ACUTE-PHASE RESPONSE AND THE HYPERCOAGULABLE STATE IN PULMONARY TUBERCULOSIS

In our experience, severe pulmonary tuberculosis (PTB) is often complicated by deep venous thrombosis (DVT). Because of the association between inflammation and haemostatic changes that can result in a hypercoagulable state, we have prospectively examined such predisposing factors in representative patients.   Sequential analyses in a control group with active PTB showed anaemia, thrombocytosis, elevations in plasma fibrinogen, fibrin(ogen) degradation products (FDP), tissue plasminogen activator (t-PA) and inhibitor (PAI-1) with depressed antithrombin III levels. Age, sex and disease matched individuals with venographically proven DVT had higher FDP (15.8 ± 14.3 v 3.2 ± 1.7 μg/ml :  P  < 0.01), t-PA (19.4 ± 14.9 v 11.3 ± 0.8 ng/ml :  P  < 0.01), and functional PAI-1 activity (11.6 ± 6.3 v 4.2 ± 4.1 :  P  < 0.01) with lower platelet counts (347 ± 110 v 563 ± 230 × 10⁹/l :  P  < 0.01). Fibrinogen levels in all patients rose during the first 2 weeks of therapy and, together with related disturbances, corrected within 12 weeks.   In conclusion, elevated plasma fibrinogen with impaired fibrinolysis coupled with a decrease in antithrombin III and reactive thrombocytosis would appear to favour the development of DVT in PTB.     

Changes in coagulation and fibrinolysis after total hip replacement and their relations with deep vein thrombosis

Postoperative changes related to coagulation and fibrinolysis and their correlation with the incidence of deep venous thrombosis (DVT) were studied in 30 patients undergoing total hip replacement. Pre- and postoperative measurements of fibrinogen, factor Xa, VIII:C, VIIIR:Ag and its electrophoretic mobility, antifactor Xa activity, antithrombin III (AT III) and its electrophoretic mobility in plasma and serum, fibrin monomers, euglobulin lysis time, fibrinogen degradation products (FDP), alpha 2-antiplasmin and plasmin-antiplasmin complexes were determined. DVT was detected by 125I-fibrinogen leg scanning in 11 patients. There was a significant and progressive increase in fibrinogen, VIII:C, VIIIR:Ag, fibrin monomers, FDP and alpha 2-anti-plasmin levels after operation and likewise a prolongation of euglobulin lysis time. There were changes in electrophoretic mobility of AT III in plasma and serum in 12 patients. The presence of plasmin-antiplasmin complexes was demonstrated in 9 patients. No correlation between the changes in coagulation and fibrinolysis and the incidence of postoperative DVT was found. We conclude that important changes occur in several parameters of coagulation and fibrinolysis after total hip replacement. Such changes are not related to the development of postoperative DVT.     

Sequential Changes in Factor VIII and Platelets Preceding Deep Vein Thrombosis in Patients with Spinal Cord Injury

The relationships between factor VIII associated activities, platelet function, and venous thrombosis were studied in 18 patients with lower limb paralysis following acute spinal cord injury (SCI). Deep vein thrombosis (DVT) was detected in 13 patients (72%). Eight of the 13 thromboses were documented between 6 and 8 d following injury while the other five episodes were noted on days 11 (two), 13, 18 and 22. The detection of thrombosis was preceded by marked increases in VIIIR:Ag and VIII:RCoF whereas VIII:C was only marginally increased. The platelet aggregation response to collagen was hyperactive by the sixth day while the platelet aggregate ratio (PAR) did not become abnormal until after DVT was detected. These studies suggest a chronology in the series of events leading to DVT in patients with lower limb paralysis following SCI. Initial elevations in VIII:Ag and VIII:RCoF are followed in sequence by increased platelet responsiveness to collagen, the occurrence of DVT, and the appearance of circulating platelet aggregates. Conceivably, VIIIR:Ag elaborated by endothelial cells alters platelet reactivity and provides an important determinant for venous thrombosis.     

