Background Thrombotic thrombocytopenic purpura (TTP) shares histologic features with disseminated intravascular coagulation (DIC) but is clinically distinct. TTP may result in myocardial hemorrhages and rapid death. We compared rapidly fatal TTP with heart involvement and DIC cases to determine if the differential diagnosis of TTP and DIC could be aided by immunohistochemical techniques. Design We examined 11 hearts from seven women and four men dying with TTP (aged 34±10 years) and 8 hearts from patients dying with DIC (five women, three men, aged 58±16 years). The diagnosis of TTP was established on histologic findings and identification of thrombocytopenia with schistocytes on premortem blood smear. Underlying conditions for TTP were recent diarrheal illness (3), autoimmune disease (3), sickle cell disease, HIV infection, cocaine abuse, and none known (2). Underlying conditions for DIC were disseminated carcinoma (4), multiorgan failure after open-heart surgery (2), pancreatitis (1), and placental abruption (1). Antibodies against platelet glycoprotein IIIa (CD61) and fibrin II were applied to formalin fixed tissue sections and detected by the avidin biotin techniques, and platelet and fibrin capillary thrombi were quantitated. Results Gross myocardial hemorrhages were present in 7/11 cases of TTP and 0 cases of DIC ( P<.001). Capillary thrombi were present in all cases by routine histologic techniques but were often difficult to discern. Platelet thrombi were strongly highlighted by stains for CD61 and seen at a density of 8.0±3.1/mm 2 in TTP versus 0.5±0.4/mm 2 in DIC ( P=.0001). In TTP, there were 12.1±5.9/mm 2 fibrin capillary thrombi and 4.8±5.8/mm 2 in DIC ( P=.05). Conclusion In the myocardium, rapidly fatal TTP is characterized by the diffuse presence of intracapillary platelet-rich thrombi, in contrast to DIC, which is characterized by predominantly fibrin thrombi. Immunohistochemical staining for CD61 and fibrin II is helpful in diagnosing TTP and distinguishing it from DIC.