ORIGINAL INVESTIGATION Warfarin-Induced Skin Necrosis and Venous Limb Gangrene in the Setting of Heparin-Induced Thrombocytopenia Abhay F. Srinivasan, MD; Lawrence Rice, MD; John R. Bartholomew, MD; Chandhiran Rangaswamy, MD; Lucy La Perna, DO; James E. Thompson, MD; Scott Murphy, MD; Kelty R. Baker, MD Background: Heparin-induced thrombocytopenia (HIT) emerged after 2 to 7 days, and consisted of warfarin- is a common, often catastrophic, syndrome that pro- induced skin necrosis (n=5) and venous limb gangrene duces the most hypercoagulable of states. Emerging thera- (n=2); 1 patient had both. This emerged with unop- peutic strategies use alternative anticoagulants; warfa- posed warfarin in 4 patients and as a direct thrombin in- rin’s place is being reexamined. Early in the course of hibitor was being withdrawn in 2. All had suprathera- warfarin therapy, there may be net procoagulant effects peutic international normalized ratios. One patient because of the inhibition of protein C. With HIT, it has required leg and breast amputations, and another one died. been suggested that unopposed warfarin can precipitate venous limb gangrene. There are also reports of warfarin- Conclusions: Because of the early effects on protein C, induced skin necrosis. We seek to confirm and increase warfarin can precipitate venous limb gangrene and/or skin awareness of the risks of warfarin with HIT. necrosis in the extreme hypercoagulable milieu of HIT. With HIT, unopposed warfarin should be avoided and Methods: We describe 6 patients with HIT seen at 3 caution is needed during transition from a direct throm- medical centers in whom frank or impending venous limb bin inhibitor. Warfarin should be initiated at modest doses gangrene, central skin necrosis, or both were tempo- in patients with HIT after platelet recovery. Implica- rally related to warfarin initiation. tions extend to warfarin initiation with other throm- botic diatheses. Results: At warfarin initiation, 5 patients had recog- nized HIT and 1 had it recognized later. Complications Arch Intern Med. 2004;164:66-70 ARFARIN, THE STAN- Logically, early warfarin effects on dard oral anticoagu- protein C could be deleterious in the ex- lant used by mil- treme hypercoagulable milieu surround- lions daily, may ing HIT. Unopposed warfarin continues Author affiliations are given at have procoagulant to be used pending wider appreciation of the end of the article. Drs Rice Wactions in the first days of use because the the risks. We describe 6 patients, all of and Bartholomew have been vitamin K–dependent natural anticoagu- whom met the established criteria for the consultants for and on the lant protein C has a shorter half-life than diagnosis of HIT (decrease in platelet count speakers bureau of Berlex most ␥-carboxylated procoagulants (fac- by 50% at an appropriate time after hep- Pharmaceuticals (which tors II, IX, and X). This helps explain the arin exposure without other likely causes). markets lepirudin for early emergence of warfarin-induced skin Our observations in these patients (seen heparin-induced in 3 medical centers over several years) thrombocytopenia) and necrosis, a microthrombotic lesion tropic GlaxoSmithKline (which to central fatty areas of the body. Patients confirm warfarin’s dangers and highlight markets argatroban for with congenital protein C deficiency are specific management considerations in the heparin-induced particularly susceptible.1,2 transition period from direct thrombin in- thrombocytopenia); Dr Rice has Heparin-induced thrombocytope- hibitors. received research support (not nia (HIT) is a common, often cata- for this study) from strophic, syndrome that produces the most GlaxoSmithKline; and Drs Rice hypercoagulable of states, with 30% to 75% REPORT OF CASES and Bartholomew have been of patients having thrombotic complica- consultants for The Medicines 3,4 Company (which markets tions. Warfarin therapy in patients with Summary data, including indications for bivalirudin for percutaneous HIT can cause progression of deep ve- heparin therapy, maximum recorded in- coronary intervention in nous thrombosis to venous limb gan- ternational normalized ratios (INRs), and patients with heparin-induced grene.5 Classic warfarin-induced skin ne- outcomes, for all patients are given in the thrombocytopenia). crosis has also been seen with HIT.5-10 Table. (REPRINTED) ARCH INTERN MED/ VOL 164, JAN 12, 2004 WWW.ARCHINTERNMED.COM 66 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Patient Summaries Overlap of Time to Onset Warfarin Warfarin and of Complications Patient Initiation a Thrombin (While Taking Signs of Maximum No. Indication for Heparin (After HIT), d Inhibitor Warfarin), d Complications Recorded INR Outcome 1 DVT (postoperatively) −1 None 6 WISN of thigh 4.0* Sepsis and death 2 Catheter flushes and 14 4 d (lepirudin) 6 WISN of left breast 4.5 Healed and discharged from DVT the hospital while taking warfarin 3 Coronary bypass and 0 6 d (lepirudin) 7 VLG of right leg 5.8 Healed and discharged from