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* From the Department of Medicine, Madigan Army Medical Center, Tacoma, WA.
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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Abstract |
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Key Words: aspirin • coronary stent • hemothorax • percutaneous transluminal coronary angioplasty • pleural effusion • rib fracture • ticlopidine
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Introduction |
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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 > 24 h after rib fracture.4 5
We describe a case 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.
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Case Report |
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Laboratory evaluation of the peripheral blood revealed the following: WBC count, 18,600/µL with a normal differential; RBC count, 2,500,000/µL; hematocrit, 24% (baseline, 41% 1 week earlier); and platelet count, 481 x 109/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 126 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 RBC count of 1,230,000/µL and a WBC count of 18,000/µL, 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.
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Discussion |
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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 reference4 in the English-language literature citing delayed hemothorax occurring > 24 h after rib fracture. Ross and Cordoba4 described two cases 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 cases, but took as long as 6 days to present in one case.11 An unusual and fatal case 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 < 4 weeks. Future studies may be helpful in defining the risk and refining the recommendations for combined antiplatelet therapies.
In conclusion, we report a case 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.
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Footnotes |
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Received for publication October 30, 1998. Accepted for publication March 3, 1999.
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