Onset Of Thrombosis Research Articles

Detection of Marked Reduction of Sensitivity to Activated Protein C prior to the Onset of Thrombosis during Puerperium as Detected by Endogenous Thrombin Potential-based Assay

Detection of Marked Reduction of Sensitivity to Activated Protein C prior to the Onset of Thrombosis during Puerperium as Detected by Endogenous Thrombin Potential-based Assay -

Sensitivity of protein C immunosensor with and without human serum albumin.

Protein C (PC) acts as an anticoagulant and antithrombotic in the hemostasis pathway. The PC deficiency can result in thrombosis and other clinical complications due to the blockage of oxygen transport. The proposed PC immunosensor is designed to diagnose a PC deficient patient prior to the onset of thrombosis and also to monitor a patient’s PC level in blood plasma. The current work focuses on the effect that non-competitive inhibitors have on the immunosensor’s sensitivity compared to pure PC samples in buffer solution. Human serum albumin (HSA) was chosen as the first testing protein because it represents approximately 55% of the proteins in human blood plasma.KeywordsHuman Serum AlbuminSample ChamberFiber Optic BiosensorQuartz Optical FiberOptical Signal IntensityThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Hereditary Thrombophilia as a Model for Multigenic Disease

IntroductionNearly 150 years ago, Virchow postulated that thrombosis was caused by changes in the flow of blood, the vessel wall, or the composition of blood. This concept created the foundation for subsequent investigation of hereditary and acquired hypercoagulable states. This review will focus on an example of the use of modern genetic epidemiologic analysis to evaluate the multigenic pathogenesis of the syndrome of juvenile thrombophilia.Juvenile thrombophilia has been observed clinically since the time of Virchow and is characterized by venous thrombosis onset at a young age, recurrent thrombosis, and a positive family history for thrombosis. The pathogenesis of juvenile thrombophilia remained obscure until the Egeberg observation, in 1965, of a four generation family with juvenile thrombophilia associated with a heterozygous antithrombin deficiency subsequently identified as antithrombin Oslo (G to A in the triplet coding for Ala 404).1,2 The association of a hereditary deficiency of antithrombin III with thrombosis appeared to support the hypothesis, first put forward by Astrup in 1958, of a thrombohemorrhagic balance.3 He postulated that there is a carefully controlled balance between clot formation and dissolution and that changes in conditions, such as Virchow’s widely encompassing triad, could tip the balance toward thrombus formation.The importance of the thrombohemorrhagic balance in hypercoagulable states has been born out of two lines of investigation: evidence supporting the tonic activation of the hemostatic mechanism and the subsequent description of additional families with antithrombin deficiency and other genetically abnormal hemostatic proteins associated with inherited thrombophilia. Assessing the activation of the hemostatic mechanism in vivo is achieved by a variety of measures, including assays for activation peptides generated by coagulation enzyme activity. Activation peptides, such as prothrombin fragment1+2, are measurable in normal individuals, due to tonic hemostatic activity and appear elevated in certain families with juvenile thrombophilia.4 In the past 25 years since Egeberg’s description of antithrombin deficiency, a number of seemingly monogenic, autosomal dominant, variably penetrant hereditary disorders have been well established as risk factors for venous thromboembolic disease. These disorders include protein C deficiency, protein S deficiency, antithrombin III deficiency, the presence of the factor V Leiden mutation, and the recently reported G20210A prothrombin polymorphism.5,6 These hereditary thrombophilic syndromes exhibit considerable variability in the severity of their clinical manifestations. A severe, life-threatening risk for thrombosis is conferred by homozygous protein C or protein S deficiency, which if left untreated, leads to death.7,8 Homozygous antithrombin III deficiency has not been reported but is also likely to be a lethal condition. Only a moderate risk for thrombosis is conferred by the homozygous state for factor V Leiden or the G20210A polymorphism.9,10 In contrast to homozygotes, the assessment of risk in heterozygotes, with these single gene disorders, has been complicated by variable clinical expression in family members with identical genotypes.11 Consideration of environmental interactions has not elucidated the variability of clinical expression. Consequently, it has been postulated that more than one genetic risk factor may co-segregate with a consequent cumulative or synergistic effect on thrombotic risk.12 A number of co-segregating risk factors have been described in the past few years. Probably the best characterized interactions are between the common factor V Leiden mutation, present in 3% to 6% of the Caucasian population,13,14 and the less common deficiencies of protein C, protein S, and antithrombin III. The factor V Leiden mutation does not, by itself, confer increased risk of thrombosis. The high prevalence of the mutation, however, creates ample opportunity for interaction with other risk factors when present.The G20210A prothrombin polymorphism has a prevalence of 1% to 2% in the Caucasian population and, thus, may play a similar role to factor V Leiden. A number of small studies have documented an interaction of G20210A with other risk factors.15-17 A limited evaluation of individuals with antithrombin III, protein C, or protein S deficiency revealed a frequency of 7.9% for the G20210A polymorphism, as compared to a frequency of 0.7% for controls.18 The G20210A polymorphism was observed in only 1 of the 6 protein C-deficient patients.18 In the present state, the elucidation of risk factors for venous thromboembolic disease attests to the effectiveness of the analytical framework constructed from the molecular components of Virchow’s triad, analyzed in the context of the thrombohemorrhagic balance hypothesis. Two investigative strategies have been used to study thromobophilia: clinical case-control studies and genetic epidemiologic studies. The latter strategy has gained considerable utility, based on the remarkable advances in molecular biology over the past two decades. Modern techniques of genetic analysis of families offer important opportunities to identify cosegregation of risk factors with disease.19 The essence of the genetic epidemiologic strategy is the association of clinical disease with alleles of specific genes. It is achieved either by the direct sequencing of candidate genes or by demonstration of linkage to genetic markers.

