Ticlopidine

A 64-year-old man presented with worsening dyspnea on exertion and hemothorax of the left chest 7 days after discharge from the hospital on ticlopidine and aspirin after coronary stent placement to his left circumflex artery. He had suffered traumatic rib fractures to the seventh, eighth, and ninth left ribs 28 days before this presentation and 21 days before starting the ticlopidine. Results of chest radiography at discharge 7 days earlier while on aspirin and after brief IV heparin had been negative except for minimal atelectasis and rib fractures barely visible on posteroanterior view. The delayed hemothorax had lowered the peripheral blood hematocrit to 23% and required tube thoracostomy drainage and blood transfusion. The delayed traumatic hemothorax in this ease occurred on treatment with ticlopidine and did not recur with continuation of aspirin alone. (CHEST 1999; 116:257-260)

Key words: aspirin; coronary stent; hemothorax; percutaneous transluminal coronary angioplasty; pleural effusion; rib fracture; ticlopidine

Ticlopidine is a potent inhibitor of platelet aggregation and acts via the adenosine diphosphate pathway. At present, ticlopidine has therapeutic indications in two common illnesses: coronary artery disease and cerebrovascular disease. Ticlopidine therapy may cause a wide range of side effects and toxicities affecting multiple organ systems, but it most commonly causes hematologic abnormalities.[1]

Rib fractures are often associated with pneumothorax or hemothorax, especially in multiple traumatic injuries such as motor vehicle accidents.[2,3] Hemothorax when associated with rib fractures usually follows within hours after the trauma. A MEDLINE search of the literature from 1966 to 1998 revealed only two references citing delayed traumatic hemothorax occurring [is greater than] 24 h after rib fracture.[4,5]

We describe a ease of delayed traumatic hemothorax presenting 28 days after rib fractures and 7 days after the addition of ticlopidine to aspirin therapy after coronary stent placement. The hemothorax had not developed while the patient was being treated for coronary ischemia with aspirin or heparin. This unusual complication of ticlopidine had not previously been reported. Common traumatic injuries such as rib fractures may occur in patients receiving ticlopidine. This report serves to raise the index of suspicion for delayed hemorrhage complicating such injuries.

CASE REPORT

A 64-year-old white man presented with a complaint of worsening dyspnea on exertion and new left pleural effusion 28 days after suffering traumatic fracture of three left ribs (Fig 1). He had previously been admitted to the hospital 10 days earlier for unstable angina and treated initially with aspirin and [Beta]-adrenergic blockade. Coronary angiography had revealed significant one-vessel disease in the circumflex artery. He received treatment with coronary angioplasty and coronary stent placement. During the catheterization, he received unfractionated heparin as an IV bolus of 8,000 U followed by an IV infusion of 1,000 U/h for 2 h. A chest radiograph obtained 1 day after the stent procedure on the day of discharge revealed mild left lung atelectasis caused by fractures of the seventh to ninth ribs (Fig 2). The rib fractures had occurred 28 days before the admission with hemothorax as a result of an accidental fall onto the wooden arm of a couch. Rib pain, which worsened on deep inspiration, had slowly improved. His discharge medications after stenting included ticlopidine, 250 mg bid, and aspirin, 325 mg/d. Dyspnea on exertion now was occurring at [is less than] 50 feet of level walking compared with a baseline of 2 blocks. Cough and sputum production had also slightly increased. He denied recurrent anginal chest pain or any other chest pain or pressure. Additional medical history included left ventricular systolic dysfunction with an ejection fraction of 35%, a remote myocardial infarction, moderate COPD, hypertension, and remote tobacco use. Review of systems was otherwise noncontributory to include a negative history for alcohol use, tuberculosis, or positive purified protein derivative test. There was no history of additional traumatic injury.

