Primary Thrombotic Microangiopathy Research Articles

Thrombotic Microangiopathy in Solid Organ Transplantation

Thrombotic Microangiopathy (TMA) is a syndrome characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. The presence of schistocytes on peripheral smear, a negative Coombs test, elevated lactate dehydrogenase, increased reticulocyte count and low haptoglobin are often the clues for MAHA. The microvascular process often targets vasculature in kidneys, brain, gastrointestinal system, heart, and skin. A timely diagnosis and treatment are often crucial to prevent severe end organ damage and death. TMA is classified into primary and secondary forms. Primary TMA includes TTP and complement mediated or atypical hemolytic uremic syndrome (aHUS), often related to a mutation or deficiency and clinically expressed in the setting of a precipitant condition. Secondary TMA is a manifestation of underlying disorder and can occur in clinical scenarios associated with autoimmune disease, malignancy, infections, SOT (Solid Organ Transplant), pregnancy, HSCT (Hematopoietic Stem Cell Transplantation), medications, or methylmalonic acidemia. Transplant associated TMA (TA-TMA) can be complement mediated or aHUS and could be related to the ischemic reperfusion injury, induction regimen, calcineurin inhibitor (CNI) use, mammalian target of rapamycin (MTOR) inhibitor use, or could be infection related. Cost, access, and turnaround time are often the limitations for certain TTP and complement specific testing. Treatment should not be delayed while waiting for such tests. Treatment must be individualized based on the underlying cause of TMA. Terminal complement blockade utilizing monoclonal antibodies directed against C5 complement is the treatment for complement mediated TMA. C5 inhibitors have also been used successfully in treatment of secondary HUS cases where, unlike aHUS, defects in complement cannot be demonstrated. Such treatment has demonstrated improvement in renal function, MAHA and platelet counts.

Utility of Different Scoring Systems for the Diagnosis of Thrombotic Microangiopathies.

To investigate the appropriateness of Bentley and plasmic scores and ADAMTS-13 activity to distinguish between primary thrombotic microangiopathies (TMA) syndromes and other thrombotic microangiopathies, as well as primary thrombotic microangiopathies (TTP, complement-related TMA, etc). Descriptive study. Place and Duration of the Study: Department of Hematology, Faculty of Medicine, from February 2013 to February 2020. Data of patients with non-immune hemolytic anaemia (MAHA) and thrombocytopenia who had ADAMTS-13 test, were analysed. Clinical and laboratory findings, Bentley and plasmic scores, and ADAMTS activity levels were compared. The patients were grouped as primary (n = 27) and secondary (n = 28) TMA, the age was median 38.0 (18-63) years in the primary TMA group and 49.5 (20-84) years in the secondary TMA group. Neurological findings were less in the secondary TMA group (p = 0.008). Plasmic score, lactate dehydrogenase, and total and indirect bilirubin levels were high and D-dimer levels were low in the primary TMA group. In the primary TMA group, a greater number of patients with high plasmic scores were found, whereas all patients in the secondary TMA group had low risk according to Bentley score. Calcium levels were high and platelet levels were low in those with ADAMTS activity level <10% (p = 0.006). The evaluation of primary TMAs demonstrated significant differences in platelet, urea, creatinine, and sodium values between the two groups. Laboratory data and clinical scores are valuable in differentiating primary and other TMA. Bentley score, Complement, Plasmic score, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura, ADAMTS-13.

Chemotherapy-Associated Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.

JS-NG-5: THROMBOTIC MICROANGIOPATHY OR MALIGNANT HYPERTENSION: WHICH COMES FIRST? A CASE REPORT FROM A TERTIARY CARE HOSPITAL

