Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism

OBJECTIVE: We previously demonstrated that patients suffering from moderate hypothyroidism were at increased risk of thrombosis contrasting with the bleeding tendency of those presenting severe hypothyroidism. The latter state is associated with hemostatic anomalies including von Willebrand type 1 disease and increased fibrinolytic capacity. With the exception of von Willebrand type 1 disease, reversibility of hemostatic changes is not established after levothyroxine replacement therapy. Therefore our objective was to analyze the reversibility of these anomalies. MATERIALS AND METHODS: We analyzed the impact of levothyroxine treatment on lipid parameters, fibrinogen, platelet count, D-dimers, alpha2 antiplasmin activity, plasminogen activity, tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor type 1 antigen (PAI-1 Ag) and coagulation factors (factor VIII coagulant, von Willebrand factor antigen, von Willebrand factor and factor IX) in 23 patients with severe hypothyroidism (TSH level > 50 mU/ I). RESULTS: Mean fibrinogen levels increased by 14.2% while t-PA Ag and PAI-1 Ag increased by 42.6 and 69%, respectively, after correction of hypothyroidism. Interestingly, post-treatment PAI-1 Ag levels tended to be higher in patients with normal-high final TSH levels than in patients with normal-low final TSH levels. Our results suggest that normalization of fibrinolysis is obtained after a transient decrease of fibrinolytic activity. We also confirmed the correction of coagulation factor abnormalities upon levothyroxine replacement therapy. CONCLUSIONS: We demonstrated that the coagulation disorders and the hyperfibrinolytic status of severe hypothyroid patients were corrected upon levothyroxine therapy. However, the clinical consequences of the transient decrease of the fibrinolytic activity during the course of TSH normalization need further studies.     

Hemostatic abnormalities in cirrhosis and tumor-related portal vein thrombosis

In order to investigate the relationship between hemostatic abnormalities and portal vein thrombosis (PVT) in hepatocellular carcinoma (HCC), platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, d-dimer, fibrinogen degradation products (FDPs), protein C, protein S, antithrombin, plasminogen, antiplasmin, coagulation factors (CFs) V, VII, VIII, IX, XI, and XIII, von Willebrand factor (vWF), prothrombin fragment 1 + 2 (PF 1 + 2), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor 1 (PAI-1) were studied in patients with HCC, cholangiocarcinoma, and metastatic liver tumors and in cirrhosis patients with or without PVT. Platelet, antithrombin, protein C, plasminogen, and CFs V, VII, IX, XI, and XIII levels of HCC group were found lower and PT, aPTT, thrombin time, vWF, FDPs, PF 1 + 2, tPA, and PAI-1 levels were higher than the control group. Our findings suggested that the abnormalities of coagulation and fibrinolysis systems have some role in provoking thrombosis of portal veins in HCC, in addition to the invasion of portal veins by hepatoma cells.     

Changes in hemostatic and fibrinolytic proteins in patients receiving L-asparaginase therapy

Hemostatic changes were evaluated in ten patients with acute lymphoblastic leukemia and lymphoma who received chemotherapy with L-asparaginase, vincristine, and prednisolone for 1 week. Following treatment, prothrombin time and activated partial thromboplastin time were significantly prolonged, while a marked decrease in fibrinogen levels was observed. The values for cross-linked fibrin degradation products, however, remained within normal limits during treatment, which excluded the possibility of disseminated intravascular coagulation. The concentrations of coagulation inhibitors (antithrombin III, protein C, and protein S), plasminogen, and alpha 2 antiplasmin also significantly decreased; however, levels of both tissue-type plasminogen activator and plasminogen activator inhibitor, which are synthesized in endothelial cells, increased during the treatment. Although a decrease was observed in concentrations of many coagulation factors, including subunits A and B of factor XIII, the activity and antigenicity of factor VII significantly increased following the treatment. From this study, we concluded that these hemostatic abnormalities caused by the administration of L-asparaginase produced a labile condition that easily inclines to bleeding or thrombosis.     

