Thrombotic Complications of Heparin Therapy
`
`Including Six Cases of Heparin -Induced Skin Necrosis
`
`PATRICK W. WHITE, M.D,,* JOHN R. SADD, M.D.,t RICHARD E. NENSEL, M.D.t
`
`From the Departments of Surgery and
`Laboratory Medicine, The Toledo Hospital, Toledo, Ohio
`
`the solution inactivation is almost instantaneous.48
`Factor X is quite sensitive to low concentrations of
`the heparin-antithrombin complex. Minidose heparin
`probably inhibits the coagulation cascade at this
`point.21 Once thrombin has been generated, much
`larger doses of heparin are required to interrupt the
`clotting process.
`In recent years, heparin has become a popular agent
`for the prevention of deep venous thrombosis (DVT)
`in postoperative or immobilized patients. Prophylactic
`measures seem warranted because pulmonary em-
`bolism is a major cause of death in patients under-
`going elective operations. Many studies have shown
`that minidose heparin reduces the incidence of DVT
`and two studies have recorded a decrease in fatal
`pulmonary emboli.27'50 More recent papers have
`stressed the complications seen with heparin in general
`and minidose prophylactic heparin in particular.
`The most common problem following the use of
`heparin is hemorrhage. In the minidose therapeutic
`trials reviewed by Pachter and Riles41 the incidence
`of hemorrhagic complications varied from 0 to 14%. In
`their own series, it was 27%. They therefore raise the
`question of whether the morbidity of the cure out-
`weighs the morbidity of the primary disease. The oc-
`currence of other nonhemorrhagic complications with
`heparin use lend further strength to this statement.
`Heparin, in rare instances, has been associated with
`thrombocytopenia and in the potentiation of arterial
`* Resident in Surgery, The Medical College of Ohio at Toledo.
`embolization. These complications have been associ-
`t Chairman, Department of Surgery, The Toledo Hospital,
`ated with prophylactic heparin use in only four pa-
`Toledo, Ohio.
`tients.24'45 Anaphylaxis is also reported with heparin7 1144
`t Director,
`but apparently has not been recognized in recent mini-
`Toledo, Ohio.
`Reprint requests: Patrick W. White, M.D., The Medical College
`dose trials.
`of Ohio at Toledo, Arlington and S. Detroit Streets, Toledo,
`Skin necrosis at the site of heparin administration is
`Ohio 43699.
`a rare occurrence. However, six patients with this com-
`Subrnitted for publication: September 13, 1978.
`0003-4932/79/1100/0595 $01.20 © J. B. Lippincott Company
`595
`
`Thrombotic complications of heparin administration were
`observed in eight patients during a two year period. At sites
`of subcutaneous heparin injection, six patients developed areas
`of the skin and subcutaneous necrosis. Systemic thrombotic
`events and thrombocytopenia were observed in two of these
`patients when they received intravenous heparin and in two
`other patients who did not have primary skin necrosis.
`The complications included peripheral ischemia in three
`patients (two requiring amputation), myocardial infarction
`in two, and a cerebral infarction in one. All patients were
`receiving heparin for at least six days before complications
`occurred. Seven patients received heparin of bovine origin.
`Heparin-induced in vitro platelet aggregation was present
`in all six of the eight patients tested. (It was marked in four
`of these patients). It is theorized that skin necrosis and the
`other thrombotic complications observed are the result of
`platelet aggregation followed by
`vivo
`heparin-induced in
`intravascular thrombosis. Heparin-induced skin necrosis is a
`rare but serious hazard encountered with prophylactic heparin
`regimens. Ifheparin-induced thrombosis is present, the further
`use of heparin is contraindicated in most instances.
`
`EPARIN IS A NATURALLY occurring, strongly acidic
`sulfated mucopolysaccharide. Many types with
`varying actions have been isolated from different
`animals and different tissues. It is not a single com-
`pound but a collection of compounds of different chain
`lengths and molecular weights which possess similar
`repeating saccharide units and functional groups.28
`The anticoagulant function of heparin is a result of its
`ability to accelerate the action of the enzyme inhibitor
`antithrombin III. Thrombin, as well as the coagulation
`factors IX, X, and XI, are slowly inactivated in the
`presence of this substance. When heparin is added to
`
`Laboratory
`
`Hematology, The Toledo Hospital,
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-1 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`Ann. Surg. * November 1979
`
`) AND NENSEL
`WHITE, SADD
`596
`,ug/ml (25 ,tM/ml) and 2 ,ug/ml (5 ,mM/ml), and
`plication were treated during a two year period at The
`soluble calfskin collagen in a final concentration of 0.2
`Toledo Hospital. All six patients were receiving bovine
`mg/ml. The final test concentrations for heparin in the
`lung heparin (Upjohn) as prophylaxis against DVT.
