vessel wall, blood flow, and blood composition.17Wintrobe M. Blood, pure and eloquent. McGraw Hill, New York1980Google Scholar One hypothesis is that the endothelium lining these lesions may not be normal (structurally or functionally), leading to abnormal interactions with blood products that initiate coagulation. A second hypothesis relates to the size of the vessels and the velocity of blood flow. Flow abnormalities occur because of variation in channel size and structural abnormalities, resulting in local pooling of blood and stasis that can further damage the endothelium and activate the coagulation process. Vascular endothelial cells play an important role in the regulation of coagulation.18Ware J.A. Heistad D.D. Platelet-endothelium interactions.N Engl J Med. 1993; 328: 628Crossref PubMed Scopus (258) Google Scholar, 19Cines D.B. Pollak E.S. Buck C.A. et al.Endothelial cells in physiology and in the pathophysiology of vascular disorders.Blood. 1998; 91: 3527PubMed Google Scholar, 20Nawroth P. Kisiel W. Stern D. The role of endothelium in the homeostatic balance of haemostasis.Clin Haematol. 1985; 14: 531PubMed Google Scholar These cells have both procoagulant and anticoagulant properties that can be activated or deactivated by endothelial damage. Blood flow has multiple influences on platelet and fluid-phase coagulations.21Turitto V.T. Hall C.L. Mechanical factors affecting hemostasis and thrombosis.Thromb Res. 1998; 92: 525Google Scholar, 22Nemerson Y. Turitto V.T. The effect of flow on hemostasis and thrombosis.Thromb Haemost. 1991; 66: 272PubMed Google Scholar Local shear can occur secondary to blood flow. These factors can induce platelet aggregation and thrombus formation or interfere with platelet adhesion, causing an increased bleeding tendency. There have been several descriptive investigations of coagulopathy in patients with VM. Enjolras and colleagues23Enjolras O. Ciabrini D. Mazoyer E. et al.Extensive pure venous malformations in the upper or lower limb: a review of 27 cases.J Am Acad Dermatol. 1997; 36: 219Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar reviewed 27 cases of extensive pure VM in the upper and lower limb and found that 88% of these patients had LIC. The coagulopathy was associated with very low levels of plasma fibrinogen and soluble complexes, increase in levels of fibrin split products, and a moderately low platelet count. This chronic consumptive coagulopathy caused episodes of thrombosis (leading to formation of phleboliths) or bleeding (hemarthrosis, hematomas, or intraoperative blood loss). The condition worsened after discontinuing the use of elastic stockings, after therapeutic intervention (embolization or surgical procedure), after spontaneous fracture of a bone in the area of VM, or during pregnancy or menses. The investigators subsequently confirmed their findings in a retrospective evaluation of 24 patients with extensive VM or venous anomalies.24Mazoyer E. Enjolras O. Laurian C. et al.Coagulation abnormalities associated with extensive venous malformations of the limbs: differentiation from Kasabach-Merritt syndrome.Clin Lab Haematol. 2002; 24: 243Crossref PubMed Scopus (163) Google Scholar Furthermore, they characterized the difference between LIC caused by these lesions and the coagulopathy that typifies KMP in certain vascular tumors. They also categorized the anomalies based on a severity scoring system (a point was given to each involved site) and found that higher VM severity scores were associated with more severe LIC. They concluded that the use of graded permanent elastic compression garments and low-molecular-weight heparin (LMWH) was an effective preventative measure. Coagulative disorders in patients with VM of the limbs and trunk were later characterized with the same findings.25Mazoyer E. Enjolras O. Bisdorff A. et al.Coagulation disorders in patients with venous malformation of the limbs and trunk.Arch Dermatol. 2008; 144: 861Crossref PubMed Scopus (136) Google Scholar The investigators underscored the high incidence of coagulopathy and pain in intramuscular VMs. Another important finding was a low von Willebrand Factor (vWF) level in 39% of patients a less than 50% vWF level in 12% of patients. vWF is a protein synthesized by endothelial cells and megakaryoctes. Low levels of vWF can lead to an increased risk of bleeding. Dompmartin and colleagues26Dompmartin A. Acher A. Thibon P. et al.Association of localized intravascular coagulopathy with venous malformations.Arch Dermatol. 