Clinical Models That Separate GpIbIXV Mediated Thrombosis from Hemostasis

Bernard-Soulier Syndrome (BSS)

BSS is rare human genetic disorder in which platelet GpIb-IX-V is absent or dysfunctional. Such patients suffer a bleeding disorder manifested by mucosal and cutaneous bleeding following hemostatic insults that are clinically trivial when platelet GpIb-IX-V is working properly (referred to as "easy bruising or bleeding"). Their bleeding times are always elevated. The impact of BSS on the development and natural history of atherothrombosis of the mid-sized arter-ies—or other vasculopathies—is not of any obvious significance, but BSS platelets show poor VWF-dependent adherence and aggregation in vitro under high-shear-stress conditions. The only acquired human disorder that resembles BSS is iatrogenic: Blood-banked platelets gradually suffer a BSS-like lesion when their ligand-binding extracellular domain of GpIba is slowly proteolyzed during storage.

Von Willebrand Disease (VWD)

VWD includes a variety of disorders defined by a deficiency or dysfunction of VWF. There are three major types of VWD. Type 1 VWD is due to a mild deficiency and type

3 VWD is due to severe or absolute deficiency. In both of these diseases VWF structure and multimerization are normal. Their clinical impact is directly proportional to the magnitude of the VWF deficiency. There are also VWD types and subtypes in which the patient suffers mild provoked bleeding because the larger normal plasma VWF multimers (not the "ultralarge" forms that participate in TTP and HUS) are deficient. Most type 2A VWD is due to the production of mutant VWF multimers that are unusually sensitive to normal proteolytic processing. Type 2A VWD is less commonly caused by mutations that interfere with the normal synthesis of plasma VWF multimers. Type 2B VWD is due to VWF mutations that render it unusually avid for platelet GpIb-IX-V; in type 2B VWD, VWF binds to GpIba even in the absence of a modulator (e.g., ristocetin) or elevated shear stress. When this happens in vivo, larger VWF multimers become depleted from blood plasma (they bind to circulating platelets) and some patients suffer a resulting "consumptive" thrombocytopenia due to platelets with surface-bound VWF being cleared from the intravascular compartment by some unknown mechanism(s). A similar loss of large VWF multimers from blood onto platelet surface GpIb-IX-V also occurs in pseudo-VWD, which is caused by mutations in the extracellular ligand-recognition domain of GpIba.

In considering the pathophysiology of VWD, two clinical observations direct two general conclusions about the function of VWF in physiology and pathology. The first conclusion is that larger plasma VWF multimers are required for normal hemostasis: Persons with type 2 or pseudo-VWD have a bleeding disorder. The second conclusion is based on the observation that direct multimeric VWF binding to GpIb-IX-V—as occurs in type 2B and pseudo-VWD—has no effect on platelet-dependent hemostasis and thrombosis in vivo independent of the fact that it causes an intravascular depletion of larger VWF multimers. This suggests that platelet-surface VWF is not an important determinant of hemostasis or thrombosis unless it becomes surface-bound by a series of specific interactions developing within the triad of Virchow.

Moderately severe underproduction thrombocytopenia (e.g., as occurs in leukemic patients who have received intensive induction chemotherapy and is defined by blood platelet concentrations of ~20,000 to 50,000/|mL) rarely causes spontaneous dermal microvascular hemorrhage (petechiae). Severe underproduction thrombocytopenia (fewer than 10,000 platelets/|L blood) inevitably causes petechiae. BSS (which is accompanied by thrombocytope-nia and giant platelets) and most VWD (in which platelet number and structure are normal) rarely cause spontaneous mucocutaneous bleeding. Severe VWD causes petechiae, albeit intermittently. These clinical observations reveal at least two things about how platelets serve as "guardians of the microvasculature." First, platelets' guardian function is in large part performed by their GpIb-IX-V complex and its capacity to recognize and bind VWF and thereupon signal the activation of aIIbb3. Second, platelet guardian function is maintained reasonably well even when platelet number or the number of GpIb-IX-V complexes or VWF multimers is very small, suggesting that evolution has "overproduced" hemostatic cells and proteins under the selective pressure of preventing hemorrhage. This may have biased our evolutionary biology towards thrombosis. The observation that only severe VWD, but not mild (types 1 and 2) VWD, appears to protect against atherothrombosis is consistent with the theory that human evolution has favored hemosta-sis over thrombosis. If this theory is correct, the hunt to discover unique mechanisms of GpIb-IX-V mediated thrombosis versus hemostasis should begin by reexamining the old axiom that "thrombosis is simply hemostasis occurring in the wrong place." If we accept this as true, we should then begin to try to figure out what it is about the "wrong place's" vascular system and rheological features that forces "hemostasis" to occur.


