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Year : 2022  |  Volume : 65  |  Issue : 4  |  Page : 898-901
Three shades of black - secondary thrombotic microangiopathy

1 Department of Pathology, IPGME&R and SSKM Hospital, Kolkata, West Bengal, India
2 Nephrology, IPGME&R and SSKM Hospital, Kolkata, West Bengal, India

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Date of Submission21-Dec-2021
Date of Decision16-Feb-2022
Date of Acceptance18-Feb-2022
Date of Web Publication21-Oct-2022


Thrombotic microangiopathy is a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ damage. Wide age distribution and the heterogeneity in presentation demand a deeper understanding into the pathogenesis of TMA. Primary TMA is distinct from TMA associated with secondary causes and remains clinically occult till a precipitating factor aggravates it. The extent and severity of renal damage caused by each of them is also distinct. The first alerting signal could be the presence of schistiocytes on peripheral smear and arteriolar thrombi on light microscopy. Thus in secondary TMA, identification of the underlying disorder is indispensible for targeted management.

Keywords: Light microscopy, secondary, thrombotic Microangiopathy

How to cite this article:
Das R, Dasgupta S, Sengupta M, Basu K. Three shades of black - secondary thrombotic microangiopathy. Indian J Pathol Microbiol 2022;65:898-901

How to cite this URL:
Das R, Dasgupta S, Sengupta M, Basu K. Three shades of black - secondary thrombotic microangiopathy. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Dec 7];65:898-901. Available from:

   Introduction Top

Thrombotic microangiopathy (TMA) is clinically defined by a constellation of the features of microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction.[1] Glomerular capillary bed and endothelial cells are the site of injury and exhibits myriad histopathological findings depending on active or chronic lesion. Classification of TMA is ever changing and depending on etiology, it is further subclassified into (i) inherited or acquired primary TMA and (ii) infection associated or secondary TMA.[2] Worldwide the secondary causes outnumber the primary causes and 53% has multiple causes.[3] Light microscopic features are nonspecific, although may suggest etiology. Immunofluorescence has a limited role unless there is coexistent immune complex glomerulonephritis or C3 glomerulonephritis (C3GN). Here we take the opportunity to share our experience during routine renal biopsy reporting.

   Case Details Top

Case I

A 28-year-old nonhypertensive, nondiabetic female delivered her first full-term baby. She was previously healthy. On the day of delivery, her blood pressure was 140/90 mmHg. She was suffering from nausea, headache, and abdominal pain. Blood pressure had risen to 180/110 mm Hg after delivery. Routine hematological investigations revealed Hb of 9.2 g/dL and 1.2 lakh/mm3 platelets. Peripheral blood smear showed the presence of schistiocytes. Serum lactate dehydrogenase was 2500 U/L. Serum creatinine was 3.8 mg/dL. Urine examination showed subnephrotic range proteinuria and active sediment. Despite antihypertensive medication, there was worsening renal function. Renal biopsy was performed at that point. Both light and immunofluorescence microscopy examinations were performed.

Total 13 glomeruli were identified. All revealed mild mesangial hypercellularity. Glomerular paralysis with intracapillary abundant erythrocytes was noted in one glomerulus. Unequivocal evidence of any endocapillary or extracapillary proliferation or neutrophilic infiltration or fibrinoid necrosis was lacking. Glomerular basement membrane was unremarkable in Jones methenamine silver (JMS) stain. Mild acute tubular injury was noted. Arteriolar onion skinning was noted. One hilar vessel showed the presence of thrombi within. Interstitial fibrosis and tubular atrophy were minimal. Immunofluorescence showed trace mesangial IgG and IgM, C3c, C1q, and kappa and lambda deposition [Figure 1]. A final diagnosis of acute TMA was made. The patient had undergone plasma exchange therapy and serum creatinine gradually declined.
Figure 1: (a) The dilated infundibular area is occluded by a thrombus. (Silver methenamine stain; original magnification 100×) [Arrow] (b) Glomerular capillary lumina are occluded by fibrin thrombi; the rest of the capillaries are congested. (Masson trichrome stain; original magnification 100×)

