Levels Of Fibrin Split Products Research Articles

Pathogenesis and diagnosis of disseminated intravascular coagulation.

Several clinical conditions, in particular those associated with a systemic inflammatory response, can cause some degree of activation of coagulation but when the procoagulant stimulus is sufficiently severe and overcomes the natural anticoagulant mechanisms of coagulation, disseminated intravascular coagulation (DIC) may occur. The clinical manifestations of DIC encompass multiorgan dysfunction caused by fibrin-platelet clots in the microcirculation, and bleeding caused by consumption of platelets and coagulation factors. Molecular mechanisms that play a role in inflammation-induced effects on coagulation have been recognized in much detail. Exposure of blood to tissue factor is the most common trigger, whereas the intravascular coagulation is propagated due to loss of function of physiological anticoagulants and impaired fibrinolysis. In patients with DIC, various abnormalities in routine coagulation parameters may be observed, including thrombocytopenia, prolonged global coagulation assays, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. A combination of readily available tests is usually sufficient in establishing the diagnosis of DIC, and for this purpose, several scoring algorithms have been developed. Some specific clinical situations may elicit coagulation responses that can be distinguished from DIC or may occur in combination with DIC, including dilutional coagulopathy, liver failure-related coagulation derangement, and thrombotic microangiopathies.

816: Hepatic and renal dysfunction with acute fatty liver of pregnancy: expected duration of recovery after delivery

pregnancy: expected duration of recovery after delivery David Nelson, Nicole Yost, F. Gary Cunningham The University of Texas Southwestern Medical Center, Obstetrics and Gynecology, Dallas, TX OBJECTIVE: Acute liver and renal dysfunction are particularly problematic in women with acute fatty liver of pregnancy (AFLP). While recovery for both begins following delivery, the time required for either is not well characterized. Our aim was to assess and provide estimates of the duration required for resolution of hepatic and renal dysfunction in AFLP. STUDY DESIGN: Clinical and laboratory findings were reviewed for women with AFLP admitted to our obstetrics service from 1980 through 2010. The diagnosis was made when severe hepatocellular dysfunction was accompanied by characteristic clinical findings and evidence for renal, hemostatic, and/or hematological aberrations; imaging studies; and/or liver histopathology. Along with clinical resolution, we analyzed a number of serially determined laboratory findings beginning after delivery and then for varying intervals up to several weeks postpartum. RESULTS: A total of 50 women with AFLP were identified during the 30-year period. They had multi-organ system dysfunction of varying severity, and although there was only one maternal death, these women had numerous medical, surgical, and obstetrical complications as well as perinatal deaths. Management included supportive care and delivery. For this study, mean levels were calculated for four serum analytes determined serially and shown in the Figure. CONCLUSION: The degree of hepatic and renal insufficiency is quite variable in severity and concordance in women with AFLP. Ongoing hepatocellular damage appears to decrease soon following delivery as reflected by rapidly declining serum aspartate aminotransferase (AST) levels. Despite this, hepatic dysfunction reverses more slowly as indicated by the prolonged recovery of cholesterol production and bilirubin clearance. Similar trends were documented for plasma fibrinogen concentrations and prothrombin generation (data not shown). Our findings indicate that renal dysfunction is caused by prerenal factors and serum creatinine concentrations decrease in a linear fashion after delivery, and in most women these will be 1 mg/dL within a week. 817 Acute fatty liver of pregnancy: characterization of associated coagulopathies and duration of their persistence after delivery David Nelson, Nicole Yost, F. Gary Cunningham The University of Texas Southwestern Medical Center, Obstetrics and Gynecology, Dallas, TX OBJECTIVE: Acute fatty liver of pregnancy (AFLP) is frequently complicated by clinically significant coagulopathy. Delivery usually arrests hepatocellular damage with subsequent production of procoagulants. At delivery, especially cesarean, blood and coagulant replacement therapy is commonly required. Although coagulation persists after delivery, its duration has not been well characterized. Our purpose was to determine the severity, causes, and duration of hemostatic dysfunction. STUDY DESIGN: Clinical and laboratory findings were reviewed for women identified to have AFLP admitted from 1980 through 2010. The diagnosis was arrived at by confirmation of severe hepatocellular dysfunction accompanied by characteristic clinical findings; laboratory evidence for renal, hemostatic, and/or hematological aberrations; imaging studies; and/or liver biopsy. Selected indicators of hemostasis were analyzed to accomplish our goals. RESULTS: A total of 50 women had AFLP with multi-organ system dysfunction of varying degrees. Although there was only one maternal death, these women had numerous medical, surgical, and perinatal complications. Treatment included supportive care and effecting delivery. Pertinent to this study, four indicators of coagulation were determined at various intervals after delivery and plotted as a function of days postpartum (Figure). CONCLUSION: Although variable in severity, coagulopathy of AFLP results from increased consumption and decreased hepatic production of procoagulants. Both the intrinsic and extrinsic pathways are affected as evidenced by frequent prolongation of the PTT and/or the INR. Hypofibrinogenemia is common and often severe, and it usually is accompanied by abnormally increased serum levels of fibrin split products or D-dimers (data not shown). Thrombocytopenia is almost universal and in about 1/5 of women platelets decreased to less than 50,000 (10^9/L). After delivery, and related to their severity, some of these derangements persist for up to a week as hepatocellular repair progresses. Poster Session V Academic Issues, Antepartum Fetal Assessment, Genetics, Hypertension, Medical-Surgical-Disease www.AJOG.org

