Role of clotting factors and fibrin structure in predisposition to atherothrombotic disease

Abstract We have studied the coagulation status of eight patients with the Chediak-Higashi syndrome (CHS), both in the chronic and the accelerated phase of the disease. It has been shown that during the accelerated phase there are coagulation abnormalities. These abnormalities include a peripheral thrombocytopenia, minor alterations of liver clotting factors, and mainly a profound hypofibrinogenemia and hypoplasminogenemia, which cause life-threatening bleedings. These disorders are of complex origin, but a fibrinolytic process, possibly primary, appears to play a significant role, since the present evidence for intravascular coagulation is not definitive. The accelerated phase of the CHS is characterized by a visceral infiltration by macrophages and lymphocytes. Therefore, we have investigated the possible role of the macrophages in the fibrinolytic process. We have found an excessive plasminogen activator (PA) production by CHS mononuclear cells in the accelerated phase and to a lesser extent in the chronic phase, except in one patient in whom no anomaly was found. Single-cell studies revealed an increased number of PA-producing cells among the monocyte- macrophage lineage rather than a higher level of production per cell. Polymorphonuclear cells (PMN) from patients with CHS were also shown to contain more PA. Slight but significant abnormalities in PA production were observed in obligatory heterozygotes (five out of nine), indicating the inherited nature of the excessive PA production. Finally, an enhanced PA production was similarly demonstrated using beige mice macrophages. The exacerbated production of PA by macrophages in the accelerated phase of the CHS can account to some extent for the coagulation abnormalities that have been observed.

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Enhanced plasminogen-activator production by leukocytes in the human and murine Chediak-Higashi syndrome

Blood ◽

10.1182/blood.v65.5.1275.bloodjournal6551275 ◽

1985 ◽

Vol 65 (5) ◽

pp. 1275-1281

Author(s):

G de Saint Basile ◽

A Fischer ◽

MD Dautzenberg ◽

A Durandy ◽

F Le Deist ◽

...

Keyword(s):

Plasminogen Activator ◽

Mononuclear Cells ◽

Chronic Phase ◽

Polymorphonuclear Cells ◽

Clotting Factors ◽

Coagulation Abnormalities ◽

Life Threatening ◽

Coagulation Status ◽

Chediak Higashi Syndrome

We have studied the coagulation status of eight patients with the Chediak-Higashi syndrome (CHS), both in the chronic and the accelerated phase of the disease. It has been shown that during the accelerated phase there are coagulation abnormalities. These abnormalities include a peripheral thrombocytopenia, minor alterations of liver clotting factors, and mainly a profound hypofibrinogenemia and hypoplasminogenemia, which cause life-threatening bleedings. These disorders are of complex origin, but a fibrinolytic process, possibly primary, appears to play a significant role, since the present evidence for intravascular coagulation is not definitive. The accelerated phase of the CHS is characterized by a visceral infiltration by macrophages and lymphocytes. Therefore, we have investigated the possible role of the macrophages in the fibrinolytic process. We have found an excessive plasminogen activator (PA) production by CHS mononuclear cells in the accelerated phase and to a lesser extent in the chronic phase, except in one patient in whom no anomaly was found. Single-cell studies revealed an increased number of PA-producing cells among the monocyte- macrophage lineage rather than a higher level of production per cell. Polymorphonuclear cells (PMN) from patients with CHS were also shown to contain more PA. Slight but significant abnormalities in PA production were observed in obligatory heterozygotes (five out of nine), indicating the inherited nature of the excessive PA production. Finally, an enhanced PA production was similarly demonstrated using beige mice macrophages. The exacerbated production of PA by macrophages in the accelerated phase of the CHS can account to some extent for the coagulation abnormalities that have been observed.

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The Role of the Liver in Biosynthesis of the Non-Vitamin K-Dependent Clotting Factors

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0028-1087125 ◽

2008 ◽

Vol 4 (01) ◽

pp. 15-28 ◽

Cited By ~ 9

Author(s):

E. Workman ◽

R. Lundblad

Keyword(s):

Vitamin K ◽

Clotting Factors

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VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding

Thrombosis and Haemostasis ◽

10.1160/th09-03-0204 ◽

2009 ◽

Vol 101 (06) ◽

pp. 1044-1050 ◽

Cited By ~ 43

Author(s):

Gabriele Spohn ◽

Andre Kleinridders ◽

F. Thomas Wunderlich ◽

Matthias Watzka ◽

Frank Zaucke ◽

...

