Winter morning surge in blood pressure after the Great East Japan Earthquake.

This study investigated the association between winter morning surge in systolic blood pressure (SBP) as measured by ambulatory BP monitoring and the housing conditions of subjects in an area damaged by the Great East Japan Earthquake. In 2013, 2 years after disaster, hypertensives who lived in homes that they had purchased before the disaster (n = 299, 74.6 ± 8.1 years) showed significant winter morning surge in SBP (+5.0 ± 20.8 mmHg, P < 0.001), while those who lived in temporary housing (n = 113, 76.2 ± 7.6 years) did not. When we divided the winter morning surge in SBP into quintiles, the factors of age ≥75 years and occupant-owned housing were significant determinants for the highest quintile (≥20 mmHg) after adjustment for covariates. The hypertensives aged ≥75 years who lived in their own homes showed a significant risk for the highest quintile (odds ratio 5.21, 95% confidence interval 1.49-18.22, P = 0.010). It is thus crucial to prepare suitable housing conditions for elderly hypertensives following a disaster.

Clinical Significance of the Serotonin Release Assay and Platelet Count Monitoring After Cardiac Surgery.

Heparin-induced thrombocytopenia (HIT) is one of the serious complications in patients who undergo cardiac surgery. However, there remains a major problem in diagnosing HIT because the current immunological assays for detection of HIT antibody have limitations. Furthermore, the clinical course of thrombocytopenia in this surgery makes it increasingly difficult to diagnose HIT. We investigated the relationship between platelet count and HIT antibody in 59 patients who underwent cardiac surgery using cardiopulmonary bypass (CPB). The number of postoperative HIT antibody-positive patients evaluated using enzyme-linked immunosorbent assay kit (polyanion IgG/IgA/IgM complex antibodies/antiplatelet factor 4 enhanced) was 37 (62.7%). In contrast, platelet activation by HIT antibody was evaluated using the serotonin release assay (SRA). More than 20% and 50% release of serotonin was obtained from 12 patients (20.3%) and 8 patients (13.6%), respectively. The levels of d-dimer were significantly different on postoperative day 14 between SRA-positive and SRA-negative groups; however, postoperative thrombus complication was not detected using sonography in the patients with positive serotonin release at all. After being decreased by the operation, their platelet count recovered within 2 weeks in both groups equally. In our study, although the patients were positive in the platelet activating HIT antibody assay, they remained free from thrombosis and their platelet count recovered after early postoperative platelet decrease. Therefore, in addition to the SRA, monitoring of platelet count might be still considered an indispensable factor to facilitate the prediction of HIT thrombosis prior to manifestation in the patients undergoing cardiac surgery using CPB.

Difference in evening home blood pressure between before dinner and at bedtime in Japanese elderly hypertensive patients.

The authors evaluated the differences between evening home blood pressure (HBP) readings taken before dinner and those taken at bedtime, which were documented in a European and a Japanese guideline, respectively. Forty-eight patients (mean age, 76.4 years) measured their evening HBP twice each day (two measurements both before dinner and at bedtime) for 14 days. The authors defined the at-bedtime (B) minus the before-dinner (D) systolic HBP as the B-D difference. The mean B-D difference was -8.7 mm Hg (P<.001). The depressor effect of bathing was significantly prolonged for 120 minutes. The B-D difference with alcohol consumption was significantly greater than that without alcohol. In the linear mixed model analysis, time after bathing ≤120 minutes and alcohol consumption were significantly associated with the B-D difference after adjustment with covariates. There was a marked difference between evening HBP values. When patients' evening HBP is measured according to the guidelines, their daily activities should be considered.

Strict Blood Pressure Control Achieved Using an ICT-Based Home Blood Pressure Monitoring System in a Catastrophically Damaged Area After a Disaster.

At the time of the Great East Japan earthquake and tsunami (March 2011), the authors developed a web-based information and communications technology (ICT)-based blood pressure (BP) monitoring system (the Disaster CArdiovascular Prevention [DCAP] Network) and introduced it in an area that was catastrophically damaged (Minamisanriku town) to help control the survivors' BP. Using this system, home BP (HBP) was monitored and the data were automatically transmitted to a central computer database and to the survivors' attending physicians. The study participants, 341 hypertensive patients, continued to use this system for 4 years after the disaster and all of the obtained HBP readings were analyzed. This DCAP HBP-guided approach helped achieve a decrease in the participants' HBPs (initial average: 151.3±20.0/86.9±10.2 mm Hg to 120.2±12.1/70.8±10.2 mm Hg) over the 4 years. In addition, the amplitude of seasonal BP variation was suppressed and the duration from the summer lowest HBP values to the winter peak HBP values was gradually prolonged. This ICT-based approach was useful to achieve strict HBP control and minimize the seasonal BP variation even in a catastrophically damaged area during a 4-year period after the disaster, suggesting that this approach could be a routine way to monitor BP in the community.