`aggregating mixture were 0.5 and 0.6 units/ml. Pre-
`Two additional patients are presented who developed
`vious studies in this laboratory had revealed that a
`ischemia of the legs while receiving heparin for sus-
`heparin concentration of 0.5 units/ml resulted in an ele-
`pected venous disease. These two patients represent
`vation of the APTT to 40 to 60 seconds.
`new cases of heparin-induced thrombocytopenia with
`Normal control specimens were always tested at the
`thrombotic sequelae. Of these two patients, one re-
`same time as patients' specimens. A second control
`ceived porcine intestinal heparin (Elkin-Sinn) and the
`group consisted of 25 patients who had recently under-
`other bovine heparin (Upjohn).
`surgery. These patients had been
`gone cardiac
`heparinized during surgery, but were free of any mani-
`festations of heparin-induced thrombosis.
`
`Methods
`
`The eight patients described in this paper were all
`admitted to surgical services for nonhematologic prob-
`lems. After the development of skin necrosis or throm-
`botic events associated with thrombocytopenia, six of
`them were seen in consultation by the authors. Two
`patients, N.R.M. and S.H., were seen after their dis-
`charge from the hospital when all lesions had resolved.
`Activated partial thromboplastin times (PTT) were
`determined on a Sherwood Lancer Coagulyzer which
`utilizes a photo electric endpoint for clot determina-
`tion. Normal range in this laboratory is 20-29 seconds.
`Platelet estimations were determined from appro-
`priate areas of peripheral blood smears by multiplying
`the average number of platelets in five high power
`fields by a factor of 10,000. Actual platelet counts were
`performed on a Coulter Thrombocounter C- a type of
`electronic particle counter.
`Blood obtained for platelet aggregation studies was
`handled in a fashion designed to minimize trauma and
`alterations. Only siliconized
`inadvertent platelet
`glass or plastic materials were used in collection
`and processing.
`Samples for aggregation studies were drawn into
`plastic syringes and immediately gently mixed with
`3.8% Citrate. Platelet rich plasma was obtained after
`centrifugation at 900 rpm and platelet poor plasma after
`centrifugation at 2400 rpm. Final platelet rich mixtures
`were standardized to about 250,000/mm3 for use in
`aggregation testing. Studies were performed on a
`Chrono-log Dual Channel model #340 Aggregometerg
`with attached dual channel 10 millivolt recorder. All
`reaction mixtures were constantly agitated and main-
`tained at 370 during the procedure. PH was not re-
`corded during the studies reported in this paper. Sub-
`sequent tests done under identical conditions have re-
`vealed a pH of 7.6 to 7.7 in the platelet rich plasma
`during and following aggregation with all the aggregat-
`ing agents.
`The standard aggregating reagents were ADP in final
`concentrations of 10 ug/ml (50 uM/ml) and 1 ,ug/ml
`of 10
`uM/ml), epinephrine in concentrations
`(5
`
`Case Reports
`
`Patient H.D. When admitted for a total hip arthroplasty, this
`49-year-old woman suffered from severe degenerative arthritis,
`hypertension and diabetes mellitus. She had lost 20 kg in prepara-
`tion for surgery, but was still obese. On the first postoperative day,
`subcutaneous heparin injections were begun. The PTT was monitored
`daily and remained normal. Ambulation progressed on a normal
`schedule. On the sixth postoperative day, a purple discoloration
`appeared on the right flank. Heparin was injected in the left flank
`later in the day and then discontinued. Within 12 hours the right
`flank contained a large band of skin necrosis (Fig. 1). An identical
`lesion later appeared on the left side. Hemorrhagic bullae de-
`veloped in 24 hours. The patient complained of severe burning
`pain for four days, but as the cuff of erythema surrounding the
`necrosis resolved, pain diminished.
`Excision with primary closure was performed 19 days later.
`Ischemic necrosis extended through the subcutaneous tissue and
`Microscopic examination revealed necrosis
`muscle.
`the
`into
`juxtaposed to normal tissue. Six months later an arthroplasty was
`performed on the opposite hip. Heparin was again administered
`for six days but was given intravenously. Platelet counts were not
`obtained. There were no complications.