Effects of treadmill exercise on platelet functions and blood coagulating activities in healthy men

The effects of treadmill exercise (up to 85% of the predicted maximum heart rate) on platelet functions and coagulating activities were studied in 26 normal men. Blood sampling for the measurements were performed from the antecubital vein at rest, at 3, 6, 9, and 12 min during exercise, immediately postexercise, and at 6 and 30 min after exercise. Measurements for blood analysis included the following: platelet sensitivity and percent aggregation to ADP, platelet counts, plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels, plasma epinephrine and norepinephrine levels, plasma fibrinogen level, activity of plasma antithrombin III, and of plasma factors VIII, IX, XI, and XII. No significant changes were induced by dynamic leg exercise in platelet sensitivities and the maximum and 3-min percent aggregation. The platelet counts increased during exercise in platelet-rich plasma without a significant change in that in whole blood. During exercise, plasma thromboxane B2 levels showed a tendency to increase, while plasma 6-keto-prostaglandin F1 alpha levels to decrease. Plasma epinephrine levels showed a tendency to increase and norepinephrine levels increased during exercise. Among coagulating factors, factor VIII activities and fibrinogen levels increased without altering activities of factors IX, XI, and XII. Antithrombin III activities also increased during exercise. In spite of significant changes in several coagulating factors, prothrombin time and partial thromboplastin time were not influenced by exercise. In conclusion, dynamic leg exercise of a moderate to high intensity produced a significantly elevated plasma level of factor VIII, fibrinogen, antithrombin III, and catecholamines without affecting the hemostatic balance in normal subjects.     

Diabetes mellitus: a hypercoagulable state

Eighty percent of patients with diabetes mellitus die a thrombotic death. Seventy-five percent of these deaths is due to cardiovascular complications, and the remainder is due to cerebrovascular events and peripheral vascular complications. Vascular endothelium, the primary defense against thrombosis, is abnormal in diabetes. Endothelial abnormalities undoubtedly play a role in the enhanced activation of platelets and clotting factors seen in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1+2 and thrombin-anti-thrombin complexes, are elevated in diabetes. The plasma levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein, and von Willebrand factor are elevated in diabetes. Conversely, the level of the anticoagulant protein C (PC) is decreased. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and an increase in plasminogen activator inhibitor type 1 (PAI-1). Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force (PCF), and the presence of higher plasma levels of platelet release products, such as beta-thromboglobulin, platelet factor 4, and thromboxane B(2), demonstrate platelet hyperactivity in diabetes. This constellation of findings supports the clinical observation that diabetes is a hypercoagulable state. This article briefly reviews the published evidence for this conclusion and the putative roles played by hyperglycemia and hyperinsulinemia in its development.     

PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects

Impaired fibrinolysis as a result of increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma is a common finding in patients with deep vein thrombosis (DVT). A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to influence the levels of PAI-1. The 4G allele was found to be associated with higher plasma PAI-1 activity (act), but contradictory results on the incidence of the 4G allele in DVT patients have been reported. The aim of this study was to analyse whether the PAI-1 promoter 4G/5G genotype increases the risk of venous thrombosis in subjects with thrombophilic defects, and to determine the distribution of the PAI-1 4G/5G genotype and its relation to plasma PAI-1 levels in 190 unrelated patients with DVT in comparison with a control group of 152 healthy subjects. No differences between the 4G/5G allele distribution in the DVT group (0.43/0.57) and in the control group (0.42/0.58) were observed. However, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects. Significantly higher PAI-1 levels were observed in DVT patients than in the controls. Our results also showed significant differences in the plasma levels of PAI-1 antigen (ag) and PAI-1 act among the 4G/5G genotypes in DVT patients. A multivariate analysis revealed that, in the DVT group, PAI-1 ag levels were influenced by the 4G allele dosage, triglyceride levels and body mass index (BMI). The influence of the 4G allele dosage on PAI-1 levels was independent of the triglyceride levels and BMI. In the control group, no significant correlation between PAI-1 levels and 4G allele dosage was observed. In conclusion, the PAI-1 promoter polymorphism was found to have an influence on PAI-1 levels in DVT patients and on the risk of venous thrombosis in subjects with other genetic thrombophilic defects.     

