A SELF-TEST IM BOARD REVIEW DAVID L. LONGWORTH, MD, JAMES K STOLLER, MD, EDITORS OF CLINICAL PETER MAZZONE, MD CRAIG NIELSEN, MD RECOGNITION Department of General Internal Medicine, Department of General Internal Medicine, 1 Cleveland Clinic. Cleveland Clinic.

A 61-year-old woman with and a

61-YEAR-OLD WOMAN with a history of rate 20. She was not in acute distress. 0seizures was transferred to our facility Examination of her skin revealed confluent from another hospital for further evaluation macular purpuric lesions involving the entire and management of a rash and a low body and face, with relative sparing of the count. palms and soles. Purpuric were also The woman was initially admitted to the found on the back of her hands and legs. other hospital 4 weeks earlier due to the onset There was also conjunctival injection with of focal seizures. An extensive evaluation periorbital edema, but mucous membranes revealed no etiology for the seizures. She was were clear. The chest was normal on ausculta- discharged home with her seizures well con- tion, and no wheezes were heard. Her cardiac trolled with phenytoin. Approximately 3 examination was normal. There was no weeks later, she noticed a diffuse rash without detectable organomegaly, and a stool test for any other associated symptoms. Her primary occult blood was positive. She had strong physician discontinued the phenytoin and peripheral pulses with no edema. substituted carbamazepine. Two days later she felt that her rash had worsened, and she • LABORATORY RESULTS AT ADMISSION became frustrated and stopped taking all of Platelet her medications. She presented to the emer- Laboratory results at the time of her admission destruction gency department 2 days later with diarrhea, to our facility are listed in TABLE 1. Her white polyuria, and polydypsia. At that time a blood blood cell count was 21.4 x 10y/L (54% neu- can be due to workup revealed a plasma glucose level of 824 trophils, 19% lymphocytes, and 15% immune or mg/dL and a platelet count of 10 x 109/L. She eosinophils), with a hemoglobin (Hgb) of was admitted to the hospital and was later 11.8 g/dL and a platelet count of 5 x 10y/L. nonimmune transferred to our facility. Results of studies were normal. processes Medical history. A review of her medical A peripheral blood smear was immediately history showed type 2 diabetes requiring reviewed, showing leukocytosis with immature insulin; asthma; and the focal seizures men- neutrophils (ie, left shift), eosinophils, and tioned above. Current and recent medications decreased . There was no evidence of included NPH insulin 40 U every morning red cell fragments, target cells, or schistocytes. and 20 U every evening; carbamazepine (stopped 2 days prior to transfer); phenytoin LOW PLATELET COUNT (stopped 9 days prior to being transferred to our facility); and albuterol and ipratropium This patient's low platelet count might bromide inhalers. Her only known drug aller- 1 result from each of the following, except gy was to glipizide. She did not smoke or drink which one? alcohol. Physical findings. On physical examina- • Drug effect tion, she appeared comfortable. Her tempera- • Pseudothrombocytopenia ture was 37.2°C, heart rate 100 bpm (regular), • Immune platelet destruction blood pressure 142/84 mm Hg, and respiratory • Nonimmune platelet destruction