2008; 144: 873Crossref PubMed Scopus (212) Google Scholar reinforced the association of LIC with VMs and reported increased D-dimer levels in patients with trunk venous anomalies, diffuse and extensive lesions, and in the presence of phleboliths. Dompmartin and colleagues27Dompmartin A. Ballieux F. Thibon P. et al.Elevated D-dimer level in the differential diagnosis of venous malformations.Arch Dermatol. 2009; 145: 1239Crossref PubMed Scopus (108) Google Scholar demonstrated that the elevated D-dimer level was highly specific for VMs and suggested its use as a biomarker for the clinical evaluation of vascular anomalies. Maguiness and colleagues28Maguiness S. Koerper M. Frieden I. Relevance of D-dimer testing in patients with venous malformations.Arch Dermatol. 2009; 145: 1239Crossref PubMed Scopus (17) Google Scholar reported that determination of D-dimer level would help diagnose certain vascular anomalies, such as VMs versus fast-flow lesions and VMs versus glomovenous malformations. They also recommended using this biomarker during therapy. There are a few reports on the risks of coagulopathy during interventional radiologic procedures.29Rhee C.Y. Spivack M. Al-Mondhiry H. Subacute consumption coagulopathy-an unusual complication of angiography.Am J Med Sci. 1975; 269: 391Crossref PubMed Scopus (4) Google Scholar Mason and colleagues30Mason K.P. Neufeld E.J. Karian V.E. et al.Coagulation abnormalities in pediatric and adult patients after sclerotherapy or embolization of vascular anomalies.AJR Am J Roentgenol. 2001; 177: 1359Crossref PubMed Scopus (64) Google Scholar analyzed coagulative abnormalities in patients undergoing embolization or sclerotherapy for vascular anomalies. They found an increased incidence of coagulopathy during injection with dehydrated alcohol or sodium tetradecyl sulfate. The coagulopathy consisted of a decrease in platelet count and fibrinogen level, an increase in prothrombin time, and a conversion from negative to positive D-dimer test result. Klippel-Trénaunay syndrome (KTS) is characterized by extensive CLVM in limbs, pelvis, and/or trunk, usually with overgrowth. Patients with this condition are prone to coagulative abnormalities, both hemorrhagic and thrombotic events, because of the extent of this combined slow-flow lesion, the abnormal venous anatomy, and the concurrent or associated lymphatic component. There are numerous reports in the literature documenting the increased incidence of coagulopathy in these patients.31Endo Y. Takahashi K. Mamiya S. et al.Factor XIII deficiency associated with Klippel-Weber disease, platelet dysfunction and cryofibrinogenemia.Acta Haematol. 1983; 69: 398Crossref PubMed Scopus (11) Google Scholar, 32Baskerville P.A. Ackroyd J.S. Lea Thomas M. et al.The Kippel-Trénaunay syndrome: clinical, radiological, and haemodynamic features and management.Br J Surg. 1985; 72: 232Crossref PubMed Scopus (196) Google Scholar, 33Baskerville P.A. Phlebologie. 1987; 40 ([in French]): 531PubMed Google Scholar, 34Joshi M. Cole S. 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Eichenfield L. et al.Pulmonary thromboembolism associated with Klippel-Trénaunay syndrome.Pediatrics. 2005; 116: e596Crossref PubMed Scopus (69) Google Scholar However, there are no prospective data on the specific mechanisms for the coagulopathy in KTS, some of which are similar to that of VMs. Patients with KTS seem to have a form of LIC that can progress to DIC after intervention, such as operation or sclerotherapy, and that can be aggravated by immobilization after these procedures. Another precipitating factor, well known to surgeons who operate on vascular anomalies in the limb, is the increased risk of bleeding with the use of a tourniquet for resection of a CLVM as well as capillary-lymphatic malformation and LVM. It is presumed that cessation of blood flow by the tourniquet causes changes in clotting factors, leading to bleeding and further DIC.45Wilgis E.F. Observations on the effects of tourniquet ischemia.J Bone Joint Surg Am. 1971; 53: 1343PubMed Google Scholar, 46Wilgis E.F. Tourniquet in reconstructive surgery of the hand.Handchirurgie. 