`Patient N.L. (Fig. 5A). This 55-year-old woman was admitted for a
`right knee arthroplasty. She was obese, hypothyroid, and had
`insulin dependent diabetes mellitus. The platelet count on ad-
`mission was grossly normal. Mild T-wave abnormalities were
`present on the electrocardiogram. Subcutaneous heparin injections
`were started two hours before the operation and continued post-
`operatively. Daily PTT's were normal. She initially did well,
`ambulating with a walker on the third day. On the eighth post-
`operative day she complained of pain in the left chest and in the
`left lower abdomen at the site of heparin injections. Within 36 hours
`a necrotic eschar surrounded by an erythematous cuff had formed
`in the left lower abdomen. Two days later a second lesion appeared
`on the right side. Subcutaneous injections were stopped on the
`following day, but the same dose was given intravenously. The
`chest pain resolved but pain in the area of necrosis became severe.
`A spiking fever to 390 developed. The fever was thought to be
`secondary to the necrotic lesions and they were excised. The entire
`layer of subcutaneous adipose tissue was necrotic, but no hematomas
`or abscesses were present.
`In the postoperative period, intermittent intravenous heparin was
`resumed. An electrocardiogram performed following surgery sug-
`gested anterior wall ischemia. Chest pain occurred on the follow-
`ing day and ischemic changes were more pronounced. The serum
`sodium was 118 and the hematocrit had fallen over two days from 32
`to 26. Three days after the excision frank changes of an inferolateral
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-2 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`597
`
`*:
`
`0
`
`.0
`CU
`.0
`
`0 0 z C
`
`U
`
`4-
`
`.0
`
`CU
`
`E
`
`._
`CU.,
`
`0*
`=
`
`~.
`
`.0
`
`(- .
`
`Vol. 190 * No. 5
`
`COMPLICATIONS OF HEPARIN THERAPY
`
`; R t2-3 s7' a,j'l7rj,,t,,
`
`Z: i; .;
`
`;
`
`|S' w _S'4__N0R_
`tifit-.'.
`.E.i.
`
`vf
`
`owSs,,3_
`I
`
`.j
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-3 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`598
`WHITE, SADL
`infarct were present. Her serum sodium had risen to 124 meg/l,
`but her level of consciousness deteriorated and she became de-
`cerebrate. Her temperature rose to 40.30 but there was no apparent
`origin for the fever. On all blood counts performed during this
`period, platelets were noted to be decreased. Heparin was dis-
`continued and by the following day the platelet count was normal.
`infarct was diagnosed by computerized axial
`A cerebral
`tomography. For three days the patient had continuous focal motor
`seizures. Thereafter, she slowly improved but was left with an ex-
`pressive aphasia and right hemiparesis.
`Patient R.U. This 50-year-old woman suffered from recurrent
`superficial bladder tumors over a three year period. Two trans-
`urethral resections, a segmental bladder resection and intravesical
`thiotepa were employed in treatment but hematuria again de-
`veloped. She was therefore admitted for a radical cystectomy.
`She also suffered from ischemic heart disease with angina pectoris.
`The platelet count on admission was normal.
`A spiking fever developed postoperatively. At re-exploration a
`necrotic ileal segment was removed, and a new conduit constructed.
`Venous thrombosis was noted in the resected specimen. In order to
`prevent thrombosis in the reconstructed conduit, heparin was ad-
`ministered. Initially, the heparin was injected into the abdominal
`wall or given intravenously. Daily PTT's were within two to 11 sec-
`onds of control. On the sixth postoperative day the buttocks be-
`came the site of injections. Two days later, a circular region of skin
`necrosis appeared. The next injection of heparin was placed just below
`this area and a second lesion developed. Heparin was discontinued
`and dipyridamole and aspirin were started. The erythematous
`borders resolved rapidly and excision was not necessary.
`Patient N.M. This 77-year-old man complained of epigastric pain
`and weight loss. On admission, the hematocrit was 41, but fell to 33
`prior to surgery; the platelet count was normal. At laparotomy, an
`unresectable gastric carcinoma was uncovered. A gastrostomy
`tube was placed and the abdomen was closed. Subcutaneous
`heparin was started two hours prior to the operation and continued
`postoperatively. Three days later the tube was found to be lying free
`in the peritoneal cavity. It was replaced under anesthesia. Ab-
`dominal distension became severe and he was unable to eat.
`A horizontal band of skin necrosis appeared in the right lower
`quadrant of the abdomen on the eighth postoperative day (Fig. 2).
`Hemorrhagic bullae were present but there was no tenderness.
