What is Thrombotic Microangiopathy (TMA)?

What is Thrombotic Microangiopathy (TMA)?

Thrombotic microangiopathy (TMA) is a life-threatening syndrome characterized by endothelial injury leading to microangiopathic hemolytic anemia (with schistocytes on blood smear), thrombocytopenia, and acute organ damage due to platelet-rich thrombi obstructing the microcirculation. 1, 2

Core Pathophysiology

TMA results from a cascade of microvascular injury:

• Endothelial damage triggers the entire process, with detachment of endothelial cells from vessel walls, particularly under high-shear conditions seen in malignant hypertension 2
• Platelet activation and coagulation occur when subendothelial surfaces become exposed, leading to formation of platelet-rich thrombi and fibrin networks 2
• Microcirculatory obstruction develops as these thrombi occlude small vessels, causing ischemic organ damage to kidneys, brain, heart, and other organs 1, 2
• Hemolysis and thrombocytopenia result mechanically as red blood cells are sheared and destroyed passing through fibrin networks (creating schistocytes), while platelets are consumed in thrombus formation 2

Clinical Definition in Hypertensive Emergencies

In the context of severe hypertension, TMA is defined as any situation where severe blood pressure elevation (typically >200/120 mmHg) coincides with Coombs-negative hemolysis—evidenced by elevated lactate dehydrogenase, unmeasurable haptoglobin, or schistocytes—plus thrombocytopenia, in the absence of another plausible cause, with improvement during blood pressure-lowering therapy. 1

Major Etiologic Categories

TMA encompasses multiple distinct disease entities with different underlying mechanisms:

Primary TMA Syndromes

• Thrombotic thrombocytopenic purpura (TTP) results from severely reduced ADAMTS13 activity (<10%), causing accumulation of ultra-large von Willebrand factor multimers that promote excessive platelet adhesion and aggregation 2, 3
• Atypical hemolytic uremic syndrome (aHUS) stems from complement dysregulation that directly damages endothelial cells 2

Secondary TMA Forms

• Malignant hypertension-associated TMA develops through a vicious cycle: pressure-induced renal natriuresis → autoregulation failure → increased vascular resistance → renin-angiotensin system activation → further microcirculatory damage 2
• Drug-induced TMA occurs with medications like mitomycin, cyclosporin, tacrolimus, and calcineurin inhibitors through direct endothelial toxicity or immune-mediated mechanisms 4, 5
• Infection-related TMA, particularly Shiga toxin-producing E. coli causing hemolytic uremic syndrome 3, 5
• Pregnancy-related TMA including HELLP syndrome and severe preeclampsia 1
• Antiphospholipid syndrome-associated TMA where antibodies promote microvascular thrombosis and complement activation 2
• Cancer-associated TMA as a paraneoplastic manifestation 6

Essential Diagnostic Features

The diagnostic triad consists of:

• Microangiopathic hemolytic anemia with schistocytes visible on peripheral blood smear, elevated LDH, and decreased/unmeasurable haptoglobin 1, 2, 7
• Thrombocytopenia from platelet consumption in microthrombi 2, 3
• Organ dysfunction, most commonly renal impairment, but can affect brain (encephalopathy, seizures), heart, or other organs 1, 3

Critical Clinical Context

TMA represents a medical emergency requiring immediate recognition and treatment, as delayed diagnosis significantly increases mortality and risk of permanent organ damage. 4, 7 The specific underlying cause determines treatment strategy—ranging from aggressive blood pressure control for malignant hypertension-associated TMA 1, 7, to plasma exchange and immunosuppression for TTP 2, 4, to complement blockade with eculizumab for aHUS 2, 4, 8.

Key Distinguishing Feature from Chronic Hypertension

Autoregulation failure is fundamental to TMA development and distinguishes it from chronic uncontrolled hypertension—patients with chronic hypertension do not develop TMA, hypertensive retinopathy, or encephalopathy despite similarly elevated blood pressures. 1 This occurs because acute severe hypertension overwhelms normal vascular protective mechanisms, while chronic hypertension allows adaptive changes that prevent microvascular injury.