Aftershock Triggers Augmented Pressor Effects in Survivors: Follow-Up of the Great East Japan Earthquake.

BACKGROUND: Previous reports focused on the significant acute effects immediately after an earthquake on an increase in blood pressure (BP) assessed by ambulatory BP monitoring. However, there have been no data on the impact of environmental triggers on the long-term response to earthquake. METHODS: We analyzed the ambulatory BP monitoring data of 8 patients who lived in the disaster area of the 11 March 2011 Great East Japan Earthquake on the day of the largest aftershock with a first tsunami warming (sirens) on 7 December 2012. RESULTS: There was no significant difference in the BP in either the period 1 hour before (median (range): 126.5 (121.5-138.0) vs. 137.8 (129.5-177.0) mm Hg, P = 0.07) or that 1 hour after (139.3 (113.0-143.5) vs. 137.5 (125.0-192.0) mm Hg, P = 0.27) the aftershock between those living at home and those who had been living in temporary housing. After the time of aftershock, the systolic BP levels at that night (124.9 (113.2-137.9) vs. 107.0 (101.9-110.1) mm Hg, P = 0.021) and systolic BP levels at the following morning (149.3 (131.0-196.2) vs. 129.5 (128.8-131.0) mm Hg, P = 0.029) were also significantly higher in those living in temporary housing at the time compared to those living in their own homes. CONCLUSION: Our data suggest that the stress of a change in living conditions following the disaster might have contributed an increased risk of cardiovascular events.

Production of Anti-platelet Factor 4/Heparin Complex Antibodies After Cardiovascular Surgery.

To study the production of anti-platelet factor 4 (anti-PF4)/heparin complex antibodies of Ig (immunoglobulin) G/IgA/IgM using enzyme-linked immunosorbent assay (ELISA; heparin-induced thrombocytopenia [HIT] antibodies) in 79 patients undergoing cardiovascular surgery, we employed Δoptical density (OD) as a marker of HIT-antibody production. The ΔODs were calculated from the differences in the ODs using ELISA. Patient were classified into 3 ΔOD ranges: ΔOD ≥ 1.0, ΔOD ≥ 0.4 to <1.0, and ΔOD < 0.4. The underlying disease, time course of the postoperative platelet count, D-dimer level, postoperative brain magnetic resonance imaging (MRI), use of cardiopulmonary bypass and postoperative thrombocytosis were not considered for the 3 ΔOD classifications. None of the 6 patients with ΔOD ≥ 1 .0 and a positive functional assay was diagnosed with HIT due to the absence of HIT-derived thrombocytopenia. In conclusion, HIT-antibody production increased until day 7 after heparin cessation and reached a trace level on day 14. It was demonstrated that HIT-antibody production is in remission unless there is any evidence of a further increase during the second week postsurgery.

Evaluation of circuit and AV fistula clotting and detection of anti-PF4/heparin complex antibodies in hemodialysis patients suspected of having heparin-induced thrombocytopenia.

A retrospective study was performed to elucidate the characteristics of heparin-induced thrombocytopenia (HIT) in newly treated hemodialysis (HD) patients who essentially required anticoagulation with unfractionated heparin (UFH). Seventy-eight patients suspected of having HIT within 3 months of starting HD with UFH were selected for this study. Their platelet counts were routinely followed, and anti-PF4/heparin complex antibodies (HIT antibodies) were measured with enzyme-linked immunosorbent assay (ELISA) until the titer became negative. The characteristics of thrombocytopenia were a platelet count of ≤150 × 10(9)/L and/or decrease of ≥30% and as caused by the intermittent use (3 times/a week) of UFH during HD. Fifty-five patients showed unexpected clotting in the extracorporeal circuit and/or arteriovenous fistula (AVF) thrombosis, while 23 patients had neither of these complications. The patients were classified into HD-related and non-HD-related thrombus groups. The impact of various combinations of the 3 clinical factors (thrombocytopenia, timing, and HD-related thrombus) and the results of ELISA as a laboratory factor were examined. A combination of 2 platelet factors (thrombocytopenia and timing) and ELISA positivity did not reveal the presence of HIT, while a combination of the 3 clinical factors and a positive ELISA improved the accuracy of HIT diagnosis. The findings on the 4-factor combination were supported by high rates of seroconversion in a serotonin release assay. Combining appropriate clinical factors and a positive ELISA may lead to the proper management of HD patients suspected of having HIT. In conclusion, while HD patients showed a drop of ≤150 × 10(9)/L or ≥30% on days 7 to 30, unexpected clotting in the circuit and/or AVF thrombosis was considered as a sign of HIT development.

