Thrombocytopenia is one of the more commonly encountered hematologic abnormalities in patients infected with the human immunodeficiency virus (HIV). It is usually attributed to the effects of HIV itself, which charcateristically cause a benign immune-mediated thrombocytopenia. There is, however, another less common but more serious clinical entity associated with thrombocytopenia. It is important for clinicians caring for HIV-infected patients to be able to recognize the syndromes of thrombotic microangiopathy (TMA), which includes the spectrum of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).1 The treatments of these TMA syndromes are distinctly different from the treatment of HIV-related thrombocytopenia, hence the importance to identify TMA.2,3 While the advancements in therapies has led to an overall decrease in disease mortality, without early recognition and intervention, the condition could be fatal.
The incidence of TTP has increased over 16-fold in the past 20 years. Some investigators speculate that this is in part due to the HIV epidemic, as institutions located in cities with a high prevalence of HIV infection have noted that most of their cases of TMA occurred in HIV-infected patients.2,4,5
Since the first described in 1987, there have been over 70 well-described cases in the literature with the incidence of both TTP and HUS reported to be higher in the HIV-infected population compared with the uninfected population.2,4-9 It is prudent to recommend that all patients presenting with TTP or HUS be screened for HIV infection, as this may be their presenting illness. It is yet to be determined if the era of highly active antiretroviral therapy (HAART) will produce a decrease in the incidence of TTP and other related TMAs.
Herein, we describe the clinical features, treatments, and outcomes of 7 episodes of TTP that occurred in 5 patients we cared for, and review the literature related to this syndrome.
A 38-year-old man with acquired immunodeficiency syndrome (AIDS) (CD4 count: 7 cells/mm3) was admitted with a recurrent episode of Pneumocystis carinii pneumonia (PCP). During treatment of PCP with clindamycin and primaquine, he developed mental status changes, fevers, renal failure, and hemolytic anemia along with thrombocytopenia.
Physical examination was remarkable for fever of 39.3°C, oral candidiasis, and a delirium. Laboratory data revealed a hemoglobin of 7.8 g/dL, a platelet count of 30,000/mm3, lactic acid dehydrogenase (LDH) of 4275 IU/L, and serum creatinine of 3.8 mg/dL. Peripheral blood smear demonstrated numerous schistocytes, while a urinalysis showed protein and hemoglobin. Prothrombin time was normal and a disseminated intravascular coagulation (DIC) screen was negative, suggesting the diagnosis of TTP.
Plasma exchange was instituted along with intravenous methyl-prednisolone and aspirin. The platelet count progressively declined to 4000/mm3 over the next 3 days, with concomitant rises in serum LDH and creatinine. In addition, intravenous immune globulin (IVIG) was ineffective, and spontaneous bleeding was evident at IV sites. Vincristine therapy was added to plasma exchange on hospital day (HD) 6, and by HD9 laboratory parameters began to improve and the patient's mental status returned to baseline. Plasma exchange, vincristine, and corticosteroid therapy were tapered over 3 weeks, with normalization of his hematologic and renal parameters. TTP recurred approximately 1 month after hospitalization and the patient and his family refused further therapy. He expired soon thereafter.
Comment: This case demonstrates the classic pentad of abnormalities that characterize TTP. The neurologic findings support the diagnosis of TTP, as opposed to HUS. His concurrent PCP infection and/or the antibiotics used to treat PCP may have contributed to the development of TTP, although both factors were not present when the patient presented with relapsed TTP. This patient's advanced immunosuppression from AIDS contributed to his poor prognosis and adverse outcome.
A 32-year-old man with AIDS (CD4 count: 20 cells/mm3) presented with a several day history of malaise, anorexia, and fever. Past history was remarkable for PCP, disseminated Mycobacterium avium complex (MAC), and oral candidiasis. He was nonadherent with his medications including: azithromycin, ciprofloxacin, rifampin, and fluconazole. He subsequently developed expressive aphasia, apraxia, and dysarthria.