atrial fibrillation the hospital while taking danaparoid sodium 4 Cardiac catheterization −3 None 3 WISN of breasts 3.2 Surgical debridement and pulmonary embolus 5 Pulmonary embolus −2 None 2 WISN of calves 6.1 Surgical debridement and discharged from the hospital while taking warfarin 6 Acute MI, coronary 0* None 4 WISN of breast 6.4 Mastectomy and bypass, and atrial and VLG of leg amputation fibrillation Abbreviations: DVT, deep venous thrombosis; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; MI, myocardial infarction; VLG, venous limb gangrene; WISN, warfarin-induced skin necrosis. *Estimated from available data. PATIENT 1 the arm remained pregangrenous and the platelet count remained about 100ϫ103/µL. Warfarin therapy was started at 5.0 mg/d on day 23, and increased to 7.5 A 58-year-old man had traumatic vertebral fractures re- mg/d on day 25. On day 26, lepirudin was discontinued quiring surgery. Postoperatively, he experienced fem- (INR, 3.1). A painful 10-cm black lesion with surround- oral vein thrombosis and pulmonary emboli. Intrave- ing ecchymoses appeared on the left breast on day 28. nous unfractionated heparin therapy was started, with a The INR was 4.5, and the platelet count was 87ϫ103/ platelet count of 441ϫ103/µL. Warfarin, 10 mg/d, was µL. Warfarin was discontinued, vitamin K was adminis- added on day 9. Heparin was discontinued when the plate- tered, and lepirudin therapy was resumed. The breast let count decreased to 120ϫ103/µL and to 83ϫ103/µL improved over several days, as the platelet count on days 10 and 11, respectively. Warfarin therapy was increased to 240ϫ 103/µL. Low-dose warfarin, 2.5 continued. On day 14, a necrotic ulcer appeared on the mg/d, was reinstituted and lepirudin was eventually dis- thigh (Figure, A). The prothrombin time was 21 sec- continued. Protein C and S levels were normal. onds (estimated INR, 4.0); the platelet count was 133ϫ103/µL, the fibrinogen level was normal, and fibrin- PATIENT 3 split products were mildly elevated. Warfarin was dis- continued, but the skin necrosis progressed and the pa- A 55-year-old man underwent coronary artery bypass sur- tient died of septicemia. gery and received intravenous heparin for 3 days post- operatively for atrial fibrillation. The platelet count on PATIENT 2 hospital discharge (day 7) was 224ϫ103/µL, but was 47ϫ103/µL on readmission 4 days later, with right leg After knee trauma and surgery, a 50-year-old woman deep vein thrombosis. Enzyme-linked immunosorbent had purulent material drained from her knee. Antibiot- and serotonin release assays confirmed HIT, and lepiru- ics were given via a central venous catheter flushed din therapy was initiated. Warfarin, 21 mg, was given for with unfractionated heparin. The platelet count was the next 3 days. On day 9, the INR was 2.7, the platelet 318ϫ103/µL. She was readmitted on day 8 for symp- count was 45ϫ103/µL, and lepirudin was discontinued. tomatic venographically demonstrated thromboses in The leg worsened. Lepirudin therapy was restarted with the right arm. Intravenous heparin was administered. warfarin. On day 13, the INR was 3.3 and warfarin therapy The readmission platelet count of 109ϫ 103/µL was continued alone. Thrombocytopenia persisted. On decreased the next day to 43ϫ103/µL, then to a nadir of day 14, worsening cyanosis of the leg gave the appear- 17ϫ103/µL. Heparin was discontinued, HIT was con- ance of impending venous limb gangrene. The INR was firmed by an enzyme-linked immunosorbent assay, and 5.8. Lepirudin therapy was resumed, warfarin was dis- lepirudin therapy was begun. Rapidly progressing arm continued, and vitamin K was administered. Signs of gan- cyanosis mandated alteplase for 2 days. A ventilation/ grene resolved over 2 days, as the platelet count in- perfusion scan showed a moderate probability of a pul- creased to normal. The patient was discharged to continue monary embolism. Lepirudin therapy was resumed, but taking danaparoid sodium. (REPRINTED) ARCH INTERN MED/ VOL 164, JAN 12, 2004 WWW.ARCHINTERNMED.COM 67 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 lepirudin was discontinued. The patient had normal pro- A tein C and S levels and negative hypercoagulability panel results. PATIENT 5 A 24-year-old woman with systemic lupus erythemato- sus received intravenous heparin for a pulmonary em- bolism. Warfarin, 10 mg/d, was added on day 3. The plate- let count decreased from 247ϫ103/µL at baseline to 83ϫ103/µL on day 5, the INR was 6.1, and painful pur- puric lesions of both calves appeared, progressing to full- thickness necrosis. HIT was diagnosed based on clinical variables and a positive enzyme-linked immunosorbent assay result. Heparin and warfarin were discontinued, as B vitamin K, fresh frozen plasma, and danaparoid were given. The patient required grafts to both legs. Recur- rent pulmonary emboli were believed to be due to cross reactivity of antibodies with danaparoid (dose, 1500 U subcutaneously twice a day; the result of serotonin re- lease for cross reactivity was positive).