`Heparin was discontinued and a skin biopsy was obtained. Several
`estimations of the platelet count were done prior to the 6nset of
`necrosis and all were normal. A numerical count on the ninth post-
`operative day was 125,000/mm3. On the following day, he became
`acutely dyspneic and a respiratory arrest followed an episode of
`vomiting. An autopsy was refused.
`Patient M.O. (Fig. 5B) This 64-year-old woman sustained afracture
`ofthe midshaft ofthe right femur. She had been in good health except
`for chronic asthma and mild arterial hypertension. She was obese
`with mild dyspnea on admission. Her hematocrit was 41% and the
`platelet count was normal. Arterial blood gases on room air were
`Po2-57, Pc02-37. After being placed in traction, her wheezing
`transiently worsened but improved with theophylline. Since she was
`at risk of developing DVT, subcutaneous heparin was started three
`days after admission. Eight days later, a purple discoloration ap-
`peared in the left lower abdomen. Within 24 hours bilateral narrow
`bands of skin necrosis were present (Fig. 3). The patient complained
`of severe burning pain and acute tenderness in the area of erythema
`surrounding the necrosis. Subcutaneous heparin was stopped, but
`the same dose was given intravenously for seven days. When
`venous access became difficult, heparin was discontinued and
`warfarin was started. Wheezing worsened and prednisone was
`started.
`
`LND NENSEL
`D A
`
`Ann. Surg. * November 1979
`
`Calf tenderness appeared the day after heparin was stopped and
`the left foot appeared mildly cyanotic. Even though she was
`adequately anticoagulated with warfarin, a continuous infusion of
`heparin was started three days later as treatment for suspected DVT.
`Warfarin was discontinued. She rapidly became confused and rest-
`less and her respiratory status worsened. On 2 1 of oxygen per min-
`ute, she had a Po2 of 53 and a Pco2 of 54. Both feet became deeply
`cyanotic and symmetric areas of skin necrosis appeared on the
`medial aspects (Fig. 4). Nevertheless, pedal pulses remained strong.
`Heparin was stopped after 48 hours. Within 24 hours she was alert
`and breathing comfortably. Four days after the heparin was
`stopped, a long leg cast was applied. The remainder of her hos-
`pitalization was uneventful. All skin lesions resolved without
`excision.
`Patient N.R.M. This 56-year-old woman had a gastric ulcer which
`did not heal during treatment with antacids and a bland diet. Be-
`cause of the possibility of cancer, she underwent a vagotomy and
`gastric resection. The ulcer was benign. Heparin was started two
`hours before the operation and continued in the postoperative
`period. On the sixth postoperative day a fever of 39.20 developed.
`The chest roentgenogram showed bilateral pleural effusions; the
`lung scan was negative. Cephalothin was started and the fever re-
`solved in 48 hours.
`On the eighth postoperative day, purple tender lesions appeared
`at heparin injection sites. Within 24 hours three areas of necrosis
`were present which progressed to formation of hemorrhagic bullae.
`The black areas were surrounded by a ring of acutely painful
`erythema. Warm saline soaks were applied and pain resolved over
`four days. Two lesions resolved after discharge, but the largest lesion
`required excision and primary closure.
`Patient A.L. (Fig. SC) This 74-year-old woman with severe
`degenerative disease of her left hip was admitted for an arthroplasty.
`Her only other medical problem was mild hypertension. The
`hematocrit on admission was 44 and the platelet count 231,000. Sub-
`cutaneous heparin was started two hours before surgery and con-
`tinued in the postoperative period.
`On the ninth postoperative day, the right leg became cold and
`pulseless. A thrombectomy was performed and a continuous heparin
`drip instituted. Thereafter, the right leg was viable but two sub-
`sequent thrombectomies on the left leg did not restore adequate cir-
`culation. All thrombi were composed of aggregates of platelets and
`fibrinogen. Heparin was stopped 16 days after the initial operation
`and on the following day, the left leg was amputated above the knee.
`Platelets were decreased in number on all estimates done between
`postoperative day ten and 17, but the count rose rapidly when
`heparin was discontinued. The PTT never rose above 38 even though
`she was receiving 24,000 units of heparin daily.
`Patient S.H. This 58-year-old man was admitted for an arthroplasty
`of the left hip. He was otherwise healthy and had a normal hematocrit
`and platelet count. Prophylactic subcutaneous heparin was started
`on the third postoperative day. The patient made a rapid uncom-
`plicated recovery and was discharged 9 days after surgery (Fig. 5D).