Treatment with cerivastatin in primary mixed hyperlipidemia induces changes in platelet aggregation and coagulation system components

Platelet activation, impairment of fibrinolysis, activation of the coagulation pathway, and dyslipidemia are important factors in the pathogenesis and progression of ischemic heart disease, and patients generally need to use an antiplatelet agent. Lipid-lowering cerivastatin, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was administered to 20 patients with primary mixed hyperlipidemia for the assessment of the effect of cerivastatin on lipid levels, plasma fibrinogen concentration, factor VII, VIII, and X levels, plasminogen and antiplasmin concentrations, platelet count, and aggregation (adenosine diphosphate [ADP], collagen, and epinephrine induced). Assessments were made immediately after 2 months of a standard lipid-lowering diet, 4 weeks of placebo administration, and 4 weeks of cerivastatin treatment. Cerivastatin achieved significant reductions in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels. The significant improvement of the lipid profile was associated with platelet aggregation reduction in vitro stimulated by ADP, collagen, and epinephrine (P < .05, P = .05, P < .005, respectively). Significantly lower levels of factor VII and fibrinogen were observed (P = .001, P < .0001) immediately after cerivastatin treatment. No significant differences were detected in factor VIII level, plasminogen and antiplasmin concentrations, and platelet count after cerivastatin treatment. It was concluded that cerivastatin in mixed hyperlipidemia can exert beneficial changes on specific hemostatic variables and platelet aggregation in addition to its positive effects on plasma lipid values.     

Evolution of blood coagulation activators and inhibitors in the healthy human fetus

Blood coagulation proteins were determined in 285 healthy fetuses from 19 to 38 weeks' gestation and compared with those of 60 normal full- term newborns and 40 adult controls. Prolongation of the coagulation screening tests, prothrombin time, activated partial prothrombin time, and thrombin clotting time, in fetuses throughout intrauterine life was explained by low levels of vitamin K-dependent factors (II, VII, IX, and X), contact factors (XI, XII, prekallikrein, and high-molecular- weight kininogen), factor V, factor VIII, and fibrinogen. Low levels of antithrombin III, heparin cofactor II, protein C and protein S, and tissue factor pathway inhibitor were also found, and these probably contributed to a satisfactory hemostatic balance. Some of these parameters were evaluated by both immunologic and functional assays to detect possible "fetal" proteins. An increase in factor levels was observed after the thirty-fourth week of intrauterine life for most of the coagulation activators and inhibitors, but only factors V and VIII reached adult values at birth. This study therefore showed that fetal hemostasis is a dynamic system that evolves gradually toward the neonatal state and then toward the adult state.     

Towards safer thrombolytic therapy

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment.     

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.     

Hemostasis during normal pregnancy and puerperium

During normal pregnancy the hemostatic balance changes in the direction of hypercoagulability, thus decreasing bleeding complications in connection with delivery. The most important initial factor for acute hemostasis at delivery is, however, uterine muscle contractions, which interrupt blood flow. Global tests such as Sonoclot signature, the Thromboelastogram, and a new method analyzing overall plasma hemostasis, all show changes representative of hypercoagulability during pregnancy. Increased endogenous thrombin generation, acquired activated protein C resistance, slightly decreased activated partial thromboplastin time (aPTT) and increased prothrombin complex level (PT) measured as international normalized ratio (INR) of less than 0.9 have been reported as well. In normal pregnancy, the platelet count is within normal range except during the third trimester when benign gestational thrombocytopenia, 80 to 150 x 10 9/L, can be observed. Platelet turnover is usually normal. Activation of platelets and release of beta-thromboglobulin and platelet factor 4 are reported. The bleeding time is unchanged during normal pregnancy. Most blood coagulation factors and fibrinogen increase during pregnancy. Factor (F) XI is the only blood coagulation factor that decreases. Blood coagulation inhibitors are mainly unchanged but the level of free protein S decreases markedly and the level of tissue factor pathway inhibitor increases. Thrombomodulin levels increase during pregnancy. Fibrinolytic capacity is diminished during pregnancy, mainly because of markedly increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta. Thrombin-activated fibrinolysis inhibitor is reported to be unaffected. The total hemostatic balance has been studied by analyses of prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, soluble fibrin, D-dimer, and plasmin-antiplasmin complex. There is activation of blood coagulation and a simultaneous increase in fibrinolysis without signs of organ dysfunction during normal pregnancy. These changes increase as pregnancy progresses. During delivery, there is consumption of platelets and blood coagulation factors, including fibrinogen. Fibrinolysis improves and increases fast following childbirth and expulsion of the placenta, resulting in increased D-dimer levels. These changes are self-limiting at normal delivery. The hemostatic changes, noted during pregnancy, normalize after delivery within 4 to 6 weeks. Platelet count and free protein S, however, can be abnormal longer. Hemostasis should not be tested earlier than 3 months following delivery and after terminating lactation to rule out influences of pregnancy. PAI-1 and PAI-2 levels decrease fast postpartum, but PAI 2 has been detected up to 8 weeks postpartum. alpha 2 -antiplasmin, urokinase, and kallikrein inhibitor levels have been reported to be increased 6 weeks postpartum.     