1972; 4: 99PubMed Google Scholar Aware of this transient coagulopathy, the surgeons know the importance of waiting and compressing the wound before closure. There are case reports of patients with slow-flow anomalies, documenting major hemorrhagic episodes that have responded to supportive therapy with fresh frozen plasma, heparin, and other antifibrinolytic agents such as tranexamic acid (TXA).38Aronoff D.M. Roshon M. Severe hemorrhage complicating the Klippel-Trénaunay-Weber syndrome.South Med J. 1998; 91: 1073Crossref PubMed Scopus (21) Google Scholar, 43Noel A.A. Gloviszki P. Cherry K.J. et al.Surgical treatment of venous malformations in Klippel-Trénaunay syndrome.J Vasc Surg. 2000; 32: 840Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Thrombotic events, including potentially fatal pulmonary emboli, are common especially after an operation, trauma, and radiological procedures; however, they can also occur spontaneously. This spontaneous prothrombotic condition is poorly explained. Venous thromboembolism has been reported to occur in a frequency ranging from 8% to 22%. In a Mayo Clinic series of 252 patients with KTS and mean age of 11.5 years, 4% of patients had pulmonary embolism (PE), 4% had deep venous thrombosis, and 15% had superficial thrombosis. Postoperatively, of 49 patients, 4% had bleeding events, 1.5% had PE, and 1.5% had deep venous thrombosis (higher than the risk in the general population).47Gloviczki P. Driscoll D. Klippel-Trénaunay syndrome: current management.Phlebology. 2007; 22: 291-298Crossref PubMed Scopus (133) Google Scholar Oduber and colleagues48Oduber C. Gerdes V. van der Horst C.M. et al.Vascular malformations as underlying cause of chronic thromboembolism and pulmonary hypertension.J Plast Reconstr Aesthet Surg. 2009; 62: 684Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar reported a series of 4 patients with chronic thromboembolic pulmonary hypertension that was thought to be caused by recurrent PE in vascular malformations. The investigators stressed the need for early detection in these patients. They also recommended the following considerations lifelong prophylactic anticoagulation in patients with proven thromboembolism, elastic compression and placement of a caval filter, and a multidisciplinary approach to these patients with a hematologist and a pulmonologist. Large draining veins presumably increase the likelihood that if a venous thromboembolism is present, the resulting pulmonary embolus could be large. Furthermore, procedures such as sclerotherapy that intentionally cause vascular stasis may predispose to clot formation. There are no data on other associated prothrombophilic states increasing the thrombotic risk in these patients. Nevertheless, it is likely that the incidence of thrombosis in these patients is greater than the combined incidence of all known inherited thrombophilic states. These slow-flow combined anomalies are risk factors for thrombosis even without a family history of thromboembolic disease. Overgrowth syndromes, such as Proteus syndrome, have associated risk for PE. Proteus syndrome is associated with disproportionate asymmetric overgrowth of body parts, cerebriform connective tissue nevi, epidermal nevi; vascular malformations; and dysregulated adipose tissue. The cause of this complication is unknown but that of the thromboembolism is thought to be enlarged veins.49Cohen M.M. Proteus syndrome: an update.Am J Med Genet C Semin Med Genet. 2005; 15: 137Google Scholar Other overgrowth syndromes may have this embolic risk because of stagnant flow in dilated anomalous veins. An example is congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis and spinal abnormalities (CLOVES) syndrome that includes ectatic thoracic and central veins. Patients with this complication are at high risk for sudden death, and some groups recommend prophylactic caval filters before interventional procedures.50Alomari A. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome.Clin Dysmorphol. 2009; 18: 1-7Crossref PubMed Scopus (120) Google Scholar Pure lymphatic malformations have been associated with minor thrombocytopenia and other more severe coagulopathies, such as DIC. Furthermore, the pathogenesis is not completely understood or well studied. Several congenital or acquired thrombophilic conditions have been identified in the general population as risk factors for venous thromboembolism. These conditions include antithrombin, protein C, and protein S deficiency; factor V Leiden mutation; C677T MTHFR gene mutation; plasminogen activator inhibitor (PAI-1) 4G/G polymorphism; hyperhomocysteinemia; antiphospholipid antibodies; lupus anticoagulant; and G20210A prothrombin gene mutation.51Nowak-Gottl U. Junker R. Kreuz W. et al.Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.Blood. 2001; 97: 858Crossref PubMed Scopus (224) Google Scholar, 52Tormene D. Simioni P. Prandoni P. et al.The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study.Blood. 2002; 100: 2403Crossref PubMed Scopus (90) Google Scholar There are other situations in which endothelial abnormalities increase the risk of thrombosis, such as sickle cell disease and malignancy.53Austin H. Key N.S. Benson J.M. et al.Sickle cell trait and the risk of venous thromboembolism among blacks.Blood. 2007; 110: 908-912Crossref PubMed Scopus (168) Google Scholar, 54Decousus H. Moulin N. Quenet S. et al.Thrombophilia and risk of venous thrombosis in patients with cancer.Thromb Res. 2007; 120: S51-S61Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 54Decousus H. Moulin N. Quenet S. et al.Thrombophilia and risk of venous thrombosis in patients with cancer.Thromb Res. 2007; 120: S51-S61Abstract Full Text PDF PubMed Scopus (36) Google Scholar In adults, genetic alterations have been shown to interact with other risk factors, such as use of oral contraceptives, trauma, immobilization, and surgical procedures, to increase the thrombotic risk. The overall risk in the presence of multiple risk factors can exceed the sum of the separate effects. There is no information about the prevalence of thrombophilic predispositions in patients with vascular anomalies. It is presumed that patients with a genetic predisposition toward thrombophilia have an increased risk for thrombosis and coagulopathy if they also have an extensive slow-flow vascular malformation, but studies of thrombophilia and vascular anomalies have not been published to date. It is important to discuss about patients with potential coagulopathy in an interdisciplinary manner. There are no prospective studies on medical management and thus evidence-based therapeutic regimens are lacking. Institutional treatment plans should be developed until prospective trials are initiated. All patients who are symptomatic with a high-risk vascular anomaly (VM, LVM, CLVM) that is diffuse or multifocal should have hematologic evaluation as a baseline and again before any surgical or interventional procedure and during pregnancy. Laboratory tests include a complete blood cell count; evaluation of prothrombin time, partial thromboplastin time, fibrinogen and D-dimer levels; and a prothrombotic assessment (ie, prothrombin gene mutation, PAI-1 polymorphism, and levels of protein C and S, thrombin-antithrombin complex, factor V Leiden, factor VIII, homocysteine, lupus anticoagulant, anticardiolipin antibody, and antithrombin III). Patients found to have abnormalities in this initial blood examination should have a hematologic consultation before an operation or interventional procedure or during pregnancy. At the authors' institution, those patients at high risk for complications are treated with LMWH (enoxaparin) for at least 2 weeks before and after an operation or radiologic intervention. Dosing is 0.5 mg/kg/dose (maximum of 60 mg/dose) once or twice a day subcutaneously (adults, 30 mg twice a day). Administering LMWH should be stopped 12 hours before the procedure and restarted 12 hours after the procedure. If LMWH is used for an extended period, heparin levels (antifactor Xa) should be determined 4 to 6 hours after subcutaneous injection. The target level of antifactor Xa should be less than 0.5 units/mL for prophylaxis.55Weitz J.I. Low-molecular-weight heparin.N Engl J Med. 1997; 337: 688Crossref PubMed Scopus (1455) Google Scholar A complete blood cell count should initially be done monthly, and dual-energy x-ray absorptiometry should be performed during long-term use of LMWH because of the risk of osteopenia. LMWH can be used daily to alleviate pain caused by inflammation, thrombosis, and formation of phleboliths in large VMs; the same dosing is used. Dosing during pregnancy may vary and should be determined by a hematologist and obstetrician specializing in maternal-fetal medicine. Patients with KTS or an extensive VM, especially if there has been a documented prior thrombotic event (eg, PE), need anticoagulation therapy for an extended period, perhaps indefinitely. These patients can be treated short term with LMWH or heparin and then the treatment can be shifted to oral vitamin K antagonists, such as warfarin (Coumadin). Some patients respond better to LMWH and have a tendency to have recurrent thrombosis after treatment with vitamin K antagonists. A few patients with acute thromboembolic events may require the placement of an inferior or superior vena caval filter in addition to anticoagulant therapy. Antifibrinolytic agents such as ε-aminocaproic acid (EACA) and TXA have been used to treat hemorrhagic coagulopathy caused by vascular anomalies.56Warrell R.P. Kempin S.J. Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate.N Engl J Med. 1985; 313: 309Crossref PubMed Scopus (77) Google Scholar, 57Morad A.B. McClain K.L. Ogden A.K. The role of tranexamic acid in the treatment of giant hemangiomas in newborns.Am J Pediatr Hematol Oncol. 1993; 15: 383PubMed Google Scholar, 58Katsaros D. Grundfest-Broniatowski S. Successful management of visceral Klippel-Trénaunay-Weber syndrome with the antifibrinolytic agent tranexamic acid (cycolcapron): a case report.Am Surg. 1998; 64: 302PubMed Google Scholar Both the agents attach to the lysine-binding sites of plasminogen and plasmin, displacing plasminogen from its fibrin surface. TXA is more potent and has a longer half-life than EACA. Widespread use has been limited because of concerns of increased risk of thrombosis; however, there are no retrospective or prospective studies. Furthermore, antiplatelet agents such as aspirin, ticlopidine, and clopidogrel have been shown to have equivocal clinical benefit, but further studies are needed. Compression garments reduce the amount of blood trapping in these lesions and probably decrease LIC. Other pharmacologic treatments, such as interferon, have been reported to be effective in improving the coagulopathy in vascular malformations. These reports are limited to personal communication and case studies. There have been no prospective studies showing efficacy.59Enjolras O. Vascular tumors and vascular malformations: are we at the dawn of a better knowledge.Pediatr Dermatol. 1991; 16: 238Crossref Scopus (29) Google Scholar, 60Apak H. Celkan T. Oskan A. et al.Blued rubber bleb nevus syndrome associated with consumptive coagulopathy: treatment with interferon.Dermatology. 2004; 208: 345Crossref PubMed Scopus (36) Google Scholar Vascular malformations are a challenging group of disorders for physicians. Treatment has mainly been surgical or through interventional procedures. Particular attention to new sclerosing agents and embolization techniques is important in improving the management of these patients. However, such agents need to address the pathophysiological differences in these malformations, because agents effective for arterial malformations may not be effective for lymphatic malformations or VMs. As with vascular tumors, medical therapy needs to be targeted at the limited knowledge of the pathophysiology of these malformations. One exciting area with great potential is the recent discovery of genetic alterations within these lesions.61Tan W.H. Baris H.N. Burrows P.E. et al.The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management.J Med Genet. 2007; 44 (62): 594-602Crossref PubMed Scopus (188) Google Scholar Some genetic alterations could serve as therapeutic targets and thus aid in treatment options. For example, the PTEN gene mutation has been identified in patients with extensive arteriovenous malformations and other anomalies.62O'Reilly K.E. Rojo F. She Q.B. et al.mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.Cancer Res. 2006; 66: 1500-1508Crossref PubMed Scopus (2146) Google Scholar Rapamycin or other mammalian target of rapamycin (mTOR) inhibitors are predicted to be effective in disorders in which the PTEN/mTOR/STAT3 pathway is affected.62O'Reilly K.E. Rojo F. She Q.B. et al.mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.Cancer Res. 2006; 66: 1500-1508Crossref PubMed Scopus (2146) Google Scholar New antithrombotic agents with similar effectiveness as LMWH need to be investigated because lifelong anticoagulation is needed after a significant thrombotic event has occurred. At present, clear and agreed-on medical management guidelines are lacking for these complications, highlighting the need for further research.
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