`Two days later he was readmitted with right sided chest pain
`and fever. A right basilar opacity was seen on the chest roentgeno-
`gram. He was treated empirically with antibiotics and improved. A
`pulmonary embolus was suspected, however, and after a perfusion
`lung scan showed multiple right basilar defects, a continuous in-
`fusion of heparin was instituted. Within hours after the first dose of
`heparin, the patient sustained an acute inferolateral myocardial
`infarct. Simultaneously, he became confused and combative. A
`ventilation scan suggested that the perfusion defects were of in-
`flammatory origin but heparin was continued because a pulmonary
`embolus rather than pneumonitis was still suspected on clinical
`grounds. His legs became cyanotic and the pedal pulses were im-
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-4 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`Vol. 190 . No. 5
`
`COMPLICATIONS OF HEPARIN THERAPY
`
`CLINICAL COURSE Of i.0
`PLATELET COUNTS
`300-T
`250
`200 *
`15SO.
`100
`
`PTT
`40 -
`SEC.xCONT 30+
`20 +
`104..
`Cj.
`T' 39..
`38
`
`599
`
`&
`
`PTTi
`
`,
`
`PC
`
`_
`
`Prodnisone
`
`PTT
`SEC - CON T
`
`CLINICAL COURSE OF N.L.
`
`20 --
`
`T
`
`40 1-
`
`339'/1
`
`Copapirin
`
`Gentamscin. OxaciNli
`C.phalothn
`
`Chet Pain
`Skin Necrosis on Left
`Arthroplsty
`4
`
`Skin Necrosis on Right
`Excision of Lesiorn
`CVA
`4
`
`I 11
`
`NEPARIN
`uIEITS/
`24 hrs
`
`15.000
`
`10,000
`
`5 00
`
`PLATELET
`ESTIMATION N
`
`N
`
`DODDON
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`16
`14
`DAYS
`
`18 20
`
`22 24
`
`26 28 30
`
`CLINICAL COLIRSE OF A.L
`
`-
`
`FIG.
`5. Graphic demon-
`stration
`of the
`hospital
`courses of selected patients.
`(a, top left) Patient N. L.
`(b, top right) Patient M.O.
`(c, bottom left) Patient A. L.
`(d, bottom right) S. H. Diag-
`onal lines: subcutaneous in-
`jection. Dotted area:contin-
`uous infusion. Vertical lines:
`intermittent intravenous.
`
`Theophylline
`
`Torbutaline
`
`Warfarm
`
`Status Asthnticus
`
`HEPARIN
`UNITS 24 hrs
`
`25.000
`
`20.000
`
`15 000
`
`10.000
`
`5.000
`
`0
`
`PLATELET ESTIMATION
`
`N
`
`i
`
`Skill N*crosis
`
`Calf;Pai
`
`.............
`
`-*-*.......
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`DAYS
`
`16
`
`18 20 22 24
`
`26 28
`
`CLNICAL COURSE OF S.H.
`
`50T-
`PTT
`SEC.xCONT 40 +-
`
`30 ..
`20
`
`10+.
`
`C
`
`PLATELET COUNTSA
`300^
`250+
`200 .
`1SO
`
`1OO
`
`PTT
`30 '
`SEC.oCONT. 20
`104.
`C39
`TI3
`
`Cephapirhn
`|- Left Thrombectomies
`Right Thrombectomny |
`|
`Arthropbsty
`4
`
`I
`
`Amputation
`fLott Leg
`
`iEPANIN
`Units 24hrs.
`
`NEPARIN
`UNfTS/ 25.000.
`24 hrs.
`
`20.000 -
`
`15.000
`
`10000.
`
`5.000
`
`Tr 39,
`38*l
`37
`
`35.000 -
`
`30,000 -
`
`25,000
`
`20,000 -
`
`15.000
`
`10.000
`
`5.000 -
`
`0
`
`0 -
`
`PLATELET
`ESTIMATIOI
`
`.
`
`.
`
`2
`
`.
`
`.
`
`4
`
`.
`
`.
`
`6
`
`.
`
`.
`
`8
`
`.
`
`.
`
`10
`
`.
`
`.
`
`.
`
`.
`
`.
`
`14
`
`12
`DAYS
`
`.
`
`.
`
`16
`
`D
`
`.
`
`18
`
`..
`20 22 24
`
`PLATELET
`ESTIMATION
`
`i
`
`Dextran
`Warferin
`
`Cephaexin-
`C4phalothin
`
`Erythromycin.
`Cephelothin
`
`Skin Necrosis
`CyanosIs df~ ,js
`
`Redntt*d
`
`Arthropbety
`07M////
`
`+
`
`D
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`DAYS
`
`16
`
`18 20 22 24 26
`
`palpable. Nevertheless, arteriography demonstrated patent vessels.