A 66-year-old woman with a history of arterial hypertension was admitted to the emergency department (ED) due to disorientation. She reported a severe headache, nausea, vomiting in the evening prior the admission; her blood pressure (BP) when the ambulance arrived was 220/100 mmHg. During admission, BP was 158/91 mmHg, pulse 95 beats/minute, oxygen saturation 88% on room air, body temperature 36.6°C. The urine examination showed that urine protein was 3+, red blood cell count 10 mg/L. The whole blood cell analysis revealed neutrophilic leukocytosis, thrombocytopenia (Table). There was 1 schistocyte seen in the peripheral blood smear. The serum creatinine and urea values were raised (Table) with elevated level of D-dimers (1690 mcg/L (&lt; 250 mcg/L)). Head CT showed no signs of hemorrhage or ischemia. Ceftriaxone, ampicillin, and acyclovir were initiated for suspected neuro-infection, she also underwent transfusion with 4 units of platelets due to thrombocytopenia. Patients GCS fell from 11 to 9 over 13 hours, therefore she was transferred to the intensive care unit (ICU). Cerebrospinal fluid analysis showed cytosis 15 cells/mcL (predominance of lymphocytes) and protein level of 1,073 g/L; PCR panel for the most common bacterial and viral meningitis agents came back negative. On day 2, lactate dehydrogenase level was raised at 3086 U/L (125–243 U/L), haptoglobin was &lt; 0.08 g/L (0.3–2.0 g/L) and Coombs test was negative. Due to worsening renal function (Table) hemodialysis was initiated. The differential diagnosis included thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome (HUS), secondary thrombotic microangiopathy (TMA), immune thrombocytopenic purpura (ITP) and disseminated intravascular coagulation (DIC). ADAMTS-13, CH50, SC5b-9 levels were tested (0.53 TV/ml (0.40–1.50 TV/ml), 60 U Eq/ml (55–75 U Eq/ml), 4689 ng/ml (200–325 ng/ml), respectively). The patient started on plasmapheresis. On day 3, fundoscopy showed cotton wool spots (ischemia) with hemorrhages and soft exudates next to the optic nerve disc; intravenous methylprednisolone pulse therapy was administered (1 g daily for three days followed by oral methylprednisolone 32 mg daily). Renal biopsy on day 5 revealed active TMA damaging the glomeruli and acute tubular necrosis. After 15 days in the ICU, she remained hypertensive and anuric despite given treatment. Moreover, pulmonary edema occurred on day 15. Malignant hypertension (MH) is characterized by severe hypertension and multi-organ ischemic complications. It can cause TMA and the overall presentation may imitate primary TMA. The approach of renal TMA in MH remains challenging. Herein, we reported a case of MHT with biopsy-proven TMA in the kidney.

CME: Notfallmanagement der thrombotischen Mikroangiopathie

CME: Diagnostic Approach and Management of Thrombotic Microangiopathy Abstract. Thrombotic microangiopathies (TMA) are characterized by organ thrombosis induced by endothelial injury. They present with thrombocytopenia, hemolytic anemia and schistocytes. In case of an underlying disease-causing TMA, the treatment of the underlying disease is essential. Primary TMAs are divided into thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome and atypical hemolytic-uremic syndrome. Differentiation of these entities is essential, as fast initiation of empiric treatment might be life-saving and disease-modifying treatments for the different entities do exist.

Platelet‐activating immune complexes identified in critically ill COVID‐19 patients suspected of heparin‐induced thrombocytopenia

BackgroundThrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID‐19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID‐19 patients may be suspected of heparin‐induced thrombocytopenia (HIT), given similar clinical features. ObjectivesWe investigated the presence of platelet‐activating anti‐platelet‐factor 4 (PF4)/heparin antibodies in critically ill COVID‐19 patients suspected of HIT. Patients/MethodsWe tested 10 critically ill COVID‐19 patients suspected of HIT for anti‐PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti‐human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS‐CoV‐2 antibodies were measured using an in‐house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin‐13 Domain (ADAMTS13) activity and the presence of anti‐ADAMTS13 antibodies. ResultsHeparin‐induced thrombocytopenia was excluded in all samples based on anti‐PF4/heparin antibody and SRA results. Notably, six COVID‐19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)‐mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS‐CoV‐2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID‐19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy. ConclusionsOur study identifies platelet‐activating ICs as a novel mechanism that contributes to critically ill COVID‐19.

Retrospective and Systematic Analysis of Causes and Outcomes of Thrombotic Microangiopathies in Routine Clinical Practice: An 11-Year Study.

