HIV-Associated Thrombocytopenia

Thrombocytopenia is perhaps the most common hematologic manifestation of HIV infection. Both impaired platelet production and increased destruction are responsible. CD4, the

receptor for HIV on T cells, has also been demonstrated on megakaryocytes, making it possible for these cells to be infected by HIV.[56] Infected megakaryocytes are prone to apoptosis

and are impaired in terms of platelet production. HIV infection also causes hyperplasia and dysregulation of B cells, which predispose to the development of immune-mediated

thrombocytopenia. Antibodies directed against platelet membrane glycoprotein IIb-III complexes are detected in some patients' sera. These autoantibodies, which sometimes cross-react

with HIV-associated gp120, are believed to act as opsonins, thus promoting the phagocytosis of platelets by splenic phagocytes. Some studies also implicate nonspecific deposition of

immune complexes on platelets as a factor in their premature destruction by the mononuclear phagocyte system.

Thrombotic Microangiopathies: Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)

The term thrombotic microangiopathy encompasses a spectrum of clinical syndromes that includes TTP and HUS. TTP, as originally defined, is associated with the pentad of fever,

thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits, and renal failure. HUS is also associated with microangiopathic hemolytic anemia and

thrombocytopenia but is distinguished from TTP by the absence of neurologic symptoms, the prominence of acute renal failure, and frequent affliction of children. Recent studies,

however, have tended to blur these clinical distinctions. Many adult patients with "TTP" lack one or more of the five criteria, and some patients with "HUS" have fever and neurologic

dysfunction. The common fundamental feature in both of these conditions is widespread formation of hyaline thrombi, comprised primarily of platelet aggregates, in the

microcirculation. Consumption of platelets leads to thrombocytopenia, and the intravascular thrombi provide a likely mechanism for the microangiopathic hemolytic anemia and

widespread organ dysfunction. It is believed the varied clinical manifestations of TTP and HUS are related to differing proclivities for thrombus formation in specific microvascular beds.

For many years, the pathogenesis of TTP was enigmatic, although treatment with plasma exchange (initiated in the early 1970s) changed an almost uniformly fatal condition into one that is

successfully treated in more than 80% of cases. Recently, the underlying cause of many, but not all, cases of TTP has been elucidated. In brief, symptomatic patients are often deficient in

an enzyme called ADAMTS 13. This enzyme is designated "vWF metalloprotease" and it normally degrades very high molecular weight multimers of von Willebrand factor (vWF).[57]

(ADAMTS 13 is unrelated to the other tissue metalloproteases that cleave extracellular matrix.) In the absence of this enzyme, very high molecular weight multimers of vWF accumulate in

plasma and, under some circumstances, promote platelet microaggregate formation throughout the microcirculation, leading to the symptoms of TTP. Superimposition of endothelial cell

injury (caused by some other condition) may further predispose a patient to microaggregate formation, thus initiating or exacerbating clinically evident TTP.

The deficiency of ADAMTS 13 may be inherited or acquired.[58] In many patients an antibody that inhibits vWF metalloprotease is detected.[57] Much less commonly the patients have

inherited an inactivating mutation in the gene encoding this enzyme. Despite these advances, it is clear that factors other than vWF metalloprotease deficiency must be involved in

triggering full-blown TTP, because symptoms are episodic even in those with hereditary deficiency of vWF metalloprotease. It is important to consider the possibility of TTP in any patient

presenting with thrombocytopenia and microangiopathic hemolytic anemia, as any delay in diagnosis and treatment can be fatal. Plasma exchange can be life saving by providing the

missing enzyme.

In contrast to TTP, most patients with HUS have normal levels of vWF metalloprotease, indicating that HUS usually has a different pathogenesis. [59] One important cause of HUS in

children and the elderly is infectious gastroenteritis caused by E. coli strain 0157:H7.[60] This strain elaborates a Shiga-like toxin that is absorbed from the inflamed gastrointestinal

mucosa. It binds to and damages endothelial cells in the glomerulus and elsewhere, thus initiating platelet activation and aggregation. Affected children present with bloody diarrhea, and a

few days later HUS makes its appearance. With appropriate supportive care, affected children often recover completely, but irreversible renal damage and death can occur in more severe

cases. HUS can also be seen in adults following exposures that damage endothelial cells (e.g., certain drugs, radiation therapy). The prognosis of adults with HUS is guarded, as it is most

often seen in the setting of other chronic, life-threatening conditions.

While DIC and thrombotic microangiopathies share features such as microvascular occlusion and microangiopathic hemolytic anemia, they are pathogenetically distinct. In TTP and HUS

(unlike DIC), activation of the coagulation cascade is not of primary importance, and hence results of laboratory tests of coagulation, such as PT and PTT, are usually normal.

Date: 2016-04-22; view: 666