Hemostatic Defects Research Articles

Coagulopathy of massive transfusion: pathophysiology and monitoring

Coagulopathy associated with massive transfusion (MT) remains an important clinical problem. The author attempted to identify the causes of coagulopathy in massively transfused, adult and previously haemostatically competent patients and to differentiate between the elective surgical and the emergency settings. A MEDLINE search was conducted for articles published on ‘massive transfusion’, ‘transfusion’, ‘trauma’, ‘surgery’, ‘coagulopathy’ and ‘haemostatic defects’. A narrative format was adopted. Coagulopathy associated with MT is an intricate, multifactorial and multicellular event. In patients undergoing elective surgery, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. Critically low levels of coagulation factors were seldom reported when whole blood was in common use. With the use of packed red blood cells (PRBC), dilution or consumption of coagulation factors has become a significant issue requiring specific treatment with, primarily, fresh frozen plasma (FFP). In the emergency setting (e.g., trauma, ruptured abdominal aortic aneurysm), tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. It has been shown that the proactive administration of platelets and FFP improves coagulation, decreases haemorrhage and improves survival in these massively bleeding patients. We can only speculate that in this specific context, the benefits of early and aggressive platelet and coagulation factor replacement are related to the ongoing consumption coagulopathy at the time of surgery.

Management of Bleeding Complications of Hematologic Malignancies

Persons with hematologic malignancies bleed for a variety of reasons, including alterations in platelet function and numbers, clotting factor deficiencies, circulating anticoagulants, and defects in vascular integrity. The management of bleeding begins with a full characterization of the hemostatic defect. Vitamin K deficiency always should be considered and excluded by clinical history and laboratory tests. Localized bleeding is treated by packing, topical hemostatic agents, dressings, vessel ligation, laser beam coagulation, or embolization. Platelet transfusions are administered for hemorrhage secondary to severe platelet dysfunction or thrombocytopenia, but usually are not indicated if there is no bleeding, even though platelets may be as low as 10,000/microL. Bleeding due to thrombocytopenia that is refractory to random-donor platelets may respond to cross-matched compatible platelets, or to recombinant factor VIIa (rFVIIa). Fresh frozen plasma is indicated infrequently; bleeding due to coagulopathies is better managed with cryoprecipitate if fibrinogen is low, or with clotting factor concentrates appropriate for the specific clotting factors found to be deficient. rFVIIa or activated prothrombin complex concentrate usually controls hemorrhage due to autoantibodies directed against factor VIII, and acquired von Willebrand's disease may be responsive to desmopressin or intravenous gamma globulin infusion. Antifibrinolytic agents often enhance other hemostatic therapies, but should be withheld if there is genitourinary bleeding or evidence of disseminated intravascular coagulation. Finally, plasmapheresis and immunoadsorption to remove paraproteins may be helpful when other measures fail to curb bleeding.

Routine coagulation tests in newborn and young infants

The diagnostic approach to haemostatic defects in the newborn is challenging and requires appropriate interpretation of coagulation tests according to reference values dependent on the postnatal age. This investigation was designed to study the postnatal development of the human coagulation system in newborn infants and to develop appropriate reference ranges for prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FBG) according at the day of birth and for the following postnatal period (days 1, 2, 3, 4, 5, 6, from 7 to 10 and from 11 to 44). The mean FBG value was already within the adult reference range in newborns at birth, the mean PT value fell within the adult reference range in infants aged 4 days or more, whereas the mean APTT value was still higher than the upper limit of the adult reference range in infants aged between 11 and 20 days. The prevalence of infants with pathological values according to the actual adult reference ranges was limited for FBG (from 24 to 7%), decreased from 92 to 8% in infants aged 0 and 11-20 days for PT, but remained elevated throughout the observational period for APTT (from 94 to 71%). The results of the present investigation demonstrate that the actual adult reference ranges for coagulation screening tests, especially PT and APTT, cannot be applied to newborns and young infants.