Burr Red Blood Cells (BC) In Patients with Disseminated Intravascular Coagulation (DIC)

AbstractAbstract 5141Burr red blood cells (BC) in patients with disseminated intravascular coagulation (DIC). Background:Angiopathic hemolysis with schistocytes occurs in a minority of DIC patients. Burr cells (BC), are morphologically homogeneous, with a serrated membrane resembling that of red cells (RBC) in a hypertonic medium. They are associated with acute renal insufficiency, and have been observed in DIC. Methods:Criteria for patient inclusion were sepsis, often with multi-organ failure and hypotension. Of the 39 patients studied, 20 had DIC, based on platelet counts <100,000, and an International Society of Hemostasis and Thrombosis score of ≥5, derived from D-dimer or fibrin split product levels, prothrombin time elevations, and fibrinogen levels. The percentages of BC and schistocytes were determined by 1000 RBC counts, without knowledge of data concerning DIC. Patients' [Hb]'s, serum creatinine and blood urea nitrogen (BUN), were recorded. Results:Five of the 20 DIC patients succumbed to their acute illness, while 15 recovered without developing renal insufficiency. The BC%'s of the 20 DIC patients ranged from 0–80%, with a median of 18% and a mean of 27%; in the 19 patients without DIC the range was 0–45%, the median 6.4% and the mean 11% (p=0.046). The schistocyte percentages in patients with and without DIC ranged from 0.20–17, and 0–78; the respective medians and means were 1.1% and 1.0%, and 3.0–5.8%. The median and mean [Hb]'s of the patients with and without DIC were 9.3 and 11, and 9.6 and 10.3, respectively. BC% did not correlate with the [Hb]. The median creatinine levels of patients with and without DIC were 0.92 and 0.93 mg/dl, though the DIC patients' BUN's were higher (medians 31 vs 15). The BC% correlated with neither the BUN nor the BUN/creatinine ratio. The median and mean serum sodium levels in patients with and without DIC were 137. Conclusion:BC's are significantly more frequent in septic patients with DIC than in those without it. BC% did not correlate with anemia, implying that BC do not cause significant hemolysis, though there was a trend to lower [Hb] in the DIC patients. BC% was much higher than that of schistocytes in both groups, and schistocyte percentages did not correlate with DIC or BC%. Because of the DIC patients' higher BUN's and BUN/creatinine ratio's, we cannot exclude a role for the factors, which caused pre-renal azotemia in BC formation. BC formation may prove to be a criterion for DIC. Disclosures:No relevant conflicts of interest to declare.

DIC: Which laboratory tests are most useful

In patients with disseminated intravascular coagulation (DIC) a variety of altered coagulation parameters may be detectable, such as thrombocytopenia, prolonged global coagulation times, reduced levels of coagulation inhibitors, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. There is not a single test, however, that is sufficiently accurate to establish or reject a diagnosis of DIC. Nevertheless, a combination of widely available tests may be helpful in making the diagnosis of DIC and can also be helpful to guide in the selection of DIC patients that require specific, often expensive, interventions in the coagulation system. More recently developed dynamic algorithms, assessing changes in coagulation parameters over sequential days, could further increase the diagnostic accuracy for DIC and may be helpful to detect early stages of coagulopathy potentially evolving into DIC.