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TABLE 1 Decreased production of platelets can be Laboratory test results caused by an insult to the hematopoietic cells (eg, from cytotoxic therapy, drugs, toxins, at the time of hospital admission infections, aplasia) or replacement of other- STUDY VALUE NORMAL RANGE wise normal marrow (eg, as in infiltration of the marrow by malignant cells, myelofibrosis). Sodium 124 mmol/L 132-146 Platelet sequestration is usually due to Potassium 4.5 mmol/L 3.5-5.0 functional hypersplenism (eg, as in cirrhosis, passive congestion, malignancy, infections). Chloride 94 mmol/L 98-110 Platelet destruction can be due to Carbon dioxide 23 mmol/L 24-32 immune or nonimmune processes. Immune Blood urea nitrogen 46 mg/dL 8-25 causes include idiopathic thrombocytopenic Creatinine 1.5 mg/dL 0.7-1.4 , transfusion-related alloimmune Glucose 685 mg/dL 65-110 thrombocytopenia, and drugs. Nonimmune Bilirubin 1.4 mg/dL 0-1.5 processes include disseminated intravascular coagulation, thrombotic thrombocytopenic Lactate dehydrogenase (LDH) 685 U/L 100-220 purpura, sepsis, mechanical destruction, and Alkaline phosphatase 340 U/L 20-120 again, drugs. Aspartate aminotransferase (AST) 35 U/L 7-40 Hemoglobin 11.8 g/dL 12-16 • THE INITIAL HOSPITAL COURSE White blood cells 21.4 x 109/L 4.0-11.0 Neutrophils 54% 40-70 On admission to oar hospital, the patient underwent hydration with normal saline and Lymphocytes 19 % 15-45 received insulin intravenously. Phenobarbital Eosinophils 15 % 1-6 was substituted for her prescription for carba- Platelets 5 x 109/L 150-400 mazepine. Red blood cells 4.05 x 1012/L 4.2-5.4 A consultation was obtained. Bone marrow aspiration was performed, and microscopic examination of the aspirate revealed a cellular marrow with megakary- Investigating a low platelet count requires an ocytes. These findings suggested a peripheral organized approach, making efficient and loss of platelets. The clinical picture and the accurate use of available diagnostic tests and results of bone marrow analysis were felt to be treatments. consistent with idiopathic thrombocytopenic First, one must determine if the low purpura. Treatment with intravenous platelet count signifies true thrombocytopenia immunoglobulin and two units of platelets was or pseudothrombocytopenia. Pseudothrom- started. bocytopenia occurs when platelets clump in Over the next 2 days the patient com- an EDTA anticoagulated tube. Platelet clumps plained of a sore throat and was noted to have are seen on the peripheral smear, and a normal a temperature of 38.3°C. She was drowsy. platelet count is obtained from a heparinized Several laboratory values during this time tube. were notable: the Hgb fell from 11.8 g/dL to Our patient's peripheral smear revealed a 10.0 g/dL, then 8.9 g/dL. The platelet count decreased number of platelets without platelet remained below 10 x 109/L (6 x 109/L). clumping. Thus, it appears that she had true Her lactate dehydrogenase (LDH) thrombocytopenia, making pseudothrombo- increased to 1844 U/L, bilirubin to 2.4 mg/dL, cytopenia the correct choice above. and AST to 105 U/L. Alkaline phosphatase decreased to 263 U/L. A dipstick urinalysis Causes of thrombocytopenia found 3+ Hgb and no bilirubin. A microscop- Thrombocytopenia can be secondary to ic examination of the urine found more than decreased production of platelets, sequestration 25 red blood cells and 11 to 25 white blood of platelets, or destruction of platelets (TABLE 2). cells per high-powered field.

210 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • NUMBER 4 APRIL 1998 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. HEMOLYSIS TABLE 2 Differential diagnosis of A decreasing level of which of the follow- thrombocytopenia by cause ing would provide evidence that hemoly- sis is occurring Caused by decreased platelet production Hematopoietic cell insult • Urine hemosiderin Cytotoxic therapy • LDH Drugs • Methemalbumin Toxins • Haptoglobin Infections Aplasia Several of the above laboratory results suggest Bone marrow replacement hemolysis. When evaluating a patient for Malignant cells hemolysis, several tests should be considered. Myelofibrosis During hemolysis, the reticulocyte count increases to compensate for the falling Hgh Caused by platelet sequestration level. LDH and bilirubin are released and thus Functional hypersplenism elevated, whereas the haptoglobin and hemo- Cirrhosis pexin levels fall as they bind to free hemoglo- Passive splenic congestion bin and are quickly cleared in the liver. Free Malignancy hemoglobin is oxidized to methemoglobin, Infection which subsequently splits from the globin por- Caused by platelet destruction tion and binds to free albumin, causing a rise Immune processes in methemalbumin levels. The heme tetramer Idiopathic thrombocytopenic purpura splits to a dimer, is filtered in the kidney, and Transfusion related is absorbed by the renal tubules, where the Drugs iron is stored as hemosiderin. As the tubular Nonimmune processes cells die, they slough into the urine, leading to Disseminated intravascular coagulation an elevated urine hemosiderin level. Thrombotic thrombocytopenic purpura During Thus, erf the choices above, haptoglobin is Sepsis hemolysis, the only one that decreases during hemolysis. Mechanical destruction Drugs the • ANALYZING THE CAUSES OF HEMOLYSIS reticulocyte