Keyword(s):

Vitamin K ◽

Knockout Mice ◽

Severe Bleeding ◽

Clotting Factors ◽

Vitamin K Cycle ◽

Severe Deficiency ◽

Epoxide Reductase ◽

Bone Calcification

SummaryVitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational γ-glutamyl carboxylation resulting in biological active so called vitamin K-dependent proteins. In turn, K>O is reduced by the enzyme VKORC1 (vitamin K epoxide reductase complex component 1) to complete the vitamin K cycle. To investigate the biological role of VKORC1 in vivo, we generated VKORC1 knockout mice. Homozygous VKORC1-deficient mice developed normally until birth. Within 2–20 days after birth, the knockout mice died due to extensive, predominantly intracerebral haemorrhage. Bleeding resulted from a severe deficiency of γ-carboxylated clotting factors. This lethal phenotype could be rescued by oral administration of vitamin K. Additionally, morphometric analysis of the limbs in VKORC1-deficient animals revealed reduced length of bone calcification relative to wild-type control mice. The observed phenotype of VKORC1 knockout mice excludes the existence of other enzymes with VKOR activity that can substitute to supply vitamin K hydroquinone required for maturation of blood clotting factors. Thus, our study underscores the essential role of VKORC1 in vitamin K-dependent γ-glutamyl carboxylation.

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RAT HEPAT0CYTES IN CULTURE INACTIVATE FACTOR Xa.

10.1055/s-0038-1643294 ◽

1987 ◽

Author(s):

G D Qureshi ◽

M Sun ◽

C Gervin ◽

H Evans

Keyword(s):

Serine Proteases ◽

Antithrombin Iii ◽

Factor Xa ◽

Rat Hepatocytes ◽

Factor X ◽

Clotting Factors ◽

Hepatocyte Cultures ◽

The Stability ◽

Stabilization Period

Plasma contains zymogens of clotting factors, which under various stimuli are activated to serine proteases. Whereas much knowledge has been gained about the activation of clotting factors, relatively little is known about inactivation of these proteases. Antithrombin III has been shown to inactivate some activated clotting factors in plasma. Studies in intact animals have suggested that activated clotting factors are mainly inactivated in the liver. To investigate more fully the role of liver in inactivating the activated factors, we studied the stability of activated factor X(Xa) in hepatocyte cultures. Monolayer cultures on non-proliferating rat hepatocytes were prepared according to the method of Bissell et al. The culture medium was chemically defined and was free from serum or serum products. After the 24 h stabilization period, 0.5 units/ml of 100% activated bovine factor Xa was co-cultured with hepatocytes for 8 h. Samples were collected at 0, ½, 1 2, 4 and 8 h and tested for Xa activity using chromogenic substrate S-2222. At the end of 8 h only 41.07% of the initial Xa activity remained. Xa inactivation was not affected by a commercially prepared unfractionated heparin (1 unit/ml) and estradiol at 12.5, 25, 125 nM, a potentiator and inhibitor of antithrombin III, respectively. Inactivation of Xa in hepatocyte cultures was inhibited by the addition of cycloheximide (10-4M). Our data suggests that factor Xa is inactivated in hepatocyte cultures by one or more hepatic derived factors which do not meet the functional characteristics of antithrombin III.

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The Role of Laser Nephelometer in the Study of Abnormal Clotting Factors: Characterization of Two Abnormal Antithrombins (AT III Padua and AT III Padua2)

American Journal of Clinical Pathology ◽

10.1093/ajcp/81.3.323 ◽

1984 ◽

Vol 81 (3) ◽

pp. 323-328 ◽

Cited By ~ 4

Author(s):

Antonio Girolami ◽

Grazia Ruzza ◽

Leopoldo Saggin ◽

Antonio Sticchi ◽

Renato Melizzi

Keyword(s):

Clotting Factors ◽

At Iii

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The Role of Vitamins in Hemostasis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647871 ◽

1975 ◽

Vol 33 (02) ◽

pp. 191-198

Author(s):

Armand J Quick

Keyword(s):

