Author + information
- Received September 28, 1996
- Revision received December 17, 1996
- Accepted December 19, 1996
- Published online April 1, 1997.
- Kazuomi Kario, MD, PhDAB,*,
- Takefumi Matsuo, MD, PhDC,
- Hiroko Kobayashi, PhDC,
- Katsuichirou Yamamoto, PhDC and
- Kazuyuki Shimada, MD, PhDA
- ↵*Dr. Kazuomi Kario, Department of Cardiology, Jichi Medical School, 3311-1, Yakushiji, Minamikawachi, Kawachi, Tochigi, 329-04, Japan.
Objectives. We sought to investigate the potentiation of acute risk factors after the Hanshin-Awaji earthquake (7.2 on the Richter scale).
Background. The frequency of cardiovascular events increases just after a major earthquake, but the causative factors have not been fully investigated.
Methods. We studied the changes in cardiovascular risk factors in 42 elderly outpatients with well-controlled hypertension living near the epicenter (Awaji-Hokudan districts) 7 to 14 days after the earthquake when the major felt-aftershocks persisted. They all experienced the highest stress grading of 6 (catastrophic stress) according to the DSM-III-R. To study the hemostatic profile and endothelial cell state, we measured the blood pressure (BP), hematocrit and lipid profiles as well as fibrinogen, a marker of fibrin turnover (d-dimer), fibrinolytic factors (plasmin-alpha2–plasmin inhibitor complex [PIC], tissue-type plasminogen activator [t-PA] antigen and t-PA inhibitor [PAI] activity) and an endothelial cell-derived marker (von Willebrand factor [vWF]).
Results. Systolic and diastolic blood pressures and other variables increased after the earthquake. Before and after the earthquake, the median (25th to 75th percentiles) systolic BP was 152 (range 142 to 164) and 170 mm Hg (range 161 to 178), respectively (p < 0.0001), and the diastolic BP was 83 (range 79 to 88) and 91 mm Hg (range 84 to 96), respectively (p < 0.0001). Of blood viscosity determinants, hematocrit was 38.1% (range 40.7% to 35.9%) and 39.7% (range 42.9% to 38.3%), respectively (p < 0.001), and fibrinogen 316 (range 272 to 360) and 335 mg/dl (range 307 to 391), respectively (p < 0.05). Von Willebrand factor was 128% (range 74% to 148%) and 148% (range 100% to 178%), respectively (p < 0.01); d-dimer was 410 (range 285 to 633) and 560 ng/ml (range 391 to 888), respectively (p < 0.0001); and PIC was 0.74 (range 0.58 to 0.91) and 0.75 μg/ml (range 0.58 to 1.1), respectively (p < 0.05). In contrast, lipid profiles did not change after the quake. When the patients were classified into the high stress and moderate stress groups according to the degrees of damage to their house and injury to family members, the levels of fibrinogen, vWF, PIC and t-PA antigen were increased only in the former group, whereas BP, hematocrit and d-dimer levels were increased in both groups. These abnormalities of acute risk factors, except for vWF, were transient and decreased to prequake levels by 4 to 6 months after the quake.
Conclusions. Earthquake-induced stress seems to induce transient increases in BP, blood viscosity determinants and fibrin turnover and to prolong endothelial cell stimulation. The potentiation of these acute risk factors might contribute to the occurrence of cardiovascular events just after a major earthquake in elderly subjects with hypertension.
(J Am Coll Cardiol 1997;29:926–33)
© 1997 by the American College of Cardiology
At 5:46 amon January 17, 1995, the southern part of Hyogo Prefecture, Japan, was struck by a major earthquake, the Hanshin-Awaji Earthquake, measuring 7.2 on the Richter scale. This was a typical earthquake in that it was most strongly felt directly above the focus; it caused 5,488 deaths and tens of thousands of other casualties (). The epicenter, the Awaji-Hokudan district of the Awaji Island, was one of the most heavily damaged districts. About one-third of the houses in the district were completely destroyed, and about one-third of the residents temporarily moved to shelters. Several reports indicate a short-term increase in the frequency of cardiovascular events after a major disaster, including earthquakes ([1–6]). In the Awaji-Hokudan district, which has a resident population of ∼11,500, there were 10 cardiovascular or sudden deaths during the 6 weeks immediately after the earthquake, as compared with three deaths during the same period in the previous year ().
