Gene/Protein Disease Symptom Drug Enzyme Compound
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A 16-year-old boy had recurrent venous thromboses and pulmonary thromboembolism that caused him pulmonary hypertension. He also had livedo reticularis, thrombocytopenia and high titer IgG antiphospholipid (cardiolipin) antibodies. In the absence of clinical and laboratory evidence of SLE, he was considered to have a primary antiphospholipid syndrome. Coagulation studies revealed a functional deficiency of protein C although it was present in normal antigenic amounts. Since both his parents had normal functional and antigenic protein C findings, his deficiency was considered acquired. The reactivity of the anticardiolipin antibodies could be decreased in a dose dependent fashion when preincubated with increasing amounts of thrombomodulin, a protein required for protein C activation at the endothelial cell membrane. This interaction of antiphospholipid antibodies with thrombomodulin may help explain the occurrence of thrombosis in some patients with antiphospholipid antibodies, despite the behavior in vitro of these antibodies as circulating anticoagulants.
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PMID:Acquired protein C deficiency in a patient with primary antiphospholipid syndrome. Relationship to reactivity of anticardiolipin antibody with thrombomodulin. 254 43

Abnormalities of hemostasis and malignancy have been recognized since the 19th century. Thrombosis and hypercoagulability are reported in as many as 60 percent of patients with malignancies. Decreased levels of protein coagulation factors, circulating anticoagulants and platelet numbers, and function changes are reported. The purpose of this work is to report a case of portal thrombosis in a patient with a myeloproliferative disorder and to review protein coagulation and platelet abnormalities associated with malignancies. The clinical laboratory assessment of these abnormalities is reviewed. The patient was a 59-year-old woman who was referred to the Vanderbilt University Medical Center with a diagnosis of septic portal vein thrombosis. After evaluation, it turned out that she had a myeloproliferative disorder and portal vein thrombosis secondary to that. Hypercoagulative states have been reported with a variety of carcinomas and other neoplasms. They may or may not be associated with acquired or genetic deficiencies of antithrombin III, protein C and/or S. Factors I, V, VIII:C, IX, and XI have all been reported as being elevated and implicated in hypercoagulability in patients with neoplasms. Increased platelet turnover and decreased survival have been noted in patients with disseminated tumors. Thromboses with lysis of the thrombus may be monitored by increased levels of fibrin degradation products, D-dimer, fibrinopeptides A and B, and platelet factor IV among others. There are frequently decreases in coagulation inhibitors including antithrombin III, protein C and protein S. These changes lead to a state of low-grade disseminated intravascular coagulopathy where thrombus formation is a more frequent occurrence than is hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombosis and coagulation abnormalities associated with cancer. 814 64

Six patients aged 3 to 14 years with lower limb vein thrombosis were included in a prospective study of deficiencies in physiological coagulation inhibitors. The laboratory evaluation included standard hemostasis tests, tests for circulating anticoagulants, immunological and functional assays of protein C, protein S, and antithrombin III, and a study of fibrinolysis. A qualitative protein S deficiency with decreased fibrinolysis and protein C deficiency were found. The family study detected asymptomatic heterozygotes in both families investigated. No antithrombin III deficiency or circulating anticoagulants were found.
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PMID:[Deficiencies of physiological coagulation inhibitors in children with venous thromboses of the lower limbs. Prospective study of 6 cases]. 835 95

Circulating anticoagulants protein C (PC) and antithrombin III (AT) are markers of, and possibly involved in the pathogenesis of, significant organ dysfunction, in patients undergoing autologous peripheral blood stem cell (PSBC) or autologous bone marrow (BM) transplantation. The effect of the stem cell source, the use of hematopoietic growth factors (GFs), and the specific preparative regimen on the incidence of organ system dysfunction or on post-transplant levels of circulating anticoagulants has not been well studied. We analyzed 205 patients in an attempt to correlate organ dysfunction and AT and PC deficiencies with these transplant-specific factors (78 BMT with GM-CSF after transplant, 95 PBSCT without GM-CSF after transplant, and 32 PBSCT with GM-CSF after transplant). Patients transplanted with PBSC had a lower incidence of pulmonary dysfunction (20 vs 40%, P = 0.006) and liver dysfunction (4 vs 13%, P = 0.05) than patients receiving BM. The use of GF after transplant did not influence the development of subsequent organ dysfunction. In multivariate analysis, the stem cell source was again predictive of pulmonary dysfunction. In contrast, although patients transplanted with PBSC also had a lower incidence of PC deficiency (50 vs 81%, P < 0.01) and AT deficiency (20 vs 54%, P < 0.01) as compared with patients receiving BM, use of GM-CSF after transplant was a more significant risk factor for the development of anticoagulant deficiency (PBSC with GF vs PBSC without GF: PC deficiency 50 vs 78%, P = 0.007; AT deficiency 20 vs 47%, P = 0.005). In the multivariate analysis GM-CSF use was the only significant risk factor for development of anticoagulant deficiency. Since the clinical significance of anticoagulant deficiency has been well shown, further studies examining these effects of hematopoietic GFs appear warranted.
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PMID:Factors predicting morbidity following hematopoietic stem cell transplantation. 905 18