Blood coagulation and fibrinolysis in patients with hyperthyroidism

Several papers concerning abnormalities of blood coagulation and fibrinolysis during hyperthyroidism, have been published. Increased von Willebrand Factor (vWF) activity and high fibrinogen levels have been reported. However, there is controversy concerning the presence of a hypercoagulable state in hyperthyroidism. We investigated various hemostatic parameters in 41 hyperthyroid patients and compared them to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with control subjects, fibrinogen, factor IX, vWF, AT III and PAI-1 were significantly increased in patients (p<0.05, p<0.0001, p<0.05, p<0.01 and p<0.0001; respectively), whereas factor X and t-PA were decreased (p<0.05). We showed that free T4 (FT3) levels were correlated with factor VIII activity (r=0.35, p<0.05). FT4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. AT III was inversely correlated with factor VII activity (r=-0.48, p<0.01). Protein C and S were correlated with vWF levels (r=0.58, p<0.0001; r=0.55, p<0.0001, respectively). Protein C was inversely correlated with t-PA (r=-0.39, p<0.01). There was a negative correlation between triglycerides, LDL-C and F X (r=-0.45, p<0.05; r=-64, p<0.01, respectively). Mean platelet volume (MPV) was correlated with anti-thyroid peroxidase (TPO) antibodies (in Graves'disease) and F IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; respectively). We found important differences in the coagulatory /fibrinolytic parameters between the hyperthyroid patients and healthy controls. Hyperthyroid patients may experience vascular endothelial dysfunction and decreased fibrinolytic activity in blood. This endothelial activation may represent a situation with a higher thromboembolic potential.     

Protein C and D-dimer are related to portal vein thrombosis in patients with liver cirrhosis

Background and Aim: To profile changes of coagulation, anticoagulation and fibrolytic factors associated with liver function failure and portal vein thrombosis (PVT) formation in chronic liver cirrhosis patients. Methods: A total of 116 cirrhotic patients admitted to our hospital from June 2006 to October 2008 were included in our study. All patients were classified into two groups: PVT group (31 patients), composed of patients with PVT and a control group (85 patients), including patients without PVT. Platelet, prothrombin time (PT), activated partial prothrombin time (APTT) and fibrinogen were measured. Also, plasma samples from the patients were analyzed for the levels of antithrombin III (AT‐III), protein C (PC), protein S (PS), D‐dimer, tissue‐type plasminogen activator as well as plasminogen activator inhibitor‐1. Statistical analyses were carried out to evaluate the correlation of specific variations with the disease status. Results: In general, the higher Child‐Pugh scores, indicating the aggravation of hepatic impairment of the patients, correlated well with the prolonged PT/APTT and increased D‐dimer, as well as decreased platelet, fibrinogen, PC and AT‐III levels in the serum. Furthermore, we found that the PC, PS and D‐dimer levels in PVT patients were 2.32 ± 0.72 mg/L, 17.14 ± 3.62 mg/L and 0.99 ± 0.36 mg/L, respectively, both representing a significant difference compared with those in the control group without PVT. Logistic regression model shows that the odds ratio value of one unit of increase of PC and D‐dimer were 0.48 and 15.57. Conclusions: Cirrhotic patients displayed dysfunctions in the coagulation, anti‐coagulation and fibrolytic systems. The development of PVT in these patients may be independently associated with the decrease of PC, PS and D‐dimer. Furthermore, decreasing PC and increasing D‐dimer may be risk factors inducing PVT in cirrhotic patients.     

Hemostatic effects of hormonal stimulation in patients with metastatic prostate cancer

