DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

RATIONALE: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. PATIENT CONCERNS: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. DIAGNOSES: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. INTERVETIONS: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. OUTCOMES: Clinical improvement ensued. At follow-up the patient is well. LESSONS: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

[Spontaneous hematoma of right angle of the transverse mesocolon: exceptional complication of anticoagulant therapy with vitamin K]. / Hématome spontané du méso de l'angle colique droit et du colon transverse compliquant un traitement par anti vitamine K: à propos d'un cas et revue de la littérature.

Spontaneous hematoma of transverse mesocolon is a rare complication of anticoagulant treatment with vitamin K. We report the case of spontaneous hematoma of right angle of the transverse mesocolon associated with a hemoperitoneum in a 32-year-old patient treated by fluindione for pulmonary embolism. The diagnosis must be made urgently. The abdominal ultrasound and the scanning confirm the diagnosis. It is important to note that surgery is indicated only in the case of complications such as the risk of rupture of the hematoma.

[Recurrent pyoderma gangrenosum-like ulcers induced by oral anticoagulants]. / Ulcérations récidivantes à type de pyoderma grangrenosum induites par les antivitamines K.

BACKGROUND: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC. PATIENTS AND METHODS: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment. DISCUSSION: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC.

Maintenance of anticoagulant and antiplatelet agents for patients undergoing peribulbar anesthesia and vitreoretinal surgery.

PURPOSE: To establish the prevalence of anticoagulation (vitamin K antagonists) and antiplatelet agent therapy in patients undergoing vitreoretinal surgery and to compare the outcome of peribulbar anesthesia and vitreoretinal surgery between users and nonusers. METHODS: We conducted a retrospective case series study in one academic center. No changes in the treatment regimen were made before surgery. Patients were divided into 3 groups: G1, patients with no anticoagulant or antiplatelet therapy; G2, patients treated with anticoagulants; and G3, patients treated with aspirin, clopidogrel, or both. RESULTS: Two hundred and six eyes (206 patients) were included. G1, 144 eyes (69.9%) without any anticoagulant or antiplatelet therapy (69.9%); G2, 12 eyes (5.8%) with anticoagulants; and G3, 44 eyes (21.4%) with antiplatelet agents. Six patients (6 eyes) (2.9%) received both anticoagulant and antiplatelet agents. The incidence of overall and mild postoperative hemorrhagic complications was similar between groups, P = 0.075 and P = 0.127, respectively. However, potential sight-threatening hemorrhagic complications were more frequent in patients receiving antiplatelet agents, P < 0.003. CONCLUSION: Peribulbar anesthesia for vitreoretinal surgery can probably be performed safely in patients receiving anticoagulants. However, retinal surgeons should be aware that severe bleeding complications are more frequent in patients receiving antiplatelet therapy.

[Skin necrosis during long-term fluindione treatment revealing protein C deficiency]. / Nécroses cutanées tardives sous fluindione révélant un déficit en protéine C.

BACKGROUND: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione. CASE REPORT: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued. DISCUSSION: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

Acute and chronic nephropathy induced by fluindione must be addressed.

BACKGROUND: Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis. METHODS: Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA. RESULTS: The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 µmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 µmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione. CONCLUSION: In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Novel nephrotoxins.

Drug and xenobiotic toxicity is an important cause of kidney injury, especially in vulnerable patients. Nephrotoxic syndromes include functional disorders; vascular injury, such as thrombotic microangiopathy; glomerular injury resulting in nephrotic syndrome or glomerulonephritis; acute tubular necrosis; acute interstitial nephritis; and crystalopathy/nephrolithiasis. Recently reported nephrotoxins are reviewed in the context of these syndromes of kidney injury.

Use the INN to avoid confusion between drugs.

Three cases of confusion between brand names have been reported in detail. Previscan (the anticoagulant fluindione) was taken instead of Permixon (saw palmetto extract for prostatic hyperplasia, "serenoa repens") or Preservision (a nutritional supplement for the prevention of age-related eye disease). These medication errors led to sometimes severe haemorrhages.