The causative factors for the increased incidence of cardiovascular events after a major earthquake remain unclear. Extreme stress like that from a major earthquake would influence the sympathetic nervous system and various cardiovascular risk factors. There are a few reports on the changes of cardiovascular risk factors after a major disaster, describing the transient increases in blood pressure (BP), heart rate and the levels of total cholesterol and triglycerides, but there are some conflicting results in these studies ([4, 7–10]). In our preliminary study, conducted when major aftershocks were still occurring, increased levels of hematocrit and fibrinogen were found among the people in the region (). Recently, hemostatic abnormalities and endothelial cell (EC) dysfunction have been recognized as cardiovascular risk factors ([11, 12]). Hemostatic abnormalities might be an acute risk factor triggering cardiovascular events after the major earthquake, as well as hemodynamic and vasoconstrictive forces ([13–15]). However, there are no reports on the effects of an earthquake on the hemostatic system or EC state.
Because of our role of providing continuous longitudinal medical care for sick people, we were able to study the earthquake-induced potentiation of cardiovascular risk factors (BP, blood viscosity determinants, lipid profiles, hemostatic profiles and EC state). In addition to the BP, we measured hematocrit, levels of lipids, fibrinogen, a marker of fibrin turnover (d-dimer), fibrinolytic factors (plasmin-alpha2–plasmin inhibitor complex [PIC], tissue-type plasminogen activator [t-PA] and t-PA inhibitor [PAI]) and an EC-derived marker (von Willebrand factor [vWF]) in the elderly patients with well-controlled hypertension living at the epicenter (in the Awaji-Hokudan district).
1.1 Study subjects.
Of ∼550 outpatients registered with the 1994 Hypertensive Care Program of the Awaji-Hokudan Public Clinic, 167 of them visited the Awaji-Hokudan Public Clinic within 14 days after the earthquake and their BP was checked. The incidence of aftershocks that could be felt was 5 to 20 times or more per day during that period. From these 167 patients, we selected for this study patients who met the following criteria: physically uninjured afebrile residents of the Awaji-Hokudan district who experienced catastrophic stress graded as 6 (maximum) according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R) (); continued use of the same medication, including antihypertensive therapy, at the times of blood examination before and after the earthquake; and availability of plasma samples that had been obtained in the morning from November 1, 1994 to January 16, 1995 (before the earthquake) and stored in the refrigerator at −70°C. Altogether, we studied 42 well-controlled hypertensive outpatients, 37 of whom (88%) were elderly (aged 61 years or older). We classified 19 of the outpatients in the high stress group, consisting of those who were homeless because their houses had been completely destroyed and who had moved to a shelter and/or those who had at least one family member seriously injured or dead. The moderate stress group consisted of the 23 outpatients who did not meet these criteria. The clinical characteristics in each group are shown in Table 1.
We also studied 16 normotensive elderly outpatients (7 men and 9 women, aged 61 to 82 years) selected using the following criteria: those who came to our clinic for blood examination within 21 days after the earthquake and those who visited our clinic again 3 to 9 months after the earthquake. Physically uninjured afebrile residents of the Awaji-Hokudan district who experienced the same catastrophic stress graded as 6 (maximum) according to the DSM-III-R, as well as hypertensive subjects, were selected. These individuals had mild dyslipidemia or glycosuria before the earthquake, but the first blood examination just after the earthquake disclosed no abnormal conditions, including overt hyperlipidemia with a total cholesterol level >260 mg/dl and diabetes mellitus with a glucose level >160 mg/dl. At the time of the blood examination 3 to 9 months after the earthquake, their systolic and diastolic BP was <140/90 mm Hg. Ten of the 16 subjects (63%) were classified into the high stress group according to the above criteria.
The body mass index before the earthquake was calculated as weight (kg)/height (m)2. The BP was measured in the sitting position using an automated sphygmomanometer (BP103N-II, Nippon Colin, Co., Ltd., Komaki, Japan) after the patient had rested for at least 5 min. The median value of three consecutive BP measurements was documented at each visit and used as the BP.