TTP and HUS are thrombotic microangiopathies (small-vessel thromboses associated with microangiopathic hemolytic anemia) due to platelet thrombi developing in the microvasculature. As more clinical and in vitro data about these diseases are generated, more debate is generated about the pathophysiological relationship between TTP and HUS. Notwithstanding this fact, or the fact that HUS and TTP are distinct clinical disorders, or the fact that TTP can be treated with plasma exchange and HUS cannot, or the fact that in HUS—but not TTP—fibrin can be found deposited in the microvasculature of the renal glomerulus and peritubular regions, or the fact that no etiological factor has yet been identified in TTP, it is nonetheless clear that both diseases share a common trigger: "unusually large" VWF multimers wreak havoc because they exist where they should not. In sporadic TTP it is an acquired deficiency of ADAMTS13, usually because of an autoantibody. In sporadic HUS it is because an enterotoxin (a shiga- or verotoxin) poisons the microvascular ECs, which respond by releasing "unusually large" VWF multimers. In familial TTP and HUS, the same pathways are involved via different mechanisms: in familial TTP there are inherited mutations in ADAMTS13 that affect its secretion, stability, or activity; and in familial HUS there is a deficiency of plasma factor H, which normally prevents or dampens complement-mediated cellular toxicity, including renal glomerular microvascular toxicity. Microan-giopathies are also associated with radiation, solid organ and bone marrow transplantation, and mitomycin, cyclosporine, or tacrolimus therapy. These rarely fall neatly into one category or another (i.e., TTP or HUS) and, except for bone marrow transplant recipients (who almost always have normal levels of ADAMTS13), it is difficult to predict or establish the relative importance of ADAMTS13 insufficiency or EC damage (and perhaps even VWF-GpIb-IX-V) in their pathogenesis.

Miscellaneous Conditions Where the Link between GpIb-IX-V and Pathology Is Uncertain

When one examines the molecular determinants of GpIb-IX-V-mediated hemostasis and thrombosis and then cross-references them with common diseases that affect the systemic or organ-specific microvasculature, certain hypotheses come to light. For example, patients who suffer from bacteremia and sepsis overproduce EC NO, which has pleiotropic effects. Is it possible that one of the effects, that of NO-mediated inhibition of platelet adhesion and activation resulting at least in part from GpIb-IX-V binding to VWF, contributes importantly to bleeding associated with sepsis? If we examine the question from the perspective of responses by many different factors occurring dynamically within Virchow's triad, and that each group of factors operates in unique microvascular compartments over a 24- to 48hour time period, the answer must be "I don't know, but maybe sometimes."

As another example, consider that solid organ (e.g., kidney, liver, or heart) transplant rejection often involves a microvasculopathy with histopathological evidence of platelet deposition, including venular deposition. Is it possible that venular platelet deposition is mediated by GpIba bind ing to VWF or P-selectin expressed on the venular EC inflamed by the storm of cytokines that accompanies graft rejection? How about the relationship between platelet-mediated hemostasis and thrombosis and the pathogenesis of brain plaques in Alzheimer's disease? Evidence supports the idea that platelet-secreted amyloid precursor protein (APP) is involved in the formation of brain plaques, but are platelets of primary importance or secondary importance, or is platelet APP an irrelevant epiphenomenon? Answers are possible only when we simultaneously examine changes in the vascular and rheological components of Virchow's triad within the cerebral microvasculature. Finally, what is the role of platelet GpIb-IX-V and VWF in the growth of cancers? Pretty solid evidence indicates that platelet aIIbb3 contributes to new capillary sprouts in several cultured malignant cell lines. How does it work, and does it work at all in vivo? Does it require activation and, if so, is it activated by VWF binding to GpIb-IX-V? We can only begin to answer these questions after we have assiduously dissected molecular mechanisms of GpIb-IX-V-mediated hemostasis and thrombosis.

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