The use of desmopressin as a hemostatic agent: A concise review

Desmopressin, a synthetic derivative of the antidiuretic hormone vasopressin, is the treatment of choice for most patients with von Willebrand disease and mild hemophilia A. Moreover, the compound has been shown to be useful in a variety of inherited and acquired hemorrhagic conditions, including some congenital platelet function defects, chronic liver disease, uremia, and hemostatic defects induced by the therapeutic use of antithrombotic drugs such as aspirin and ticlopidine. Finally, desmopressin has been used as a blood saving agent in patients undergoing operations characterized by large blood loss and transfusion requirements, but studies suggest that this is not as effective as other methods. This review briefly summarizes the current clinical indications on the use of desmopressin as a hemostatic agent.

Renal Allograft Venous Thrombosis Is Salvageable

Background Renal vein thrombosis (RVT) is an uncommon but serious complication. It usually occurs early after surgery. While compression of the renal vein is the most common cause, early rejection and hemostatic defects are other known causes. The symptoms are nonspecific and diagnosis is often delayed. Ultrasonography and renal isotope scan findings may resemble acute rejection or acute tubular necrosis. Patients and Methods We retrospectively reviewed the records of 684 recipients who were transplated between November 1993 and May 2006. The diagnosis of RVT was suspected by an unexplained drop in urine output, rise in serum creatinine, or hematuria, and confirmed by Doppler ultrasound and isotope scanning. Urgent exploration was performed in all suspected cases. Results Seven incidences of biopsy-proven RVT were encountered, including 3 associated with hematoma and 1 with rejection. Four grafts were from cadaveric donors. Three grafts were salvaged. Conclusions The incidence of RVT in the present series was 1%. All cases developed in the first 2 weeks after transplantation. It was more common in adults, in female recipients, and in cadaveric grafts. Early diagnosis and intervention were the keys to salvage.

Investigating people with mucocutaneous bleeding suggestive of primary hemostatic defects: a low likelihood of a definitive diagnosis?

People with mucocutaneous bleeding represent a major subtype of hematologic clinical presentations but simultaneously present a substantial diagnostic challenge. On the one hand, bleeding symptoms are frequent in the general population, but their clinical relevance may be difficult to assess. For

Risk of excessive bleeding associated with marginally low von Willebrand factor and mild platelet dysfunction.

Bleeding symptoms are so commonly reported that it is not known whether they associate causally or coincidentally with mild but measurable primary hemostatic defects. OBJECTIVES/PATIENTS/METHODS: In order to evaluate if the mild primary hemostatic defects are truly causative of increased bleeding symptoms, we surveyed a population of healthy teenagers for bleeding symptoms. Using a case-control approach, we then estimated the risk of excessive bleeding associated with low von Willebrand factor (defined as VWF below the 5th percentile of a normal reference population), and with mild platelet dysfunction [PD, defined as concurrent reduced platelet aggregation responses to two agonists (adenosine diphosphate and epinephrine)]. Excessive bleeding was present in 63 out of 809 teenagers (7.8%). Among the 49 cases who were tested for VWF, low values by three measures were more commonly present than in 166 controls, specifically, ristocetin cofactor (RCo) activity [20.4% vs. 5.4%, odds ratio (OR) 4.5], collagen binding (14.3% vs. 4.2%, OR 3.8), and antigen level (20.4% vs. 6.0%, OR 4.0). The low RCo values ranged from 35 to 45 U dL(-1) except for a single case with 26 U dL(-1). Of the 47 teenagers with excessive bleeding who underwent platelet aggregation studies, reduced responses were more common than in controls (12.8% vs. 4.4%, OR 3.2). Twenty-nine per cent of cases with excessive bleeding had either low RCo or PD. Almost one in three teenagers who report excessive bleeding is likely to have a measurable hemostatic disturbance manifested either by marginally low VWF (by three measures) or by mild PD.