There are several ways to organize the causes count rises to of hemolysis. One way is to divide the causes counter the into intrinsic red blood cell abnormalities and Review of our patient's subjective and abnormalities not intrinsic to red blood cells objective problems revealed the characteristic falling Hgb (TABLE 3). pentad of thrombotic thrombocytopenic pur- Intrinsic abnormalities can be congenital, pura (see below). such as membrane defects (eg, spherocytosis, elliptocytosis) and enzymopathies (eg, glucose- • THROMBOTIC THROMBOCYTOPENIC 6-phosphate dehydrogenase deficiency), or PURPURA acquired, such as lead poisoning, paroxysmal nocturnal hemoglobinuria, and renal failure. Most patients with thrombotic thrombocy- Extrinsic abnormalities include microan- 3 topenic purpura will have all of the follow- giopathy (eg, disseminated intravascular coag- ing laboratory results, except which one? ulopathy, thrombotic thrombocytopenic pur- pura, eclampsia, and malignant hyperten- • Low hemoglobin sion), hypersplenism, sepsis, and immune • Creatinine above 1.5 mg/dL causes (eg, drugs, infections, lymphoma, colla- • Normal coagulation studies gen vascular diseases). • Elevated LDH

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TABLE 3 thrombocytopenia are usually severe at pre- sentation. Fever is uncommon initially but Differential diagnosis invariably develops. Neurologic manifesta- of hemolysis tions, including headache, confusion, cranial Intrinsic red blood cell abnormalities nerve palsies, seizures, and coma can progress Congenital rapidly. Renal dysfunction is manifested by an Membrane defects abnormal urinary sediment. Fewer than 20% (eg, spherocytosis, eliiptocytosis) of patients develop a serum creatinine above Enzymopathies 1.5 mg/dL; therefore, this is the correct (eg, glucose-6-phosphate answer. dehydrogenase deficiency) Acquired Associated underlying disorders Lead poisoning Thrombotic thrombocytopenic purpura is Paroxysmal nocturnal hemoglobinuria associated with a definable underlying disor- Renal failure der in 15% of cases. Pregnancy, collagen vas- cular diseases, allograft rejection, and infec- Extrinsic red blood cell abnormalities tion (Escherichia coli 0157:H7) lead the list. Microangiopathy Laboratory findings include evidence of Disseminated intravascular coagulation hemolysis (see above), normal coagulation Thrombotic thrombocytopenic purpura studies, and a peripheral blood smear showing Eclampsia polychromasia, stippling, nucleated red cells, Malignant hypertension and schistocytes. Bone marrow aspirate reveals Hypersplenism normoblastic hyperplasia and increased Sepsis megakaryocytes. Biopsy of the skin, muscle, Immune causes and gingiva has a low diagnostic yield. Drugs Infections (eg, Epstein-Barr virus, • TREATMENT OF CHOICE Mycoplasma) Biopsy of the Lymphoma Exchange plasmapheresis is the treatment of Collagen vascular diseases skin, muscle, choice for thrombotic thrombocytopenic pur- pura, although its exact mechanism of action and gingiva is unknown. Plasmapheresis is felt to be more has a low effective than plasma infusion alone. Many Thrombotic thrombocytopenic purpura is a other therapies have been used, either with diagnostic syndrome of disseminated thrombotic occlu- disappointing results or with success in only a yield sions of the microcirculation, with five char- few cases. These include splenectomy, prosta- acteristics: cyclin, antiplatelet drugs, corticosteroids, and • Hemolytic anemia vincristine. Platelet transfusions should be • Thrombocytopenia avoided unless evidence of life-threatening • Neurologic symptoms hemorrhage is present, as acute deterioration • Fever in status has been reported (more platelets • Renal dysfunction available to form microthrombi, leading to Microthrombi and fibrin networks are laid further end-organ damage). Intravenous down in the small vessels, although the reason immunoglobulin has not been proven effec- is unclear. Red blood cells are damaged by these tive and may even be harmful. networks and are destroyed in the spleen or the Currently, after treatment with plasma- microcirculation. Platelets are either consumed pheresis, 80% to 90% of patients survive the in the microthrombi or damaged and removed first episode with no sequelae or minimal by the reticuloendothelial system. sequelae. Approximately one third experi- Only 40% of patients go on to develop the ence a relapse within 10 years, usually full pentad, and even fewer have the full pen- responding to the same therapy as the initial tad at initial presentation. Anemia and episode.

