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Chapter 15 Vascular Growth in Health and Disease 161

Angiogenesis and Antiangiogenesis in Hematopoietic most extensive clinical experience is in the area of cancer, where some
toxicities (e.g., hypertension, proteinuria, fatigue, hypothyroidism)
Malignancies have been observed in this setting, along with hematologic side effects,
mainly thrombosis and/or bleeding. While cancer patients are prone
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The vascular bone marrow stroma plays a pivotal role in leukemogen- to thrombosis, antiangiogenic therapy increases the risk of venous
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esis. Indeed, angiogenesis, increased vascular density, and increased thromboembolism or arterial thrombosis. The risk varies depending
levels of angiogenic growth factors have all been observed in the bone on the agent and the type of cancer, and is exacerbated by accompany-
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marrow of patients with hematopoietic malignancies. VEGF may play ing chemotherapy or hormonal therapy. Thrombosis is of particular
multiple roles in this context, including as (1) vascular growth stimula- concern in patients with multiple myeloma who receive thalidomide
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tor; (2) paracrine growth factor for leukemic stem cells ; and (3) inducer derivatives in combination with anthracyclins and dexamethasone. In
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of angiocrine interactions between these cells and the endothelium. this case the reported risk of thrombosis may be as high as 75%. Beva-
Consequently, a wide spectrum of antiangiogenic agents, including cizumab may increase the risk of arterial thrombosis up to twofold in
VEGF antagonists (bevacizumab, sorafenib, sunitinib, cediranib), are patients with solid tumors, especially in the elderly with additional risk
under investigation for the treatment of hematologic disorders, such as factors. These estimates are variable, however (0.9% to 19.4% according
acute myelogeneous leukemia, chronic myelogeneous leukemia, acute to different studies), and drug specific, because small-molecule tyrosine
lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin kinase inhibitors acting on VEGFR are less likely to trigger venous
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lymphoma, multiple myeloma, and others. Additional agents with thromboembolism (0% to 3%; also see Chapters 126 and 149). 36
antiangiogenic activity have also been explored, including bortezomib Bleeding complications were also recorded with several of these
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and antiinflammatory antiangiogenics (thalidomide and lenalidomide), agents, ranging from minor to life threatening. In general, however,
some of which are already in human use in hematologic malignancies antiangiogenic agents are relatively well tolerated, and their side
(e.g., in mantle cell lymphoma, multiple myeloma, and myelodysplastic effects are usually manageable with careful monitoring and standard
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syndrome; see Medinger and Mross for review, also Chapter 55). supportive care. 6
Hematologic Complications Associated With Blood SUMMARY
Vessel–Directed Agents
The functional integration of the vascular system, bone marrow, and
Manipulation of endothelial and mural cells in the course of pro- and circulating blood results in a high degree of biologic interdependence
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antiangiogenic therapy creates the potential for side effects. The in health and disease (Fig. 15.5). While this may not always be
Reciprocal interactions involving Vasculature
Parenchymal and Mediators and Vascular
circulating cells mechanisms cells
Organ parenchyma Cytokines and chemokines Endothelium
Stromal cells Adhesion molecules Mural cells
Hematopoietic cells Extracellular matrix Pericytes
Inflammatory cells Extracellular nucleic acids
Leukemic cells Intercellular junctions
Cancer cells Extracellular vesicles
Stem cells Regulation of angiogenesis
Regulation of vasculogenesis
Vascular remodeling
Endothelial activation

Tissue vascularization
Blood supply/perfusion
Barrier functions
Hemostasis
Angiocrine effect
Stem cell niche
Growth control
Dormancy control

Disease contexts involving interactions between vascular and peri-/intravascular cells
Leukemia Thromboembolism Vascular aging
Lymphoma Bleeding disorders Atherosclerosis
Solid tumors Inflammation Vascular neoplasia
Autoimmune diseases Sepsis Vascular malformations
Anticancer therapy Anticoagulation Antiangiogenic therapy
Fig. 15.5 THE RECIPROCAL INTERDEPENDENCE OF VASCULAR, NONVASCULAR, AND
BLOOD CELLS IN HOMEOSTASIS AND DISEASE. In multicellular organisms blood flow connects all
constituent cells to each other and to the external environment (oxygen supply, nutrition, regulation, migra-
tion). The ubiquitous presence of blood vessels, vascular cells, circulating cells, soluble mediators, and blood
components defines and integrates multiple functions of organs and tissues in health and disease. Examples
of processes, disease states, and therapies that epitomize this web of relationships are described in this chapter.