Background: Thrombotic microangiopathies (TMAs) are highly suspected in patients showing mechanical hemolytic anemia, thrombocytopenia, and haptoglobin consumption. Primary [thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome] and secondary TMA are considered. Even if ADAMTS13 measurements and alternative complement pathway explorations have greatly improved the ability to identify primary TMA, their diagnosis remains difficult, and their frequency relative to that of secondary TMA is undetermined. The objectives of the present study were, therefore, to describe the etiologies, management, and the outcomes of patients presenting with TMA in real-life clinical practice.Methods: We conducted a retrospective study between 01/01/2008 and 31/12/2018 that included all consecutive patients presenting with biological TMA syndrome at admission or developing during hospitalization. Patients were identified from the laboratory databases, and their medical files were reviewed to confirm TMA diagnosis, to determine etiology, and to analyze their therapeutic management and outcomes.Results: During this period, 239 patients with a full TMA biological syndrome were identified, and the TMA diagnosis was finally confirmed in 216 (90.4%) after the cases were reviewed. Primary TMAs (thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome) were diagnosed in 20 of 216 patients (9.3%). Typical HUS was diagnosed in eight patients (3.7%), and the most frequent secondary TMAs were HELLP syndrome (79/216, 36.6%) and active malignancies (30/219, 13.9%). ADAMTS13 measurements and alternative complement pathway analyses were performed in a minority of patients. Multiple factors identified as TMA triggers were present in most patients, in 55% of patients with primary TMA, vs. 44.7% of patients with secondary TMA (p = 0.377). Death occurred in 57 patients (23.4%) during follow-up, and dialysis was required in 51 patients (23.6%). Active malignancies [odds ratio (OR) 13.7], transplantation (OR 4.43), male sex (OR 2.89), and older age (OR 1.07) were significantly associated with death.Conclusion: Secondary TMAs represent many TMA causes in patients presenting a full TMA biological syndrome during routine clinical practice. Multiple factors favoring TMA are present in about half of primary or secondary TMA. ADAMTS13 and complement pathway were poorly explored in our cohort. The risk of death is particularly high in patients with malignancies as compared with patients with other TMA.

Thrombotic microangiopathies: First report of 294 cases from a single institution experience in Argentina.

IntroductionIntroduction: Thrombotic microangiopathies (TMAs) are rare disorders associated with fatal outcomes if left uncared for. However, healthcare problems in developing countries tend to limit medical assistance to patients.MethodsMethods: We prospectively studied an Argentine cohort of 294 consecutive patients from 2013 to 2016. Patients’ subcategory classification relied on clinical symptoms and presence or absence of trigger events associated with TMA.ResultsMain suspected disorders were the primary TMAs known as thrombotic thrombocytopenic purpura (TTP) (n = 72/294, 24%) and atypical haemolytic uraemic syndrome (aHUS) (n = 94/294, 32%). In acute phase, demographic parameters for acquired TTP (aTTP) (n = 28) and aHUS (n = 47) showed that both groups were characterised by a young median age (37 and 25 years, respectively) and female predominance (60% and 86%). Median of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity was significantly lower in aTTP than in aHUS group (1.4% vs 83%) and was associated with a more severe thrombocytopenia (15 × 109 vs 53 × 109/L). Creatinine (Cr) and urea (Ur) were significantly increased in aHUS compared to aTTP subjects (Cr: 3.7 vs 0.7 mg/dL, Ur: 118 vs 33 mg/dL). Gastrointestinal and neurological symptoms were more frequent in aHUS and aTTP, respectively.ConclusionThe first description of a TMA cohort in Argentina revealed similar clinical presentations to those of other countries.

Ocular manifestations of primary thrombotic microangiopathy

The article reviews literature on ocular manifestations of primary thrombotic microangiopathy. Thrombotic microangiopathy is a clinical and morphological syndrome that characterizes a systemic disseminated lesion of the microcirculatory bed, it is a special type of vascular damage that combines thrombosis and inflammation of the vascular wall leading to occlusion of the vessel lumen, causing ischemic damage to various organs and tissues. The classic types of primary thrombotic microangiopathy are thrombotic thrombocytopenic purpura, shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) and atypical hemolytic uremic syndrome. Thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome are characterized by ischemic damage to the visual organ as a result of suspected thrombotic microangiopathy in the microcirculatory bed of the eye. The clinical picture of ocular manifestations of these diseases is similar, however the damage to the eye in the form of ischemic Purtscher-like retinopathy is more characteristic of atypical hemolytic uremic syndrome, which may be due to chronic uncontrolled activation of the alternative complement pathway in this disorder. Timely initiation of systemic therapy of the underlying disease in most cases leads to complete restoration of visual functions. A thorough ophthalmological examination of patients with these diseases is required.