Physical examination was remarkable for a temperature of 37.3°C and the neurologic findings previously stated. Laboratory data showed a hemoglobin of 7.1 g/dL, platelet count of 85,000/mm3, and schistocytes on peripheral blood smear. Serum LDH was elevated at 2064 IU/L, creatinine was above his baseline at 1.1 mg/dL with a urinalysis significant for hemoglobin and protein. A DIC panel was negative and a presumptive diagnosis of TTP was made. Computerized tomography of the head was normal. A bone marrow biopsy was without evidence of mycobacterial infection or neoplastic processes. The patient declined plasma exchange and corticosteroid therapy. He had intermittent follow-up over the next 3 months and continued to experience his presenting symptoms. He also continued to demonstrate laboratory evidence of TTP. Approximately 3 months after the initial diagnosis of TTP, he was readmitted with worsening thrombocytopenia, schistocytosis, and an LDH of 3957 IU/L. He accepted comfort care only and expired soon thereafter.
Comment: This case demonstrates the potential chronicity of TTP without treatment. TTP likely contributed to his ultimate death, but a postmortem examination was not obtained. Evidence supporting a recurrence of MAC disease was noted when a blood culture yielded MAC after the patient had expired. It is possible that this recurrence of an opportunistic infection contributed to this case of TTP. As was evident in the prior case, AIDS patients with advanced immunosuppression generally have a short survival after the development of TTP.
A 34-year-old woman with AIDS (CD4 count: 190 cells/mm3) presented with a 5-day history of transient blurry vision and left-sided weakness with paresthesias. There was no history of opportunistic infections. Medications included zidovudine and trimethoprim-sulfamethoxazole. Admission platelet count was 13,000/mm3 with a stable hemoglobin level and normal coagulation studies. A presumptive diagnosis of HIV-related thrombocytopenia was made.
Therapy with IVIG was instituted without improvement in her platelet count. Over the next several days, she developed a fever of 38.2°C with progressive neurologic symptoms including headache, left-sided weakness, and paresthesias. A head CT scan was normal, as was examination of the cerebrospinal fluid. The platelet count declined to 6000/mm3, while the hemoglobin decreased to 10 mg/dL with a peripheral blood smear demonstrating moderate schistocytes; LDH concomitantly rose to 1979 IU/L. The creatinine remained normal, but the urinalysis showed protein and hemoglobin. DIC screen was negative. A diagnosis of TTP was made and treatment was started with plasma exchange daily for 6 days. There was a resolution of fevers and neurologic symptoms along with a progressive normalization of laboratory results. She was discharged on HD13 and has been without recurrence of TTP for the past 6 years. She remains well, although has had progression of her HIV illness and failure of many HAART salvage regimens.
Comment: This case demonstrates a rapid response to standard plasma exchange therapy, as well as a sustained remission from TTP. Initially diagnosed with idiopathic thrombocytopenic purpura (ITP), with an isolated thrombocytopenia, subsequently she manifested signs, symptoms, and laboratory findings consistent with TTP. Sequential occurrence of ITP and TTP in HIV-infected patients has been previously described in the literature.10 This rapid and sustained response to therapy may be related to the patient's higher CD4 cell count at the time of presentation of her illness and the lack of AIDS-defining illness.
A 34-year-old man with HIV infection (CD4 count: 340 cells/mm3) presented with complaints of fatigue, epistaxis, dizziness, dysarthria, and paresthesias in his left arm. He had no prior history of opportunistic infections. He admitted to regular intranasal cocaine use in the preceding 2 years and last used cocaine the day of admission. Physical examination was remarkable for fever of 37.9°C, a defect in his nasal septum, and a petechial rash on his lower extremities.
Laboratory data showed a platelet count of 7000/mm3 with a hemoglobin of 5.9 g/dL. His coagulation studies were normal and a DIC screen was negative. A peripheral blood smear showed many schistocytes. His serum LDH was elevated at 4644 IU/L with a total bilirubin of 2.3 mg/dL, and his creatinine was mildly elevated at 1.1 mg/dL (baseline 0.8 mg/dL) with hemoglobinuria. A diagnosis of TTP was made, and therapy consisting of plasmapheresis, corticosteroids, and packed red blood cell transfusions was begun. Within 72 hours, the platelet count recovered to more than 300,000/mm3 with a hemoglobin greater than 10 g/dL and LDH and bilirubin trended downward. He signed out against medical advice after 5 days of therapy and prior to finishing the prescribed course of plasmapheresis. He did successfully complete a drug rehabilitation program.