Clinical evaluation of acute systemic reaction and detection of IgG antibodies against PF4/heparin complexes in hemodialysis patients.

Heparin-induced thrombocytopenia (HIT) is a pathophysiological syndrome caused by platelet-activating antibodies that recognize PF4/heparin complexes. The abrupt onset of HIT following intravenous bolus heparin is known as an acute systemic reaction. Clinical features of this type of HIT may be similar to those of common complications during hemodialysis. The aim of the study was to identify whether the clinical features of the acute systemic reaction are caused by HIT or dialytic complications. Twenty-seven dialytic patients who had thrombocytopenia and clinical features of an acute systemic reaction were enrolled out of 202 HIT-suspected patients. Thirteen patients had HIT confirmed due to the presence of positive functional and immunoassays. Eight of the thirteen patients presented with acute systemic reactions due to HIT. The most common symptom of acute systemic reaction was dyspnea. The other nineteen patients, involving both HIT and non-HIT patients, had dialysis-complicated ASR. The major feature of the acute systemic reaction in hemodialysis was hypotension and its relevant symptoms. An immunoassay for the detection of IgG antibodies against PF4/heparin complexes (HIT-IgG) showed the wide-range linearity of the calibration curve by employing three concentrations of recombinant mouse monoclonal antibodies for PF4/heparin complexes. The results are expressed as micrograms of IgG in one milliliter. Significantly high levels in thirteen HIT patients were compared with levels in fourteen non-HIT patients. The highest median of 1,530 µg/ml (IQR: 3,267-813) was obtained in the presence of HIT associated with an acute systemic reaction. In HIT patients who did not show characteristics of an HIT-derived acute systemic reaction, the median was 339 µg/ml (1,178-834). Despite showing a positive ELISA, nine non-HIT patients without any platelet-activating antibodies showed a value of 97 µg/ml (166-56). The lowest median of 8.3 µg/ml (11-6) was in non-HIT patients with a negative ELISA. In conclusion, measurements of HIT-IgG -specific antibodies can facilitate an appropriate estimation in hemodialysis patients of whether the clinical features of an acute systemic reaction are caused by HIT or dialytic complications.

Morning blood pressure surge, morning platelet aggregation, and silent cerebral infarction in older Japanese hypertensive patients.

OBJECTIVE: To examine whether or not the extent of morning blood pressure surge (MBPS), defined as a morning SBP increase from sleep SBP, is associated with that of platelet aggregation, coagulation/fibrinolytic activity, and silent cerebral infarction (SCI) in older hypertensive patients. METHODS: Sixty hypertensive patients aged at least 60 years (mean age 70.6 years; 40% men) underwent measurement of morning spontaneous small-sized platelet aggregation (SPA) detected by a light scattering intensity method, measurement of circulatory levels of von-Willebrand factor (vWF), noradrenalin, and plasma renin activity (PRA), and brain MRI. RESULTS: The extent of MBPS, but not 24-h SBP, was associated with circulatory levels of noradrenalin, PRA, vWF, and spontaneous SPA (all P < 0.05); the association between MBPS and spontaneous SPA remained significant even after adjustment for significant covariates (P < 0.001). The patients with multiple (more than three per person) SCIs had a significantly greater extent of MBPS (43.3 vs. 31.8 mmHg), morning spontaneous SPA (20 471.9 vs. 4850.9 × 10(5) × 2 mV counts 10 min), and higher circulatory vWF (196.6 vs. 150.1%) compared with those without it (all P < 0.01). On multiple regression analysis, the odds ratio for multiple SCIs with a +1 SD increase of MBPS was 2.0, that of morning spontaneous SPA was 3.0, and that of circulatory morning vWF level was 3.3 (all P < 0.05). When MBPS increase and either platelet aggregation or vWF increases were entered into the same model, the latter parameters, but not the MBPS, were associated with multiple SCIs (both P < 0.05). CONCLUSION: The extent of MBPS was associated with increased activity of morning platelet aggregation in older hypertensive patients.

