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Calciphlaxis or Warfain-Induced Skin Necrosis

Calciphlaxis or Warfain-Induced Skin Necrosis. ZT, Nephrologist. Case report. 61 year female, ex-smoker (10 pack years) p/w swollen legs x 4 weeks small bilateral leg calf ulcer: swollen, tender, erythematous x 1 week papuric rash (arms, shoulder, face) x 1 week B/G:

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Calciphlaxis or Warfain-Induced Skin Necrosis

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  1. Calciphlaxis or Warfain-Induced Skin Necrosis ZT, Nephrologist

  2. Case report 61 year female, ex-smoker (10 pack years) p/w • swollen legs x 4 weeks • small bilateral leg calf ulcer: swollen, tender, erythematous x 1 week • papuric rash (arms, shoulder, face) x 1 week B/G: ESRF (pre-dialysis) due to HTN & DM T2DM Retinopathy (Blind Rt eye, reduced vision Lt eye), Nephropathy Rx: OHA (DiamicronSR 30mg mane) Obesity HTN Hypercholestrolemia

  3. New onset rash: 3-4 week before admission

  4. New onset rash: 3-4 week before admission

  5. Investigations Hb 95, WCC 12.8, Neutrophil 11.4, MCV 79.3 Na 141, K 4.9, HCO3 17, Urea 37.8, Cr 683 Ca 2.05, PO4 2.73, Mg 0.84 Albumin 27, LFT-normal Troponin 0.78 HbA1C 6.7 Wound swab (leg); occasional stap aureus, skin flora Blood culture: negative Urine M/C/S: negative

  6. CXR on arrival

  7. ECG (Day 1)

  8. Issues on arrival Issues: • ESRF: requiring dialysis • Bilateral leg ulcers • New onset Atrial flutter (Troponin) Management • Antibiotic (Tazosin) • Doppler lower limbs to exclude DVT • Duplex lower limbs & Vascular review • Cardiac Echo, Cardiology review • HD via permacath

  9. Cardiac Echo (Day 2)

  10. Doppler lower limbs

  11. VQ SPECT VENTILATION/PERFUSION LUNG SCAN Ventilation and perfusion SPECT study was performed. . REPORT Ventilation in both lungs is mildly non uniform. Corresponding perfusion images show moderate sized, wedge shaped, mismatched perfusion defect in the anterior segment of upper lobes bilaterally, and in the right middle lobe anteriorly. Matching abnormalities are also noted in the left mid lung posteriorly. COMMENT The scan features are consistent with recent multiple pulmonary embolism.

  12. Progress • Heparin infusion >warfarin (48 hour overlapping) for PE. • Ongoing intermittent atrial flutter (CCU stay x 2 days in weekends) • Medical management for possible IHD, coronary angiogram later

  13. Skin biopsy

  14. Skin biopsy (Right shoulder)

  15. Day 6 post warfarin

  16. Skin biopsy (leg) MICROSCOPY REPORT:1. Right leg ulcerSpecimen of skin to mid-dermis. The epidermis shows focal mild parakeratosis and is separating from the dermis at the dermo-epidermal junction with a cleft containing small quantities of red blood cells. There is variable mild spongiosis and pyknosis in the keratinocytes. Underlying dermis demonstrates dilated capillaries with haemorrhage throughout. There is a mild neutrophil infiltrate slightly more marked adjacent to vessels but no fibrinoid change or karyorrhectic debris; the pattern is not suggestive of vasculitis. Some of the vessels show thrombosis with other densely packed red blood cells or platelet fibrin aggregates.The appearances support microvascular thrombosis with superficial haemorrhage and probable early infarction. Vasculitis is not supported.DIAGNOSIS:1. Right leg ulcer- microvascular thrombosis with probable early infarction

  17. Ca-Po4-PTH iPTH 565 pg/ml (Ref:10-16) 59.5 pmol/L(Ref: 1.1-6.8) Vit D 27 nmol/L

  18. Progress Management • Cease warfarin • Clexane 1mg/kg (Anti Xa level monitoring) • CT/MRI for confusion: Bilateral infarct • RIP

  19. Calciphylaxis • Calciphylaxis (CPX) of the skin is a rare and potentially life-threatening syndrome (60-80% mortality) characterized by systemic medial calcification of the arterioles (small vessels) that leads to ischemia and subcutaneous necrosis. It is first described in 1962. • It is usually, but not invariably, seen in the setting of secondary hyperparathyroidism and end staged renal failure with elevation of the serum CaPO4 product. • Calciphylaxis has also been reported in patients without ESKD. • CPX usually manifests with painful (excruciatingly)violaceous skin lesions that typically progress to non-healing ulcers with underlying tissue necrosis. • It usually develop on areas with greatest adiposity including abdomen, buttock, and thigh. • It is also known as the “vascular calcification–cutaneous necrosis syndrome”.