MED-TMA: A clinical decision support tool for differential diagnosis of TMA with enhanced accuracy using an ensemble method

Considering difficulties in on-site ADAMTS13 testing and the performance instability of PLASMIC score according to ethnicity, we developed a prediction tool, MED-TMA (machine learning (ML) method for differential diagnosis (DDx) of thrombotic microangiopathy (TMA)) to support clinical decision. Data from 319 patients visiting 31 hospitals in Korea clinically diagnosed with primary TMA was randomly separated by 2:1 into two groups – the development dataset (D-set, n = 212), the validation dataset (V-set, n = 107). Feature elimination was conducted to select optimal clinical predictors. We developed the model with the selected features using ML methods, verifying using V-set. After the feature elimination using 19 clinical variables, five variables were selected with high importance value. Among nine ML methods, four ML methods were chosen considering the Area Under the Curves (AUC) and the correlation between the methods using D-set. We developed MED-TMA based on an optimized ensemble model with the selected four ML methods resulting in AUC values of 0.945 and 0.924 in D-set and V-set, respectively. In addition to the binary outcome, MED-TMA was capable of providing a probability for DDx of TMA. The ensemble approach driven MED-TMA showed comparable accurate and intuitive decision support for DDx of TMA to that of the existing models based on a single ML method. We provide a web-based nomogram for the appropriate use of effective but costly therapeutics to treat TMA patients (http://hematology.snu.ac.kr/medtma/).

The conundrum of postpartum thrombotic Microangiopathy: case report and considerations for management

BackgroundMicroangiopathic hemolytic anemias and thrombocytopenias in pregnant or postpartum women constitute an interdisciplinary diagnostic and therapeutic challenge in the evaluation of thrombotic microangiopathies (TMA), where urgent care must be considered.Case presentationWe here report the case of a 21-year-old Somali woman, who was delivered by emergency caesarean section at 35 weeks of gestational age with acute dyspnea, placental abruption and gross edema due to severe preeclampsia/HELLP syndrome. After delivery, she developed acute kidney failure and thrombotic microangiopathy as revealed by kidney biopsy. The lack of early response to plasma exchange prompted extensive laboratory workup. Ultimately, the patient completely recovered with negative fluid balance and control of severe hypertension.ConclusionsThis case report emphasizes the importance to differentiate between primary TMA syndromes and microangiopathic hemolytic anemias due to systemic disorders. Delayed recovery from preeclampsia/HELLP syndrome and malignant hypertension can clinically mimic primary TMA syndromes in the postpartum period.

Etiology and Outcomes of Thrombotic Microangiopathies.

Thrombotic microangiopathies constitute a diagnostic and therapeutic challenge. Secondary thrombotic microangiopathies are less characterized than primary thrombotic microangiopathies (thrombotic thrombocytopenic purpura and atypical hemolytic and uremic syndrome). The relative frequencies and outcomes of secondary and primary thrombotic microangiopathies are unknown. We conducted a retrospective study in a four-hospital institution in 564 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period. We estimated the incidence of primary and secondary thrombotic microangiopathies, thrombotic microangiopathy causes, and major outcomes during hospitalization (death, dialysis, major cardiovascular events [acute coronary syndrome and/or acute heart failure], and neurologic complications [stroke, cognitive impairment, or epilepsy]). We identified primary thrombotic microangiopathies in 33 of 564 patients (6%; thrombotic thrombocytopenic purpura: 18 of 564 [3%]; atypical hemolytic and uremic syndrome: 18 of 564 [3%]). Secondary thrombotic microangiopathies were found in 531 of 564 patients (94%). A cause was identified in 500 of 564 (94%): pregnancy (35%; 11 of 1000 pregnancies), malignancies (19%), infections (33%), drugs (26%), transplantations (17%), autoimmune diseases (9%), shiga toxin due to Escherichia coli (6%), and malignant hypertension (4%). In the 31 of 531 patients (6%) with other secondary thrombotic microangiopathies, 23% of patients had sickle cell disease, 10% had glucose-6-phosphate dehydrogenase deficiency, and 44% had folate deficiency. Multiple causes of thrombotic microangiopathies were more frequent in secondary than primary thrombotic microangiopathies (57% versus 19%; P<0.001), and they were mostly infections, drugs, transplantation, and malignancies. Significant differences in clinical and biologic differences were observed among thrombotic microangiopathy causes. During the hospitalization, 84 of 564 patients (15%) were treated with dialysis, 64 of 564 patients (11%) experienced major cardiovascular events, and 25 of 564 patients (4%) had neurologic complications; 58 of 564 patients (10%) died, but the rates of complications and death varied widely by the cause of thrombotic microangiopathies. Secondary thrombotic microangiopathies represent the majority of thrombotic microangiopathies. Multiple thrombotic microangiopathies causes are present in one half of secondary thrombotic microangiopathies. The risks of dialysis, neurologic and cardiac complications, and death vary by the cause of thrombotic microangiopathies.