Additional impact of morning haemostatic risk factors and morning blood pressure surge on stroke risk in older Japanese hypertensive patients.

AIMS: Stroke events occur most frequently in the morning hours. Impaired haemostatic activity and morning blood pressure (BP) surge, defined as the morning BP increase from sleep, have individually been associated with stroke risk in general or hypertensive populations. However, their combined impact on the risk of a stroke remains unknown. METHODS AND RESULTS: A total of 514 hypertensive patients aged > 50 years (mean 72.3 years; 37% men) underwent 24 h BP monitoring, measurement of haemostatic risk factors [plasma fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and prothrombin fragment 1+2(F1+2)], and brain MRI at baseline. The incidence of stroke was prospectively ascertained. During an average of 41 months (1751 person-years), there were 43 stroke events (ischaemic, 30; haemorrhagic, 5; undefined, 8). On multivariable analysis adjusted for confounding factors, the hazard ratio [HR (95% confidence interval (CI)] for stroke in the highest vs. lower quartiles of PAI-1 was 2.5 (1.3-4.6), that for F1+2 was 2.6 (1.4-5.0), and that for the morning BP surge was 1.2 (1.1-1.4; all P< 0.01). In particular, the ratio was substantially higher in cases with the highest quartile of both PAI-1 and F1+2 levels compared with those with the lower quartiles of both parameters (HR: 8.2; 95% CI: 3.7-18.2; P< 0.001). Among the patients with the highest quartile of the morning BP surge (n= 128), the multivariable HR (95% CI) for the highest vs. lower quartiles of PAI-1 was 3.4 (1.3-9.1) and that for F1+2 was 3.3 (1.3-8.7) (both P< 0.05). CONCLUSION: High levels of plasma PAI-1 and F1+2, as well as an excessive morning BP surge, are independently and additively associated with an increased risk of stroke in older hypertensive patients.

Heparin-induced thrombocytopenia in two patients undergoing abdominal aortic aneurysm surgery.

We have experienced 2 cases of heparin-induced thrombocytopenia during unfractionated heparin treatment for disseminated intravascular coagulation after surgery for an abdominal aortic aneurysm. In the first case, as a symptom of disseminated intravascular coagulation gradually improved with antithrombin concentrates and heparin treatment, mesenteric artery thrombosis suddenly occurred, associated with a >50% decrease in platelet count on the 11th day. Although the platelet counts were increasing due to heparin cessation, clinical symptom and coagulation abnormalities worsened to multiple organ failure. In the second case, the platelet count decreased to <10 x 10(4)/microL on the 13th day after the start of unfractionated heparin anticoagulation along with continuous hemodiafiltration, which was indicated for postoperative renal failure. The extracorporeal circuit clotted frequently under an adequate dose of unfractionated heparin. Serologically, heparin-platelet factor 4 complex antibodies were repeatedly detected by enzyme-linked immunosorbent assay. Argatroban, a direct thrombin inhibitor, was introduced as an alternative to unfractionated heparin, and the platelet count improved with a decrease in titers of the antibodies. Disseminated intravascular coagulation is a common complication in cases of abdominal aortic aneurysm and is usually treated in association with unfractionated heparin. It is important to recognize the onset of heparin-induced thrombocytopenia that acute declines in the platelet count and appearance of thrombosis with positive for heparin-platelet factor 4 complex antibodies would suddenly occur in clinical course of disseminated intravascular coagulation.

Management of uremic patients with heparin-induced thrombocytopenia requiring hemodialysis.

Medical records of 122 patients with suspected heparin-induced thrombocytopenia on dialysis were reviewed. Method of dialysis in heparin-induced thrombocytopenia patients with bleeding from various causes (including surgical interventions) and how to cope with blood access occlusion induced by heparin-induced thrombocytopenia were studied. Of 122 patients, 17 who met the criteria of >30% thrombocytopenia, clots in the extracorporeal circulation, positive for heparin/PF4 complex antibodies, and improvement from heparin-induced thrombocytopenia with the use of an alternative anticoagulant or another strategy for heparin-induced thrombocytopenia were chosen. Argatroban was uneventfully introduced in 12 patients having neither bleeding nor blood access failure. In all, 2 of 5 patients were treated with peritoneal dialysis. The others requiring a regional anticoagulant were given nafamostat mesilate. Argatroban as an alternative provides effectively anticoagulation in patients with heparin-induced thrombocytopenia on dialysis. In patients with heparin-induced thrombocytopenia with bleeding and its associated risk, nafamostat mesilate was an alternative. Peritoneal dialysis also was applied in cases of blood access failure due to heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia in a uremic patient requiring hemodialysis: an alternative treatment and reexposure to heparin.

Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially serious complication of hemodialysis, and subsequent reexposure to heparin after the disappearance of antiheparin-PF4 complex antibodies (HIT antibody) has been controversial. We report a 60-year-old woman who was sensitized to unfractionated heparin (heparin) as anticoagulant during hemodialysis (HD) and heparin flush on a nonsession day. The patient suddenly developed acute systemic reactions with acute pulmonary embolism a few minutes after manipulation with heparin flush on day 9, a nonsession day. Although there was no evidence of pulmonary embolism on a pulmonary scintigram on the next day, the fifth HD session was discontinued owing to recurrence of acute systemic reactions and massive clots in the dialyzer 30 min into the session. After confirmation of the presence of HIT antibody and maturation of vascular access fistula, a sixth HD session was carried out with argatroban, a synthetic direct thrombin inhibitor, with a bolus of 10 mg and continuous infusion of 0.5 mg/kg/hr as an alternative to heparin. Optimal dose adjustment of argatroban through activated partial thromboplastin time (APTT) monitoring led to a bolus of 5 mg and continuous infusion of 0.15 mg/kg/hr. The patient's HD treatment at the same doses 3 times a week followed an uneventful course over 6 months. HIT antibody was seronegative about 40 days after the cessation of heparin treatment. Reexposure to heparin was attempted with the monitoring of HIT antibody and platelet counts before and after the sessions on day 210. The titers of HIT antibody compared with before the level of reexposure showed a transient insignificantly small peak, and dialysis with heparin has been maintained to date with no recurrence of HIT. The measurement of HIT antibody titer could be useful in assessing not only the effect of argatroban to replace heparin but also in predicting the recurrence of HIT due to reexposure.

Anti-heparin/PF4 complexes by ELISA in patients with disseminated intravascular coagulation.

Heparin-induced thrombocytopenia (HIT) is known to complicate disseminated intravascular coagulation (DIC), but rarely to be complicated by DIC. We measured the titers of anti-PF4/hepatin complex antibodies by ELISA (HIT-Elisa) and examined 4 parameters of coagulation and fibrinolysis [D-dimer, thrombin/antithrombin complex (TAT), plasmin/alpha2-plasmin inhibitor complex (PIC), and antithrombin levels] in 80 patients with DIC diagnosed by a DIC scoring system. Fourteen patients were HIT-Elisa-positive, 11 of whom received heparin. In 3 of these 11 patients, platelet counts were < or =10 x 10(9)/l and/or reduced by more than 50% for 5-10 days after the heparin (2 patients treated with renal replacement therapy for chronic uremia and postoperative renal failure, and 1 with DIC from a solid tumor). The 3 patients had an optical density reading of >1.0 and a high level of IgG for HIT antibodies, and were thus considered to have DIC complicated with HIT (DIC-HIT). The other 8 patients had optical density readings of 0.4-1.0, and it was unclear whether their thrombocytopenia was caused by HIT alone or by sustained DIC. There were no significant differences in platelet counts and the 4 parameters of coagulation and fibrinolysis between the patients with DIC-HIT and DIC patients with a weakly positive result (0.4-1.0). No differences were observed in platelet counts, or levels of D-dimer and antithrombin between HIT-Elisa-positive and -negative DIC patients. However, the HIT-Elisa-negative patients showed significantly higher levels of TAT and PIC, presumably reflecting DIC-related hypercoagulability. In conclusion, DIC patients treated with heparin occasionally showed HIT antibody seroconversion and developed HIT. HIT-Elisa could assist in the diagnosis of HIT.

Frequency of anti-heparin-PF4 complex antibodies (HIT antibodies) in uremic patients on chronic intermittent hemodialysis.