  20. Calciphylaxis from Nonuremic Causes: A Systematic Review Sagar et al, CJASN 2008

  21. Presentation

  22. Development of organ damage in calciphylaxis Wilmer et al, Seminar in dialysis 2002

  23. Pathogenesis • Inhibitors of vascular calcification • Fetuin-A • (reduced in inflammatory conditions) • Matrix Gla protein • (Vit K dependent) • Chronic inflammation • Portein C & Protein S • (Vitamin K dependent • Produced by liver)

  24. Biochemical abnormalities • Hyperphosphataemia >1.7mmol/l (>5 mg/dl), raised in 68% of cases. • CaxP >5.6–12 mmol/l (>70 mg2/dl2), raised in 33% of cases. • Serum calcium: normal or mildly raised >2.6 mmol/l (>10.5 mg/dl) in 20% of cases. • Serum parathyroid hormone: mild to moderately raised, >2–3 ´ upper limit of normal, raised in 80% of patients. • Raised urea/creatinine. • Anaemia of chronic renal insufficiency. • Neutrophil leucocytosis due to wound sepsis. • Mildly raised serum alkaline phosphatase due to hyperparathyroid bone disease. • Low, or low-normal, levels of protein C or protein S antigen have been documented in calciphylaxis patients. The causative role of protein C or protein S abnormalities in calciphylaxis is uncertain. There are no specific laboratory findings in patients with calciphylaxis

  25. Survival Weening et al J AM ACAD DERMATOL 2007

  26. Survival Weening et al J AM ACAD DERMATOL 2007

  27. Survival (Parathyroidectomy/Debridment) Weening et al J AM ACAD DERMATOL 2007

  28. Tissue biopsy • It can also be argued that the diagnosis of calciphylaxis can only be made by a biopsy that shows appropriate calcification of small arterioles or venules. • The problem with performing skin biopsies in calciphylaxis is the poor likelihood of healing the biopsy site. The dystrophic calcification at the area of biopsy trauma can become the primary cutaneous lesion that fails to heal and becomes infected. • Performa biopsy only when a unique area of skin involvement requires the exclusion of disease processes listed above, or when a unique location of the lesion (an acral location, for example) is present. We have also performed biopsies when myopathy exists. • Overall, the specificity and sensitivity of skin biopsies in the diagnosis of calciphylaxis have not been determined, nor have definitive criteria for making the diagnosis been established.

  29. Histology Essary et al, Definitive histologic criteria for making the diagnosis has not been established.

  30. Treatment Hyperphosphatemia: non-calcium/non-aluminium binders Normalize serum PTH level with cinacalcet in stead of vitamin D analogues. Cinacalcet may serve as an alternative to parathyroidectomy. Wound care debridment/skin grafting, adequate pain control Parathyroidectomy should also be considered for ESRD patients with refractory hyperparathyroidism. Discontinuation of warfarin therapy should be considered. Sodium thiosuphate (STS) The consensus on most of the case reports and series is that STS treatment is utilized until there is almost complete resolution of the lesions and patients have reported less pain. Novel and experimental therapies  Bisphosphonate Hyperbaeric oxygen

  31. Warfarin-induced skin necrosis Warfarin-induced skin necrosis typically occurs during the first several days of warfarin therapy, often in association with the administration of large loading doses. The skin lesions occur on the extremities, breasts, trunk, and penis and marginate over a period of hours from an initial central erythematous macule. Only about one-third of patients with warfarin-induced skin necrosis have underlying protein C deficiency. Biopsies demonstrate diffuse microthrombi within dermal and subcutaneous capillaries, venules, and deep veins, with endothelial cell damage, resulting in ischemic skin necrosis and marked red blood cell extravasation. Treatment  Immediate intervention after diagnosis is required to prevent rapid progression and to minimize complications. Therapy should consist of immediate discontinuation of warfarin, administration of vitamin K, and infusion of heparin at therapeutic doses. Administration of a source of protein C (FFP or Purified Protein C concentrate) should be seriously considered in patients with hereditary protein C deficiency.

  32. Discussion Points • Prevalence of DVT & PE in ESRF ESRF>general population? • PE management Retreatment of warfarin Screening for Protein C/S deficiency When? Patient? Family? • Calciphylaxis management Sodium thiosulphate (positive case reports and series) Bisphosphonate (positive case reports and series) Cinacalcet Hyperbaric oxygen therapy (positive case reports and series)

  33. A CASE REPORT OF CALCIPHYLAXIS: SEQUENTIAL CALCIPHYLAXIS AND WARFARIN INDUCED SKIN NECROSIS Joel Riley, Zaw Thet, Emmanuel D’Almedia, Shane Carney, Alastair Gillies Department of Nephology, Dialysis & Transplantation John Hunter Hospital, University of Newcastle, NSW Introduction: Calciphylaxis(CPX) a potentially life-threatening condition seen in chronic kidney disease and some other conditions. The cause of CPX is multifactorial, but its precise mechanisms are unclear. Some patients who are at risk of developing CPX may require warfarin therapy for thromboembolic disease. Case report: Conclusion: Calciphylaxis and warfarin induced skin necrosis in practice may be difficult to distinguish. Warfarin use may precipitate or exacerbate calciphylaxis and ischaemic stroke by accelerating vascular calcification via inhibition of Matrix GIa protein and Gas-6.

  34. Sequential Calciphlaxis Warfain-Induced Skin Necrosis Any question?

  35. Xeroradiography • Xeroradiography identifies extraosseous calcification better than plain film imaging. • Using mammogramgrade film, xeroradiography of areas with suspicious skin lesions is often helpful in showing extremely small vessel calcification that is consistent with calciphylaxis. Xeroradiography also identifies large vessel calcification that occurs commonly in patients with diabetes or renal failure. Limitations: • This type of radiography is compromised in abdominal and thigh lesions due to tissue thickness. • The technique used to obtain the study can be quite painful, as it involves compressing the affected calciphylaxis extremity between two plates.

  36. 3 phase bone scan (Technetium 99m methylene diphosphate bone scintography) Further studies are needed to define the role of routine bone scanning

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