PFA-100 closure times in preoperative screening in 500 pediatric patients

Three to five percent of patients undergoing surgery have either an acquired or congenital platelet defect or von Willebrand disease (vWD). The predictive value of preoperative coagulation screening is questionable. PFA-100 is now routinely used in preoperative screening in our pediatric outpatient service. We wanted to assess whether the PFA-100 would help to identify patients with primary haemostatic defects or if the additional use of PFA-100 would add to the problem of unnecessary pathologic preoperative laboratory values resulting in delay of surgical procedure. We investigated 500 children consecutively seen in our outpatient service before surgery. Blood cell count, aPTT, PFA-100 closure times (CT) were done in all patients. If abnormalities were found, the patient was presented to a haemostatic expert. vWF:AG, R:Cof and factor VIII were analysed in all patients with prolonged closure times and APTT values. One hundred twenty-six patients (25.2%) showed abnormalities in APTT and/or PFA-100. Further investigations in 89 of these 126 patients did not yield a specific diagnosis; neither diagnostic criteria for impaired haemostasis were found by questionnaire. None of these 89 patients had a bleeding complication during surgery. Forty-eight patients showed prolonged CTs. Twelve patients with low vWF:AG were detected, 10 of these patients were found by PFA-100. Four of these patients did present with normal APTT values. Our study shows that similar to the APTT the PFA-100 is probably only a good screening method when a haemostatic defect in a patient is clinically likely, especially to screen forVWD, and the test should not be used in general unselective screening.

Treatment of Warfarin-Associated Intracerebral Hemorrhage: Literature Review and Expert Opinion

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Prevalence of Cross Reactive Epitopes to Bovine Factor Va Light Chain Fragments in Normal and Patients Plasma.

Several reports have described the presence of antibodies to bovine coagulation factors, such as factor V, prothrombin and factor X in plasma samples obtained from patients exposed to topical bovine thrombin. Other reports have also demonstrated the presence of anti-bovine coagulation factors in patients who have not been exposed to bovine thrombins, suggesting that anti-bovine protein antibodies can be generated in normal individuals. It has been suggested that surgical patients treated with topical bovine thrombin develop specific antibodies to bovine factor V which may be responsible for the bleeding and thrombotic complications. However, there is no definitive clinical study demonstrating a relationship between the apparent hemostatic defects and the presence of bovine factor Va antibodies. It was hypothesized that bovine factor Va antibodies are usually present in patients plasma because of the exposure to dietary bovine products. To test this hypothesis plasma samples from patients with end state renal disease (ESRD)(n=80), acute coronary syndrome (ACS)(n=160), burns (n=40) and healthy normal volunteers (n=140) were profiled for the presence of human factor V antigen (HFVA), bovine FVa antigen as measured by using a modified Elisa method and western blotting methods where bovine factor Va light chain fragment is used as a probe. In contrast to the normals (89±12%), the factor V antigen levels were found to be increased in the ESRD (148±30%), ACS (164±41%) and burn (145±27%) patients. Thus, there appears to be an up regulation of factor V antigen in these patients. All of the groups tested for the presence of immunoreactive material to the bovine factor Va light chain exhibited 2–3 ug/ml levels which were not significantly different. However, in the western blotting studies all groups exhibited cross reactivity with the factor Va light epitopes. There were bands present in the molecular weight range of 22, 36, 45 and 97 Kda in both the ESRD and burn patients. In the ACS patients there was an additional band observed at 166 Kda. These observations underscore the notion that bovine antifactor Va antibodies are non-specific and highly prevalent in both the surgical/interventional patients and normal population. A possible explanation for the presence of these antibodies is that most normal individual and patients problem are exposed to bovine proteins. Moreover, the higher prevalence of these antibodies in the ESRD and ACS patients may be due to additional exposure to heparin and aprotonin.

Changes in ADAMTS 13 Activity and Von Willebrand Factor Parameters during Acute Dengue Infection.

Dengue virus causes febrile illnesses: Dengue Fever (DF) and less frequently a life-threatening illness, Dengue Hemorrhagic Fever (DHF). The pathophysiology of hemostatic defect in dengue infection is thought to relate to the direct effect of virus or cytokines on endothelial activation. To study the state of endothelial activation during dengue infection, we measured plasma levels of von Willebrand factor antigen (vWF:Ag), vWF-collagen binding assay (vWF:CBA), and ADAMTS 13 activity in 42 children (20 with DF and 22 with DHF) during 3 phases of illness: febrile, toxic, and convalescent phase. 38 healthy children comprised as controls. Our data shows that both VWF:Ag and vWF:CBA levels were significantly higher in dengue patients (p ≤ 0.001 in both DF and DHF patients) versus controls. DHF patients had significantly higher of VWF: Ag (p = 0.01, versus DF). ADAMTS 13 activity levels were significantly decreased only in DHF patients during 3 phases of the illness (febrile; mean 78%; p = 0.016, toxic; mean 68%; p<0.001 and convalescent; mean 69%; p<0.001 compared to mean 104% of the controls). Compared to DF patients, DHF patients had significantly lower plasma concentrations of ADAMTS 13 activity during the febrile, toxic and convalescent phase (p = 0.039, p = 0.002 and p =0.003, respectively). Endothelial cell activation is a hallmark of dengue infection especially in DHF patients; indicated by a significant rise in VWF:Ag and vWF:CBA and a reciprocal decline in ADAMTS 13 activity.

