Warfarin-Induced Skin Necrosis and Venous Limb Gangrene in the Setting of Heparin-Induced Thrombocytopenia

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 Early in the course of hibitor was being withdrawn in 2.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 thrombotic diatheses. Results: At warfarin initiation, 5 patients had recognized 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 actionsW 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.

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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 discontinued, 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 postoperatively 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.

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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 embolism. Warfarin, 10 mg/d, was added on day 3. The platelet 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 release for cross reactivity was positive). Argatroban therapy was substituted. Warfarin was reintroduced at 1 mg/d, and escalated slowly, overlapping with argatroban for 15 days. A hypercoagulability evaluation revealed only an elevated anti–cardiolipin IgG level (without a lupus anticoagulant).

PATIENT 6

C A 72-year-old woman received alteplase and heparin for an acute myocardial infarction. The platelet count was 190ϫ103/µL. She underwent coronary artery bypass graft- ing several days later. Warfarin was given for postopera- tive atrial fibrillation. Four days postoperatively, she developed pain and discoloration of the left breast, right leg, and left foot (Figure, C). The INR was 6.4 and the platelet count was 68ϫ103/µL. The breast and venous leg lesions rapidly progressed. She required a mastectomy and a below-the-knee amputation, and eventually a left transmetatarsal amputation. Five weeks later, she was readmitted with upper extremity swelling. Ultraso- nography confirmed axillary-subclavian and femoral venous thromboses. The platelet count decreased from A, Necrotic ulcer on the thigh of patient 1. B, Necrotic breasts from patient 4. 126ϫ103/µL to 26ϫ103/µL after 3 days of intravenous C, Necrotic foot in patient 6. heparin therapy. Subcutaneous enoxaparin sodium therapy produced the following acute systemic reac- PATIENT 4 tion: flushing, tachycardia, and tachypnea. An inferior vena cava filter was placed, and argatroban was given for A 53-year-old woman was treated with intravenous hep- 2 weeks. A hypercoagulability profile showed anti– arin for a pulmonary embolism. On day 4, warfarin cardiolipin antibodies and a low protein S level. therapy, 10 mg, was begun. The platelet count de- ϫ 3 creased to 86 10 /µL on day 7, the INR was 3.2, and COMMENT heparin was discontinued. The result of an enzyme- linked immunosorbent assay for heparin-induced anti- Warkentin et al5 described the syndrome of venous limb bodies was positive. Three days later, violaceous discol- gangrene complicating HIT and related it to warfarin use. oration of both breasts developed and progressed to full- Compared with unaffected patients, those with venous thickness skin necrosis (Figure, B). Warfarin was limb gangrene had higher prothrombin INRs, lower pro- discontinued and lepirudin therapy was instituted as the tein C activities, and persistently elevated thrombin- platelet count reached a nadir of 22ϫ103/µL. Extensive antithrombin complexes. This syndrome caused more surgical debridement of both breasts was performed. War- limb amputations with HIT than did arterial thrombo- farin therapy was later resumed at 1 mg/d, and in- ses. It occurred in 12% of patients with HIT and venous creased gradually until the INR was therapeutic; then, thrombosis given warfarin (with or without ancrod). Like