`A diagnosis of "phlebitis with associated vasospasm" was made.
`As general deterioration continued, he had vivid hallucinations
`and severe leg pain. Warfarin and dextran were employed. The
`popliteal pulses disappeared and areas of skin necrosis appeared
`on both feet as well as large areas on the right thigh and left flank.
`Since the latter areas of necrosis were considered to be subcutaneous
`hemorrhage, all anticoagulants were stopped. Platelets were esti-
`mated only on the last day of treatment. They were noted to be
`markedly decreased.
`Within four days the patient's pain resolved and he was mentally
`alert. The left flank lesion was debrided and covered with multiple
`skin grafts. The right leg was amputated below the knee. Pathologic
`examination revealed skin and subcutaneous necrosis, but very mild
`ischemic changes in the calf muscles. Severe atherosclerosis af-
`fected the tibial arteries but they were patent. Recent thrombi
`filled the veins.
`
`Ten weeks after admission the patient suffered a second myo-
`cardial infarct. Heparin was continuously infused for 6 days with-
`out complications. The patient was discharged three weeks later.
`
`Results
`Table 1 summarizes the characteristics and admitting
`diagnoses of the six patients who developed skin
`necrosis at injection sites. All six patients were receiv-
`ing subcutaneous bovine heparin as a prophylactic
`measure against DVT. Five were recovering from a
`surgical procedure and one was immobilized following
`a femoral fracture. The patients ranged in age from 49 to
`77. All were Caucasian and five were women. All five
`women had two or more separate necrotic lesions,
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-5 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`600
`
`Patient
`
`H.D.
`N.L.
`R.U.
`N.M.
`M.O.
`N.R.M.
`
`WHITE, SADD AND NENSEL
`
`Ann. Surg. * November 1979
`
`TABLE 1. Charac-teristics of Patients with Skin Necrrosis
`
`Age
`
`Sex
`
`Primary Disease
`
`Other Diseases
`
`49
`55
`50
`77
`60
`56
`
`F
`F
`F
`M
`F
`F
`
`Degenerative arthritis
`Degenerative arthritis
`Bladder cancer
`Gastric cancer
`Femoral fracture
`Benign gastric ulcer
`
`Diabetes mellitus, obesity, hypertension
`Diabetes mellitus, obesity, hypothyroidism
`Ischemic heart disease
`
`Obesity, asthma
`Diabetes mellitus
`
`Procedure
`
`Hip arthroplasty
`Knee arthroplasty
`Ileal conduit
`Laparotomy
`
`Partial gastrectomy
`
`most of which were larger than the single lesion in the
`single male patient. Three patients were diabetic and
`three had undergone major osseous trauma.
`The total daily heparin dosage varied from 9,000 to
`20,000 units (Table 2). Six to nine days after treatment
`had begun, most patients complained of pain at the in-
`jection sites. Only patient N.M. denied discomfort. The
`quality of the pain was most often described as burn-
`ing. Within 6-12 hours of the first complaint, areas of
`necrosis had appeared. Over the next 24 hours the
`necrotic margins became well demarcated. The lesions
`were surrounded by a cuff of painful erythema. Over
`a period of four to six days, the inflammation resolved
`and the pain disappeared. All lesions were on the
`anterior abdominal wall except for one woman who
`received her final injections in the buttocks. Lesions
`of the abdominal wall often lay on a horizontal axis as if
`following a dermatomal distribution. The lesions on the
`buttocks of patient R.U. were circular. Bullae filled
`
`TABLE 2. Heparin Therapy and Results in
`Patients with Skin Necrosis
`
`Patients
`
`Dosage
`
`H.D.
`
`5,000 Q6H
`
`N.W.
`
`5,000 Q8H
`
`R.U.
`
`N.M.
`
`M.O.
`
`5,000 Q12H
`
`5,000 Q8H
`4 days
`3,000 Q8H-
`5 days
`5,000 Q8H
`
`N.R.M.
`
`5,000 Q12H
`
`Onset of
`Necrosis (Days
`After Heparin
`Instituted)
`
`6
`
`8
`
`8
`
`9
`
`9
`
`8
`
`Site & Size
`(in cm.)
`
`Abdomen
`R-30 x 10
`L-4 x 1
`Abdomen
`R-6.5 x 1.5
`L-3 x 2
`Buttocks
`2 lesions 2.5 x 2.5
`Abdomen
`R-10 x 5
`
`Abdomen
`R-25 x 3
`L-12 x 4
`Abdomen
`R-approximately
`12 x 10
`L-2 small lesions
`
`with serous fluid usually appeared soon after the
`necrotic lesions were demarcated. Three lesions were
`excised with primary closure of the defects, but only
`one was removed during the acute phase. A fourth
`lesion was biopsied.
