Comment on Saner et al. The Yin and the Yang of Hemostasis in End-Stage Liver Disease. J. Clin. Med. 2023, 12, 5759.

We congratulate you on a quality review of the article on hemostasis in end-stage liver disease by Saner FH et al [...].

Frequency of abnormal biphasic aPTT clot waveforms in patients with underlying disorders associated with disseminated intravascular coagulation.

Abnormal biphasic waveform (BPW) patterns were previously reported when the activated partial thromboplastin time (aPTT) was performed in plasma from patients with disseminated intravascular coagulation (DIC). In this study, the prevalence of the BPW was examined in a cohort of 508 hospitalized patients with elevated fibrinogen degradation products (FDP) levels (>10 microg/mL). The presence of a BPW was automatically flagged by the MDA analyzer when the slope of the precoagulation phase in the waveform exceeded a threshold value of -0.25%T/sec. In our cohort, 76 patients (15%) were diagnosed with overt DIC according to the criteria recently proposed by the International Society of Thrombosis and Haemostasis (ISTH), whereas 96 patients (18.9%) were diagnosed with DIC following the criteria of the Japanese Ministry of Health and Welfare (JMHW). The JMHW and ISTH criteria agreed in 93% of cases (kappa coefficient 0.76). The concordance between both scoring systems was high in patients with infection but low in solid cancer. The BPW appeared in 65 patients (12.8%), with the highest prevalence (23.6%) in patients with infection. The BPW was more prevalent in the subgroup of patients with DIC: 59.2% and 47.9% for DIC diagnosed by ISTH and JMWH scores, respectively. The prevalence of the BPW was particularly high in patients with DIC and infection: 86.4% and 75.0% for DIC diagnosed by ISTH and JMWH scores, respectively. For the total cohort, the presence of the BPW was significantly associated with DIC. Odds ratios were 29.9 and 19.0 for ISTH and JMWH scores, respectively (p<0.0001). The BPW showed a moderate sensitivity (59.2% for the ISTH score; 47.9% for the JMWH score), but a high specificity (95.4% for both scores). Waveform analysis of the aPTT potentially provides a practical tool in risk assessment of critical care patients, in whom development of DIC is known to worsen the prognosis.

Lipoprotein-complexed C-reactive protein and the biphasic transmittance waveform in critically ill patients.

The 'biphasic transmittance waveform' (BTW) refers to a decrease in light transmittance that often occurs prior to clotting in coagulation assays of critically ill patient plasmas. It correlates with disseminated intravascular coagulation and mortality. The present work shows that the BTW is due to the rapid formation of a precipitate and a coincident change in turbidity in re-calcified plasma. The precipitate was isolated from patient plasma and contained lipids typical of very low density lipoprotein (VLDL), plus the proteins apolipoprotein B-100 and C-reactive protein (CRP). Precipitation also occurred in normal plasma supplemented with CRP. In addition, CRP precipitated with VLDL and intermediate density lipoprotein, but not low density lipoprotein or high density lipoprotein. The Kd value for the CRP/VLDL interaction is 340 nM. The IC50 value of Ca2+ for complex formation is 5.0 mM, and epsilon-aminocaproic acid inhibits the process. In 15 plasmas with the BTW from critically ill patients, CRP was highly elevated (77-398 microg/mL) and VLDL cholesterol ranged from 0.082 to 1.32 mM. The magnitude of the turbidity change on re-calcification correlated well with the calculated level of the CRP/VLDL complex. Thus, the Ca2+-dependent formation of a complex between CRP and VLDL accounts for the BTW.

Use of lyophilized calibrant plasmas for simplified international normalized ratio determination with a human tissue factor thromboplastin reagent derived from cultured human cells.