He continued to do well until 2 years later, when he again developed fatigue, weakness, insomnia, intermittent epistaxis, and low-grade fevers. His medications included zidovudine, lamivudine, and dapsone. He had been drug-free for 2 years. Physical examination was significant for a temperature of 38.3°C, pale conjunctiva without icterus, and scattered petechiae on his lower extremities. Laboratory data revealed a platelet count of 5000/mm3 with a hemoglobin of 5.6 g/dL with a normal coagulation profile. DIC screen was negative. A peripheral smear showed moderate schistocytes. His creatinine had risen from a baseline of 0.8 to 1.2 mg/dL and a urinalysis revealed hematuria. Serum LDH was increased at 6139 IU/L and total bilirubin was 2.5 mg/dL. A diagnosis of recurrent TTP was made, and treatment with plasma exchange and corticosteroids was begun. His platelet count and hemoglobin normalized after 5 days of plasma exchange, with a coincident decrease in LDH and bilirubin. He was discharged on HD8 and has been without recurrence of TTP to date 4 years later. His HIV disease has been well controlled with HAART.
Comment: This case illustrates the recurrent nature of TTP 2 years after his initial episode. With each episode, the patient responded quickly to therapy. These good outcomes may reflect the nature of his early stage of HIV illness and overall a lesser degree of immunosuppression. One may be inclined to attribute his first episode to the use of cocaine, but with his second episode 2 years later, the patient had been drug-free, confirmed by drug testing. Recently, the patient developed a third episode of TTP (not included in Table 1) 5 years after his previous episode. The patient had discontinued his antiretrovirals 6 months prior to this episode, which may have contributed to his TTP recurrence. His CD4 cell count was 300 cells/mm3 and he had previously been virologically suppressed (VL <50 copies/mL). He once again responded promptly to plasmapheresis therapy and resumed HAART.
A 42-year-old male with AIDS (CD4 count: 39 cells/mm3) presented with memory loss, paranoia, and absence seizures. Past medical history included recurrent oral candidiasis, ITP, and syphilis. Medications were zalcitabine, trimethoprim-sulfamethoxazole, naproxen, and megestrol. Physical examination was remarkable for a temperature of 39.6°C, cachexia, and memory impairment. Laboratory studies revealed a platelet count of 21,000/mm3 and a hemoglobin of 7.7 g/dL. Review of the peripheral blood smear showed many schistocytes. Serum LDH was 1948 IU/L with a total bilirubin of 2.0 mg/dL. Coagulation and renal function studies were normal, but a urinalysis revealed moderate hemoglobin. DIC screen was negative. Computerized tomography of the head, EEG, and lumbar puncture were unremarkable and a diagnosis of TTP was made.
Therapy with aspirin, prednisone, and plasma exchange was initiated. Mental status cleared, but hematologic parameters showed minimal response. His hospital course was complicated by necrotizing bowel with Clostridium septicum sepsis, which necessitated a bowel resection. A therapeutic splenectomy was also done at the time of surgery. Following a complicated hospital course, and with only a modest improvement in his platelets and hemoglobin after 9 days of plasma exchange, he elected to have no further treatment of TTP. Platelet count at the time of discharge was 17,000/mm3, LDH remained elevated at 2227 IU/L and the peripheral smear continued to demonstrate schistocytes.
On follow-up over the next 5 months and without further intervention, the hemoglobin stabilized at 10 g/dL, the platelet count returned to a normal value over 200,000/mm3, and the peripheral blood smear no longer showed schistocytes. He was seen regularly in clinic thereafter, and did well until 5 months later, when he presented with an altered mental status, hypothermia (32.4°C), and acute renal failure. A platelet count of 31,000/mm3 and a hemoglobin of 7 g/dL were noted, as well as the return of many schistocytes on peripheral smear. Serum LDH was elevated at 3047 IU/L and creatinine had risen to 1.9 mg/dL. He was diagnosed with relapsed TTP, and plasmapheresis and corticosteroids were instituted. He failed to respond and had a progressive decline in mental status and oliguric renal failure requiring dialysis. His laboratories also demonstrated progressive TTP, with a rising LDH (17,800 IU/L) and no sustained improvement in his hemoglobin or platelet count. He was discharged to hospice and expired soon thereafter.