[Acute immuno-allergic interstitial nephritis after treatment with fluindione. Seven cases]. / Néphropathie interstitielle aiguë immuno-allergique après traitement par fluindione. A propos de sept cas.

We report seven cases of patients treated with fluindione, who presented with acute renal failure, associated with clinical features of allergy: poor status, fever, dyspnea, lymphadenopathy and erythroderma. All patients had elevated eosinophil counts. Renal biopsy disclosed in all cases a tubulo-interstitial nephritis with or without granuloma. The responsibility of fluindione, an oral anticoagulant widely used in France could be demonstrated. To our knowledge, there are only three reports of single cases of acute renal failure related to fluindione published so far to date. This serious side effect of fluindione should be recognized.

[Acute interstitial nephritis of fluindione: about three cases]. / Néphropathie interstitielle aiguë à la fluindione: à propos de trois cas.

Acute interstitial nephritis is a frequent cause of acute renal failure, representing about 10% of all biopsied cases. Early recognition of drug-induced acute immunoallergic interstitial nephritis prevents the development of severe chronic renal injury. The list of imputable drugs includes phenindione, a vitamin K antagonist. Fluindione which is also an indanedione derivative is another vitamin K antagonist. We report three biopsy-proved cases of fluindione related acute interstitial nephritis with recovery of renal function after drug withdrawal and prednisone therapy.

Severe hemorrhagic syndrome due to similarity of drug names.

The names of many drugs look or sound like those of other drugs, which leads to confusion and potentially harmful medication errors. We report a nearly fatal permutation between two drugs including a vitamin K antagonist that resulted in a 68-year-old man being admitted to the emergency department with severe, spontaneous hemorrhagic syndrome. Such problems can be alleviated through actions by regulatory agencies, pharmaceutical manufacturers, health care professionals, and patients.

Acute immuno-allergic interstitial nephritis caused by fluindione.

Fluindione is a vitamin K antagonist that is commonly prescribed for the treatment of cardiovascular disease and venous thromboembolism in France. Bleeding is the most common side effect of fluindione, whereas hypersensitivity reactions are rare. We describe here a patient with acute immuno-allergic interstitial nephritis caused by fluindione. Initial symptoms included fever, eosinophilia, low albuminuria, microscopic hematuria, eosinophiluria and acute renal failure. Kidney biopsy showed severe interstitial nephritis with interstitial edema, inflammatory infiltrates and tubulorrhexis. Fluindione withdrawal and corticosteroid treatment resulted in rapid recovery of renal function. A review of the literature revealed a very low incidence of fluindione-induced interstitial nephritis, with variable renal and extra-renal signs. Early recognition of this rare complication may prevent the development of severe chronic renal injury.

[Mesenteric hematoma: Unusual complication of a long term oral anticoagulation therapy]. / Hématome mésentérique: rare complication d'un traitement anticoagulant oral au long cours.

Authors report a case of a 77 years old man who developed a small bowel mesenteric hematoma as consequence of an unusual complication from a long term oral anticoagulation treatment. Computed tomoangiography helpfully suggests diagnosis of a mesenteric hematoma and refuts an organic cause as vascular anomalies, by an equivalent method to conventional angiography, noninvasely. In our case report, patient's deterioration justified an emergency surgery corroborating medical imager findings. Authors review the rare cases previously reported.

Oral anticoagulation therapy during pregnancy in patients with mechanical mitral valves: a prospective study.