Hemostatic Defect in Baboons Autotransfused Treated Plasma to Simulate Shed Blood

Nonwashed shed blood may contain products of clotting and fibrinolytic, and antifibrinolytic substances. This study was done to determine how autotransfusion of nontreated plasma and plasma treated with urokinase with and without aprotinin affected hemostasis in healthy baboons. A 500-mL volume of blood was collected from the baboon, a 250-mL volume of plasma was isolated, and the RBCs were reinfused. Three baboons were autotransfused untreated plasma. Four baboons received plasma that had been treated with 3000 IU/mL urokinase at +37 degrees C for 30 minutes. Eight baboons received plasma that had been treated first with urokinase 3000 IU/mL at +37 degrees C for 30 minutes and then with aprotinin (1000 KIU/mL). Bleeding time, fibrinogen degradation products (FDP), D-dimer, and alpha-2 antiplasmin levels were measured. During the 4-hour period following autotransfusion of the urokinase-aprotinin-treated plasma, the levels of D-dimer and FDP were significantly higher and fibrinogen and alpha-2 antiplasmin levels were significantly lower than those levels seen after the autotransfusion of nontreated plasma. FDP and D-dimer levels showed significant positive correlations with prothrombin time (PT) and activated partial thromboplastin time (aPTT). A significant negative correlation was observed between thrombin time (TT) and fibrinogen level. A significant positive correlation was observed between bleeding time and D-dimer level and a significant negative correlation between the bleeding time and the fibrinogen level. The infusion of a volume of urokinase or urokinase-aprotinin treated autologous plasma equivalent to 15% of the blood volume was not associated with a bleeding diathesis in healthy baboons.

Elevated fibrinogen fragment levels in uremic plasma inhibit platelet function and expression of glycoprotein IIb‐IIIa

Hemostatic dysfunction is frequently noted in uremia, but the mechanisms responsible for it are poorly understood and are assumed to be multifactorial. Preliminary findings from our laboratory suggest that elevated levels of circulating fibrinogen fragments (FF) might contribute to the hemostatic defect in uremic patients. Defibrinated plasma obtained from chronic hemodialysis (HD) patients as well as normal subjects were examined by SDS-PAGE and immunoblotting and quantified by an immunoassay. In addition, endogenous FF isolated from normal and uremic plasma using affinity chromatography were examined by flow cytometry for their effect on glycoprotein (GP) IIb-IIIa receptor expression and tested for their ability to inhibit platelet aggregation. The mean FF concentration in uremic plasma (1.14 +/- 0.85 mg/ml) was noted to be eight times greater than in normal plasma (0.15 +/- 0.01 mg/ml) (P < 0.05). Moreover, the mean FF level decreased by 48.25% following HD (from 1.14 +/- 0.85 mg/ml to 0.59 +/- 0.33 mg/ml; P < 0.05). SDS-PAGE and immunoblotting experiments showed that the decrease was observed in both medium-sized (20-60 kDa) as well as large (>100 kDa) FF. Further, FF isolated from uremic plasma inhibited platelet aggregation by (46.8 +/- 18.1)% (P < 0.05) and the GP IIb-IIIa receptor expression by (28.0 +/- 7.6)% (P < 0.05 vs. control). The results show that (1) FF levels are elevated in uremic plasma, (2) HD results in significant decrease in FF and (3) endogenous FF inhibit platelet function, presumably via competitive binding to the fibrinogen receptor GP IIb-IIIa. The decrease in plasma levels of FF > 100 kDa following HD suggests that adsorption to the dialysis membrane contributes to their removal.