Hemostatic abnormalities are common in patients with metastatic malignancy and are attributed, in part, to materials secreted by tumor cells. Tumor stimulation might therefore cause further perturbation of hemostasis. This article reports observations on the effects of androgen stimulation on multiple hemostatic parameters in patients with metastatic prostate cancer. Testosterone was given before chemotherapy in an experimental protocol designed to increase tumor sensitivity to cytotoxic agents. The following parameters were measured on day 0 (before) and days 2 and 4 of fluoxymesterone administration: PT, APTT, platelet count, plasma betathromboglobulin (BTG), platelet factor 4 (PF4), fibrinogen, fibrin(ogen) split products (FSP), factor VIII coagulant activity (VIII C), von Willebrand factor antigen (vWF Ag), fibrinopeptide A (FPA), antithrombin III (AT III), and protein C antigen (PC). Ten patients were studied during 17 cycles of hormonal stimulation. Baseline levels of BTG, PF4, fibrinogen, FSP, factor VIII C, vWF Ag, and FPA were significantly elevated compared with normal control. Although androgen stimulation resulted in elevation of BTG, FPA, and FSP levels by day 4 in many patients, the changes for the entire group were not statistically significant. Other parameters remained unchanged or were only slightly elevated. Two patients developed laboratory evidence of disseminated intravascular coagulation (DIC) but were clinically unaffected. Our data suggest that most patients with metastatic prostate cancer show evidence of ongoing activation of platelets, coagulation, and fibrinolysis. In a few individual patients, androgen stimulation of this hormonally dependent tumor may cause further activation of platelets, coagulation, and fibrinolysis.     

Levels of thrombin--antithrombin-III complex and factor VIII activity in relation to post-operative deep vein thrombosis and influence of prophylaxis with a low-molecular-weight heparin

In a randomized doubled-blind placebo-controlled study, plasma levels of thrombin-antithrombin-III (TAT) and factor VIII activity (VIII:C) were measured pre-operatively and on days 1, 3, 5 and 7 post-operatively in 70 consecutive patients undergoing total hip replacement. Patients received either a subcutaneous injection of low-molecular-weight heparin (LMWH) or placebo once daily. Post-operative deep vein thrombosis (DVT) was diagnosed by bilateral phlebography. The levels of TAT and VIII:C both increased significantly after operation and were not significantly influenced by LMWH. Thirty-three patients in whom post-operative DVT developed had a significantly lower level of VIII:C on day 7, compared with patients without DVT.     

β-Thromboglobulin, Platelet Production Time and Platelet Function in Vascular Disease

Plasma beta-thromboglobulin (beta TG) levels were measured in 103 healthy controls and 112 patients suffering from either peripheral vascular disease (PVD), or cerebrovascular disease (CVD) or deep vein thrombosis (DVT). Plasma beta TG was significantly elevated in 46 PVD patients and 24 recent DVT patients compared to controls, but did not differ significantly in 18 chronic DVT and 24 old CVD patients. In addition, heparin neutralizing activity (HNA) and platelet aggregation induced by adenosine diphosphate, 1-epinephrine and thrombin were compared in 33 out of the 46 PVD patients to 33 controls. The mean HNA was significantly shorter in the PVD patients than in controls. The rate and extent of platelet aggregation were increased in PVD patients compared to controls, but the difference was not statistically significant. Platelet production time (PPT) was measured in 20 controls, 35 PVD patients, nine chronic DVT and 12 chronic CVD patients; significantly shorter PPT was only observed in 14 patients with advanced PVD compared to controls, suggesting increased platelet consumption in these patients. All four assays (plasma beta TG, HNA, platelet aggregation and PPT) were performed in 25 patients; no correlation between the four tests was found in these patients suggesting that the tests were measuring various aspects of platelet function. These results suggest that in vivo platelet consumption as well as platelet aggregation and 'release reaction' are presumably enhanced in PVD and recent DVT patients and that plasma beta TG and PPT assays may be better and more specific indicators of in vivo platelet activation than in vitro platelet aggregation test.     

Activated protein C resistance, Leiden mutation, anticoagulant proteins and fibrinogen levels in patients with deep venous thrombosis

Resistance to activated protein C (APC-R) is the leading cause of deep vein thrombosis (DVT). Deficiencies of protein C (PC) or its cofactor protein S (PS) are less frequent. Resistance usually results from nucleotide substitution (1691 GA) in the factor V gene (Leiden mutation). We searched for APC-R and the Leiden mutation (FVL) and measured the activities of PC, PS, antithrombin III (AT III) and Fb levels in patients with DVT. The results were analyzed against a history of thrombosis (idiopathic, risk factor related). We enrolled 29 patients aged 50 years or younger, with first symptoms of thrombosis detected before the age of 40 years. The control group consisted of 25 healthy volunteers of similar age. APC-R was established using Accelerimat (bioMerieux) assays. APC-R was diagnosed when the normalized sensitivity coefficient "r" was < 0.9. FVL was detected with the SSP-PCR (sequence specific primers-polymerase chain reaction) method. Abnormal APC-R "r" values were found in seven DVT patients (24%). Heterozygous (G/A genotype) form of the Leiden mutation was confirmed in six of them (all had a history of recurrent thrombosis). FVL carriers demonstrated lower PC levels in comparison with controls and DVT without FVL. Eight patients (27%) had PS activities below the cut-off point (60%). The deficiency in six of them was not associated with other abnormalities. Patients with recurrent thrombosis had markedly higher concentrations of Fb (usually without FVL) and reduced AT III activities. The study has shown that the APC-R test is useful for FVL screening. The Leiden mutation, elevated levels of Fb and reduced activities of PC are the main factors predisposing to DVT and its recurrence. Reduced activity of PS is usually an isolated abnormality tending to predispose to a single DVT episode.     