Antithrombins Wibble and Wobble (T85M/K): Archetypal Conformational Diseases With In Vivo Latent-Transition, Thrombosis, and Heparin Activation

The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main β-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6°C) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0°C), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband's plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation.© 1998 by The American Society of Hematology.

Antithrombins Wibble and Wobble (T85M/K): Archetypal Conformational Diseases With In Vivo Latent-Transition, Thrombosis, and Heparin Activation

The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main β-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6°C) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0°C), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband’s plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation.© 1998 by The American Society of Hematology.

Prevalence of antiphospholipid-related antibodies in unselected patients with history of venous thrombosis.

Antiphospholipid antibodies (aPL) are heterogeneous and are now accepted to be mainly phospholipid-protein-dependent antibodies. Although these antibodies are classically associated with thrombosis, their clinical relevance remains to be established. The subgroups of antibodies characterized by their proteic targets were reported to be more appropriate thrombotic markers. We analysed the prevalence of a large panel of antiphospholipid-related antibodies (aPLR), comprising antibodies directed to phospholipid-protein complexes and to different protein cofactors (beta2GPI, prothrombin, annexin V and protein S), in 122 consecutive unselected patients who had experienced at least one venous thrombotic event. The presence of lupus anticoagulants was assessed with an integrated assay using hexagonal phase phospholipids. Two types of aPL (APA and anti-beta2GPI-PL) were measured using a mixture of phospholipids containing cardiolipin and goat serum or human beta2GPI, respectively, as a source of protein cofactor. Our results show a similar prevalence, close to 15%, of lupus anticoagulants, APA and anti-beta2GPI-PL. In contrast, antibodies to beta2GPI were detected in only 8% of the patients, and very few patients had antibodies directed to other proteins. Of the 35 patients having at least one positive aPLR, 17 were classified as severe, because they had recurrent or early onset of thrombosis (< 35 years). The distribution of aPLR between severe and mild cases was not significantly different except for lupus anticoagulants. Our results clearly indicate that lupus anticoagulant is the only aPLR test to be strongly associated with the severity of thrombosis.