Hypercoagulable states and strokes

Several hematologic disorders and hemostatic defects increase risk of ischemic stroke. A common feature of these disorders is the creation of a prothrombotic state, now commonly referred to as "hypercoagulable state." Hematologic diseases such as essential thrombocythemia, polycythemia vera, and thrombotic thrombocytopenic purpura clearly cause stroke. Effective treatment is now available for these disorders. Association of hemostatic defects with stroke risk is still at the investigational stage. Although a number of factors such as soluble thrombomodulin, fibrinogen, factor VIII, von Willebrand factor, and plasminogen activator inhibitor-1 are associated with stroke risk, their predictive values remain unknown. Furthermore, causal relationship has not been established.

Massive transfusion and coagulopathy: pathophysiology and implications for clinical management

To review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both elective surgical and trauma settings, and to recommend the most appropriate treatment strategies.Medline was searched for articles on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." A group of experts reviewed the findings.Coagulopathy will result from hemodilution, hypothermia, the use of fractionated blood products and disseminated intravascular coagulation. The clinical significance of the effects of hydroxyethyl starch solutions on hemostasis remains unclear. Maintaining a normal body temperature is a first-line, effective strategy to improve hemostasis during massive transfusion. Red cells play an important role in coagulation and hematocrits higher than 30% may be required to sustain hemostasis. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. In trauma patients, tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. The use of platelets and/or fresh frozen plasma should depend on clinical judgment as well as the results of coagulation testing and should be used mainly to treat a clinical coagulopathy.Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial and multicellular event. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding.

Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRγ deficiency

AbstractFibrillar collagens are among the most potent activators of platelets and play an important role in the initiation of thrombosis. The glycoprotein VI (GPVI)/FcRγ-chain complex is a central collagen receptor and inhibitors of GPVI produce a major defect in arterial thrombogenesis. In this study we have examined arterial thrombus formation in mice lacking the GPVI/FcRγ-chain complex (FcRγ–/–). Using 3 distinct arterial thrombosis models involving deep vascular injury, we demonstrate that deficiency of GPVI/FcRγ is not associated with a major defect in arterial thrombus formation. In contrast, with milder vascular injury deficiency of GPVI/FcRγ was associated with a 30% reduction in thrombus growth. Analysis of FcRγ–/– platelets in vitro, using thrombin-dependent and -independent thrombosis models, demonstrated a major role for thrombin in overcoming the thrombosis defect associated with GPVI/FcRγ deficiency. Inhibition of thrombin in vivo produced a much greater defect in thrombus formation in mice lacking GPVI/FcRγ compared with normal controls. Similarly, thrombin inhibition produced a marked prolongation in bleeding time in FcRγ–/– mice relative to wild-type mice. Our studies define an important role for thrombin in overcoming the hemostatic and thrombotic defect associated with GPVI/FcRγ deficiency. Moreover, they raise the interesting possibility that the full antithrombotic potential of GPVI receptor antagonists may only be realized through the concurrent administration of anticoagulant agents.

Pharmacological approaches to reducing blood loss and transfusions in the surgical patient

To review the efficacy, effectiveness and safety of hemostatic drugs to reduce surgical blood loss.Analysis of randomized controlled trials and meta-analyses exploring the efficacy of desmopressin, aprotinin, lysine analogues and recombinant activated factor VII (rFVIIa) on clinically important endpoints.Although potentially useful in surgical patients with mild hemophilia or type I von Willebrand's disease, desmopressin has no proven benefit in patients without previous hemostatic defects. Aprotinin has been studied extensively in cardiopulmonary bypass surgery, with evidence of a blood sparing effect. Additional benefits are suggested. The drug is less consistently effective in liver transplantation and major orthopedic surgery. Although rare, hypersensitivity reactions to aprotinin may occur, especially on re-exposure. Tranexamic acid can reduce blood transfusion in cardiac surgery, liver transplantation and total knee arthroplasty surgery with a satisfactory safety profile. Epsilon aminocaproic acid has not been investigated adequately, despite its widespread use. While rFVIIa may be beneficial in controlling massive coagulopathic bleeding in trauma and surgical patients, there is currently no evidence to support its prophylactic use in elective surgical patients.Aprotinin and tranexamic acid are valuable pharmacologic options for reducing surgical bleeding. The expected benefit of these drugs is highly dependent on the actual blood usage for a given procedure at the institutional level. More studies using clinically significant endpoints are necessary to assess the relative efficacy and optimal dosing of these drugs.