The hemostatic effect of bovine peptide-B from fibrinogen

Bovine peptide-B from fibrinogen was active in the hemostasis of rat tail arterioles. The time of bleeding exhibits an inverse log proportionality to the concentration of bovine peptide-B. The peptide produced a 10-fold decrease in the time of bleeding at the highest concentration tested. Prolonged incubation of the peptide with the system was unnecessary and it appeared to participate immediately as a hemostatic agent. These findings suggest that hemostasis was due to vasoconstriction since coagulation time remained constant as the bleeding time decreased with increasing concentration of peptide-B. Bovine peptide-B is interpreted as a physiological substance which probably acts on some smooth muscle receptor.     

Improved prognosis of fulminant hepatic failure (FHF) after plasma derivative replacement therapy. Enhanced proteolysis of hemostatic proteins confirmed by proteinase-inhibitor complexes determination

In fulminant hepatic failure disturbances of blood coagulation are caused by both delayed synthesis and increased consumption of hemostatic proteins. The enhanced turnover of clotting factors and inhibitors may be induced by thrombin and plasmin after activation of the coagulation system by thromboplastic material and activators of plasminogen released from necrotic liver cells. Additionally, proteases such as elastase released from granulocytes, may be involved when infectious complications occur. The immunologic determination of the specific proteinase-inhibitor complexes thrombin-antithrombin III, plasmin-alpha 2 antiplasmin, and elastase-alpha 1 antitrypsin is of great diagnostic value to verify and differentiate the proteolysis of hemostatic proteins. Five patients with FHF were treated with plasma derivatives (FFP and AT III concentrates) until the liver had recovered and resumed synthesis of clotting factors and their inhibitors. The coagulation parameters normalized, bleeding complications and microcirculatory failure could be prevented. The data suggest that a comprehensive substitution of plasma components improves considerably the prognosis of acute liver failure.     

Hemostasis in Crohn's disease: low factor XIII levels in active disease

Massive gastrointestinal hemorrhage sometimes occurs in Crohn's disease. To examine the possible role of acquired disorders of hemostasis contributing to such events, several laboratory indicators of hemostasis (APT time, Normotest, platelet count, bleeding time, fibrinogen, factor VIII activity, vWF:Ag, factor X, factor XIII, antithrombin III, fibrinopeptide A, and B beta(15-42] were studied in 10 patients with active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) and 10 patients with quiescent disease (CDAI less than 150). Marked thrombocytosis was seen in three patients with active disease. Factor VIII activity and fibrinogen levels were significantly elevated in patients with Crohn's disease (p less than 0.001), and the factor VIII activity levels were significantly higher (p less than 0.05) in the patients with active disease than in those with quiescent disease. Factor XIII levels were significantly lower (p less than 0.02) in patients with active disease. Three of the patients with active disease had factor XIII levels below the lower reference limit. The two patients with the lowest levels had hemorrhagic diarrhea and spontaneous bleeding from the rectal mucosa. Fibrinopeptide A and B beta(15-42) levels were significantly elevated in both groups. The other coagulation analyses were essentially normal in both patient groups. The results suggest that factor XIII deficiency acquired through gastrointestinal leakage may contribute to gastrointestinal hemorrhage in some patients with active Crohn's disease.     

Antithrombin III, plasminogen and alpha 2 antiplasmin in jaundice. Clinical usefulness and prognostic significance.