Hemostasis and Thrombosis in Critically Ill Patients

A large number of critically ill patients will develop hemostasis and thrombosis issues during their clinical course. These problems may vary from excessive blood loss due to a myriad of causes; to widespread intravascular fibrin formation and consequent multiple organ dysfunction as a result of systemic inflammation; to the development of venous thromboembolic complications. Some patients will present with simultaneous bleeding and thrombotic complications, which will render the appropriate treatment even more complex. Both anticoagulant and prohemostatic drugs belong to the most frequently prescribed agents for patients in the intensive care unit (ICU).[1] [2] In addition, in critically ill patients, coagulation abnormalities often occur. A variety of changes, such as thrombocytopenia, prolonged global coagulation tests, reduced levels of coagulation inhibitors, or high levels of fibrin split products, may reflect various disease mechanisms. Also, some patients may have a marked coagulopathy that is not readily revealed by routine coagulation tests. In all cases, a proper differential diagnosis is required, as various underlying causes may require totally different therapeutic approaches. In this issue of Seminars in Thrombosis and Hemostasis, various topics regarding the diagnostic and therapeutic management of hemostasis and thrombosis issues in critically ill patients are discussed.

Adverse Effects of Postoperative Infusion of Shed Mediastinal Blood

Postoperative infusion of shed mediastinal blood has been used in an effort to decrease blood usage after cardiac operations. Recent experience has suggested that this practice may actually lead to a delayed increase in bleeding. In a prospective, randomized study, 40 patients undergoing coronary artery bypass grafting with shed mediastinal blood collected in a cardiotomy reservoir were divided into two equal groups and studied during their first 4 hours in the intensive care unit. Shed mediastinal blood was directly infused in group I (n = 20), whereas in group II (n = 20), it was not. In group II, if a sufficient volume of red cells was present to allow processing (n = 5), washed red cells were infused. Variables studied before and after infusion were the amount of blood lost and infused, homologous blood transfused, complete blood count and differential, serum fibrinogen, fibrin split products, D-dimers, clotting factors, prothrombin time, activated partial thromboplastin time, thromboelastograms, plasma-free hemoglobin, complement factors C3 and C4, creatine kinase and its MB isoenzyme, and body temperature. After infusion of shed mediastinal blood, elevated levels of fibrin split products and D-dimers were found in significantly more patients in group I. The thromboelastogram index was normal in 76% of patients in group II but in only 12.5% in group I. Group I also had an increase in band neutrophils, a greater number of febrile patients, higher serum levels of creatine kinase, its MB isoenzyme, and plasma-free hemoglobin, and greater blood loss during hours 3, 4, and 5 in the intensive care unit. The volume of red cells in shed mediastinal blood (hematocrit, 9% to 10%) was small, resulting in clinically insignificant autotransfusion when infused directly, and insufficient for cell processing in most patients. These data support those in previous studies that direct infusion of shed mediastinal blood does not save substantial amounts of autologous red cells and can cause a delayed coagulopathy and other adverse effects that may be harmful to patients postoperatively.

Extracorporeal membrane oxygenation: Preliminary results in patients with postcardiotomy cardiogenic shock

Long-term survival at our institution for postcardiotomy cardiogenic shock patients supported with the BioPump is 36% (29/80 patients). A heparin-coated extracorporeal membrane oxygenator (ECMO), first introduced in 1991, may reduce organ injury associated with cardiopulmonary bypass. The device can be employed rapidly because it connects directly to the cardiopulmonary bypass cannula. In an effort to improve our results in the treatment of postcardiotomy cardiogenic shock, we used ECMO in 21 patients with this syndrome and accompanying complications. The patients were divided into three groups: group 1, ECMO after coronary artery bypass grafting; group 2, ECMO after mitral valve operation; and group 3, ECMO after open heart operation with prolonged cardiac arrest. Survival in group 1 was 80% with 12 of 14 patients discharged to home. All three deaths were caused by cardiac failure. Bleeding complications in this group were moderate. There was no evidence of disseminated intravascular coagulation, and levels of fibrin split products remained within the normal range. Postoperative complications included stroke (2), renal failure (1), mediastinitis (1), and prolonged respiratory failure (6). Mortality in group 2 was 100%. The major problem limiting recovery was left ventricular distention secondary to inadequate left ventricular decompression. Mortality in group 3 was 100%; all 4 died of brain death. Extracorporeal membrane oxygenation without left ventricular drainage clearly is not effective in patients undergoing mitral valve operations as it does not effectively decompress the left ventricle, but it was highly effective in treating postcardiotomy cardiogenic shock in our coronary artery bypass grafting patients. Extracorporeal membrane oxygenation also proved to be safe as the patient-related complications of stroke, renal failure, and mediastinitis were low. Our preliminary success with heparin-coated ECMO now needs to be confirmed by studies from other centers with larger groups of patients.