212 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • NUMBER 4 APRIL 1998 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. • FURTHER HOSPITAL COURSE TABLE 4

The next day the patient again was drowsy Adverse effects of phenytoin and complained of "feeling down." Her labo- Concentration-dependent reactions ratory values continued to deteriorate. Her Nystagmus LDH increased to 2149 U/L, bilirubin Ataxia increased to 2.9 mg/dL, and her AST Incoordination decreased slightly to 98 U/L. Her hemoglobin Dysarthria continued its fall, to 7.4 g/dL, as did her platelet count, to 6 x 109/L. Lethargy Her haptoglobin was less than 6 mg/dL Nausea (normal range 37-246 mg/dL), and her Vomiting peripheral blood smear revealed red blood cell Epigastric pain fragments. As she was being prepared for plasmapheresis, she went into cardiopul- Idiosyncratic reactions monary arrest. Resuscitation efforts were Gingival hyperplasia unsuccessful. Hirsutism It appears that the patient had thrombot- ic thrombocytopenic purpura. However, this Rash does not explain all of her problems, such as Toxic epidermal necrolysis rash and eosinophilia. These raise the suspi- Stevens-Johnson syndrome cion of a drug reaction. Aplastic anemia Hepatitis SI PHENYTOIN'S ADVERSE EFFECTS Phenytoin hypersensitivity syndrome

Which of the following adverse effects of 4 phenytoin is idiosyncratic?

• Nystagmus within 3 weeks to 3 months after starting The rash and • Ataxia phenytoin therapy. African Americans have eosinophilia • Nausea the highest incidence. Rash is one manifesta- • Gingival hyperplasia tion: or maculopapules may be point to a seen, and the rash may exfoliate, show follic- drug reaction The adverse effects of phenytoin can be divid- ular accentuation with pustules, or lead to ed into those that increase in frequency and or toxic epidermal severity with the plasma concentration of the necrolysis. drug and those that are idiosyncratic (TABLE 4). Other manifestations include edema Nystagmus, ataxia, incoordination, dysarthria, (prominent facial edema is characteristic), lethargy, nausea, vomiting, and epigastric pain pharyngitis, conjunctivitis, adenopathy, are all concentration-dependent. hepatosplenomegaly, fever, anorexia, myopa- Idiosyncratic reactions include gingival thy, and diarrhea. hyperplasia, hirsutism, acne, many varieties of Laboratory manifestations of phenytoin rash (including toxic epidermal necrolysis and hypersensitivity syndrome include leukocyto- Stevens-Johnson syndrome), aplastic anemia, sis with eosinophilia, elevated transaminases, hepatitis, and the phenytoin hypersensitivity Coombs-negative hemolytic anemia, intersti- syndrome. Thus, of the choices listed, gingival tial nephritis, and thrombocytopenia. hyperplasia is the only idiosyncratic adverse Phenobarbital and carbamazepine can effect. cause a similar reaction that is indistinguish- able from phenytoin hypersensitivity syn- Phenytoin hypersensitivity syndrome drome. In susceptible patients, the detoxifica- The phenytoin hypersensitivity syndrome tion of the reactive arene oxide metabolites of occurs in 1 in 1,000 to 1 in 10,000 patients these aromatic anticonvulsants is abnormal.