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Case II

A 48-year-old known hypertensive male patient presented at emergency with chief complaints of nausea, dizziness, and epistaxis. On admission, his blood pressure was 180/110 mmHg. He had hemoglobin of 9.0 g/dL and with the presence of schistocytes in peripheral blood smear and thrombocytopenia. Serum creatinine was 4.2 mg/dL and increased to 6.9 mg/dL after admission [Figure 2]. He had undergone hemodialysis and renal biopsy was performed after that. Two cores were obtained and send in formalin and normal saline, respectively.
Figure 2: (a) Small interlobular artery shows edematous intima containing few myointimal cells (“mucoid intimal hyperplasia”). (Silver methenamine stain; original magnification 100×) [Arrow] (b) Focal reduplication of the glomerular capillary basement membranes. (Silver methenamine stain; original magnification 100×)

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Light microscopy revealed 21 glomeruli among which 2 were globally and 2 were segmentally sclerosed. The nonsclerosed glomeruli (19) and tufts showed diffuse and global both mesangial matrix expansion and hypercellularity. Two glomeruli showed cellular crescents (one circumferential and one segmental). Unequivocal evidence of any endocapillary hypercellularity or neutrophilic infiltration or fibrinoid necrosis was lacking. Glomerular basement membrane showed double contouring in JMS stain. Tubules showed mild atrophy. Interstitium showed mild fibrosis with focal lymphoplasmacytic infiltrate. Arterioles showed mucoid intimal changes. Hilar vessel of one glomerulus revealed intraluminal thrombus. Interstitial fibrosis and tubular atrophy was 20%. Immunofluorescence was noncontributory except nonspecific entrapment of IgM and c3c in sclerosed glomerulus. A final diagnosis of acute on chronic TMA was made. Antihypertensive was administered and the patient showed gradual improvement.

Case III

An 18-year-old female without prior history of diabetes mellitus or hypertension presented with a history of mild-to-moderate grade fever along with symmetrical small joint polyarthralgia for the last 3 months. The patient also had a history of bipedal edema, frothy urine, generalized weakness, and alopecia for the last one and half month. Urine examination showed proteinuria of 1.1 g/day and hematuria. Other laboratory investigations suggested anemia of chronic disease (Hb 7.4 g/dL), serum creatinine 0.6 mg/dL, high inflammatory markers, low C3 and C4, borderline positive dsDNA, and 2+ homogenous antinuclear antibody (ANA). Hence, a renal biopsy was performed.

Light microscopy showed 11 glomeruli among which one revealed segmental sclerosis with adhesion. Rest (10) and the nonsclerosed tuft revealed mild mesangial hypercellularity along with variable number of intracapillary neutrophils. Glomerular basement membrane revealed ischemic wrinkling. Unequivocal evidence of any endocapillary or extracapillary hypercellularity or fibrinoid necrosis was lacking. Tubulointerstitial compartment showed mild perivascular chronicity. Intraluminal patchy organized thrombus was noted within arterial lumen. A final diagnosis of thrombotic microangiopathy was made. Direct immunofluorescence revealed full house mesangial (IgG, IgM, IgA, C3c, C1q, kappa, and lambda) immune complex deposition [Figure 3]. On further investigation, both lupus anticoagulant and anticardiolipin antibody of IgG type were detected. The patient was managed with the treatment of systemic lupus erythematous and with anticoagulation.
Figure 3: (a) An interlobular artery contains fresh and recanalized thrombus. (Silver methenamine stain; original magnification 100×) (b) An interlobular artery contains fresh and recanalized thrombus. (Masson trichrome stain; original magnification 100×)

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   Discussion Top

TMA is a microocclusive disorder with variable clinical manifestations ranging from clinically silent states to life-threatening catastrophic TMA.[4] Endothelial cell damage is the telltale feature and the consequent microvascular ischemia resulting from red blood cells fragmentation, platelet aggregation, and thrombus formation plays a significant role.[5] Diagnosis is initiated by the identification of clinical triad of thrombocytopenia, microangiopathic hemolytic anemia, and various signs and symptoms of organ ischemia.[5] Confirmatory diagnosis is only established with a tissue biopsy.

TMA is broadly classified as primary and secondary TMA. Primary TMA occurs when there is a genetic defect: atypical hemolytic uremic syndrome (aHUS) with complement gene mutations; thrombotic thrombocytopenic purpura (TTP) with ADAMTS13 mutations; Cobalamin C deficiency–mediated TMA; diaycylglycerol kinase e (DGKE) TMA or acquired abnormality: TTP with ADAMTS13 autoantibody and aHUS with complement factor H (CFH) autoantibodies. Secondary TMA occurs when other disease states cause a paradoxical activation of the complement proteins. The causes are varied ranging from infection, autoimmune diseases, malignancy, transplantation, malignant hypertension pregnancy or drugs.[6] However, there is a considerable overlap between the two types and secondary TMA outnumbers the primary. This necessitates recognition of the correct etiology as treatment is directed against the underlying cause. Successful management of secondary TMA has a huge impact on the prognosis of the patient.

