Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism.

RATIONALE: Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown. OBJECTIVE: We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure. METHODS AND RESULTS: C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain-like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was <3 hours after CC injection. However, combining Nec-1s (necrostatin-1s) prophylaxis given 1 hour before and DNase I 3 hours after CC injection completely prevented kidney failure and infarcts. In vitro, CC did not directly induce plasmatic coagulation but induced neutrophil extracellular trap formation and DNA release mainly from kidney endothelial cells, neutrophils, and few from platelets. CC induced ATP release from aggregating platelets, which increased fibrin formation in a DNase-dependent manner. CONCLUSIONS: CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.

Renal cholesterol crystal embolism in the setting of warfarin use.

A 73-year-old man presented for evaluation of weakness and black tarry stools that occurred 1 day prior to admission. His medical history is significant for diabetes mellitus, stage 3 chronic kidney disease and deep vein thrombosis on warfarin. He was admitted to the hospital and was found to have acute kidney injury and gastrointestinal bleeding due to a supratherapeutic International Normalized Ratio. His hospital course was complicated by persistent decline in his renal function. He was given intravenous fluid resuscitation, fresh frozen plasma and packed red blood cells for his acute blood loss anaemia. Urinalysis was consistent with acute tubular necrosis. Given the persistent rise in creatinine, a kidney biopsy was obtained, and was significant for mild inflammatory changes, without evidence of vasculitis or allergic interstitial nephritis. Histopathological examination with tissue fixation revealed cholesterol embolisation. Given that he had no recent endovascular procedure or instrumentation, this atheroembolic event was attributed to his warfarin use.

Cholesterol embolisms as possible adverse drug reaction of direct oral anticoagulants.

The Netherlands Pharmacovigilance Centre Lareb has received two reports of cholesterol crystal embolisms associated with the use of a direct oral anticoagulant (DOAC). The European pharmacovigilance database contains several other cases concerning this association, and one report was published in the scientific literature. Cholesterol crystal embolisms were described in association with the use of several other antithrombotic drugs, although the role as an independent risk factor is not conclusive. The case series described in this article, indicates the possibility of an adverse drug reaction when a patient develops cholesterol crystal embolisms while using a DOAC.

Cholesterol Crystal Embolism Induced by Direct Factor Xa Inhibitor: A First Case Report.

An 80-year-old man presented at our hospital with renal failure. He had been treated with edoxaban, an oral direct factor Xa inhibitor, for deep vein thrombosis for 10 months prior to admission. Although the pulses in his bilateral pedal arteries were palpable, cyanosis was present in the bilateral toes. Laboratory data indicated azotemia and eosinophilia. A skin biopsy confirmed a diagnosis of cholesterol crystal embolism (CCE). Because no invasive vascular procedure was performed, we assumed that CCE was related to edoxaban. To the best of our knowledge, this is the first case report suggesting CCE induced by an Xa inhibitor.

The purple toe syndrome in female with Factor V Leiden mutation successfully treated with enoxaparin.

Purple toe syndrome is a rare complication of warfarin therapy. It occurs usually after 3 to 8 weeks of therapy and it is caused by cholesterol emboli from atheromatous plaque. Sudden onset of pain in affected area, typically in toes and feet, is the main characteristic of the syndrome. We describe a case of a 65-year-old female with purple toe syndrome after 6 weeks of warfarin. Indication of warfarin was a proximal deep venous thrombosis, which developed after prolonged immobilization. Factor V (FV) Leiden and persistent high FVIII activity were found as additional eliciting factors for venous thromboembolism. After warfarin withdrawal and enoxaparin treatment, symptoms disappeared promptly but a slight discoloration of the toe persists.

Cholesterol embolization syndrome following thrombolysis during acute myocardial infarction.

BACKGROUND: Cholesterol embolization syndrome (CES) is the result of atherosclerotic plaque erosion and subsequent dislodgement of cholesterol crystals from the core of the plaque to the peripheral arteries. The source of emboli is usually located in the aorta, whereas the most commonly affected organs are the skin and the kidneys. CASE REPORT: The case of a 69-year-old male with cyanotic painful discoloration of his toes following thrombolysis for acute myocardial infarction 1 month previously is presented. Both transesophageal echocardiography and magnetic resonance aortography showed a diffuse ulcerated atherosclerotic plaque in the course of descending thoracic aorta, while a skin biopsy of the cyanotic toes revealed cholesterol crystals in the lumen of the small diameter arteries. CONCLUSION: Cholesterol embolizations from the aorta are difficult to treat and may end in renal failure. Since treatment options are limited without proven efficacy, increased awareness by the clinicians is needed.

Cholesterol embolization syndrome induced by thrombolytic therapy.