1.2 Blood collection and sample processing.
The postearthquake blood samples in the well-controlled hypertensive patients were obtained in the morning from January 23 (7th day after the earthquake) to January 30, 1995 (14th day after the earthquake). Blood samples for hemostatic determinations were collected into disposable siliconized vacuum glass tubes containing 0.1 vol of 3.8% trisodium citrate, and blood from the second tube was used for the hemostatic assay. Samples were centrifuged at 3,000gfor 15 min at room temperature within 3 h of collection to separate plasma, which was stored in plastic tubes at −70°C until laboratory determinations were performed. These samples were processed in the same manner as those which had been collected from the same patients from November 1, 1994 to January 16, 1995, and stored.
The samples for the determination of other routine variables were collected into plain tubes, which were centrifuged at 3,000gfor 15 min at room temperature. After separation, the serum samples were stored at 4°C and analyzed within a few days. The samples for blood count and hematocrit were collected into tubes containing EDTA-2K and analyzed within the same day. These collection and preparation methods for the variables determined without freezing were performed throughout the study in the same manner both before and after the earthquake.
The variables that were increased just after the earthquake (fibrinogen, vWF, d-dimer, PIC and t-PA antigen) were measured again in 37 of the same hypertensive patients and normotensive healthy elderly subjects 4 to 6 months after the earthquake, when the shelters in the Hokudan district had closed and the refugees had moved back into their repaired houses or temporary housing, and daily life was considerably improved and nearly normalized to the lifestyle previous to the earthquake.
1.3 Laboratory assay.
For the measurement of hemostatic variables, the samples before and 7 to 14 days after the earthquake obtained from the same patients were arranged alternatively and assayed within the same run. The first-thawed sample was used for the measurement of d-dimer, t-PA antigen and PAI activity.
Fibrinogen was determined using the one-stage clotting assay employing a fully automated coagulation analyzer (CA3000, Toa Medical Electrics, Kobe, Japan) (). The plasma levels of vWF, PIC and t-PA antigen were determined with enzyme-linked immunosorbent assay (ELISA) kits (Diagnostica Stago, Asnières, France; Teijin, Tokyo, Japan; Biopool, Umea, Sweden, respectively). d-dimer levels were determined by two methods: one an ELISA (Diagnostica Stago) () and the other a latex photometric immunoassay (LPIA) system (LPIA-100, Mitsubishi Kasei Co., Tokyo, Japan) (). Tissue-type plasminogen activator inhibitor activity levels were determined using a commercial venom-based assay Stachrom PAI (Diagnostica Stago). For vWF assay, the value for commercially available pooled plasma (CTS Standard Plasma, Behringwerke AG, Germany) was taken as 100%.
The serum total cholesterol level was determined using a commercial enzyme assay kit (Wako, Osaka, Japan). Serum high density lipoprotein (HDL) cholesterol was determined using an enzymatic procedure after precipitation with phosphotungstic acid (Wako, Osaka, Japan). Lipoprotein (a) was measured with an ELISA kit (Biopool, Umea, Sweden) (). Blood count and hematocrit were measured using an automated analyzer (NE6000, Toa Medical Electrics, Kobe, Japan).
1.4 Accuracy and reference values of the measured variables.
In our assay laboratory, the coefficient of variation was 2.5% for the fibrinogen assay, 3.8% for the vWF assay, 3.0% for the d-dimer ELISA assay, 3.8% for the d-dimer LPIA assay, 3.3% for the PIC assay, 3.3% for the t-PA antigen assay and 4.3% for PAI activity assay.
The reference values (10th to 90th percentiles) in 38 healthy normotensive control subjects aged 60 to 79 years (18 men and 20 women) measured at our laboratory were 210 to 369 mg/dl for fibrinogen, 92% to 156% for vWF, 208 to 635 ng/ml for d-dimer (ELISA), <0.1 to 1.2 μg/ml for d-dimer (LPIA), 0.49 to 1.1 μg/ml for PIC, 2.8 to 14 ng/ml for t-PA antigen and 2.0 to 12 U/ml for PAI activity.
1.5 Statistical analysis.
Data are shown as the mean value ± SD or median (25th to 75th percentile). The nonparametric Wilcoxon rank-sum test was used for the comparison of the differences in the metabolic variables before and after the earthquake within the same patients. The unpaired ttest or Mann-Whitney Utest was used for the comparison of the variables between two independent groups. In addition, the Spearman correlation coefficient was calculated for the pairs of variables. A p value <0.05 was considered to indicate a significant difference.