Diffusion- and perfusion-weighted NMR imaging study of middle cerebral artery thrombotic focal ischemia and rt-PA intervention in rat

Objective : Investigation of the biophysical changes of a new rat model of cerebral artery thrombotic stroke in rat with or without thrombolytic treatment using diffusion- (DWI) and perfusion- (PWI) weighted MR imaging. Setting : Henry Ford Health Sciences Center, Detroit, MI, USA. Materials and Methods : A thrombus was induced at the origin of the middle cerebral artery (MCA) by injection of thrombin via an intraluminal catheter placed in the intracranial segment of internal carotid artery. Rats were treated with a recombinant tissue plasminogen activator (rt-PA) ( n = 8) or were untreated ( n = 10). DWI and PWI were performed before, during and after induction of thrombosis from 1 h to 7 days. Results : After onset of thrombosis in both rt-PA treated and control animals, the apparent diffusion coefficient of water (ADC w ) and cerebral blood flow (CBF) values in the ischemic region significantly declined from the preischemic control ADC w and CBF values ( P < 0.01). However, mean CBF in the rt-PA treated group was elevated at 4 h of thrombosis compared to the untreated control group and a significant difference in CBF between the two groups was detected at 48 h after thrombosis ( P < 0.05). Conclusion : These data support the application of magnetic resonance imaging (MRI) to a model of cerebral thrombosis, and demonstrate that DWI and PWI provide real time and dynamic data on the evolution of a thrombotic cerebral lesion with and without thrombolysis.

Direct imaging of deep-vein thrombosis with magnetic resonance imaging

amounts of signal. Reduction in TI, and thus increased signal on a TI-weighted sequence, induced by methaemoglobin, can be exploited directly to image DVT. Imaging was done with a 1·5T scanner (Siemens, Erlangen) with a phased-array spine coil for the lower legs and body coil for the pelvis. A TI-weighted magnetisation prepared 3-D gradient echo (MPRAGE) sequence with a selective water excitation RF pulse (TR 10·3, TE 4·0 FA 15, TI 20, TD 1000, FOV 3133500, matrix 1603256) was acquired in the coronal plane. The matrix size and TI were chosen so the middle lines of k-space, ie, effective TI, occurred at approximately 800 ms, the null point for blood, assuming a blood TI of 1200 ms. The scan acquisition was just over 5 ! s min. The pelvis and both legs could be imaged in two acquisitions. Images were assessed for the presence of below knee, above knee, and pelvic thrombus. Ten patients with venographically proven acute DVT were imaged with MRI. All tolerated MRI scanning. All areas of DVT diagnosed by venography were depicted by MRI: nine below knee, eight above knee, and two pelvic thromboses. MRI demonstrated greater proximal extension in two patients and occult contralateral disease in one. In addition to the major deep veins, thrombus extension was also seen within the profunda femoris vein in one patient (figure) and involvement of the major superficial veins was seen in one patient. These additional areas of involvement could not be verified because of the limitations of the conventional venographic technique. These initial results suggest MRI may be a non-invasive and accurate means of diagnosing DVT. With this technique, DVT detection relies on sufficient maturation of thrombus to provide generation of high signal. False negative results could arise if insufficient time has elapsed for the generation of methaemoglobin and its associated high signal intensity on TI-weighted MR imaging. In-vitro imaging suggests that TI shortening is obtained as soon as blood clots. From our own in-vitro experience this may take up to 7 days, though the model used did not attempt to reproduce the in-vivo intravenous environment which may have significant effects on clot maturation. In the clinical setting, precise changes in signal intensity over time are more difficult to determine as the exact onset of thrombosis in not known. It remains to be seen whether the MR signal characteristics of clot can be used to predict clot behaviour, response to treatment, or potential for pulmonary embolisation.