TMA in pregnancy can be in the form of primary TMAs, namely, complement-mediated aHUS and TTP, or associated with secondary causes like eclampsia, preeclampsia, and hemolysis, elevated liver enzyme, and low platelet count (HELLP) syndrome, which represents a continuous spectrum. HELLP has an incidence of 0.2% to 0.8% of all pregnancies.[7] Disseminated intravascular coagulation (DIC) and deranged liver enzymes are classically associated with HELLP syndrome. It is caused due to excess syncytiotrophoblast derived proteins (e.g., the soluble form of the protein FMS-like tyrosine kinase 1 [sFlt1] and soluble endoglin, which are endothelial vascular receptors growth factor and transforming growth factor). They being anti angiogenic cause endothelial dysfunction. Our first case represented the secondary spectrum of TMA in pregnancy and was treated with plasma exchange after prompt delivery of the fetus.

Malignant hypertension is a clinical syndrome characterized by severe hypertension and organ damage, including progressive renal failure, heart failure, and encephalopathy, and often associated with microangiopathic hemolytic anemia. One-third of patients with malignant hypertension may present with TMA, of which complement abnormalities are found in 35% to 65%. Renin-angiotensin-aldosterone system (RAAS) activation causes vasoconstriction. To compensate this, there is paradoxical secretion of vasodilators like nitric oxide by the endothelial cells. However, angiotensin II predominates and releases various proinflammatory cytokines causing endothelial injury and coagulation cascade activation. This can occur as TTP/HUS or can present as secondary TMA.[8] Primary TTP usually presents with severe thrombocytopenia and undetectable levels of ADAMTS13. However, in secondary TMA, only mild-to-moderate thrombocytopenia is seen. Yet confirmation can only be arrived after ADAMTS13 level measurement. However, in a resource-limited setting as ours, testing for ADAMTS is not feasible. A multiparametric scoring system has been formulated in view of this limitation known as the PLASMIC score.[9] PLASMIC score is calculated based on seven variables: platelets, hemolysis, cancer, transplant, MCV, INR, and creatinine. A score of equal to or greater than 6 is diagnostic for TTP and demands plasma exchange.[10] In our case, the score was 5 and antihypertensive was administered.

The vascular lesions of lupus nephritis can present as TMA in three forms.[11] Of these, secondary TMA due to antiphospholipid antibodies (aPLs) may have a double hit pathogenesis. First, aPLs can regulate clotting and fibrinolytic pathways by interacting with proteins. Also, aPLs inhibit natural anticoagulants like antithrombin 3, protein C, and annexin A5. They also prevent fibrinolysis. Next, they activate endothelial cells, platelets, and monocytes through the interaction with membrane-bound proteins and receptors via NF-jB and mitogen-activated protein kinases (MAPKs) pathway. A disintegrin-like and metalloproteinase with a thrombospondin type 1 motif 13 (ADAMTS-13), which has powerful and natural anti-thrombotic activity, was confirmed to contribute to renal TMA in lupus nephritis.[12] Lupus vasculopathy with immune complex deposition responded to immunosuppressive therapy with plasmapheresis. However, secondary TMA due to aPLs had to be immediately put on anticoagulation and managed accordingly.[13] Immediate initiation of anticoagulation therapy showed dramatic response in our case.

The pathological hallmark of TMA is arteriolar and capillary thrombus formation. The light microscopic findings are nonspecific like fibrinoid necrosis, intimal and subintimal fibrin deposition along with fragmented RBCs, thrombosis, and endothelial cell proliferation. However, some findings may point to etiology. The presence of fibrin-rich glomerular thrombi suggests HUS. Similarly, the presence of platelet-rich thrombi and glomeruloid body exhibiting active angiogenesis characterized by proliferation of capillary-sized vascular bed lined by plump endothelial cells suggest TTP. Again malignant hypertension and systemic sclerosis show the presence of arterial thrombi, while endotheliosis is seen in preeclampsia. Lastly organized thrombus with focal cortical atrophy indicates underlying antiphospholipid syndrome (APLS). The role of immunofluorescence microscopy is very limited. It helps us to identify background glomerular diseases like lupus nephritis and C3GN.