The plasma levels of prostanoids and plasminogen activator inhibitor-1 in primary and secondary thrombocytosis.

An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of plasminogen activator inhibitor type 1 (PAI-1), the inhibitor of fibrinolysis; and thromboxane A2 and 6-keto-PGF1 alpha, the products of endoperoxides, in 16 patients affected with clonal thrombocytemia as compared with 16 patients with reactive thrombocytosis and 15 normal controls. In the clonal thrombocytemia group, plasma levels of PAI-1 antigen and activity were significantly higher than both reactive thrombocytosis and control group. Plasma levels of 6-keto-PGF1alpha were significantly higher in the clonal thrombocytemia group than the other two groups and also higher in the reactive thrombocytosis group than the control group, which was also significant. This study confirms that arachidonate metabolism is frequently deranged in patients with thrombocytosis and hypofibrinolysis due to increased PAI-1 plasma levels as shown in the clonal thrombocytosis group. This may explain the thrombotic tendency in myeloproliferative disorders.     

Tissue plasminogen activator levels change with plasma fibrinogen concentrations during pregnancy

To investigate the relationship between coagulation activities and the fibrinolytic system during normal pregnancy, we measured the plasma concentrations of coagulation factors, antithrombin III (AT III), D-dimer, tissue plasminogen activator (tPA), total protein S (TPS), and plasminogen activator inhibitor type 1 (PAI-1) in 436 apparently healthy pregnant, postpartum, and nonpregnant women. There were no significant changes in AT III, TPS, and factor XI concentrations during pregnancy and puerperium. However, factor VII, VIII, IX, and XII activities increased gradually as pregnancy progressed, reached maximum values in the third trimester, and returned to nonpregnant levels by 5-8 weeks postpartum. Plasma D-dimer levels in the third trimester of pregnancy were 1.23+/-0.42 micro g/ml, significantly higher than for the first trimester (0.34+/-0.16 micro g/ml, P<0.01). The tPA antigen levels averaged 1.8-fold higher in the late third trimester than in the first trimester; the plasma fibrinogen concentrations averaged 1.6-fold higher in the late third trimester than in the first trimester. Compared to the peak values during pregnancy, tPA levels averaged 39.8% lower and plasma fibrinogen concentrations averaged 40.0% lower at 5-8 weeks postpartum. The tPA levels correlated strongly with the plasma fibrinogen concentrations ( r=0.52, P<0.01). In short, this study shows that tPA levels change in parallel with plasma fibrinogen concentrations during and after normal pregnancy.     

Which tests are most useful in distinguishing between reactive thrombocytosis and the thrombocytosis of myeloproliferative disease?

In an attempt to distinguish between thrombocytosis in myeloproliferative disease (MPD) and reactive thrombocytosis (RT) the following aspects of platelet structure and function were evaluated: platelet size, platelet aggregation and adhesion, dense granule and alpha granule components. In addition plasma fibrinogen and von Willebrand factor antigen (vWFag) were measured. In all parameters measured there was a significant difference between normals and both categories of thrombocytosis, however there was considerable overlap between MPD and RT. Plasma fibrinogen emerged as the best single test to discriminate between MPD and RT, levels of less than 5.0 g/l indicating MPD and greater than 5.0 g/l indicating RT.     

Plasma cofactors of platelet function: correlation with diabetic retinopathy and hemoglobins Ala-c.