Changes in the number and volume of platelets in male elderly persons, and effects of various factors on them

Platelets are deeply involved in the onset of thrombosis, such as cerebral thrombosis and myocardial infarction. In large-sized platelets, the enzyme activity is increased, and adhesion and release potential as well as coagulability are also increased, resulting in particularly active involvement in thrombogenesis. This indicates that changes in the platelet count (PLT) and mean platelet volume (MPV) reflect the state of thrombogenesis. However, there have been only a relatively few reports on PLT and MPV in the elderly, although thrombosis frequently occurs in this population. Therefore, we measured platelet parameters in men without thrombotic diseases, hematological diseases, hepatic diseases, or malignant tumors, in order to determine changes in PLT and MPV in aged men and the effects of various factors (hypertension, hyperlipidemia, diabetes, obesity, and smoking/drinking) on these changes. A total of 2,061 men, aged 30-83 (264 cases in their 30s, 810 cases in their 40s, 742 cases in their 50s, 209 cases in their 60s, 32 cases in their 70s and 3 cases in their 80s), were used as subjects. In addition, 36 men aged 30-34 (mean age 32.6 +/- 1.2 years) and 35 men aged over 70 (mean age 73.0 +/- 3.5 years) were designated as the young and aged groups, respectively. Compared with the young group, the frequency of hypertension and that of diabetes were significantly higher or tended to be higher in the aged group, whereas the frequency of smoking tended to be smaller in the aged group.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful delayed thrombolysis with tissue plasminogen activator for recurrent arterial thrombosis secondary to protein S deficiency

Thrombolysis with low dose intraarterial recombinant tissue type plasminogen activator (rtPA) for arterial thrombosis has produced good results. 1 rtPA is specific for fibrin bound plasminogen and is more efficient than streptokinase in intraarterial thrombolysis. 2 Before undertaking thrombolysis the limb must be viable and not requiring immediate surgical intervention but no consensus exists as to the maximum time limit from the onset of thrombosis to when treatment can be used. 3'4 There have been no previous reports of using rtPA for delayed thrombolysis in the presence of a hypercoagulable state. We report a case of successful thrombolysis with rtPA in the upper limb of a patient with protein S deficiency presenting with symptoms present for over 6 months.

Problems of Oral Anticoagulation in an Adult with Homozygous Protein C Deficiency and Late Onset of Thrombosis

We describe a 57-year-old woman with homozygous protein C deficiency and mild thrombotic manifestations consisting of three spontaneous distal deep vein thromboses occurring after the age of 45. Previous surgery and pregnancies had been uneventful. Low but detectable protein C antigen and activity levels (both 20%) were discovered on the occasion of skin necrosis induced by oral anticoagulation. This therapy was interrupted because of skin necrosis and several episodes of disseminated intravascular coagulation (DIC) at the initiation of treatment despite a cautious protocol. No recurrent thromboembolic event has occurred in our patient using prophylactic doses of low molecular weight heparin for 24 months. New therapeutic approaches might be the administration of low molecular weight heparin or oral anticoagulation associated with protein C replacement in the induction period. This case reflects the variability of expression of protein C deficiency as well as the potential hazards of antivitamin K anticoagulation in this disorder.

Prophylaxis of Thrombosis in a Pregnant Woman with Congenital Antithrombin III Deficiency: Changes in Hemostatic Molecular Markers before the Onset of Thrombosis

Prophylaxis of Thrombosis in a Pregnant Woman with Congenital Antithrombin III Deficiency: Changes in Hemostatic Molecular Markers before the Onset of Thrombosis

Severe neonatal protein C deficiency: Prevalence and thrombotic risk

Severe deficiencies of protein C, a pivotal coagulation-regulatory protein, have been reported in neonates as an apparently transient condition. In this prospective study, cord blood was collected at 193 deliveries and assays of protein C were correlated with clinical status, other coagulation results, and outcome. Protein C levels of less than 0.1 unit/ml were found most frequently in preterm infants with respiratory distress, infants of diabetic mothers, and infants of twin gestations. Levels of protein C correlated with levels of factor VIII activity but did not correlate with markers of consumptive coagulopathy. A protein C level less than 0.1 unit/ml was significantly correlated with the subsequent onset of thrombosis, even when the effects of gestational age and birth weight were excluded. Low cord blood levels of protein C may reflect delayed maturation or increased turnover in certain infants and appear to convey an independent risk of thrombosis, but the critical concentration of protein C necessary to maintain neonatal hemostasis is not known.