Vitamin K ◽

Physiological Mechanism ◽

Factor Vii ◽

Clotting Factors ◽

The Third ◽

Abnormal Bleeding ◽

Vitamin Q ◽

Tissue Thromboplastin ◽

And Control

SummaryThe physiological mechanism to prevent and control abnormal bleeding is dependent on three vitamins (C, K, and Q). Two of these are unequivocally established as essential for hemostasis while the existence of the third (Q) is supported by experimental evidence and by clinical and therapeutic observations (Quick 1972; Quick 1974). The interrelationship of these three vitamins has remained moot except for clue observations. Both vitamins C and K have a key structure in their molecules which supplies a redox mechanism, ascorbic acid and 2-methyl, 1,4-naphthoquinone, respectively. Both vitamins are concerned with growth. Lack of vitamin C, which clinically is the basic defect in scurvy, does not appear to cause a defect in blood coagulation while vitamin K affects the clotting mechanism by being essential for the production of four distinct clotting factors: prothrombin, factors VII, IX and X.In this presentation an attempt is made to correlate the action of the vitamin K-dependent clotting factors grouping them in a diagram to show how two systems of thrombin formation exist, one being essentially intrinsic, the second extrinsic requiring tissue thromboplastin and factor VII. The possible interlocking of vitamin Q in this mechanism is presented.

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Experimental Thrombocytopenia Induced by Busulphan (Myleran) in Rabbits: Extremely Low Platelet Levels and Intact Plasma Clotting System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651236 ◽

1968 ◽

Vol 19 (03/04) ◽

pp. 570-577 ◽

Cited By ~ 4

Author(s):

S. A Evensen ◽

M Jeremic ◽

P. F Hjort

Keyword(s):

Alkylating Agent ◽

Normal Values ◽

Coagulation System ◽

Lag Phase ◽

Injection Level ◽

Minimum Level ◽

Clotting Factors ◽

Clotting System ◽

Plasma Coagulation

SummaryThe effects of 2 intraperitoneal injections of the alkylating agent Busulphan (each of 25 mg/kg body weight, 3 days between injections) on the circulating elements of the blood and on the plasma coagulation system in rabbits have been investigated.Platelets fell progressively after a lag-phase of 7 days, reached a mean minimum level of about 3 % of the pre-injection level in 14 days, and then returned slowly towards normal values. Bleeding was an occasional complication and a rare cause of death. Granulocytopenia developed synchronously with the fall in platelets. The plasma clotting factors remained intact.We conclude that this is a useful experimental model for studies on the role of platelets in hemostasis and thrombosis.

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Thromboelastometry Variables in Neonates with Perinatal Hypoxia

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0040-1709473 ◽

2020 ◽

Vol 46 (04) ◽

pp. 428-434 ◽

Cited By ~ 4

Author(s):

Aikaterini Konstantinidi ◽

Rozeta Sokou ◽

Andreas G. Tsantes ◽

Stavroula Parastatidou ◽

Stefanos Bonovas ◽

...

Keyword(s):

Perinatal Asphyxia ◽

Fetal Distress ◽

Clinical Findings ◽

Perinatal Hypoxia ◽

Clotting Factors ◽

Increased Risk ◽

Neonatal Liver ◽

Coagulation Status ◽

Α Angle

AbstractPerinatal hypoxia is associated with an increased risk of coagulation disorders by enhancing the consumption of platelets and some clotting factors due to the associated severe hypoxemia, acidemia, and compromised oxygen and blood supply to the neonatal liver and bone marrow. Thromboelastometry (TEM), which estimates the dynamics of blood coagulation, may represent an attractive tool for studying the coagulation status of these neonates. We aimed at assessing the hemostatic profile of neonates with perinatal hypoxia using the standard extrinsically activated TEM (ex-TEM) assay. In total, 164 hospitalized neonates with perinatal asphyxia and/or fetal distress comprised the study subjects, and 273 healthy neonates served as controls. Ex-TEM assay was performed, SNAPPE (Score for Neonatal Acute Physiology Perinatal Extension) was calculated, and clinical findings and laboratory results were recorded in all study subjects. Hypoxic neonates expressed a prolonged clotting time (CT) and clot formation time (CFT) and reduced amplitude at 10 minutes (A10), α-angle, and maximum clot firmness compared with healthy neonates. Furthermore, asphyxiated neonates had a significantly prolonged CT and CFT and reduced A10 and α-angle compared with neonates with fetal distress. Hypoxic neonates demonstrate a hypocoagulable ex-TEM profile relative to healthy neonates, indicating a potential role of TEM in the early detection of coagulation derangement in perinatal hypoxia.

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