BACKGROUND: For monitoring of treatment with oral anticoagulants, the clotting time obtained in the prothrombin time (PT) test is transformed to the International Normalized Ratio (INR) with use of a system-specific International Sensitivity Index (ISI). The calibrant plasma procedure (CPP) is an alternative approach to INR calculation based on the use of a set of lyophilized plasmas with assigned INRs. METHODS: With the CPP, a linear relationship is established between log(PT) and log(INR), using orthogonal regression. CPP was validated for Simplastin HTF, a new human tissue factor reagent derived from cultured human cells. CPP precision was assessed as the CV of the slope of the regression line. The accuracy of the CPP was determined by comparing the INR obtained with the CPP with that obtained with the established ISI-based reference method. INRs of the calibrants were assigned by different routes: by manufacturer (consensus labeling) or by use of Simplastin HTF or International Reference Preparations (IRPs; rTF/95 or RBT/90). RESULTS: The mean CV of the CPP regression slope ranged from 1.0% (Simplastin HTF reagent-specific INR) to 2.4% (INR assigned with rTF/95). INRs calculated with the CPP were similar to those obtained with the reference method, but when the routes for assigning INRs to the calibrant plasmas were compared, the mean difference in INR between CPP and the reference method was smaller with Simplastin HTF reagent-specific values. In several (but not all) cases, this difference was significant (P <0.05, t-test). CONCLUSION: CPP can be used for local INR determination, but better precision and accuracy are obtained with reagent-specific INRs compared with INR assignment by consensus labeling or IRP.

Utility of activated partial thromboplastin time waveform analysis for identification of sepsis and overt disseminated intravascular coagulation in patients admitted to a surgical intensive care unit.

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described in association with overt disseminated intravascular coagulation. This abnormality, a biphasic waveform, is caused by the in vitro formation of Ca2+-induced complexes between very low density lipoprotein and C-reactive protein. We have evaluated the diagnostic utility of aPTT waveform analysis for identifying patients with overt disseminated intravascular coagulation and sepsis. DESIGN: Observational study investigating the predictive value of biphasic waveform for the diagnosis of sepsis and overt disseminated intravascular coagulation. SETTING: Surgical intensive care unit of a university hospital. SUBJECTS: We studied 331 consecutive patients admitted to the intensive care unit during a period of 6 months. INTERVENTIONS: Laboratory analyses, including prothrombin time, aPTT, aPTT waveform analysis, fibrinogen, D-dimer antigen, and platelet count. MEASUREMENTS AND MAIN RESULTS: At the most sensitive threshold value of the waveform variable for detection of the biphasic waveform (slope_1 = -0.05 %T/sec), this abnormality was detected in 54 of 331 patients (16.3%) at admission and 95 of 331 patients (28.7%) during the entire course of intensive care unit treatment. At this threshold, 59.3% of patients with a biphasic waveform on admission and 45.3% with a biphasic waveform during the total intensive care unit course were diagnosed with sepsis. Depending on the threshold value of slope_1, the sensitivity of aPTT waveform analysis for detection of sepsis varied between 22% and 55% at admission and between 48% and 74% during the entire intensive care unit stay. The specificity for sepsis varied between 92% and 98% and between 81% and 94%, for admission and total intensive care unit course, respectively. Biphasic waveform showed a comparable specificity for the diagnosis of overt disseminated intravascular coagulation, albeit at a lower sensitivity. CONCLUSIONS: As an adjunct to routine coagulation testing in intensive care unit patients, aPTT waveform analysis is an elegant means for the rapid and highly specific identification of patients with sepsis.

Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca(++)-dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation.

A decrease in light transmittance before clot formation, manifesting as a biphasic waveform (BPW) pattern in coagulation assays, was previously correlated with the onset of disseminated intravascular coagulation (DIC). In this study of 1187 consecutive admissions to the intensive care unit, the degree of this change on admission predicts DIC better than D-dimer measurements. Additionally, the BPW preceded the time of DIC diagnosis by 18 hours, on average, in 56% (203 of 362) of DIC patients. The BPW is due to the rapid formation of a precipitate and coincident turbidity change on recalcification of plasma. The isolated precipitate contains very-low-density lipoprotein (VLDL) and C-reactive protein (CRP). The addition of CRP and Ca(++) to normal plasma also causes the precipitation of VLDL and IDL, but not LDL or HDL. The K(d) of the CRP/VLDL interaction is 340 nM, and the IC(50) for Ca(++) is 5.0 mM. In 15 plasmas with the BPW, CRP was highly elevated (77-398 microg/mL), and the concentration of isolated VLDL ranged from 0.082 to 1.32 mM (cholesterol). The turbidity change on recalcification correlates well with the calculated level of the CRP-VLDL complex. Clinically, the BPW better predicts for DIC than either CRP or triglyceride alone. The complex may have pathophysiological implications because CRP can be detected in the VLDL fraction from sera of patients with the BPW, and the VLDL fraction has enhanced prothrombinase surface activity. The complex has been designated lipoprotein complexed C-reactive protein.