Thrombin and Plasmin Activity and Platelet Activation in the Development of Venous Thrombosis

This study was designed to determine whether venous thrombosis is associated with a characteristic pattern in the plasma concentrations of fibrinopeptides and platelet alpha granule proteins. Patients undergoing elective craniotomy for tumor or vascular abnormality were studied prospectively for venous thrombosis with the 125I-fibrinogen uptake test and with daily measurement of the plasma concentrations of FPA (fibrinopeptide A), TIFPB (thrombin-increasable fibrinopeptide B reflecting Bβ 1-42), and βTG (β-thromboglobulin). Eighteen patients developed venous thrombosis and 14 did not. In the 14 patients who did not develop thrombosis, the mean FPA level was highest on the day after surgery and exceeded the TIFPB level so that the ratio of FPA to TIFPB, which is ≤0.5 in normals, was 1.2. During the next 14 days, both FPA and TIFPB levels were elevated, but the FPA/TIFPB ratio was not significantly different from the preoperative value. βTG and PF4 levels showed no clear pattern of change in the postoperative period. In 10 of the patients who developed thrombosis, the time of onset of thrombosis was documented by a change in the leg scan from negative to positive. In these 10 patients, the mean FPA level rose to equal the TIFPB level, producing an FPB/TIFPB ratio of approximately 1.0 for the 4 days preceding the change of the leg scan from negative to positive (p

The natural history and aetiology of deep vein thrombosis after total hip replacement.

A study of the natural history and aetiology of deep vein thrombosis in 499 patients after total hip replacement is presented. Deep vein thrombosis was diagnosed by scanning the leg for 125Iodine-labelled fibrinogen for a period of 14 to 18 days and by ascending phlebography. It has been shown that deep vein thrombosis occurs ater than in patients who have undergone abdominal operations, and the risk period is longer. The peak of onset of thrombosis is on the fourth day after the hip replacement. Attempts at prophylaxis using subcutaneous heparin or intermittent pneumatic compression of the calves delay the appearance of thrombosis. Analysis of possible aetiology factors shows that the age of the patient, the degenerative disease of the hip, the surgical approach, and under-transfusion of blood, all have a significant effect on the incidence of thrombosis.

Serotonin blockade during experimental coronary thrombosis

The protective effect of methysergide on accumulating serotonin within the myocardium, during acute and chronic coronary thrombosis was evaluated in two groups of dogs. The first group of 15 dogs was pretreated with methysergide (100 μg/Kg. B.W., intravenously) and an equal number of dogs in the second group served as the control. An occluding intracoronary thrombus was produced in each dog by the closed chest placement of a thrombogenic wire into the left anterior descending (LAD) coronary artery, via catheter technique, under x-ray visualization. Blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral resistance (TPR), and contractile force ( dP dt ) were determined before and at 1, 3, and 5 hours (acute phase) after the onset of thrombosis. These variables were measured again at 1 and 8 days (chronic phase) after verified occlusion. The sums of the mean Q wave (ΣQ) and S-T segment (ΣS-T) amplitudes from 14 ECG precordial mapping sites were also calculated in six dogs of each group at these chronic time periods. Several biochemical variables were measured in the active phase from coronary venous blood specimens collected through the fifth hour. Histological examinations were also performed in the acute and chronic phases on control and pretreated hearts. During the aforementioned sampling times, certain hemodynamic variables decreased significantly (p < 0.05) in the control dogs, but less significant changes were found in the methysergide pretreated animals. There were similar differences in the mean concentration of certain biochemical variables between the two groups, in the acute stages of thrombosis, with less significant changes in the methysergide pretreated dogs. Generally, there were less necrotic changes in the methysergide hearts at the eighth day but histological differences between the two groups were inconclusive in the acute phase. It appears from this study that the cardiodynamic and biochemical integrity was sustained by blocking the action of serotonin within the affected myocardium during myocardial infarction due to thrombotic occlusion of the LAD coronary artery.