In this prospective study, antithrombin III, plasminogen and alpha 2 antiplasmin which are synthetised by the liver were measured and compared with the Normotest, Thrombotest and fibrinogen concentrations in 92 consecutive jaundiced patients. Antithrombin III appeared to be the most discriminant coagulation test in differentiating hepatocellular from cholestatic jaundice. A high correlation was observed between antithrombin III, plasminogen and alpha 2 antiplasmin values suggesting that the liver synthesis of these parameters was closely linked. The prognostic significance of the blood coagulation tests in patients with jaundice has been studied. In parenchymatous liver disease, antithrombin III, plasminogen and alpha 2 antiplasmin were superior to the Normotest, Thrombotest and fibrinogen concentrations in predicting the prognosis of the patients at the time of admission. In cholestatic jaundice, however, none of the blood coagulation tests studied had a prognostic significance.     

Update on tumor cell procoagulant factors

Tumor cells produce tissue factor, cancer procoagulant, plasminogen activators and other factors that interact with the coagulation system, the fibrinolytic system and vascular or blood cells such that they can upset the normal homeostasis and balance between activation and inhibition of the coagulation and fibrinolytic systems. These activities play a role in tumor cell growth and metastasis, vascular wall function, and hemostasis. Proteases and their inhibitors are intimately involved in all aspects of the hemostatic, cell proliferation and cellular signalling systems. This review provides a brief examination of recent observations in this complex interaction of cellular and hemostatic factors.     

Contact (prekallikrein) and fibrinolytic (plasminogen/antiplasmin value) system in the physiopathology of vascular complications of diabetes

Both micro and macro-angiopathy involve interaction of blood vessel and plasma factors which may be altered in diabetes. Little is known concerning changes in contact and fibrinolysis factors as prekallikrein, plasminogen and fast antiplasmin in diabetes. We tested also the plasminogen/antiplasmin ratio in 151 diabetics and 64 normal subjects (18 to 74 years old). Our conclusion is:--the absence of correlation between the clinical characteristic of diabetes and prekallikrein level,--the decrease of plasminogen/antiplasmin ratio in complicated diabetes,--in complicated diabetes, correlation between antithrombin III, VIII factor and fibrinogen levels, perhaps, in relation with inflammation signs.     

Potential role of new technological innovations in nonvariceal hemorrhage

The present armamentarium of endoscopic hemostatic therapy for non-variceal upper gastrointestinal hemorrhage includes injection, electrocautery and clips.There are newer endoscopic options such as hemostatic sprays, endoscopic suturing and modifications of current options including coagulation forceps and over-the-scope clips. Peptic hemorrhage is the most prevalent type of nonvariceal upper gastrointestinal hemorrhage and traditional endoscopic interventions have demonstrated significant hemostasis success. However, the hemostatic success rate is less for other entities such as Dieulafoy's lesions and bleeding from malignant lesions. Novel innovations such as endoscopic submucosal dissection and peroral endoscopic myotomy has spawned a need for dependable hemostasis. Gastric antral vascular ectasias are associated with chronic gastrointestinal bleeding and usually treated by standard argon plasma coagulation(APC), but newer modalities such as radiofrequency ablation,banding, cryotherapy and hybrid APC have been utilized as well. We will opine on whether the newer hemostatic modalities have generated success when traditional modalities fail and should any of these modalities be routinely available in the endoscopic toolbox.     

Mechanisms of thrombus formation and lysis

Maintenance of a patent vasculature is critical to provide nutrient blood flow to dependent tissues. This is normally facilitated by vessels composed of actively nonthrombogenic endothelium and blood that contains both nonactivated platelets and inactive coagulation proenzymes. Following vessel injury, active hemostasis results from vasoconstriction, adherence and aggregation of activated platelets, and coagulation enzyme activation. The resulting thrombus contains a mixture of blood cells and the insoluble product of coagulation, fibrin, which further stimulates the activation of another blood enzyme system known as the fibrinolytic system. This results in the conversion by plasminogen activators of the circulating plasma proenzyme plasminogen into the active fibrinolytic enzyme plasmin, which dissolves the clot into degradation products. Vascular patency ultimately is restored and healing is thus facilitated. The hemostatic system is highly regulated by a variety of processes. Derangement of regulation can lead to disease manifesting either as thrombosis or hemorrhage. Furthermore, improved understanding of the molecular interactions involved in these processes has led to design of newer therapeutic interventions targeted toward amelioration of the sequelae of thromboembolic disease.     