Continuous Arteriovenous Rewarming

We evaluated a technique for treating hypothermia that uses extracorporeal circulation but does not require heparin or pump assistance. Hypothermia to 29.5 degrees C was induced in eight anesthetized dogs, and thermistors placed in the pulmonary artery, liver, bladder, esophagus, rectum, muscle, and skin. Four experimental animals were rewarmed by creating a fistula which connected arterial and venous femoral lines to an interposed counter-current heat exchanger. External rewarming was used in four controls. Bleeding time (BT), coagulation profile (PT, PTT, TT), and cardiac output (CO) were measured during rewarming. Core temperature (T) rose significantly faster with CAVR (0.00001). Average time to rewarming was 45 min, vs. 4 hrs in controls. Haptoglobin, platelet, fibrinogen, and fibrin split product levels were unaffected. Continuous arteriovenous rewarming (CAVR) improved T, CO, BT, and coagulation profile faster than any method yet reported not requiring heparin or cardiac bypass. The application of CAVR in post-traumatic hypothermia warrants further investigation.

The Platelet Count in Carcinoma of the Lung and Colon

Platelet counts were evaluated in 714 patients with advanced non-small cell lung cancer (N-SCLC), small cell carcinoma of the lung (SCCL), and colon cancer entered to a clinical trial. Patients had not received prior chemotherapy. Platelet counts were not different in patients who had received radiation therapy prior to entry to the study. In comparison to the other tumor types, patients with N-SCLC demonstrated an increased prevalence of thrombocytosis (counts greater than 400,000/mm3), higher platelet counts at the time of entry to the study, higher over all mean platelet counts, relative preservation of high platelet levels during disease progression, and no relationship between platelet numbers and the amount of chemotherapy given. By contrast, platelet counts in patients with SCCL were negatively correlated with the absolute amount of cyclophosphamide and adriamycin given, and declined most dramatically with disease progression and death. Platelet numbers did not correlate with fibrinopeptide A or fibrin split product levels suggesting that disseminated intravascular coagulation or fibrinolysis may have had less influence on platelet numbers than certain other factors. By contrast, significant correlations were found for all three tumor types between platelet numbers and other indicators of bone marrow function including anemia, total leukocyte count, and absolute neutrophil count; and the fibrinogen level. Based upon these findings, we postulate that the host response to malignancy, possibly in the form of production of bone marrow-stimulating cytokines, may play a prominent role in regulation of platelet counts in these (and perhaps other) neoplasms, and that a particularly prominent and persistent degree of marrow stimulation exists in patients with N-SCLC.

Abnormalities of blood coagulation tests in patients with cancer.

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

COAGULATION STUDIES ON PATIENTS WITH SICKLE CELL DISEASES

Repeated measurements of coagulation factor activities were done on blood from 16 patients with Sickle Cell Disease over a one year period. Sixty-two coagulation profiles were available for analysis during well periods and 12 profiles on 6 patients were obtained during painful crisis. The profiles included measurements of the prothrombin time, partial thromboplastin time, thrombin time, platelet count, quantitation of Factors I, II, V, VII, VIII, IX, X, XI, XII, measurement of fibrin split products, fibrin monomer, and platelet aggregation with collagen ADP and epinephrine. Factor II was significantly lower than normal, platelet counts were significantly increased, and platelet aggregation with collagen epinephrine and ADP were impaired in approximately one-third of patients in. the absence of known injestion of platelet active drugs. Fibrin monomer as measured by radioactive amine incorporation (JCI 50:2235, 1971) was increased once in each of 4 patients but there were no increased levels of fibrin split products in the serum and no significant differences in results during well and painful crisis periods. Therefore, no evidence of chronic intravascular coagulation was found. The decreased concentration of prothrombin may be a result of liver impairment. The increased platelets and abnormal aggregation are unexplained.

Fibrinolytic activity and fibrinogen split products in exercise proteinuria

Increased fibrinogen reactive material in the form of D and E fragments was identified in post-exercise urine from healthy individuals. No evidence for native fibrinogen in urine was found. Studies on 4 persons after severe exercise showed a striking rise in fibrinolytic activity with no significant change in fibrinogen, plasminogen or fibrin split product levels. Increased plasmin activity was found in 2 out of 4 exercise urines concentrated 30 times. A significant increase in urinary FSP can be the result of a physiological mechanism and does not necessarily reflect a pathological process.