Reports on phenindione toxicity have limited its use as an oral anticoagulant. Our aim was to evaluate its risks in pregnant women. Thirty-one pregnancies in 29 women with mitral (+/-aortic) St. Jude mechanical valves were followed-up prospectively. Eighteen patients received phenindione. Eleven patients (37.9%) received in addition to phenindione 225 mg dipyridamole, which was given in three doses. The target INR was 2.5-3.5 in the former and 2-2.5 in the latter treatment. A fortnight before delivery, intravenous heparinotherapy was substituted. There were no maternal complications, apart from a single postpartum hemorrhage (3.2%). After the deliveries the results were: 26 mature babies (83.9%), 3 premature babies (9.7%) and 2 cases of stillbirth (6.4%). Outcome was dose related; being 57.2+/-20.9 mg/day for mature babies and 82.5+/-11.2 mg/day for prematures and stillbirths (P=0.016). Phenindione provided safe and effective anticoagulation during pregnancy. A larger study is necessary to confirm the relationship between the dosage and outcome.

Standard versus low-level anticoagulation combined to low-dose dipyridamole after mitral valve replacement.

BACKGROUND: Although the addition of 300 mg dipyridamole to oral anticoagulants has been shown to decrease thromboembolic events after cardiac valve replacement, reports of combined therapy were few and some showed significant dipyridamole-related side effects and intolerance. The aim of this study was to compare the clinical effect of a standard monotherapy (targeting an international normalized ratio - INR - between 2.5 and 3.5) to a less intensive regimen (targeting an INR between 2 and 2.5) combined to a small dose of dipyridamole (225 mg/day). METHODS: Between January 1990 and December 1998, 486 young rheumatic patients with a St Jude mitral valve prosthesis were assigned to follow either standard monotherapy (294 patients) or low-level combined therapy (192 patients). Phenindione has been the anticoagulant of choice. Up to a maximum daily dose of 100mg, patients failing to achieve their target INR range were shifted to warfarin therapy. Prothrombin time was checked monthly and asymptomatic patients with a too low or a too high INR (<1.3 or >5) were briefly hospitalized for INR control. Complete blood picture, renal and hepatic profiles and full echocardiographic study were done biannually. RESULTS: With the exception of a significantly larger left atrium in patients on low-level combined therapy (P=0.001), both groups were comparable as regards to age and sex distribution, number of patients with atrial fibrillation, left atrial thrombus and history of stroke. Patients were monitored for 1712.6 pt yr and follow-up was 96.7% complete. No phenindione-related complications were observed (mean dose 62.3+/-21.4 mg), 20 patients (4.1%) had failed to achieve their target INR range and were switched to warfarin and only three patients (1.6%) had tolerable dipyridamole-related side effects. Compared to standard monotherapy, patients on low-level combined therapy showed significantly lower annualized rates: thromboembolism (1.6 vs 0.43%: risk reduction 71%; P=0.05), thromboembolism and hemorrhage (2.7 vs 0.7%: risk reduction 72%; P=0.005), death due to valve thrombosis or stroke (1.17 vs 0. 14%: risk reduction 81%; P=0.04) as well as both non-fatal (3.3 vs 1. 57%: risk reduction 51%; P=0.04) and total late postoperative complications (5.35 vs 3.14%: risk reduction 40%; P=0.04); respectively. However, total late mortality (32 patients; 1.8% per pt yr) was comparable among both groups. CONCLUSION: Low-level anticoagulation with phenindione combined to low dosage of dipyridamole was clinically more effective than the higher standard monotherapy. With respect to the prescribed doses, both drugs were well tolerated by almost all patients. Use of dipyridamole did not influence overall patients' survival.

Massive ovarian haemorrhage complicating oral anticoagulation in the antiphospholipid syndrome: a report of three cases.

We report three cases of severe haemorrhagic rupture of luteal ovarian cyst requiring surgical haemostasis in young women treated with long-term oral anticoagulation for antiphospholipid syndrome (APS) who used no contraception. At the time of bleeding, the international normalized ratios were 3.78, 4.24, and 7.11. Anticoagulation was resumed post-operatively, in association with antigonadotropic progestins to induce ovulatory suppression. A systematic use of these progestins should probably be discussed in young women receiving long-term warfarin for APS. Ovarian haemorrhage must be considered when such patients develop acute abdominal pain.