Cholesterol embolization syndrome (CES) induced by thrombolytic therapy is a rare syndrome with a high incidence of morbidity and mortality. The variability in clinical presentations may cause a delay in diagnosis of CES. This article presents a comprehensive review of the English literature from January 1980 to December 2007 identifying all published case reports of CES induced by thrombolytic therapy. Multiple electronic databases were searched and relevant reference lists were hand searched to identify all case reports. Thirty cases of thrombolytic-induced CES were identified. Indications for thrombolysis were acute myocardial infarction (28 patients) and deep venous thrombosis (two patients). Skin and renal involvement were the most common presentations. Skin manifestations included livedo reticularis, rash, and skin mottling. Other clinical symptoms included cyanotic toes, gastrointestinal bleeding, or perforation, myalgias, retinal emboli, and CNS involvement. Morbidity and mortality were high. Outcomes included chronic hemodialysis in eight patients, four patients underwent amputations, seven patients developed or had progression of their chronic kidney disease, and seven deaths occurred.CES presents as multiorgan dysfunction and should be considered in the differential diagnosis of the symptom complex that may develop after thrombolytic therapy. Diagnosis of CES can be difficult as a result of the variable clinical presentations. A thorough clinical history and physical examination are essential first steps in establishing a diagnosis. Confirmatory diagnosis requires biopsy of the target organs. Measures to reduce the likelihood of recurrence should be taken and include avoidance of anticoagulation therapy and vascular procedures. Unfortunately, therapy remains supportive and the outcome is invariably poor.

Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.

BACKGROUND: Clopidogrel is a prodrug requiring metabolism by cytochrome P450 3A (CYP3A) isoenzymes, including CYP3A5, in order to be active. It is controversial whether clopidogrel interacts with CYP3A inhibitors. We investigated the influence of CYP3A5 polymorphism on the drug interaction of clopidogrel. METHODS: In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 non-expressor genotype (*3 allele) and 16 who had the CYP3A5 expressor genotype (*1 allele) with and without pretreatment with itraconazole, a potent CYP3A inhibitor. A platelet aggregation test was performed at baseline, 4 hours, 24 hours and 6 days after clopidogrel administration. In phase 2, we compared clinical outcomes of 348 patients treated with clopidogrel after successful coronary angioplasty with bare-metal stent implantation according to their CYP3A5 genotype; the primary end point was a composite of atherothrombotic events (cardiovascular death, myocardial infarction and non-hemorrhagic stroke) within 1 and 6 months after stent implantation. RESULTS: In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5 expressor genotype than among those with the non-expressor genotype: 24.9% (standard deviation [SD] 13.9%) v. 6.2% (SD 13.5%) at 4 hours (p < 0.001); 27.7% (SD 16.5%) v. 2.5% (SD 8.3%) at 24 hours (p < 0.001); and 33.5% (SD 18.6%) v. 17.8% (SD 13.8%) at day 7 (p < 0.01). In phase 2, atherothrombotic events occurred more frequently within 6 months after stent implantation among the patients with the non-expressor genotype than among those with the expressor genotype (14/193 v. 3/155; p = 0.023). Multivariable analysis showed that the CYP3A5 polymorphism was a predictor of atherothrombotic events in clopidogrel users. INTERPRETATION: People with the CYP3A5 non-expressor genotype are vulnerable to drug interactions between clopidogrel and CYP3A inhibitors. This phenomenon may be associated with worse outcomes in patients with the non-expressor genotype who are given clopidogrel after coronary angioplasty and implantation of bare-metal stents.

[Contrast-media-induced nephrotoxicity]. / Kontrastmittel-induzierte Nephropathie. Klinik und Prävention.

The use of diagnostic and therapeutic catheterization is increasing and so is the exposure to radiocontrast media. As a consequence, an increasing incidence of contrast media-associated nephropathy is being observed. This article reviews pathogenesis, clinical symptoms and preventive measures of contrast media-associated nephropathy. Most important prophylactic measures is identification of high-risk patients, careful selection to be exposed to contrast media, application of non-ionic low osmolality or -- most recently -- iso-osmolality contrast media, adjusted hydration with isotonic saline before/during catheter interventions, and potentially the administration of acetylcysteine.

[Cholesterol crystal embolisation in the course of treatment with low-molecular-weight heparins]. / Emboliile cu cristale de colesterol în cursul tratamentului cu heparine cu greutate moleculara mica.

Cholesterol crystal embolisation is a rare complication of anticoagulant treatment of ulcerative atheromatosis to the great arteries. The embolisation is susceptible to affect both, the somatic and the visceral territory; clinical diagnosis is difficult, mainly because of the similarity between the embolisation symptoms and those produced by a complication of primary disease. The diagnosis is certain when the pathological examination reveal the presence of cholesterol crystal in arteriolar lumen, surrounded by inflammatory- cellular reaction (foreign-body reaction). This paper presents three cases in which we noticed clinical manifestation suggestive for cholesterol crystal embolisation, at patients in treatment with low-molecular weight heparins. The complications which were reported in case of cholesterol crystal embolisation could be extremely severe, specially visceral embolisation, they may lead to patient's death.

[Case of cholesterol crystal embolism occurring after treatment of cerebral infarction with urokinase].

A 74-year-old man with hypertension and diabetes mellitus was admitted to our hospital because of acute exacerbation of chronic renal failure after treatment with urokinase for a cerebral infarction. A percutaneous renal biopsy was performed to examine the cause of renal damage, revealing glomerulosclerosis and cholesterol clefts in the small arteries. Subsequently eosinophil was increased to 21% and livedo reticularis was found in the patient's foot. A skin biopsy was performed, and cholesterol clefts were again found in the small arteries. For the reason, our diagnosis was cholesterol crystal embolism. Although 30 mg of prednisolone was administered, the patient's renal function did not improve and maintenance hemodialysis therapy was necessary. This is a rare case of cholesterol crystal embolism caused by urokinase without any invasive vascular procedures.