Physical examination revealed a man who appeared ill and older than stated age with the following vital signs: temperature, 36.6 [degrees] C; respiratory frequency, 24 breaths/min; pulse oximetry, 92%; pulse, 68 beats/min; and BP, 119/55 mm Hg. Chest examination revealed crackles at the right base and decreased breath sounds over the lower half of the left lung field, with corresponding dullness to percussion and decreased tactile fremitus. Cardiac examination revealed regular rate and rhythm without murmur, rub, or gallop. There was no jugular venous distention or hepatojugular reflux. Abdominal examination was unremarkable. Rectal examination was negative for occult blood. Extremity examination revealed stable 2+ pitting edema to the knees bilaterally with skin changes consistent with chronic stasis with normal sensation.

Laboratory evaluation of the peripheral blood revealed the following: WBC count, 18,600/[micro]L with a normal differential; BBC count, 2,500,000/[micro]L; hematocrit, 24% (baseline, 41% 1 week earlier); and platelet count, 481 x [10.sup.9]/L. Coagulation studies revealed a prothrombin time of 11.3 s and a partial thromboplastin time of 28 s. The results of electrolyte and glucose tests were normal, and renal function tests revealed the BUN level at 39 mg/dL and creatinine level at 1.7 mg/dL compared with baseline values of 20 mg/dL and 1.1 mg/dL, respectively. The results of liver function tests were normal except for an alkaline phosphatase of 19.6 U/L (normal, 36 to 124 U/L). The results of antinuclear antibodies were found to be normal. ECG revealed normal sinus rhythm with nonspecific ST-wave and T-wave changes.

The decline in hematocrit, a new left pleural effusion, and absence of signs or symptoms consistent with GI bleeding suggested the diagnosis of hemothorax, and pleural fluid analysis confirmed it. Thoracentesis with analysis of the pleural fluid revealed an BBC count of 1,230,000/[micro]L and a WBC count of 18,000/[micro]L, with a differential count of 45% neutrophils, 46% lymphocytes, 1% eosinophils, and 8% macrophages. The results of a culture and a Gram's stain of the fluid were negative for bacteria. Chest CT scan excluded retroperitoneal hemorrhage.

Ticlopidine therapy was discontinued, but the aspirin therapy was continued to prevent stent occlusion. The patient received a transfusion with 3 U of packed RBCs. His hematocrit rose to 31% and remained stable (at 30.5%) until discharge. Initial chest tube placement yielded a return of 1.6 L of bloody fluid in the first 15 min and an additional 0.7 L during the first 24 h after chest tube placement. Output amounted to 0.3 L during the second day. At that time, instillation of urokinase increased output to approximately 0.75 L per day. The chest tube was removed after 4 days with substantial improvement. A follow-up chest radiograph several months later revealed no effusion.

DISCUSSION

We have reported a case of delayed traumatic hemothorax presenting 28 days after rib fractures and 7 days after the addition of ticlopidine to aspirin therapy after stent placement. This unusual complication of ticlopidine had not previously been reported. Common traumatic injuries such as rib fractures may occur in other patients receiving ticlopidine. This report serves to raise the index of suspicion for delayed hemorrhage complicating such injuries in patients receiving combined antiplatelet therapy.

Rib fractures occur in 7 to 10% of multiple trauma admissions.[2,3] Motor vehicle accidents represent the most common cause of rib fractures.[2,6,7] Rib fractures are often associated with other injuries such as pneumothorax or hemothorax in one third of cases and extremity fractures, splenic injury, hepatic injury, CNS injury, and thoracic aorta injury in others.[2,3,8,9] As the number of rib fractures increases, so does the mortality, such that with seven or more rib fractures the mortality approaches 30%.[2,8] Approximately 50% of rib fractures will not be detected by plain posteroanterior chest films; however, most will be detected on physical examination of the conscious patient.[10]