Intravascular Coagulation and Fibrinolysis in Human Renal Disease

JAMES J. CORRIGAN, Jr. (Emory University School of Medicine, Atlanta, Ga.): What happens to the fibrolytic split products in inflammatory disease in general? Can you venture a guess as to what the half-life of the split products might be? And, in studies that we have done and reported by others, we have noted that there is a high titer of a material that is antithrombin in the alpha-2-macroglobulin fraction in addition to the antiplasmin; so that thrombosis in the nephrotic syndrome is probably not simply on the basis of elevated antiplasmins.Dr. STIEHM: Fibrin split products increase in inflammation and infection. Using a sensitive technique like hemagglutinin inhibition, elevations of fibrin split products are frequently noted; this may be a useful test for sepsis. The half-life of fibrin split products is from 3 to 6 h. Limited studies on antithrombin levels in the nephrotic syndrome have disclosed no abnormalities; I will await your data with interest.LYMAN A. PAGE (Stanford University School of Medicine, Palo Alto, Calif.): Is defective fibrinolysis seen as nonnephrotic hypoalbuminemia and analbuminemia?The second question is whether you have tried to correlate the presence of fibrin split products in the urine with the extent of renal failure. It seems to me you are drawing some important inferences from the absence of correlation between urinary and plasma fibrin split products.Dr. STIEHM: In patients with chronic renal disease with low albumin, there was no defect in fibrinolysis. We have not studied any patients with analbuminemia.In any type of chronic renal failure urine fibrin split products may be elevated; therefore, when one is using urine fibrin split product levels as an indicator of transplant rejection, one should take into consideration the degree of azotemia. A urine fibrin split product level is significant only if it is markedly above what we would expect from other uremic patients with the same degree of renal failure. Currently we are relating levels of azotemia with urine fibrin split product levels.HAROLD M. MAURER (Medical College of Virginia, Richmond, Va.): Have you used the ethanol gelation test to detect intravascular coagulation? How sensitive is this test compared with the test for fibrin split products in serum?Dr. STIEHM: We have had limited experience with this procedure. The ethanol gelation test is positive in marked intravascular coagulation with defibrination. I do not believe, on the basis of limited studies, that it is of value in the study of subtle and localized intravascular coagulation.GERALD S.GILCHRIST (Children's Hospital of Los Angeles, Los Angeles, Calif.): I noticed that 37% of the patients had fibrin split products in their serum. Larger numbers have it in their urine. Can you explain the large percentage of serum positive patients in the light of the apparent defect in fibrinolysis? Secondly, with regard to the hemolytic-uremic syndrome, I find difficulty in accepting your classification of the syndrome as a manifestation of generalized intravascular coagulation. Most studies would support the concept that this is a localized phenomenon with no consistent evidence of vascular involvement outside of the kidney.Dr. STIEHM: There is a disagreement whether fibrin split products can occur in the presence of a defective fibrinolytic system. In my experience, I have never seen a fibrinolytic system so defective that fibrin split products are not generated even in the presence of markedly decreased plasminogen levels. Fibrin split products may be falsely negative if insensitive techniques such as agar diffusion are used. Secondly, I regard the hemolytic-uremic syndrome as an illness not limited to the kidney, with central nervous system and peripheral vascular involvement. At autopsy I believe there is evidence for intravascular coagulation.JACK RESNICK (Naval Hospital, San Diego, Calif.): What type of correlation do you find between the biopsy evidence of fibrin or fibrinogen in the kidney, and the urine and serum fibrin split products?Dr. STIEHM: We have not as yet had extensive experience correlating urine fibrin split products with biopsy evidence of deposited fibrinogen. We have found poor correlation between serum levels of fibrin split products and immunofluorescent evidence of a fibrinogen.

Fibrin Split Products in Serum of Newborn: Possible Technical Errors

The paper of Drs. Stiehm and Clatanoff1 indicates that the cord blood of 65% of vaginally delivered and 58% of C-section delivered normal infants contains very significant (5—30 mg/100 ml) amounts of fibrin split products (FSP). These elevated levels of FSP fall to zero by 24 hours of age. Our recently published data agree that normal infants 12 to 48 hours of age rarely show increased levels of FSP. However, regarding cord blood, our unpublished data are distinctly different than that reported by Drs. Stiehm and Clatanoff.