Comment: This case demonstrates the adjunctive use of splenectomy in the treatment of TTP, which he concurrently underwent during his bowel resection in further attempts to treat his TTP. It appears that splenectomy may have transiently treated his TTP, as he was without signs, symptoms, or laboratory values consistent with TTP for 5 months after the procedure. Splenectomy has been advocated in patients with TTP, which is refractory to plasma exchange or antiplatelet agents. Experience with this treatment modality is limited. His course is also remarkable for the refractory nature of his TTP, with the relapse episode being quite aggressive, which is probably attributable to his advanced AIDS immunosuppression. It also underscores the importance of considering relapse in a patient who has had a previous episode.
While the etiology of TTP remains elusive, it has clearly been associated with a myriad of conditions, from various medications to infectious agents.11-14 It has long been proposed that infection with HIV predisposes patients to TTP and other TMAs since 1984, when Boccia et al15 described the first case of HUS in a patient with AIDS. This was followed by Jokela et al7 in 1987, who reported the first case of TTP in an HIV-infected patient. There has been a marked rise in cases reported per year since the early 1990s, correlating with the AIDS pandemic.9 This indirect epidemiologic evidence is supported by several early case series originating from areas of the country with a large incidence of reported AIDS cases.2,4,5 The first series was reported by Leaf et al4 from 1985 to 1987 in New York, who noted that 28% of 14 patients with TTP were HIV infected. Similarly, Ucar et al5 found 7 of 50 patients from 1979 to 1990 in Miami with TTP to have HIV infection. This was followed more recently with another series reported from New York that demonstrated that the percentage of patients with TMA and HIV increased to over 50% between 1990 and 1996.2 Subsequent case reporting and reviews by other investigators confirmed this epidemiologic observation.
While some TMA cases appeared to be idiopathic and perhaps secondary to the direct effects of HIV,16 many investigators report that these patients had coexisting AIDS-defining illnesses such as, Pneumocystis carinii pneumonia, Kaposi sarcoma, cytomegalovirus or cryptococcal meningitis.4,6,17,18 In addition, several medications that are frequently used in the management of HIV-infected patients, such as fluconazole, acyclovir, and valacyclovir, have been implicated as a cause of TTP or TMA syndromes.11
TTP and TMA have been reported in all stages of HIV infection, but, it does appear to be more often seen with advanced immunosuppression and lower CD4 cell counts.13,19 More than two-thirds of patients reported in the literature with TTP had CD4 cell counts below 100 cells/mm3. An association with viral load has not been mentioned, as most data pre-date the availability of HAART and this testing modality.
TTP is characterized by endothelial cell damage and platelet deposition with consequent thrombosis. Postmortem examinations of patients who have died of TTP have demonstrated extensive thrombosis of the small vessels of most organs, with the exception of the liver and lung.20 Interestingly, there generally is no inflammatory reaction at the site of endothelial damage, although immunohistochemical staining demonstrates immunoglobulin, platelets, complement, and fibrin within the hyaline thrombi.2,21
There are probably many factors contributing to the pathophysiology of the disease, including the unusually large von Willebrand factor multimers (UlvWF) released during endothelial cell injury,22 antibodies that inhibit von Willebrand factor-cleaving protease,23 cytokines,24,25 and platelet aggregating factors.26 In addition, some host-specific and some exogenous infections such as viruses like CMV,27,28 or medications may also play a role in the pathogenesis.11
Clinical Spectrum of Illness/Definition
It has been recognized that the disease of TMA exists as a spectrum of clinical illness characterized by hematologic and vascular abnormalities and therefore, clinical presentations may vary.29 For example, a CNS microangiopathy causes the neurologic symptoms that define TTP, while a lack of neurologic abnormalities and severe renal dysfunction define HUS. Some patients may possess many characteristic features of TTP, but not the classic pentad.14 Therefore, sometimes TTP or TMA may be difficult to diagnose, because there is no single clinical or laboratory feature that is pathognomonic of TMA. If a fairly stable patient has sudden onset of the pentad of characteristic features, the diagnosis should be considered. In addition, it is important to evaluate for the presence of disseminated intravascular coagulation (DIC) prior to making a diagnosis of TTP, as clinically these entities may appear similar.
In several series of HIV-infected patients with TTP, few patients presented with the complete diagnostic pentad of fever, neurologic symptoms, anemia, thrombocytopenia, and renal failure, with the majority only demonstrating 3 symptoms.4,8 The diagnostic triad of anemia, thrombocytopenia, and neurologic dysfunction is the most common combination of symptoms present in 75% of the patients reported in the literature.6,7,18,30-32 In our series, all of our patients presented the pentad of TTP (Table 1).