Clot formation is the final result of interaction among multiple plasma proteins; after activation, it results in the conversion of fibrinogen to fibrin and cross-linking of fibrin by activated factor XIII, which stabilizes the formed clot. Deficiency or functional abnormality of the factors involved in these reactions causes bleeding disorders. Natural inhibitors of clotting factors include antithrombin III, protein S, and protein C. When activated, these proteins inactivate specific clotting factors, providing a regulatory mechanism that serves to control the coagulation response and limit the extension of the clot. Physiologic or natural inhibitors should not be confused with acquired inhibitors of coagulation factors, which are discussed in this review. Inhibitors to coagulation factors, also known as circulating anticoagulants, are antibodies that neutralize specific clotting proteins, thereby interfering with their normal function. Antibodies may be directed against isolated clotting factors, as is the case with factor VIII or IX inhibitors. On the other hand, the antiphospholipid antibodies are known to develop against multiple coagulation proteins. In contrast to patients with antibodies against isolated clotting factors, who commonly present with spontaneous bleeding, individuals with antiphospholipid antibodies may be asymptomatic or present with venous or arterial thrombosis. In this article I refer to inhibitors developing in patients with hemophilia A or other congenital factor deficiency as alloantibodies, and to spontaneous formation of antibodies in patients without prior history of hemorrhagic diathesis as autoantibodies. The antiphospholipid antibodies are discussed separately.
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PMID:Inhibitors to clotting factors. 932 77

Hemostatic abnormalities associated with malignancy have been described since the middle of the 19th century. Abnormalities associated with hypercoagulability and hemorrhage are reported in various percentages of patients depending upon the underlying neoplasm and the type of therapy. Changes in the quantitative and qualitative aspects of protein coagulation factors, anticoagulant proteins, circulating anticoagulants, platelets, and vascular responses have been noted. Clinical or subclinical disseminated intravascular coagulopathy (DIC) and associated paradoxical bleeding are common. Hemorrhage may be associated with a decrease of particular coagulation factors or alterations of vascular integrity and platelet numbers or function in various combinations. Evaluation of hemostatic abnormalities associated with cancer (HAAC) includes a careful history and physical examination, assessment of the prothrombin and activated partial thromboplastin times, platelet count, a test for fibrin or fibrinogen degradation products, and assay of fibrinogen levels. Specific findings may suggest the need for tests for naturally occurring protein anticoagulants (e.g., protein S, protein C, and antithrombin III), coagulation inhibitors, abnormalities of the fibrinolytic system, or other esoteric tests. Testing for F1 + 2 and fibrinopeptide A may be useful in determining early activation of prothrombin and thrombin, respectively, and a clue to incipient onset of DIC. Besides the disease, therapies for cancer can alter hemostatic activity. Chemotherapy has been reported to be associated with venous and arterial thromboses, cerebrovascular events, and coagulopathies. Radiation therapy decreases platelet production, particularly if the active bone marrow has been included in the field. Laboratory evaluation of HAAC requires consideration of the type of malignant disorder, the history and physical condition of the patient and any therapy.
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PMID:Hemostatic abnormalities associated with cancer and its therapy. 943 35

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Activated factor VII, but not factor VII antigen, decreased significantly on HRT as compared with placebo. The coagulation inhibitors antithrombin, protein C, and TFPI, but not protein S, all showed significant sustained decreases in the HRT group as compared with placebo. Antithrombin and protein C decreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by 29-30%. In multivariate analysis, only TFPI activity was a significant predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.
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PMID:The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial. 1137 67