`Table 3 lists the known drugs which the eight re-
`ported patients received immediately prior to their ad-
`
`TABLE 3. Medications Received by Patients with
`Thrombotic Complications of Heparin
`Medications Received Prior
`to Onset of Skin Necrosis
`or Thrombotic Event
`
`Medications Taken
`Prior to Admission
`
`Patient
`
`H.D.
`
`N.L.
`
`R.U.
`
`N.M.
`
`M.O.
`
`Ibuprofem
`Percodan
`Chlorthalidone
`Furosemide
`Triavil
`Fenoprofen Calcium
`Insulin
`Dessicated thyroid
`
`Dipyridamole
`Bufferin
`Triavil
`Pentazocine
`
`Percodan
`Flurazepam
`
`Hydrochlorthiazide
`Asbron
`
`Cephapirin
`Ibuprofen
`Meperidine
`Promethazine
`
`Cephapirin
`Insulin
`Meperidine
`Secobarbital
`Cephazolin
`Cephalexin
`Gentamicin
`Ampicillin
`Pentazocine
`Secobarbital
`Cephalothin
`Prochlorperazine
`Meperidine
`Promethazine
`Warfarin
`Prednisone
`Theophylline
`Terbutaline
`Meperidine
`Cephalothin
`Meperidine
`Cephapirin
`Meperidine
`
`Cephalothin
`Erythromycin
`Warfarin
`Dextran
`Morphine Sulfate
`
`N.R.M.
`
`None Recorded
`
`A.L.
`
`S.H.
`
`Phenylbutazone
`Indomethacin
`Ibuprofen
`Aspirin
`Chlorthalidone
`Phenylbutazone
`Indomethacin
`Aspirin
`Dessicated Thyroid
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-6 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`Vol. 190 * No. 5
`
`COMPLICATIONS OF HEPARIN THERAPY
`
`601
`
`X CHANCE
`IN
`OPTICAL
`DENSITY
`
`100-
`
`*0-
`
`so-
`
`70
`
`*0
`50
`
`40-
`
`30-
`
`20-
`
`10-
`
`P.C. 125,000
`
`N
`
`C
`
`o
`
`~
`
`~~~~1mm"-I
`
`PATIENT N.M.
`
`Platelet aggrega-
`FIG. 6.
`tion studies. (a, top left) Pa-
`tient N.M. (b, top right)
`Patient M.O. (c, bottom left)
`Patient N.R.M. (d, bottom
`right) Patient A.L.
`
`P.C. 170,000
`
`PATIENTY N1.O.
`
`P.C. 100,000
`
`100-
`
`.0-
`
`so-
`
`70-
`
`*0-
`
`so-
`
`40-
`
`30-
`
`20-
`
`10-
`
`100-
`
`*0-
`
`50-
`
`70
`
`SO0
`
`SO
`
`40
`
`30
`
`20
`
`10-
`
`c
`PATIENT M.-,
`
`C
`
`N
`
`PATIENT N.R.M.
`
`I
`
`A.L.
`
`PATIENT A.L.
`
`C-COLLAGEN 0.2 mg./mI. NH-OVINE NEPARIN 0.5-0.6 U"Its/mI.
`E -Epimephrlne SMM/mI.
`
`mission and during their hospital stay prior to the oc-
`currence of the skin necrosis or the thrombotic com-
`plication. Four of the six patients with skin necrosis
`and six of the total of eight patients were receiving
`nonsteroidal anti-inflammatory drugs on a regular basis
`before admission. Aspirin, ibuprofen, fenoprofen cal-
`cium, phenylbutazone and indomethacin all belong to
`this class of drugs. After being started on heparin only
`one patient received any of these drugs. Patient H.D.
`received ibuprofen on the first postoperative day but
`it was then discontinued. Thus six patients had a
`common history of chronic antiinflammatory drug use
`with cessation at the time of surgery or in the immediate
`postoperative period. It is also of note that seven of
`the eight patients received a cephalosporin derivative
`in the week prior to the appearance of necrosis.
`Little data on coagulation functions were recorded
`during the initial phases of necrosis. Prothrombin times
`were not obtained for any of the patients on the initial
`day of skin necrosis. Partial thromboplastin times were
`obtained for three patients and all were normal. None
`of the patients had platelet counts on the initial day of
`necrosis, but two patients had normal counts on the
`succeeding day and one had normal values two days
`before and two days after. After the lesions appeared,
`heparin was discontinued in four of the patients, but
`continued by the intravenous route in two others. In
`these two patients, platelet counts fell rapidly and both
`sustained complications possibly related to acute
`vascular occlusion.