Hemothorax associated with rib fractures usually follows within hours after the trauma. A MEDLINE search of the literature from 1966 to 1998 revealed only one reference[4] in the English-language literature citing delayed hemothorax occurring [is greater than] 24 h after rib fracture. Ross and Cordoba[4] described two eases of delayed hemothoraces 3 and 4 days after rib fractures. A report in the Chinese-language literature (abstracted in English) also cited multiple rib fractures, vascular injuries, and foreign body retention among the causes of delayed hemothorax.[5] Penetrating traumatic injury to the internal mammary artery has also caused delayed hemothorax in which the hemothorax presented within 4 h of injury in most eases, but took as long as 6 clays to present in one case.[11] An unusual and fatal ease of delayed hemothorax in a 12-year-old girl resulted from an atypical dissection of a traumatic carotid aneurysm a week after a sledding accident.[12] Iatrogenically induced delayed hemothoraces caused by procedures such as subclavian access for hemodialysis, as well as vascular surgery with prosthetic graft placement, have been reported.[13,14]

We believe that the ticlopidine is responsible for the development of the delayed hemothorax in our patient. Ticlopidine, a thienopyridine derivative, is structurally and functionally unrelated to other platelet aggregation inhibitors such as aspirin, sulfinpyrazone, and dipyridamole. Aspirin, which is commonly used in coronary artery disease and cerebral vascular disease, inhibits platelet aggregation through the arachidonic acid pathway. Ticlopidine appears to act through the adenosine diphosphate pathway by inhibiting the platelet 2-methylthio-adenosine diphosphate-binding receptor subtype and the adenosine diphosphate-induced exposure of the fibrinogen binding site of the platelet glycoprotein IIb/IIIa receptor.[15,16]

Ticlopidine has different effects from aspirin in comparison studies of induction of platelet aggregation. Ticlopidine administered at 200 mg qd significantly reduced the amount of platelet aggregation caused by adenosine diphosphate (59% decrease) and platelet activating factor (48% decrease), but did not significantly affect the aggregation induced by arachidonic acid (17% decrease). Aspirin administered at 300 mg qd significantly reduced arachidonic acid- and adenosine diphosphate-induced aggregation by 83% and 37% decrease, respectively, but did not significantly reduce the platelet activating factor-induced aggregation (28% decrease).[17] Additional studies showed that ticlopidine potentiates the inhibitory effects of aspirin and other nonsteroidal anti-inflammatory drugs on the collagen-induced platelet aggregation. Aspirin had no effect on the inhibition of the adenosine diphosphate-induced platelet aggregation by ticlopidine.[18]

Multiple-dose ticlopidine causes inhibition of the adenosine diphosphate-induced platelet aggregation within 24 to 48 h after initiating therapy. A two- to threefold increase in bleeding times has been reported with ticlopidine. Maximal effects are achieved within 3 to 7 days after initiating therapy. These effects persist after withdrawal of ticlopidine for the lifetime of the platelet.[1,19]

We hypothesize that ongoing microvascular trauma from recurring displacement of unstable rib fractures caused small recurrent hemorrhages, which in the presence of ticlopidine antiplatelet therapy resulted in the hemothorax. We infer that platelet plug stability while on aspirin alone had been sufficient to maintain hemostasis. The additional effects of ticlopidine may have caused platelet plug instability, which, in the setting of ongoing microvascular trauma, resulted in hemorrhage and development of the hemothorax.

Ticlopidine therapy is associated with a wide range of side effects and toxicities, including gingival hemorrhage, hemarthrosis, hematuria, bleeding from the arterial junction of an arteriovenous shunt, and postoperative bleeding, as well as neutropenia, thrombocytopenia, and anemia and thrombotic thrombocytopenic purpura. GI side effects include dyspepsia, gastritis with bleeding, abdominal pain, nausea, and diarrhea. Hepatic effects include elevated liver function test results and cholestatic jaundice. Dermatologic effects most commonly consist of maculopapular or urticarial rashes and promptly resolve with discontinuation of ticlopidine.[1,20] There have been no reports to date that ticlopidine impairs wound healing. Also we are unaware of any thrombolytic or fibrinolytic effects of ticlopidine.

For the present time, it appears reasonable to carefully monitor patients who have had similar blunt trauma injuries after starting ticlopidine. Delay of elective interventions requiring ticlopidine or selection of other alternatives appears appropriate in patients after blunt trauma, fractures, and possibly invasive procedures. The "safe" interval to begin ticlopidine after injury remains to be determined, but appears to be not [is less than] 4 weeks. Future studies may be helpful in defining the risk and refining the recommendations for combined antiplatelet therapies.