2.1 Earthquake-induced potentiation of cardiovascular risk factors in hypertensive patients.
Table 2shows the changes in BP and metabolic variables, including hemostatic factors after the earthquake. Systolic and diastolic BPs were significantly higher after the earthquake, whereas heart rate did not significantly change. The hematocrit level was increased, whereas the lipid profiles (total cholesterol, HDL cholesterol and lipoprotein [a] levels) did not change significantly. With regard to hemostatic profiles, the percentage of the 42 hypertensive patients with a value exceeding the reference value was 19% for fibrinogen, 21% for vWF, 24% for d-dimer (ELISA), 17% for d-dimer (LPIA), 12% for PIC, 19% for t-PA antigen and 14% for PAI activity. The levels of fibrinogen, d-dimer and PIC were significantly increased after the earthquake. The level of vWF was also significantly increased after the earthquake, whereas the t-PA antigen and PAI levels did not change significantly. There were no significant differences in the changes in these cardiovascular variables, including hemostatic variables between samples obtained days 7 to 10 after the earthquake and those obtained 11 to 14 days afterward.
When we classified the prothrombotic state as an excess value for two or more of the six variables of fibrinogen, d-dimer, PIC, vWF, t-PA antigen and PAI activity, prothrombotic status before the earthquake was not found to be directly related to the degree of earthquake-induced potentiation of acute risk factors (data not shown).
When we analyzed these data separating for smokers and nonsmokers, we found no significant differences with regard to the earthquake-induced potentiation of acute risk factors (data not shown).
2.2 Earthquake-induced stress and potentiation of cardiovascular risk factors.
Analysis of the changes discussed earlier in the two groups classified according to the degree of the earthquake-induced stress revealed that the BP, hematocrit and d-dimer levels were significantly increased after the earthquake in both the moderate and high stress groups (Table 3and Fig. 1), whereas the fibrinogen, vWF, PIC, and t-PA levels were significantly increased only in the high stress group (Fig. 2). The two groups did not differ in any clinical characteristics (Table 1).
2.3 Correlations between d-dimer and other cardiovascular risk factors.
Table 4shows the relations between the levels of d-dimer levels and other variables after the earthquake in the 42 hypertensive patients. The d-dimer level was positively correlated with heart rate (r = 0.492, p < 0.005), fibrinogen (r = 0.454, p < 0.005), EC-derived markers (vWF: r = 0.383, p < 0.02; t-PA: r = 0.391, p < 0.02) and PIC (r = 0.605, p < 0.0001), although it was not correlated with other variables.
2.4 Follow-up of patients with earthquake-induced potentiation of cardiovascular risk factors.
When we studied these variables again in 37 of the same hypertensive patients 4 to 6 months after the earthquake (Table 4and Fig. 1), we found that all of the levels except for that of vWF were decreased compared with those found 7 to 14 days after the earthquake. The vWF level (median [25th to 75th percentiles]) remained high, even 4 to 6 months after the earthquake, being 156% (range 120% to 177%) in all 37 patients, 144% (range 114% to 171%) in the moderate stress group and 158% (range 121% to 185%) in the high stress group.
During the 6-month follow-up period, only one patient developed clinically overt cardiovascular events. This patient, whose d-dimer levels were extremely high (>2000 ng/ml) before the earthquake, had coronary artery disease and was classified in the high stress group. Although she had not noticed chest pain in the year preceding the earthquake, 3 to 7 weeks after the earthquake she noticed chest pain lasting for 2 to 5 min (one episode every 2 to 3 weeks). This chest pain ceased after the start of the nitroglycerin administration, revealing a self-limited course, resolving 8 weeks after the earthquake. Her d-dimer level continued to increase >4000 ng/ml 4 to 6 months after the earthquake.
2.5 Earthquake-induced potentiation of cardiovascular risk factors in normotensive subjects.
In the normotensive elderly control subjects, a decline in BP, heart rate, hematocrit, d-dimer and vWF levels was recognized 3 to 9 months after the earthquake, compared with the levels just after the earthquake (Table 5). The changes in variables, except for vWF, were essentially the same as those in the well-controlled hypertensive patients; the vWF level remains high in the hypertensive patients.
We have clarified that the increased BP and blood viscosity determinants and enhanced fibrin turnover with EC hyperstimulation occurred just after this major earthquake in hypertensive elderly subjects exposed to high levels of stressful living at the epicenter. The potentiation of these acute risk factors was dependent on the degree of earthquake-induced stress sustained.
