Introduction

Physiological hemostasis and pathological thrombosis take place within a complex in vivo milieu. The complex variables that modulate prohemostatic and prothrombotic responses are probably best organized by examining them within Virchow's triad. Virchow's triad reminds us that hemostasis and thrombosis are regulated by the simultaneous interactions among blood (cells and soluble constituents), blood vessel (endothelium, subendothelium, and smooth muscle), and blood flow (related to diameter, branching, turbulence, and obstruction) (Figure 1). In considering the variables that affect—and perhaps differentiate—glycoprotein (Gp) Ib-IX-V-dependent hemostasis and thrombosis, one should begin by examining features within Virchow's triad that are unique to the microcirculation, the site of hemostasis.

The most unique feature of the microcirculation is its blood vessels. The afferent arterioles are defined as 100 mm descending to <10 mm in diameter, with little subendothe-lium separating the luminal endothelium from the vascular smooth muscle cell layer. The capillary bed is comprised of an extensive collateral network of tiny (about 6 mm) thin-walled vessels that function in gas, solute, or cell exchange and transport. The capillaries are in some cases discontinuous (e.g., "sinusoidal" capillaries as are found in the bone marrow, liver, and spleen) or fenestrated (e.g., "transport" capillaries as are found in endocrine organs and the renal glomeruli). In the brain, the capillaries are tightly joined to one-another to create a barrier for selective transport and exchange. Capillaries then converge into widening branches of the efferent venules, which expand in size from tens to hundreds of microns in diameter, and possess two important features: fenestrae that permit egress of cells and proteins adluminally and valves that prevent backflux into the capillary network. These features of the microcirculatory vascular network vary depending on their location, and it should be emphasized that unique anatomical and functional characteristics can be found in unique capillary beds, such as the skin, skeletal muscle, brain, liver, kidney, lungs, and heart. Such unique characteristics undoubtedly influence an organ's vulnerability to specific hemostatic and thrombotic challenges, although the mechanisms by which these influences develop are in most cases unknown.

Figure 1 The elements within Virchow's triad that direct hemostasis or thrombosis in the microcirculation. The microcirculation—which is generally defined by a vascular lumen diameter less than 100 mm—encompasses three vessel beds of strikingly different morphology and rheology: arterioles, capillaries, and venules. Each possesses a unique repertoire of physiological and pathological attributes and responses. Distribution refers to where the majority of blood platelets are found within a cross-sectional vessel lumen. VWF, von Willebrand factor; TTP, thrombotic thrombocytopenic purpura; HUS, haemolytic-uremic syndrome; ADAMTS13, a disintegrin and met-alloproteinase with thrombospondin type-1 motif 13; EC, endothelial cell; TFPI, tissue factor pathway inhibitor; WBC, white blood cell; PSGL-1, P-selectin glycoprotein ligand-1. (see color insert)

ARTERIOLE

CAPILLARY

VENULE

Centrifugal Distribution High Shear Stress Vessel Wall VWF Vessel Wall Collagen Platelet Activation

Even Distribution Low Shear Stress

Thrombin Platelet Activation

ARTERIOLE

CAPILLARY

VENULE

Centrifugal Distribution High Shear Stress Vessel Wall VWF Vessel Wall Collagen Platelet Activation m in o m S

o oc

TTP/HUS High Shear Stress Large VWF Multimers ADAMTS13 Deficiency EC Damage

Even Distribution Low Shear Stress Thrombin/TFPI Balance Platelet Activation

Even Distribution Low Shear Stress Thrombin/TFPI Balance Platelet Activation

Even Distribution Low Shear Stress

Thrombin Platelet Activation

INFLAMMATION Low Shear Stress Vessel Wall P-selectin EC Released VWF WBC Mac-1/PSGL-1 Thrombin

Rheological principles governing microvascular hemostasis and thrombosis emanate from its unique anatomic features. High shear stress (up to 60 dyn/cm2) "feed" arterioles bifurcate into branch arterioles at intervals of about 200 mm, with declining flow velocities and shear stress as branches narrow (for example a first branch shear stress of 20 dyn/ cm2 and a fourth branch shear stress of 9 dyn/cm2). At branch points there is turbulence, increased resistance and even backflux as cyclical blood flow overcomes afferent arteriolar autoregulatory vasoconstriction triggered with every cardiac diastolic relaxation. As blood enters the extensively branched capillary bed, shear stress decreases further. There are very few published data that provide one with precise measurements of shear stress or other rheological parameters in capillaries, but estimates based on viscosity calculations and flow and pressure measurements leading into and out of capillaries indicate that physiological capillary blood flow is low flow velocity and generates low shear stresses. The branching postcapillary venules then converge into efferent vessels of increasing diameter and capacitance and gradually increasing—but still low—shear stress (less than 5 dyn/cm2). Venular backflux is limited by tiny two-cusped valves even when low flow and high capacitance result in venular segmental flow reversal. Flow turbulence decreases and flow velocity increases as smaller venular branches come together into larger venules and, eventually, small veins (more than 100 mm in diameter).

The unique anatomy and rheology of the microvascula-ture direct the activity of the platelets, coagulation proteins, red cells, and leukocytes in hemostasis and thrombosis, and the behavior of blood within the microcirculation directs vascular and rheological responses. Although the dynamics of these interactions exceed the boundaries of simplification, their complexity is best appreciated from a perspective that brings time into the biological framework: Every element of Virchow's triad—whether pro- or antihemostatic or pro- or antithrombotic—works within a response that occurs over time. This is important for the blood vessel (e.g., vascular smooth muscle vasoreactivity will constrict or dilate an afferent arteriole) and for blood flow (e.g., a nonde-formable 7-|mm red cell will obstruct a 4-|mm capillary), but it is absolutely essential for the physiology and pathophysi-ology of the blood. In considering how the microvascular environment interacts bidirectionally and temporally with the blood to promote hemostasis and thrombosis, two fundamental observations require emphasizing. The first is that high shear stress (i.e., arteriolar) hemostasis and thrombosis are predominantly platelet mediated, with the coagulation proteins and other blood cells playing an important but secondary role (e.g., as vaso-occlusion causes flow and shear stress to diminish, red cells, leukocytes, and fibrin accumulate in the nascent thrombus). The second is that low shear stress thrombosis (i.e., capillary and venular) is predominantly fibrin mediated, with red cells and leukocytes playing essential primary roles, and platelets generally coming into the picture secondarily in response to coagulation factor activation (e.g., the generation of thrombin) or leukocyte recruitment (e.g., P-selectin glycoprotein ligand-1 on leukocytes bound to inflamed or damaged postcapillary venules will recruit activated platelets expressing P-selectin). There is, however, one example of a platelet-initiated low shear stress (venular) response. Platelets attach and roll along inflamed venule endothelium and the transitory contacts that mediate this response are both Gplb-IX-V mediated: platelet Gplba binding to venular P-selectin and platelet Gplba binding to venular EC surface VWF. It is noteworthy that these interactions do not lead to significant thrombus accrual, suggesting that elevated shearing stresses are required for platelet-dependent thrombosis to occur in the microvasculature.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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