Recombinant-activated factor VII as hemostatic therapy in eight cases of severe hemorrhage from esophageal varices.

BACKGROUND AND AIMS: There are several treatment options for gastroesophageal variceal hemorrhage. In severe cases, bleeding persists and is associated with a dismal outcome. The coagulation disorders might be correlated with risk of bleeding in patients with portal hypertension. The administration of activated recombinant factor VII corrects prothrombin time transiently in nonbleeding patients with cirrhosis as well as in bleeding ones. The aim of this study was to assess the hemostatic efficacy of activated recombinant factor VII in bleeding esophageal varices. METHODS: Between May 2001 and September 2002, 112 patients with cirrhosis and an episode of acute esophageal variceal bleeding were admitted. On an open basis with a single intravenous dose of 4.8 mg of recombinant factor VII, we treated 8 patients experiencing severe and active hemorrhage from esophageal varices unresponsive to pharmacologic therapy, endoscopic therapy, or balloon tamponade. RESULTS: Eight (7%) of 112 patients met entry criteria. Hemostasis was achieved in all the cases after recombinant activated factor VII therapy. Rebleeding and mortality rates were 25% and 50% (2 and 4 patients), respectively. CONCLUSIONS: In our experience, recombinant activated factor VII achieves hemostasis in bleeding esophageal varices unresponsive to standard treatment.     

How I treat patients with von Willebrand disease

Von Willebrand disease (vWD) is a frequent inherited disorder of hemostasis that affects both sexes. Two abnormalities are characteristic of the disease, which is caused by a deficiency or a defect in the multimeric glycoprotein called von Willebrand factor: low platelet adhesion to injured blood vessels and defective intrinsic coagulation owing to low plasma levels of factor VIII. There are 2 main options available for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1 vWD, who account for approximately 70% to 80% of cases. This nontransfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor 3 to 5 times and thereby corrects both the intrinsic coagulation and the primary hemostasis defects. In patients with the more severe type 3 and in most patients with type 2 disease, desmopressin is ineffective or is contraindicated and it is usually necessary to resort to plasma concentrates containing both factor VIII and von Willebrand factor. Concentrates treated with virucidal methods should be preferred to cryoprecipitate because they are equally effective and are perceived as safer. (Blood. 2001;97:1915-1919)     

The elastase-mediated pathway of fibrinolysis

Plasmin and elastase degrade fibrin and inhibit the blood coagulation system by degrading key proteins. Elastase can facilitate plasmin expression via an alternative pathway of plasminogen activation. Elastase modifies plasminogen to yield a zymogen that is a better substrate for activators than native plasminogen. Furthermore, elastase inactivates the inhibitor system of plasmin and plasminogen activators without affecting plasmin and plasminogen activators. While plasmin activity develops from a blood zymogen as a consequence of activators synthesized and secreted by endothelium and possibly other cells, elastase is secreted in an active form primarily by polymorphonuclear leukocytes. Plasmin and elastase may play mutual roles in thrombolysis, inflammation, and tumour invasion and metastasis.     

Thrombolytic therapies: the current state of affairs.

Thrombotic occlusive diseases are manifested in several disorders that have significant morbidity and mortality, including acute myocardial infarction, pulmonary embolism, deep venous thrombosis, and cerebrovascular accidents. This review summarizes the recently published literature covering thrombolytic therapies in these diseases, with particular attention to comparisons between the fibrin-specific tissue plasminogen activators (alteplase, reteplase, and tenecteplase) and the nonfibrin-specific activators (streptokinase or urokinase plasminogen activator). These agents act to convert plasminogen to plasmin, which in turn cleaves fibrin as part of the lysis process. Fibrin-specific activators were anticipated to be more efficacious and safer than nonspecific agents in thrombolytic occlusive diseases because of their pathophysiologically restricted mechanism of action. However, the fibrin-specific activators also lyse physiological hemostatic plugs, which can result in costly adverse events. Efficacy of fibrin-specific tissue plasminogen activators has been shown to be generally equivalent, with similar mortality rates compared with nonspecific agents; however, fibrin-specific agents may be associated with an increased incidence of intracerebral hemorrhage and with increased costs. Therefore, it appears that given equivalent efficacy, nonfibrin-specific activators, such as streptokinase or urokinase, may be a safer choice in many thrombotic situations.