Recently, investigators reported that any of the characteristic features of TTP or HUS may be randomly found in hospitalized AIDS patients. While one or more of these findings may be present, the patient may not have the triad or pentad that is diagnostic of clinical disease. It appears that HIV-infected patients with CD4 cell counts less than 50 cells/mm3 and Stage C disease were more likely to possess these features.33
While over 70 cases of TTP or TMA in HIV-infected patients have been reported in the literature, many of these lack important clinical data (eg, CD4 cell counts, urinalysis) to adequately compare clinical presentations and outcome. For purposes of our review, we included data from 64 cases, which were fairly complete and consistent in their reporting (Table 2).2,5,6,8,10,16,17,30,32,34-45
Fever, a relatively nonspecific symptom, has been described in over 70% of previously reported cases of HIV-infected patients with TTP. When it is present, it is usually seen concurrently with anemia and thrombocytopenia. This finding can be of limited clinical value, and the absence of fever should not dissuade clinicians from considering the diagnosis of TTP.
Neurologic dysfunction in HIV-related TTP also exists on a spectrum with presentations varying from mild headache to focal neurologic deficits, seizures, or coma.4,6-8 Over 90% of reported cases demonstrated some form of neurologic symptom. Our series reflects this array of symptoms, with patients experiencing symptoms from mild headache to psychosis and seizures that may fluctuate in severity.
Thrombocytopenia was present in virtually all previously reported cases, with platelet counts ranging from 3000 to 90,000/mm3 (mean 28,400 ± 28,439/mm3). Despite severe thrombocytopenia in some cases, hemorrhage is very infrequent and when seen has often been attributed to recent drug-induced effects on platelets from the use of aspirin or nonsteroidal anti-inflammatory agents.2,8 Often these patients did not have the lowest platelet counts. Two of our patients demonstrated bleeding, one from IV sites in a patient with refractory TTP, and one with epistaxis, who used intranasal cocaine.
Classically, peripheral blood smears reveal schistocytes indicative of microangiopathic hemolytic anemia (MAHA). In some cases, patients may have over 70% of their erythrocytes fragmented in this manner. Occasionally, the peripheral smear will be less dramatic, with few fragmented red blood cells noted. This finding may be extremely important for the clinician, as lack of classic and an impressive degree of schistocytosis may delay the important initiation of therapy.
Like other aspects of TTP, renal dysfunction exists on a spectrum, which can include anything from an abnormal urinalysis to renal failure. Generally, most patients had an increase in serum creatinine with a mean reported in reviewed cases of 2.4 ± 2.2 mg/dL. In cases where urinalyses were reported, over 65% had abnormalities; most commonly, hematuria and proteinuria were noted. In some cases, serum creatinine was only modestly elevated, including 3 of our cases, but urinalysis demonstrated significant abnormalities.
Elevations of serum LDH, which is indicative of hemolysis, is another well-described finding seen in all patients with TTP. Levels may be extremely high, although the degree of elevation of LDH does not appear to correlate with disease severity or outcome in the HIV-infected patient with TTP.2,6,8 In addition, serum LDH is frequently used as a marker of response to therapy, particularly with the use of plasma exchange therapy.
HIV-related ITP versus HIV-related TMA
It is of paramount importance that a clinician caring for HIV-infected patients be able to clearly distinguish between HIV-related ITP and TMA. Because HIV-associated TMA occurs in a cohort of patients with a higher incidence of immune thrombocytopenia, the thrombocytopenia may incorrectly be attributed to ITP and the laboratory and clinical features of TMA may be overlooked, hence the diagnosis never considered.2,3 Fever, MAHA, neurologic symptoms, or renal failure are not present in ITP. HIV-related ITP is a generally benign condition caused by the binding of immune complexes and/or antiplatelet antibodies to the platelet.46 There usually is an improvement in thrombocytopenia with the use of antiretroviral agents.3 The observation that patients may have HIV-related ITP either before or after the diagnosis of TMA raises the possibility that there may be an overlap between the 2 disorders, but this is not supported by the available literature.10
Treatment strategies used for HIV-related TTP or TMA have been extrapolated from the successful treatment of idiopathic TTP in noninfected patients.47,48 Over the years, the mainstays of therapy in the treatment of TTP, regardless of the etiology, has included plasma therapy (exchange, pheresis, or infusion),47-49 antiplatelet agents,50,51 immunosuppressive agents (corticosteroids, vincristine),47,52-54 and splenectomy.55-57 Using these various therapies, Bell et al47 found a 91% survival rate among 108 patients treated appropriately for TTP-HUS. All of these treatment modalities, as well as the implementation of antiretroviral therapy,43 have been useful in the management of HIV-related TTP. The advent of HAART, along with its consequential suppression of viral activity, has likely reduced the risk of TTP among HIV-infected patients, as well as served as indirect therapy for TTP. Unfortunately, this has yet to be demonstrated formally. Interestingly, Case 4 in our series did develop a third episode of TTP after discontinuation of HAART.