What the Internist Should Know about Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is a group of diseases that are life-threatening and can lead to end organ damage (EOD) due to ischemia caused by microthrombi in capillaries and arterioles. TMAs can affect any organ system but usually affect the kidney, intestines, and nervous system. The triad of TMA is Coombs-negative hemolytic anemia with schistocytes seen on peripheral smear, thrombocytopenia (platelets under 150,000 or a decrease of 25% or more from baseline), and evidence of ischemic EOD. Primary TMAs include Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and atypical HUS (aHUS). Pathophysiologically, all of these diseases are caused by aggregation of von Willebrand Factor (vWF) multimers, via different mechanisms, which eventually leads to thrombus formation. TTP and aHUS benefit from plasma exchange (PEX), whereas HUS is treated symptomatically. Urgent recognition with timely treatment is crucial to managing these potentially life-threatening conditions.

Acute Kidney Injury in Cancer Patients.

Renal complications are a relevant clinical issue in patients with cancer; conversely, cancer in patients affected by kidney diseases is a growing problem mainly due to the aging of the general population. Onco-Nephrology is a novel subspecialty addressing these issues. Acute kidney injury (AKI) is an important cause of morbidity and mortality in cancer patients, and recognizes a number of different causes, which can impact, directly and indirectly, on kidney function. Furthermore, the appearance of AKI may have a tremendously negative impact on oncological treatments, often denying cancer patients active and life-prolonging treatments. Overall, patients with cancer are at risk of AKI, which could be caused by antineoplastic treatments, sepsis, metabolic disturbances, hematopoietic stem cell transplantation, primary thrombotic micro-angiopathies, and direct involvement of the kidney by hematological malignancies and also by solid cancer, in particular kidney and urothelial malignancies. Key Messages: (1) AKI is a frequent and increasing complication of cancer. (2) There is a bidirectional relationship between cancer and kidney disease, and in both cases, AKI is more likely to happen. (3) AKI in patients with cancer is associated with increased morbidity and mortality. (4) In cancer patients, a multidisciplinary approach and early intervention may reduce the incidence of AKI and its life-threatening consequences. (5) Onco-Nephrology is a growing area of nephrology that requires clinicians to have a better understanding of the renal complications of cancer including AKI.

Clinical dissection of thrombotic microangiopathy.

Differential treatment strategies are applied in thrombotic microangiopathy (TMA) according to the sub-classifications. Hence, it is worthwhile to overview clinical manifestations and outcomes of overall TMA patients according to sub-classifications. We analyzed TMA patients whose serum lactate dehydrogenase levels >250IU/L, with the presence of schistocytes in their peripheral blood smear, or with typical vascular pathologic abnormalities in their renal biopsy. We compared clinical manifestations including overall survival (OS) and renal survival according to TMA causes. A total of 117 TMA patients (57 primary and 60 secondary TMA) were analyzed. Renal symptom was the most common manifestation in whole patients, while renal function at diagnosis was worst in pregnancy-related TMA group. Primary TMA patients had more frequent CNS symptom and hematologic manifestation compared to secondary TMAs. Among secondary TMAs, pregnancy- and HSCT-related TMA patients showed prevalent hemolytic features. During 150.2months of follow-up, 5-year OS rate was 64.8%. Poor prognostic factors included older age, combined hematologic and solid organ malignancies, lower hemoglobin levels, and lower serum albumin levels. There was no significant difference in OS between primary and secondary TMAs. Seventy-eight percent of patients experienced AKI during TMA. Five-year death-censored renal survival rate was poor with only 69.2%. However, excellent renal outcome was observed in pregnancy-associated TMA. TMA showed various clinical manifestations according to their etiology. Notably, both OS and renal survival were poor regardless of their etiologies except pregnancy-associated TMA. Physicians should differentiate a variety of TMA categories and properly manage this complex disease entity.