Acquired von Willebrand's disease associated with gastrointestinal angiodysplasia: a case report

Acquired von Willebrand syndrome (AVWS) is a rare and probably underestimated bleeding disorder which mimics most of the clinical symptoms and laboratory features of hereditary von Willebrand disease (VWD) in patients devoid of both personal and family history of bleeding diathesis. In this study, we present a case of 55 yrs male patient, presented with gastrointestinal bleeds since three years, diagnosed to have AVWS with inhibitors. From this study it is concluded that AVWS is rare and it is important to diagnose this bleeding disorder so that appropriate treatment with plasmapheresis and IV:Ig can effectively correct the haemostatic defect and manage severe bleeding in these patients.

A propensity score case‐control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery

Cardiac surgery with cardiopulmonary bypass may result in excessive fibrinolysis and platelet (PLT) dysfunction, resulting in impaired hemostasis and excessive blood loss. Prophylactic use of the antifibrinolytic drugs aprotinin and tranexamic acid is thought to prevent these hemostatic defects. Their relative clinical utility and safety in high-transfusion-risk cardiac surgery, however, is not known. Using propensity scores, 449 patients who received aprotinin for high-transfusion-risk cardiac surgery were matched to 449 patients who received tranexamic acid from a pool of 10,870 consecutive patients who underwent cardiac surgery at a single center, 586 of whom received aprotinin and the remainder of whom received tranexamic acid. The two matched groups were well balanced in terms of measured perioperative variables. Blood product transfusion rates were similar in the aprotinin and tranexamic acid groups: red blood cells, 79 percent versus 76 percent (p = 0.3); PLTs, 56 percent versus 50 percent (p = 0.06); and plasma, 66 percent versus 61 percent (p = 0.1). Adverse events rates were comparable in the two groups, except for renal dysfunction (defined as a greater than 50% increase in creatinine concentration during the first postoperative week to >100 micromol/L in women and >110 micromol/L in men or a new requirement for dialysis support), which occurred in 24 percent (107/449) of aprotinin patients and 17 percent (75/449) of tranexamic acid patients (p = 0.01). Aprotinin and tranexamic acid have similar hemostatic effectiveness in high-transfusion-risk cardiac surgery. Within the confines of propensity score matching, our results suggest that aprotinin may be associated with renal dysfunction.

Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis.

Prospective studies of the epidemiology and clinical significance of low plasminogen activator inhibitor type 1 (PAI-1) activity are lacking. To evaluate the prevalence of low PAI-1 activity in patients with a bleeding tendency in comparison with a normal population. In 586 consecutive patients, referred because of bleeding symptoms, we added analyses of PAI-1 activity and tissue plasminogen activator complex with PAI-1 (t-PA-PAI-1) to the routine investigation, consisting of platelet count, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, von Willebrand factor activity, and antigen. Controls were 100 blood donors and 100 age- and sex-matched healthy individuals. The latter were also evaluated regarding the previous bleeding episodes. The bleeding history was classified as clinically significant or not, and the criteria were fulfilled in 75% of the patients and 18% of the healthy controls. The routine laboratory investigation of the patients was negative in 57%. Low PAI-1 activity, defined as <1.0 U mL(-1), was found in 23% of the patients and in 13% and 10% of the blood donors and healthy controls, respectively (odds ratio and 95% CI, 2.04; 1.11-3.77 and 2.75; 1.39-5.42, respectively). The difference remained statistically significant after the adjustment for body mass index, use of estrogens, sex and age (odds ratio for patients vs. healthy controls 3.23; 95% CI, 1.22-8.56, P = 0.019). The distribution of the 4G/5G genotypes in the patients was not different from that of two control populations. No specific symptom predicted for low PAI-1, which did not aggravate the clinical picture in association with the other hemostatic defects. Low tPA-PAI-1 was not associated with the increased bleeding tendency. Low PAI-1 activity is common in patients with a bleeding diathesis, but it is a risk factor of minor clinical importance and not associated with specific bleeding manifestations.