Section 10 -

Thrombotic Microangiopathy Donna J. Lager, M.D. Matthew Lewin, M.D.

Case 9: Thrombotic Microangiopathy A 53 year old man presented with hemoglobin of 8.3 gm/dl and marked thrombocytopenia (45 K/mm3). On review of his peripheral blood smear, numerous schistocytes were noted. His creatinine had increased to 3.3 mg/dl from a previous baseline of 1.0 mg/dl There are a group of diseases that demonstrate a similar histologic appearance called thrombotic microangiopathies. It has been postulated that the common event that leads to these diseases is endovascular endothelial damage that leads to a state of hypercoagulation. The disease processes that lead to thrombotic microangiopathy include malignant hypertension, scleroderma, Hemolytic-Uremic Syndrome (HUS), Thrombotic Thrombocytopenic Purpura (TTP) and post-partum renal failure, among others. In this discussion we will focus on general considerations of thrombotic microangiopathy and in particular HUS and TTP. Clinical Presentation and Diagnosis: HUS and TTP both present with decreased platelets and evidence of hemolysis. The term thrombotic microangiopathy describes the overall histologic findings of microvascular damage and thrombosis. Hemolytic-Uremic syndrome classically has been described with renal symptoms and dysfunction as the predominant disease. In classic TTP, on the other hand, neurologic symptoms predominate. However, it has become clear that patients with HUS can have some neurologic symptoms and those with TTP can have some renal dysfunction. Many believe that HUS and TTP are the same disease process and represent a spectrum of organ involvement. Laboratory Findings: Laboratory findings typically include signs of hemolysis including decreased hemoglobin, together with schistocytes and decreased platelets. This is usually combined with a negative Direct Coomb's test to rule out autoimmune hemolysis, Morphologic Findings The morphologic findings that define thrombotic microangiopathy are: Hyperplastic arterioscerlosis. This is the typical onion skinned appearance that is described with malignant hypertension. The lumen is nearly completely occluded and fragmented red blood cells are often seen in the vessel wall. Fibrinoid necrosis of the vessel. While described as "necrosis" this is typically comprised of pink amorphous fibrin within the vessel wall and extending into the media of the vessel wall. This material often extends into the vascular pole of the glomerulus. Thrombi in glomerular capillary loops. This is often seen in HUS and TTP and can be a continuation of the vascular process described above. These thrombi are also observed in humoral rejection of transplanted kidneys. Additional glomerular findings can include endothelial cell swelling, bloodless glomeruli, mesangiolysis and occasional "double contouring." These histologic findings can be reminiscent of a proliferative immune-complex mediated process such membranoproliferative glomerulonephritis (MPGN), however true electron dense immune complex deposits are not seen. Immunoflouresence can demonstrate scattered deposits for C3 and IgM, however, strong staining for IgG and the light chains are not present. Certain histologic findings can help in the distinction between the different causes of thrombotic microangiopathy. Scleroderma/Malignant Hypertension: Typically the mucoid intimal hyperplasia predominates. Fibrinoid necrosis of the vessel is seen most commonly in malignant hypertension. Scleroderma is said to more commonly involve the medium sized arteries while malignant hypertension involves the arterioles, however though this is a soft sign and is not always helpful. HUS/TTP: Usually the vascular thrombosis predominates in HUS/TTP with involvement of the glomerular capillary loops and arterioles near the vascular poles. Bone Marrow Transplantation and Chemotherapy: Extensive mesangiolysis is often seen, especially with mitomycin therapy. References: Renal Biopsy Interpretation, Ed. FG Silva, VD D'Agati, T Nadasdy, Churchill Livingstone, 1996 Churg J, Strauss L, Renal involvement in thrombotic microangiopathies. Semin Nephrol 5:46 1985 John HD, Thoenes W, The glomerular lesions in endotheliotropic hemolytic nephroangiopathy (hemolytic uremic syndrome, malignant nephroscerlosis, post partal renal insufficiency) Pathol Rs Pract 173:236 1982 Gaber LW et al, Renal Pathology in Preeclamplsia, Clin Obstet Gynecol 1:971 1987 Streiff M, Bell WR, Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, Curr Opin Hematol 1:274 1993 Remuzzi G, Ruggenenti P, The Hemolytic Uremic Syndrome Kidney Int 48:2 1995