3.1 Mechanism of earthquake-induced potentiation of acute risk factors.
The precise mechanism of the earthquake-induced potentiation of these acute risk factors remains unknown. The extreme stress of a major earthquake would be a causative factor. Similarly, during the Iraqi missile war, also a highly stressful condition, the incidence of acute myocardial infarction and sudden cardiac death among Israeli civilians was increased, and emotional stress due to fear of missile attack probably would have been a causative factor ([21, 22]). In the period of blood collection in this study, major aftershocks occurred 5 to 20 times or more per day in our Awaji-Hokudan district, and the subjects studied were continuously frightened during that period. Stress is reported to cause increased levels of hematocrit and fibrinogen (major determinants of blood viscosity), to induce rheologic changes in blood flow () and to elevate BP (). Emotional stress in atherosclerotic monkeys leads to changes in EC and exacerbates coronary artery atherosclerosis (). Adrenaline and noradrenaline released during stress may have several effects, including strong potentiation of platelet aggregation in response to aggregating agents, vessel wall damage, release of t-PA and vWF from ECs and coronary artery spasm ([25, 26]). Thus, the increased catecholamine levels associated with stress may enhance spasms, vessel injury, formation of platelet-rich thrombi and subsequent fibrin turnover.
The transiently increased blood viscosity and hemostatic abnormalities found in our patients might partly be attributed to the drastic changes in their lifestyle due to the catastrophic events, because many had to abandon their homes and live in shelters, and the composition of their diet would also have drastically changed. Hemoconcentration could result from diminished water intake secondary to the prolonged psychological stress and profound change in sociologic status. As some of the subjects were under physical stress from the effort to put their residences in order during the study period, the physical exertion after the earthquake might also have induced fibrinolytic activation and subsequent elevation of t-PA, d-dimer and PIC (). Cigarette smoking may have increased their consumption in response to the stress, but we found no significant differences in the earthquake-induced potentiation of acute risk factors between smokers and nonsmokers.
3.2 Earthquake-induced prothrombotic state.
The plasma d-dimer levels were clearly elevated just after the earthquake. Because the assays for d-dimer have different standards and the antibodies are different, we measured the plasma d-dimer levels using two assay methods, ELISA and LPIA ([18, 19]), and we obtained the same result for both assays. Plasma d-dimer is released from cross-linked fibrin, and its level reflects the state of fibrin formation and its degradation (fibrin turnover) in blood vessels. Because the half-life of plasma d-dimer is about 8 h, it would be a more reliable indicator of in vivo activation of the hemostatic system than other activation markers of coagulation (such as prothrombin fragment 1 + 2 or thrombin–antithrombin III complex) with shorter half-lives (). In a previous study, the increase of plasma d-dimer levels showed sensitivity to various mild physiologic and pathologic prethrombotic conditions (normal aging, atherosclerotic disease, bed-ridden state, malignancy, etc.), as well as to overt thrombosis (disseminated intravascular coagulation, deep vein thrombosis and pulmonary thromboembolism) ([18, 19, 28]). In our high stress group, PIC, an activation marker of fibrinolysis, and t-PA antigen levels after the earthquake were also increased. Thus, our results indicate that the major earthquake induced the rapid fibrin turnover with hyperfibrinolysis in the elderly patients studied. The positive correlation we observed between the plasma fibrinogen and d-dimer levels just after the earthquake (Table 4) might reflect fibrin turnover induced by hypercoagulability due to hyperfibrinogenemia. This enhanced fibrin turnover would probably be a factor predisposing to clinical cardiovascular events in elderly patients just after earthquake, but it would probably also be transient, given that the d-dimer level in our outpatients had returned to normal 4 to 6 months after the earthquake (Fig. 1).
3.3 Earthquake-induced EC stimulation.
An increase in vWF, a glycoprotein stored in ECs and secreted into the circulation by various types of EC stimulation (), has been reported to parallel the degree of EC damage, and the plasma level of vWF is widely used as an indicator of EC dysfunction ([29–31]). Endogenous t-PA is also released from ECs in response to various stimulations (). The plasma t-PA antigen level is a predictor of future myocardial infarction and stroke (), suggesting that this antigen is a marker of EC stimulation by a latent atherosclerotic process (EC dysfunction). The vWF and t-PA levels were significantly increased after the earthquake in the high stress group, suggesting that an extreme stress like a major earthquake could induce EC stimulation. A positive correlation was observed between the d-dimer level and each of the levels of EC-derived markers (vWF and t-PA) (Table 4), indicating that earthquake-induced EC stimulation might be associated with the fibrin turnover.