We studied 29 diabetic patients (eight without and 21 with retinopathy) and 29 matched control subjects for hemoglobins Ala-c and plasma levels of fibrinogen, von Willebrand factor, and factor VIII/von Willebrand factor antigen. Hemoglobins Ala-c were elevated in all diabetic patients, regardless of retinopathy (P less than 0.001); fibrinogen was elevated only in those with retinopathy (P less than 0.001); and plasma von Willebrand factor was clearly elevated in those with proliferative retinopathy and minimally, if at all, elevated in those with background or no retinopathy. Plasma from five diabetic patients with proliferative retinopathy and five control subjects was tested for its ability to enhance the ADP-induced platelet aggregation of normal or von Willebrand platelet-rich plasma; no differences were found. We conclude that elevated levels of fibrinogen and von Willebrand factor, both recognized plasma cofactors of platelet function, are associated with proliferative diabetic retinopathy. A plasma factor that enhances ADP-induced platelet aggregation could not be found in diabetic plasma, and we doubt that increased von Willebrand factor is responsible for its finding by others.     

Platelet reactivity, fibrinogen and smoking

40 young healthy male volunteers (20 habitual smokers and 20 non-smokers) were investigated with respect to platelet reactivity, plasma fibrinogen and coagulation factor VIII. Smokers had significantly lower systolic blood pressures and higher venous platelet counts. The results for ADP-induced platelet aggregation, plasma concentrations for the 2 alpha-granule proteins, beta-thromboglobulin and platelet factor 4, did not differ between the 2 study groups involved; nor was there any difference between serum thromboxane B2 formation or plasma factor VIII:C activity. However, as compared to non-smokers, plasma fibrinogen levels were significantly higher among the smokers.     

A regimen for antithrombin III substitution in patients with acute lymphoblastic leukemia under treatment with L-asparaginase.

BACKGROUND AND METHODS. Seventeen adult patients with acute lymphoblastic leukemia (ALL) treated with L-asparaginase (20,000 IU/m2 on six alternate days) were infused with antithrombin III (AT III) concentrates (Kybernin P, Behring). Substitution therapy was aimed at increasing the reduced AT III concentration usually found in these patients, since AT III deficiency is thought to be associated with an increased risk of thrombosis. Two schedules of AT III administration, different in dosage, timing and duration were evaluated. The first 7 patients (group A) received a fixed dose of 2,000 U every day for 6 times, starting with the second L-asparaginase (L-ase) infusion, independently of their plasma AT III levels. In the following 10 patients (group B), 20-25 U/Kg b.w. were administered daily for 7 times only when the plasma AT III level was lower than 60% with plasma fibrinogen higher than 100 mg/dl and platelet count higher than 50 x 10(9)/l, or when AT III was below 40%. Thirteen patients who received L-ase without AT III substitution served as controls. RESULTS AND CONCLUSIONS. Both substitution regimens resulted in mean plasma AT III nadir values significantly (p less than 00.1) higher than in the controls. Our data suggest that, in ALL patients receiving L-ase according to the L20 protocol, satisfactory plasma AT III levels may be assured with infusions of 20-25 U/Kg b.w./day for 7-10 days, starting by day 2 of L-ase treatment.     

Abnormal coagulation and deep venous thrombosis in patients with advanced cancer

Many studies have demonstrated increased coagulation activation in cancer patients and have shown evidence of chronic, low-grade disseminated intravascular coagulation, although most patients remained asymptomatic. In general, patients have not been screened for deep venous thrombosis (DVT). We screened 98 patients with advanced malignancy for DVT using light reflection rheography. Coagulation profiles of DVT and non-DVT groups were studied. We found a high prevalence of DVT (50%) on screening. Overall, the patients had raised levels of fibrinogen (66% patients), factor VIII:C (43%), fragment 1 + 2 (71%) and TAT levels (89%). Patients with DVT had a significantly lower level of fibrinogen than those without (4.0 g/dl, SD 1.4, compared with 4.7 g/dl SD 1.6, P = 0.04). There was no significant difference in other coagulation or liver function tests between the DVT and non-DVT groups. The wide variation of results makes their interpretation difficult and unlikely to be of predictive value in estimating individual thrombotic risk.     

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.