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This is inherited in an autosomal-codominant pattern. MAY MANAGEMENT OF THE DIFFICULT AIRWAY Immediate discontinuation usually leads May 2 Omni International Hotel, Cleveland to total recovery without sequelae. Deaths have been reported with severe liver disease, UPDATE ON HEADACHE MANAGEMENT May 6 , or sepsis, or upon accidental Omni International Hotel, Cleveland reexposure. Corticosteroids are not effec-

DERMATOLOGY: MAY THERAPY tive. May 13 (morning only) Omni International Hotel, Cleveland Our patient's clinical presentation and course are in keeping with thrombotic throm- 5TH ANNUAL CONFERENCE ON INFLAMMATORY BOWEL DISEASE bocytopenic purpura secondary to the pheny- May 29-30 toin hypersensitivity syndrome, of which there is one previous case report by Hirsh (see 21 ST ANNUAL MIDWEST GLAUCOMA SYMPOSIUM May 29-30 Suggested Reading). Unfortunately, although Ritz-Carlton Hotel, Cleveland phenytoin therapy was discontinued early in JUNE her course, both of the drugs that were substi- OCCUPATIONAL AND ENVIRONMENTAL MEDICINE IN THE 21 ST CENTURY: NEW APPROACHES TO OLD PROBLEMS tuted—ie, carbamazepine and phénobarbi- June 4-5 tal—can lead to the same reaction in suscepti- Omni International Hotel, Cleveland ble patients. ü TENTH ANNUAL INTENSIVE REVIEW OF INTERNAL MEDICINE June 7-12 • SUGGESTED READING Renaissance Cleveland Hotel

Bithell T. Thrombotic thrombocytopenic purpura and other A U C U S T forms of nonimmunologic platelet destruction. In: Lee CR, 15TH INTERNATIONAL FIBRINOGEN WORKSHOP August 13-15 Bithell T, Foerster J, AthensJ, Lukens J, editors. Wintrobe's Renaissance Cleveland Hotel Clinical Hematology. 9th ed. Philadelphia: Lea and Febiger, 1993; 1356-1373. HORIZONS IN PULMONARY AND CRITICAL CARE MEDICINE August 27-28 Bourgeois BF. Pharmacologic intervention and treatment of childhood seizure disorders: relative efficacy and safety of PEDIATRIC BOARD REVIEW antiepileptic drugs. Epilepsia 1994; 35 Suppl 2:18-23. August 31-September 4 Conger LA Jr, Grabski WJ. Dilantin hypersensitivity reac- SEPTEMBER tion. Cutis 1996; 57:223-228. ENDOCRINOLOGY BOARD REVIEW September 10-12 Gillis S. The thrombocytopenic purpuras. Recognition and management. Drugs 1996; 51:942-953. COMPUTERS IN CARDIOLOGY 1998 September 13-16 Renaissance Cleveland Hotel Graves NM, Ramsay RE. Phenytoin and fosphenytoin. In: Wyllie E, editor. The Treatment of Epilepsy: Principles and OPHTHALMOLOGY Practice. 2nd ed. Philadelphia: Williams and Wilkins, September 18-19 1996:833-838.

ADOLESCENT MEDICINE Hirsh LF. , thrombotic thrombocytopenic purpura, September 25 and stroke after aneurysm surgery. Surgical Neurology 1982; 17:426-428. OCTOBER INTERNATIONAL TRANSPLANT CONFERENCE ADDRESS: Peter Mazzone, MD, Internal Medicine Residency October 2^1 Cleveland Marriott Hotel at Key Center Program, P39, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. HEART FAILURE October 9-10 Renaissance Cleveland Hotel

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