The aim of this study was to determine the frequency of heparin/platelet factor (PF) 4 complex antibodies in 305 uremic patients treated with chronic intermittent hemodialysis using unfractionated heparin or low-molecular-weight heparin for 3 months. Heparin-induced thrombocytopenia (HIT) antibodies were detected by ELISA in 7 patients (2.3%) who had no history of HIT. Two patients abruptly developed HIT associated with the formation of clots in the extracorporeal circuit after they were found to be carrying HIT antibodies. These patients were suspected to have a similar trigger: an increased dose of recombinant human erythropoietin (rHuEPO). The drug might induce parallel changes in hematocrit (Ht) levels and platelet counts until the onset of HIT. After the onset of HIT, a parallel phenomenon between Ht and platelet counts was not found because of the thrombocytopenia due to HIT. Although HIT onset has been reported during the initial phase of dialysis sessions, there have been few reports on the onset of HIT in uremic patients on dialysis with long-term heparin anticoagulation. In this study, HIT was observed in 2 uremic patients on chronic dialysis with intermittent use of heparin. In some patients on chronic intermittent dialysis carrying HIT antibodies, HIT may occur following rHuEPO treatment. The presence of HIT should be borne in mind in chronic dialysis patients carrying HIT antibodies for 3 months or more.

Preexisting antibodies to platelet factor 4-heparin complexes in patients with acute coronary syndrome who have no history of heparin exposure.

Preexisting heparin-induced thrombocytopenia (HIT) antibodies are detected in some patients who have not previously been exposed to any kind of heparin. However, the role of preexisting HIT antibodies in acute coronary syndrome (ACS) is still unknown. This study was carried out to clarify the role of preexisting HIT antibodies in patients with ACS. Forty patients with ACS who had not been exposed to any kind of heparin via the venous or subcutaneous route or heparin-coated materials and had undergone percutaneous coronary intervention (PCI) under heparin anticoagulation within 6 h from the onset of ACS were chosen from the medical records in the cardiac emergency department. As a control of the ACS patients, 51 patients with angina pectoris who underwent elective PCI under heparin anticoagulation were chosen in the same manner as the ACS patients. Preexisting HIT antibodies were detected by ELISA in 6 patients. Two of the 6 patients developed HIT and 1 patient experienced thrombosis requiring intracoronary thrombolytic therapy. Thrombotic complications during and immediately after PCI in the very early stage after heparin administration were found in 4 of 6 patients with preexisting HIT antibodies. The frequency of preexisting HIT antibodies in ACS patients was significantly increased in comparison with that in non-ACS patients. The odds ratio of the risk of thrombotic complication between ACS and non-ACS patients was estimated at 8.82 (95% CI: 1.3-63). Also, preexisting HIT antibodies in ACS patients significantly increased the risk of thrombotic complications compared with ACS without preexisting HIT antibodies. In conclusion, ACS patients with positive HIT antibodies have an increased risk of thrombotic complications during PCI performed under anticoagulation with heparin.

Role of platelet factor 4-heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis.

Heparin-induced thrombocytopenia (HIT) is a severe complication in patients on hemodialysis (HD). It has been reported that platelet factor-4 (PF-4)-heparin complex antibody (HIT antibody) plays an important role in the pathogenesis of this serious complication. In the present study, we investigated the role of HIT antibody in the pathogenesis of thrombotic complications including shunt failure, cerebrovascular disease (CVD) and atherosclerosis in patients on dialysis. Plasma concentration of HIT antibody in patients on HD was 0.143+/-0.008 (n=105). This was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD: 0.087+/-0.006, p=0.0008, n=22) and in non-dialysis patients (0.113+/-0.011, p=0.0011, n=12). There was a significant negative correlation between HIT antibody and the duration of dialysis. However, no significant correlation was found between HIT antibody and other factors including age, dose of heparin, platelet count and hemoglobin. There was a significant correlation between the number of failed arteriovenous fistula and HIT antibody levels. In addition, in patients with a history of CVD, plasma concentrations of HIT antibody were significantly higher compared with patients without CVD (CVD(+): 0.200+/-0.029 vs. (-): 0.127+/-0.005, p<0.0001). It is possible that genetic factors may also play a role in the expression of HIT antibody. From these data, it appears possible that HIT antibody plays an important role in the pathogenesis of thrombosis in patients on HD. Further studies are needed to clarify the role of HIT antibody in the pathogenesis of thrombotic episodes in these patients.

[Heparin-induced thrombocytopenia (HIT): pathogenesis, laboratory test, and treatment].