3.4 Earthquake-induced BP elevation and change in lipid profile.
In previous reports on the changes in cardiovascular risk factors after a major disaster, a transient increase in BP or an increases in heart rate was found ([7, 8]). In the present study period (7 to 14 days after the earthquake), the BP elevation was not accompanied by an increase in heart rate. Factors other than sympathetic arousal might have contributed to the BP elevation in our patients. An increased white-coat effect might be responsible for this phenomenon. In our preliminary study, in the majority of the well-controlled hypertensive patients, office BP was temporarily increased after the earthquake and then decreased to the pre-earthquake level within 4 weeks after the major felt-aftershocks ceased (). Some patients with white-coat hypertension developed sustained hypertension with an enhanced white-coat BP effect that lasted for several months after the earthquake (), but this sustained hypertension was not so established that it persisted past 1 year after the earthquake, when the daily lives of the patients had returned to normal (). We could not find any change in lipid levels after the earthquake, although the levels of total cholesterol and triglycerides were increased in another reported study (). This discrepancy might be due to the time of the study after the earthquake and the nutritional status of the people. Our study was conducted from 7 to 14 days after the earthquake, when the food supply was limited. In contrast, the previous study documenting an increase in total cholesterol and triglycerides was conducted from 2 to 6 weeks after the earthquake (), when the chronic stress might have prompted overeating of lipid-rich foods sent from neighboring areas.
3.5 Points to consider and study limitations.
In conducting this study, we took great care to avoid several sources of bias. We carefully excluded any patients who suffered from direct earthquake trauma and febrile patients, because we knew that trauma and minor infection could elevate plasma levels of acute phase reactants (fibrinogen and vWF) and d-dimer. In addition, for all of the hypertensive patients studied, plasma samples collected in the winter were available (November 1 to the day before the earthquake), as fibrinogen levels are known to show seasonal variation, with plasma levels increasing in the winter (). One of the limitations of this study is that the subjects were not representatives of the overall population, but ones at higher risk. We had not stored the samples of normotensive healthy control subjects before the earthquake. Thus, it is not definitive whether the observed results are specific for the hypertensive subjects or not. The reduction of hemostatic factors in the hypertensive patients was essentially the same as that in the normotensive elderly subjects, although several months after the major earthquake, the vWF level remained high in the hypertensive patients, whereas it had decreased in the normotensive subjects. Irreversible EC dysfunction after a major earthquake might be a hypertension-specific event.
The time frames of previous studies documenting the increased cardiac death rate were restricted to within the first few days after the stressful major events ([1–3, 6]). Thus, the earlier data would be of even greater value. Our study period was conducted for at least 1 week after the major event, but we found the significant potentiation of acute risk factors. There were no significant differences between the magnitudes of changes in these acute risk factors at 7 to 10 days after the earthquake and those at 11 to 14 days. Thus, the potentiation of the acute risk factors, which might be greater just after the earthquake and persist for at least a few weeks, could trigger cardiovascular events after the earthquake in those with predisposing atherosclerotic disease.
Earthquake-induced stress increased BP and blood viscosity determinants and enhanced fibrin turnover with EC stimulation in a group of hypertensive elderly subjects. An earthquake might trigger the cardiovascular events through the potentiation of these acute risk factors. Further investigation of the mechanisms triggering cardiovascular events after a major event such as a major earthquake is a necessary part of the strategy for the prevention of cardiovascular disease.
☆ This work was supported in part by grants from the Foundation for the Development of the Community, Tochigi, Japan; from the Osaka Gas Group Welfare Foundation, Osaka, Japan; and from the Heparin Conference, Tokyo, Japan.
- blood pressure
- Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised
- endothelial cell
- enzyme-linked immunosorbent assay
- latex photometric immunoassay
- t-PA inhibitor
- plasmin-alpha2–plasmin inhibitor complex
- tissue-type plasminogen activator
- von Willebrand factor
- Received September 28, 1996.
- Revision received December 17, 1996.
- Accepted December 19, 1996.
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