`
`In vitro platelet aggregation studies were performed
`in four of the patients with skin necrosis at heparin
`injection sites, and also in the two patients with prob-
`able thrombotic complications of heparin. In no case
`was spontaneous platelet aggregation noted over a 20
`minute test period. All samples had a normal single
`phase response to ADP. Curves resulting from stim-
`ulation with epinephrine, collagen, and bovine heparin
`in four of the patients appear in Figure 6. Aggrega-
`tion with epinephrine yielded a normal biphasic curve
`except in patient S.H. who was receiving aspirin. Sec-
`ondary phase aggregation was not present in this
`patient. The aggregation curve following collagen stim-
`ulation was normal in all samples except that obtained
`from A.L. In this patient the response was delayed
`and of low amplitude. The cause of the poor response
`was not apparent. Table 4 lists the results obtained
`when bovine and porcine heparin were added to platelet
`rich plasma. The addition of bovine heparin caused sig-
`nificant aggregation in one to five minutes in five of the
`six patients tested. The curves generated by heparin
`most closely resembled those seen with collagen. Four
`of the eight patients were tested with porcine heparin.
`In two patients, H.D. and N.R.M., the response was
`comparable to that seen with bovine heparin. Patient
`A.L. responded strongly to bovine heparin but had no
`response to procine heparin. S.H., the one patient who
`did not respond to bovine heparin, had a weak response
`to porcine heparin. This last patient was the only pa-
`tient who is known to have received aspirin in the week
`
`WAVEFORM TECHNOLOGIES, INC.
`Exhibit 2015-7 (IPR2017-01051)
`Dexcom, Inc. v. WaveForm Technologies, Inc.
`
`

`

`602
`
`Patient
`
`H.D.
`N.L.
`R.U.
`N.M.
`M.O.
`N.R.M.
`
`A.L.
`S.H.
`
`TABLE 4. ReK'Slts ot Platelet Aggregaltion Stuidies
`
`Interval Since
`Last Heparin
`
`16 Months
`N.T.
`N.T.
`I Day
`I Day
`5 Weeks
`5 Months
`I Day
`2 Months
`
`Degree of
`Aggregation
`
`Bovine
`
`Porcine
`
`+
`
`++
`++
`++
`+
`++
`0
`
`+
`
`N.T.
`N.T.
`N.T.
`+
`0
`+
`
`prior to the performance of aggregation studies.
`Heparin-induced aggregation was not observed in any
`patient in the two control groups. All controls re-
`sponded normally to the other agents. Microscopic
`examination of the excised specimens and the one
`biopsy revealed extravasation of red cells into the
`dermis and subcutaneous tissue. Inflammation was
`minimal in the skin biopsy taken from patient N.M.
`approximately 36 hours after the onset of apparent
`necrosis. Other specimens were obtained 5-19 days
`after the onset of necrosis and showed marked lym-
`phocytic infiltration. The veins and capillaries were
`occluded by fibrin thrombi, but the arteries appeared
`spared. There was no evidence of vasculitis. The speci-
`men from patient N.M. was the only one tested for
`immunoglobulin and complement deposits. This speci-
`men had a fine granular deposit of IgM and comple-
`ment C'3 along the dermal-epidermal junction but not
`in vascular or perivascular tissue. This patient had no
`history of schleroderma.
`
`Discussion
`Skin necrosis at the site of heparin injections has
`been previously reported in only six patients. O'Toole40
`reported four patients in 1973. After five to nine days of
`treatment, erythema developed at injection sites and
`progressed to frank necrosis of skin and underlying
`fat. One middle-aged woman was given subcutaneous
`heparin following a total hip arthroplasty. A necrotic
`lesion developed on the seventh postoperative day,
`heparin was discontinued, and 36 hours later she had
`pulmonary embolization. When 6,000 units of heparin
`was administered intravenously, she gradually became
`confused and hypotensive. Administration of epi-
`nephrine reversed these symptoms, warfarin was used
`for anticoagulation, and the patient recovered.
`Hume25 reported a patient in 1973 who developed
`4 areas of skin necrosis on his abdomen while re-
`ceiving 5,000 units of heparin every eight hours. He
`was recovering from a total hip replacement. A his-
`
`WHITE, SADD AND NENSEL
`
`Ann. Surg. o November