Proper 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. This article emphasizes the hematologic complications and management of these patients.
Proper 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.
Vascular tumors
The most common vascular tumor is the hemangioma of infancy that can be simple or complex and may be associated with other anomalies. 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). 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.
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.
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 Merritt 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. 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, 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.
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. 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 ).
| Features | KHE/TA | VM/LM/LVM/CLVM |
|---|---|---|
| Hematologic Features | ||
| Platelets | Very low | Low |
| Fibrinogen | Significantly decreased | Decreased |
| PT/aPTT | Normal or increased | Increased |
| D dimer | ↑ | ↑↑ |
| Pathogenesis | Platelet trapping Fibrinogen consumption | Stasis and thrombin activation on abnormal vasculature |
| Management | Pharmacologic treatment Avoid platelets No heparin | Sclerotherapy Resection LMWH Compression |
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. This condition has also been called multifocal lymphangioendotheliomatosis with thrombocytopenia because it was identified lymphatic histomorphologic features. The associated thrombocytopenia is in the range of 10,000 to 70,000 cells/mm 3 . 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.
Vascular malformations
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. 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. 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. 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. 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.
VMs
There have been several descriptive investigations of coagulopathy in patients with VM. Enjolras and colleagues 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. 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. 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 colleagues 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 colleagues 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 colleagues 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. Mason and colleagues 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 (CLVM)
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. 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. 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). 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). Oduber and colleagues 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.
Vascular malformations
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. 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. 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. 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. 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.
VMs
There have been several descriptive investigations of coagulopathy in patients with VM. Enjolras and colleagues 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. 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. 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 colleagues 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 colleagues 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 colleagues 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. Mason and colleagues 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 (CLVM)
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. 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. 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). 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). Oduber and colleagues 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.
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