Pregnancy-associated TMAs due to aHUS have a dismal prognosis. They show incomplete penetrance with infection as the most common trigger. The majority shows poor prognosis with the development of end-stage renal disease. Secondary TMA can show improvement in clinical condition within 48–72 h just by removing the trigger that is centered on fetal extraction followed by removal of the placenta. In patients with malignant hypertension resulting in secondary TMA, prognosis depends on the soluble and glomerular deposition of C5b-9. Thus, patients with massive tissue deposition of C5b-9 more often progressed to end-stage renal disease (ESRD; 72% vs. 38%) than patients with minor deposition, irrespective of complement genetic status. The patients with significant complement activation also had more glomerular thrombi. This is an important pathological finding as patients refractory to antihypertensive need to be started on Eculizumab.[14] Such patients are seen to have a poor prognosis. Secondary TMA due to aPLs has a life-threatening course.[15] Early anticoagulation is the life saving drug proven in such cases.

   Conclusion Top

Considering the fact that TMA has multifaceted etiologies and outcomes, a search for specific etiologies should be made. Complement pathway study is a breakthrough in this genre and the research for complement inhibitors holds a promising result for the future.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Brocklebank V, Wood KM, Kavanagh D. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol 2018;13:300-17.  Back to cited text no. 1
Bayer G, Tokarski FN, Thoreau B, Bauvois A, Barbet C, Cloarec S, et al. Etiology and outcomes of thrombotic microangiopathies. CJASN 2019;14:557-66.  Back to cited text no. 2
Henry N, Mellaza C, Fage N, Beloncle F, Genevieve F, Legendre G, et al. Retrospective and systematic analysis of causes and outcomes of thrombotic microangiopathies in routine clinical practice: An 11-year study. Front Med 2021;8:566678.  Back to cited text no. 3
Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease, Professional Edition e-Book. Elsevier Health Sciences; 2014.  Back to cited text no. 4
Valério P, Barreto JP, Ferreira H, Chuva T, Paiva A, Costa JM. Thrombotic microangiopathy in oncology–A review. Transl Oncol 2021;14:101081.  Back to cited text no. 5
Aigner C, Schmidt A, Gaggl M, Sunder-Plassmann G. An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy. Clin Kidney J 2019;12:333-7.  Back to cited text no. 6
Coppo P; French Reference Center for Thrombotic Microangiopathies. Management of thrombotic thrombocytopenic purpura. Transfus Clin Biol 2017;24:148-53.  Back to cited text no. 7
Palma LMP, Sridharan M, Sethi S. Complement in secondary thrombotic microangiopathy. Kidney Int Rep 2021;6:11-23.  Back to cited text no. 8
Oliveira DS, Lima TG, Benevides FL, Barbosa SA, Oliveira MA, Boris NP, et al. Plasmic score applicability for the diagnosis of thrombotic microangiopathy associated with ADAMTS13-acquired deficiency in a developing country. Hematol Transfus Cell Ther 2019;41:119-24.  Back to cited text no. 9
Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: A general approach to diagnosis and management. CMAJ 2017;189:E153-9.  Back to cited text no. 10
Song D, Wu LH, Wang FM, Yang XW, Zhu D, Chen M, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther 2013;15:R12.  Back to cited text no. 11
Ding Y, Tan Y, Qu Z, Yu F. Renal microvascular lesions in lupus nephritis. Ren Fail 2020;42:19-29.  Back to cited text no. 12
Sekine A, Hasegawa E, Hiramatsu R, Mise K, Sumida K, Ueno T, et al. Two types of renovascular lesions in lupus nephritis with clinical thrombotic thrombocytopenic purpura. Case Rep Nephrol Dial 2015;5:192-9.  Back to cited text no. 13
Shibagaki Y, Fujita T. Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP): Can we differentiate one from the other?. Hypertens Res 2005;28:89-95.  Back to cited text no. 14
Pattanashetti N, Anakutti H, Ramachandran R, Rathi M, Sharma A, Nada R, et al. Effect of thrombotic microangiopathy on clinical outcomes in Indian patients with lupus nephritis. Kidney Int Rep 2017;2:844-9.  Back to cited text no. 15

Correspondence Address:
Moumita Sengupta
244 AJC Bose Road, Kolkata- 700 020, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1237_21

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