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 our patient 6, one patient with gangrene also developed Beyond implications toward the recognition and classic central skin necrosis. Other case reports6-10 docu- management of HIT, our observations bear generally on ment warfarin-induced skin necrosis complicating HIT. the optimal initiation of warfarin therapy. It is increas- The warfarin-induced skin necrosis with HIT seems clini- ingly clear that protein C inhibition before effective pa- cally identical to the classically described syndrome in ralysis of procoagulant pathways is more than a theo- terms of onset in the first days of warfarin use and pre- retic concern. In fact, early warfarin exacerbation of dilection for fatty areas of the body. As in patients with thrombotic diatheses has been reported with hereditary other thrombotic diatheses in whom frequently more than protein C deficiency,1,2 with cancer-related dissemi- one hypercoagulable state coexists, it is not surprising nated intravascular coagulation,17 and now confirmed with that some of our patients had additional thrombotic risk HIT. While there may be low-risk situations in which war- factors (patients 5 and 6). Our series confirms the dan- farin can be initiated unopposed, prudence dictates ad- gers of venous limb gangrene and skin necrosis when ini- equate systemic anticoagulation before warfarin use in tiating warfarin therapy in patients with HIT. any active thrombotic process. In a warfarin-naı¨ve pa- Our patients illustrate a gamut of HIT clinical sce- tient, we endorse initial doses of 5 mg/d,18 sometimes lower narios. In patients 1, 4, and 5, heparin was discontinued in situations such as HIT. for acute HIT, then unopposed warfarin was initiated or continued. In patient 6, HIT was initially unrecognized. Accepted for publication January 24, 2003. We emphasize that the emergence of warfarin-induced From the Section of Hematology-Oncology, Depart- skin necrosis or worsening venous thrombosis should alert ment of Medicine, Baylor College of Medicine, Houston, Tex to the possibility of underlying HIT; patient 6 could have (Drs Srinivasan, Rice, and Baker); the Section of Vascular been spared further morbid and life-threatening compli- Medicine, Department of Cardiovascular Medicine, The cations. In patients 2 and 3, there was some delayed- Cleveland Clinic Foundation, Cleveland, Ohio (Drs Bar- onset component to the HIT,11 and both had warfarin- tholomew and La Perna); the Division of Cardiology, De- related complications emerge during overlap with partment of Internal Medicine, University of Michigan Health lepirudin therapy. To our knowledge, we are the first to System, Ann Arbor (Dr Rangaswamy); the Division of He- report that in patients with HIT, the transition period from matology/Oncology, Department of Medicine, Hospital of a direct thrombin inhibitor to warfarin can be poten- the University of Pennsylvania, Philadelphia (Dr Thomp- tially dangerous. Others12 have begun to recognize war- son); and American Red Cross Blood Services and the De- farin-induced worsening of venous thromboses in pa- partment of Medicine, University of Pennsylvania, Phila- tients with HIT during the transition from the direct delphia (Dr Murphy). thrombin inhibitor lepirudin or argatroban. Argatroban This study was presented in part at the American So- has significant effects on prothrombin INR, which in- ciety of Hematology 43rd Annual Meeting; December 2, 2001; troduces challenges with warfarin overlap (as noted on Orlando, Fla. the package insert), yet this is a double-edged sword, with Corresponding author and reprints: Lawrence Rice, MD, risks not only of anticoagulation overshoot with bleed- Section of Hematology-Oncology, Department of Medi- ing but also of warfarin-related prothrombotic effects if cine, Baylor College of Medicine, 6565 Fannin, Mail Stop the argatroban is discontinued (or even held) prema- 902-Main, Houston, TX 77030 (e-mail: [email protected]). turely. While lepirudin has less effect on the prothrom- 13 bin INR, recent exhortations to reduce doses to mini- REFERENCES mally therapeutic levels during warfarin transition may raise similar dangers. 1. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG. Protein In the extreme prothrombotic milieu of HIT, alter- C and the development of skin necrosis during anticoagulant therapy [letter]. 14 native anticoagulants should be administered. Most pa- Thromb Haemost. 1983;49:251. tients will require transition to warfarin for the indica- 2. Eby CS. Warfarin-induced skin necrosis. Hematol Oncol Clin North Am. 1993;7: tion that first mandated anticoagulation, for thromboses 1291-1300. 3. Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Se- that arose secondary to HIT, or for protection from the ex- min Hematol. 1998;35(suppl 5):9-16. 4,14,15 treme risk of new thrombosis in isolated HIT. Sev- 4. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytope- eral precautions could minimize the risks of warfarin ini- nia. Am J Med. 1996;101:502-507. tiation in patients with HIT, including (1) first waiting for 5. Warkentin TE, Elavathil LJ, Hayward CPM, et al. The pathogenesis of venous limb the platelet count to increase to near normal as the HIT is gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-812. “cooled”; (2) initiating modest doses, avoiding an over- 6. Shahak A, Posan E, Szucs G, et al. Coumarin-induced skin necrosis following shoot of the target INR; and (3) shunning unopposed war- heparin-induced thrombocytopenia and thrombosis. Angiology. 1996;47:725- farin and assuring adequate levels of an alternative anti- 727. coagulant during transition. Wallis et al16 observed no 7. Warkentin TE, Sikov WM, Lillicrap DP. Multicentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia. Am J Hematol. 1999; increase in thrombotic events with warfarin treatment in 62:44-48. 51 patients with HIT, 16 with HIT-related thromboses. 8. Drakos P, Uziely B, Nagler A, et al. Successful administration of low molecular Warfarin doses were modest (mean, 3.5 mg); therapy was weight heparin in a patient with heparin-induced thrombocytopenia and coumarin- started several days before HIT in many patients or a mean induced skin necrosis. Haemostasis. 1993;23:259-262. of 3 days after HIT in half the patients, when the platelet 9. Celoria GM, Steingart RH, Banson B, et al. Coumarin skin necrosis in a patient ϫ 3 with heparin-induced thrombocytopenia: a case report. Angiology. 1988;39:915- count was generally 100 10 /µL. In all our patients, as 920. in prior reports, thrombotic complications correlated with 10. Potzach B, Unkrig C, Madlener K, Greinacher A, Muller-Berghaus G. APC resis- supratherapeutic prothrombin INRs. tance and early onset of oral anticoagulation are high thrombotic risk factors in

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 patients with heparin-associated thrombocytopenia (HAT) [abstract]. Ann He- bocytopenia: alternative anticoagulants are improving patient outcomes. Post- matol. 1996;72(suppl 1):A6. grad Med. 2002;112:85-89. 11. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced throm- 15. Wallis DE, Workman DL, Lewis BE, et al. Failure of early heparin cessation as treat- bocytopenia. Ann Intern Med. 2002;136:210-215. ment for heparin-induced thrombocytopenia. Am J Med. 1999;106:629-635. 12. Smythe MA, Warkentin TE, Stephens JL, et al. Venous limb gangrene during over- 16. Wallis DE, Quintos R, Wehrmacher W, Messmore H. Safety of warfarin antico- lapping therapy with warfarin and a direct thrombin inhibitor for immune heparin- agulation in patients with heparin-induced thrombocytopenia. Chest. 1999;116: induced thrombocytopenia. Am J Hematol. 2002;71:50-52. 1333-1338. 13. Nguyen PH, Baker KR, Rice L. The magnitude of protime INR effect by the direct 17. Warkentin TE. Venous limb gangrene during warfarin treatment of cancer- thrombin inhibitor lepirudin in patients with heparin-induced thrombocytope- associated deep venous thrombosis. Ann Intern Med. 2001;135:589-593. nia. Blood. 2002;100(suppl): 130b/Abstract 4001. 18. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg 14. Rice L, Nguyen P, Vann A. Preventing complications in heparin-induced throm- and 10-mg warfarin therapy. Arch Intern Med. 1999;159:46-48.

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