In conclusion, we report a ease of transfusion-requiring delayed hemothorax presenting 4 weeks after traumatic rib fractures. Hemothorax developed while the patient was receiving combination antiplatelet aggregation therapy with aspirin and ticlopidine to prevent coronary stent thrombosis. No hemothorax had developed earlier when the patient was receiving aspirin and brief IV heparin for coronary ischemia. Hemorrhage resolved after discontinuing ticlopidine.

REFERENCES

[1] Di Perri T, Pasini FL, Frigerio C, et al. Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration. Eur J Clin Pharmacol 1991; 41:429-434

[2] Ziegler DW, Agarwal NN. The morbidity and mortality of rib fractures. J Trauma 1994; 37:975-979

[3] Shorr RM, Critteden M, Indeck M, et al. Blunt thoracic trauma: analysis of 515 patients Ann Surg 1987; 206:200-205

[4] Ross RM, Cordoba A. Delayed life-threatening hemothorax associated with rib fractures. J Trauma 1986; 26:576-578

[5] Fang XH. Delayed hemothorax after chest injuries: report of 31 cases. Chung Hua Wai Ko Tsa Chih 1992; 30:212-213, 254

[6] Newman RJ, Jones IS. A prospective study of 413 consecutive care occupants with chest injuries. J Trauma 1984; 24:129-135

[7] Kaplan BH, Crowley A. Seatbelt effectiveness and cost of non-compliance among drivers admitted to a trauma center. Am J Emerg Med 1991; 9:4-10

[8] Wilson RF, Murray C, Antonenko DR Nonpenetrating thoracic injuries. Surg Clin North Am 1977; 57:17-36

[9] Poole GV, Myers RT. Morbidity and mortality rates in major trauma to the upper chest. Ann Surg 1981; 193:70-75

[10] Pate JW. Chest wall injuries. Surg Clin North Am 1989; 69:59-70

[11] Ritter DC, Chang FC. Delayed hemothorax resulting from stab wounds to the internal mammary artery. J Trauma 1995; 39:586-589

[12] Kaplan JA. Delayed fatal hemothorax due to traumatic carotid dissection: a case report of a previously unreported cause of death. J Forensic Sci 1994; 39:552-556

[13] Waldman RP, Donner M, Bilsky AC, et al. Delayed onset of hemothorax: an unusual complication of subclavian access for hemodialysis. Nephron 1984; 37:270-272

[14] Kondob S, Moizumi Y, Akasaka J, et al. A case of hemothorax occurred two months after graft replacement of descending thoracic aorta with hemashield arterial prosthesis [abstract]. Nippon Kyobu Geka Gakkai Zasshi 1995; 43:96-99.

[15] Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993; 4:252-261

[16] Cahill M, Mistry R, Barnett DB. The human platelet fibrinogen receptor: clinical and therapeutic significance. Br J Clin Pharmacol 1992; 33:3-9

[17] Uchiyama S, Sene R, Nagayama T, et al. Combination therapy with low dose aspirin and ticlopidine in cerebral ischemia. Stroke 1989; 20:1643-1647

[18] Thebault J-J, Blatrix CE, Blanchard JF, et al. The interactions of ticlopidine and aspirin in normal subjects. J Int Med Res 1977; 5:405-411

[19] Panak E, Maffrand JP, Picard-Fraire C, et al. Ticlopidine: a promise for the prevention and treatment of thrombosis and its complications. Hemostasis 1983; 13(suppl 1):1-54

[20] Noble S, Goa KL. Ticlopidine: a review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischemia and stroke. Drugs Aging 1996; 8:214-232

(*) From the Department of Medicine, Madigan Army Medical Center, Tacoma, WA.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.

Manuscript received October 30, 1998; revision accepted March 3, 1999.

Correspondence to: CPT Michael W. Quinn, MD, Department of Pulmonary and Critical Care Medicine, Brooke Army Medical Center, Ft. Sam Houston, TX 78234

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