Plasma exchange therapy in sepsis

Sepsis is a systemic inflammatory syndrome in response to an infection. With the current resuscitation practice, up to 16% of children with severe sepsis and septic shock still progress to develop multiple organ failure (MOF), a condition that is associated with poor outcome. In this review, we focus on the thrombotic microangiopathic paradigm for the development of sepsis-induced MOF. We describe the clinical observations, emerging experimental and laboratory evidence supporting the concept that sepsis-induced MOF may be a secondary thrombotic microangiopathy, manifest as thrombocytopenia-associated MOF. Drawing the pathologic similarities such as a disintegrin and metalloprotease with thrombospondin motifs-13 deficiency, impaired ultra-large von Willebrand factor multimers proteolysis, and von Willebrand factor-rich microthrombi and therapeutic success with plasma exchange in treating thrombotic thrombocytopenic purpura, a primary thrombotic microangiopathy, we propose a rationale for the role of plasma exchange therapy for sepsis and thrombocytopenia-associated multiple organ failure.

VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP.

Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e. g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognised, but its therapeutic implications have not yet been determined. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. In conclusion, prospective clinical trials on the effectiveness of protease replacementin vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP.

Characteristics of Primary Thrombotic Microangiopathy in Patients with and without Human Immunodeficiency Virus: Thirteen Year Experience at the University of Maryland

Background: Thrombotic microangiopathy (TMA) is a syndrome characterized by thrombocytopenia and microangiopathic hemolytic anemia. TMAs can be primary or secondary to variety of clinical conditions: pregnancy, malignancy, autoimmune diseases and medications. Human immunodeficiency virus (HIV) infection is associated with thrombotic thrombocytopenic purpura (TTP), although the pathophysiology and clinical presentation has not been well-defined.Methods: In an urban center with a 3% prevalence of HIV infection, we retrospectively reviewed the charts of patients who underwent therapeutic plasma exchange (TPE) for TTP from January 2000 to December 2013 after IRB approval. The aim of our study is to describe and analyze the clinical differences seen in primary TMA with or without HIV infection. Differences of laboratory data between the 2 groups were assessed using the t -test.Results: Of 188 patients requiring TPE over 13 years at our urban tertiary medical center, 31 (17%) were HIV-positive and 154 (83%) were HIV negative. HIV-positive patients had median age of 43 years (range, 26-65), 30 (96%) black, 23 (74%) female, 23 (74%) with primary TMA. HIV-negative patients had a median age of 46 years (range, 16-82) 92 (59%) black and 104 (66%) female, 54 (35%) with primary TMA. Fifteen of 31 HIV-positive patients (48%) presented with comorbid infections caused by bacterial, viral, fungal and opportunistic organisms, whereas only 29 of the 157 (18%) HIV-negative patients presented with concomitant infection.The following comparisons were made between HIV-positive (n=23) and negative (n=54) patients with primary TMA. Laboratory data revealed that hemoglobin was lower (mean Hb: 7.0 vs 8.1 g/dL, P=0.03) and renal failure was more severe (mean creatinine 2.3 vs 1.6, P=0.04) in HIV-positive patients compared with HIV-negative. There was no statistically difference between 2 groups in LDH and platelet counts. ADAMTS13 level was available in 6/23 HIV positive and 18/54 HIV-negative primary TMA patients. The level <10% was seen in 11 HIV-negative patients. ADAMTS13 level of HIV-positive patients ranged from 14 to 74 (Sample collection was delayed in 3/6 patients). All HIV-positive cases showed immunosuppression, with a mean CD4 count of 124 cells/ µL, ranging from 2 to 444 cells/ µL. Regarding treatment, HIV-negative patients required an average of 23% more TPE sessions (18 vs. 15) than HIV-positive patients. Steroids, intravenous immune gamma-globulin and rituximab were used in both groups. Mortality and complications were similar in both groups.Discussion: The frequency of 1 in 5 patients with TMA also having HIV at the University of Maryland is one of the highest frequencies reported in the literature outside of South Africa. Our study suggests that HIV-positive patients might have a thrombotic microangiopathy triggered by an infection more commonly than patients without HIV. The absence of ADAMTS13 deficiency was notable in our HIV-positive patients. However, delayed sample collection in 3/6 patients might limit the significance of this data. The etiology of TMA in HIV infection remains unclear. Prior studies have suggested that a HIV-specific mechanism such as B cell dysregulation as a result of T cell depletion; cytokine production and HIV infection of endothelial cells play a role. The limited number of patients seen individual centers precludes controlled clinical trials to study the efficacy of treatment for this serious disease. Future prospective collaborative research studies are needed to expand our knowledge of TMA in HIV-positive populations. DisclosuresNo relevant conflicts of interest to declare.