The cornerstone of treatment of TTP is plasma therapy.47,48,58 Plasma infusion revolutionized the treatment of TTP in the 1980s, producing a significant decrease in TTP-related mortality and improved survival rates to 85-90%.48,58,59 Since then, a randomized, controlled study demonstrated that plasma exchange is more effective than plasma infusion.48
Plasma exchange has become the standard treatment of HIV-infected patients with TTP or TMA.2,8,48 Most case series of HIV-associated TTP have successfully used plasma exchange as the primary treatment, with the 2 largest series demonstrating the efficacy of this approach.2,8 Rarick et al8 found that 13 of 14 patients who received plasma exchange therapy had a complete response, compared with 4 patients who failed to respond to other therapies, including steroids, plasma infusion, and RBC infusions. Hymes and Karpatkin2 reported similar results with plasma exchange providing excellent response rates compared with the other available therapies. These series also demonstrated that rapid diagnosis and initiation of therapy were important and influenced survival. Similarly, in other cases reviewed where treatment and outcome data were reported, there appeared to be an 80% response rate when plasma exchange was instituted and an average survival of 1 year.
It appears that patients who develop neurologic symptoms as part of their symptom complex of TMA are more likely to have classic TTP and are more responsive to plasma exchange therapy.11,45 In contrast, one study of drug-induced TMA-like syndrome associated with valacyclovir had less severe thrombocytopenia, less frequent neurologic symptoms, and a lower response rate to plasma therapy.11
The other previously mentioned modalities have been used in refractory cases or as adjunctive therapy to the plasma exchange.
In general, the retrospective reviews of the literature report a poor prognosis for patients with HIV-related TTP or TMA with few patients surviving longer than 24 months even with therapy.6,8,18,60 In patients who did not receive therapy, survival was generally less than 60 days.
However, the literature, as well as our case series, supports that outcome and survival after HIV-related TTP or TMA may be related to the stage of HIV infection and the severity of immunosuppression at the time of diagnosis, rather than to the diagnosis of TTP.2,11,19 The duration of response to therapy also appears to depend on the CD4 cell count at the time of illness. In reviewed cases where CD4 cell counts were reported, patients with CD4 cell counts greater than 100 cells/mm3 had a mean survival of 2 years, while those patients with CD4 cell counts of less than 100 cells/mm3 had a mean survival of 6 months.
Two of our patients, who had higher CD4 cell counts and no AIDS-defining illnesses at the time of their TTP episodes, are alive and well at 4 and 7 years, respectively, after their last episode of TTP. In addition, one of these patients has had 2 additional episodes at 2 and 5 years after his initial episode and once again responded quickly to plasma exchange. The sustained response may, in part, be due to the aggressive management of his HIV infection with HAART as evident by this third episode that occurred after interruption of therapy.
Although the diagnosis may be elusive at times, it is imperative that physicians caring for HIV-infected patients be aware of the increasingly frequent reports of illness consistent with TMA or TTP. Early diagnosis and appropriate therapy with plasma exchange therapy may be lifesaving and provide significant benefits. However, overall prognosis in patients who have advanced HIV disease when they develop TMA or TTP is poor. Treatment of any underlying conditions that may have precipitated TMA should also be undertaken. Aggressive therapy for HIV disease to lessen the degree of immunosuppression, as well as implementation of prophylaxis for opportunistic infections, is probably helpful. The effect HAART will have on the incidence of TMA in HIV-infected patients remains to be seen, but will probably be significant.
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