Significance of platelet volumetry

Since heterogeneity of circulating platelets is present, we have analyzed what kind of platelets and what factors in platelets do play an important role in thrombogenesis. Using 51 healthy young men and women (22.2±4.6 years in mean±SD), 17 patients in acute stage of thrombosis such as myocardial infarction or cerebral thrombosis (The two-week period following the onset of thrombosis was called the acute stage), 19 patients in the recovery stage of thrombosis and 8 DIC patients, their platelet volume, aggregability and adenine nucleotides content were measured. In healthy volunteers, platelet count was 30.1±5.9×104/μl, platelet mode volume was 4.21±0.56, mean volume was 5.32±0.42 and median volume was 4.66±0.47μ3. There was a significant correlation between platelet mode volume and 5 minutes aggregation induced by 3μM ADP (r=0.375, p<0.02). On the one hand, there was not significant correlation between platelet volume and slope of aggregation curve, intensity of primary and secondary aggregation. In acute stage of thrombosis, platelet volume (mode, mean and median) was significantly smaller than those of the healthy (p<0.05). In recovery stage of thrombosis, platelet volume, especially mode was larger than those of the healthy. In DIC, platelet mode volume was significantly smaller than that of the healthy (p<0.05), while the difference was not found in mean and median volume. ADP content in platelets was significantly decreased in acute thrombosis (p<0.05), while ADP and ATP contents were significantly decreased in DIC as compared to those in the healthy. There was a significant correlation between platelet volume and their adenine nucleotides contents (r=0.347, p<0.025 in ATP and r=0.537, p<0.05 in ADP). Platelet aggregation decreased in DIC and increased in acute thrombosis.These results suggest that large platelets have a large amount of adenine nucleotides and easily are consumed in thrombus formation. In thrombus formation, there may be an enhancement of release phenomenon in platelets.

Risk factors in stroke: a clinical study in Mexican patients.

Mexicans hospitalized between July, 1967, and June, 1968, with clinically diagnosed stroke provided information on risk factors in a population from which little systematically collected information on stroke exists. The patients were beneficiaries of ISSSTE, a government-sponsored health care system. Postmortem examination in 20 patients indicated virtually 100% validity of diagnosis. Cerebral thrombosis, hemorrhage and embolus occurred in a ratio of 6:2:1. There was no sex difference in stroke frequency. Thrombosis and hemorrhage increased with age; embolus occurred more often in younger patients. Thrombosis tended to occur when at repose and in individuals with sedentary occupations; the opposite was found with hemorrhage and embolus. Obesity did not seem to predispose to stroke. Hypertension, heart disease and diabetes mellitus emerged as common antecedent conditions. There was a morning peak in onset of thrombosis and hemorrhage and an afternoon peak for embolus. No relation of onset to holidays or stress was noted. Thrombosis, hemorrhage and embolus all were associated with increased ambient temperature, and with low, slightly decreased and high humidity, respectively. An August-September (end of rainy season) peak in seasonal frequency occurred. The risk factors previously identified as being important mainly in northern populations seemed to be important in this Mexican population as well. Thus, ethnic and cultural variability exerted little effect on stroke frequency.

Myocardial infarction and oral contraceptives.

The case of a 29 year old woman who had an acute myocardial infarction while on Ortho-Novum 2 is reported. She had no other predisposing factor for early onset of coronary thrombosis suggestive that oral contraceptives played some role in causation of it. Time between starting medication and onset of thrombosis was 15 months. The patient also had involvement of the anterior descending branch of the left coronary artery as in cases reported by Dalgaard and Davis. Author has little doubt that oral contraceptives can cause coronary artery thrombosis in a selected group of patients.

Experimental intracoronary thrombosis and selective in situ lysis by catheter technique

Acute myocardial infarction was produced in a group of 20 dogs after the selective placement of a thrombogenic copper wire by catheter technique into either the anterior descending or circumflex branch of the left coronary artery. The time of onset of thrombosis ranged from 1 to 4 hours. The resulting thrombus was enzymatically lysed 1 to 24 hours after the occlusion, and signs of infarction were demonstrated. The lysing agent was delivered directly into the coronary artery, by means of a catheter to the site of the thrombus. Minimal amounts of the enzyme were used, and complete canalization of the obstructed vessel was achieved in all cases in which lysis was attempted. In 16 dogs, there was a definite improvement in the hemodynamic and biochemical indexes after lysis and reestablishment of blood flow.