Heparin-induced thrombocytopenia(HIT) due to immunological mechanisms is known as an important adverse reaction to heparin treatment, and heparin treatment should be applied while keeping in mind the risk of onset of HIT 5-14 days after the initiation of heparin. The presence of HIT had not been fully recognized in clinical practice in Japan despite the management of HIT being well confirmed in Western countries. Recognition of HIT has increased since argatroban, a direct thrombin inhibitor, obtained the approval of the FDA for prevention and treatment of HIT. Although the incidence of HIT in Japan has not yet been clarified, there is some evidence that HIT is encountered in critically ill patients undergoing heparin anticoagulation. Clinical diagnosis of HIT is performed by means of thrombocytopenia of a drop of 50% or 100 x 10(30/microl for 5 -14 days after starting heparin treatment. Confirmatory laboratory tests examine whether the patients have antibodies against heparin/PF4 complexes or not. Two assay tests for detecting heparin/PF4 complex antibodies are available in Japan. As a functional test, the heparin-induced platelet aggregation method is easily performed and the result is obtained in a short time. The result of the test has, however, been misleading due to the selection of donors. Low platelet activity of the donors on the addition of heparin induces a negative response in spite of positive antibodies in the sample. Before testing samples, it is important to check heparin reactivity of the donor's platelets. Enzyme immunoassay detecting the antibodies is available as a commercial kit. Sensitivity obtained by enzyme immunoassay is very high and often introduces false-positives. Careful attention to interpretation of the result is required. Treatment of HIT should be started at the time of recognition of thrombocytopenia while antibody testing for HIT is performed. As an alternative anticoagulant to heparin, argatroban should immediately be applied to avoid complication of thrombosis. Thrombocytopenia and hypercoagulability quickly recover to the preheparin level by the appropriate use of argatroban.

Incidence of heparin-PF4 complex antibody formation and heparin-induced thrombocytopenia in acute coronary syndrome.

A multicenter prospective study on the rate of seroconversion of antibodies to heparin-PF4 complexes (heparin-induced thrombocytopenia [HIT] antibodies) during and after heparin treatment for 4 weeks was carried out in Japanese patients with acute coronary syndrome (ACS). A total of 254 ACS patients treated with heparin were enrolled consecutively from 12 facilities of cardiology. Two patients with preexisting HIT antibodies were excluded from the analysis. The total seroconversion rate for four weeks during and after heparin treatment was 8.7% (n=22, 95% confidence interval [CI]: 5.9-13.1), including values of 3.2% (n=8) at the end of heparin infusion and 5.5% (n=14) at 4 weeks. Among 22 seroconverted patients, four developed HIT and two of the four had the complication of thrombosis. The incidence of HIT was 1.6% (n=4, 95% CI: 0.04-3.1). The risk for thromboembolic development was higher in the seroconverted patients (odds ratio, 17.4, 95% CI: 5.2-58.4, p<0.0001) than nonconverted patients. An analysis of factors affecting the seroconversion rate was carried out. The seroconversion rate for ACS patients who underwent percutaneous coronary intervention (PCI; n=163) was 12.3%, significantly higher than the 2.3% in patients who did not undergo PCI (n=89), leading to an odds ratio of 6.1 (95% CI: 1.4-26.7, p=0.009). A significant odds ratio was obtained for each factor affecting the seroconversion: 3.5 (95% CI: 1.3-9.9, p=0.014) for more than 5 days of heparin infusion, 3.0 (95% CI: 1.2-7.6, p=0.035) for a thrombotic history and 2.7 (95% CI: 1.1-6.8, p=0.039) for hyperlipidemia. No other factor, including age or diabetes mellitus, contributed to the seroconversion. Therefore, PCI, duration of heparin treatment and thrombotic history facilitated the seroconversion in ACS patients. PCI patients treated for more than 5 days with heparin showed a maximal seroconversion rate of 18.3% (95% CI: 13.8-22.2). This high rate in PCI patients did not interact with age, type of underlying disease of unstable angina or myocardial infarction or thrombotic history. In conclusion, ACS patients demonstrating seroconversion are at risk of thromboembolic development due to the likelihood of immunomediated endothelial dysfunction. The increase in the rate of seroconversion in ACS patients would be affected by factors such as PCI with mechanical stress, longer duration of heparin treatment, thrombotic history and presence of hyperlipidemia. If PCI is undertaken with heparin anticoagulation for more than 5 days, seroconversion would easily occur, and the seroconverted patients could subsequently suffer from HIT.