[Combined aortic and pulmonary valve stenosis, changes in primary hemostasis and partial deficiency of factor XII in Noonan's syndrome].
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Aortic Valve Stenosis↗
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Involvement of the extrinsic pathway in the activities of low molecular weight heparins.
Anticoagulant effects of the three LMW heparins (LMWHs) Enoxaparine, Fragmin, Logiparin and of unfractionated heparin (UFH) were compared. The heparins were added to plasma to nominal concentration of 0.2 and 0.5 anti XaU/ml plasma. Dilute tissue thromboplastin (TTP) and CaCl2 were added to platelet poor plasma (PPP), platelet rich plasma (PRP) and citrated blood. Thrombin activity was recorded with chromogenic substrate. In PPP, UFH was definitely more inhibitory than LMWH. In PRP, 0.2 U/ml of LMWHs were about as effective as UFH. At 0.5 U/ml PRP, UFH and Logiparin were more effective than Enoxaparine and Fragmin. Factor XII deficient plasma was very sensitive to heparin, and UFH and Logiparin were again more inhibitory. In whole blood, fibrinopeptide A determinations showed that UFH was more inhibitory than LMWH. We conclude that the net anticoagulant effects of these heparins result from interactions with platelets in addition to accelerated inactivation of clotting factors. The in vivo anticoagulant effect of these drugs can therefore not be predicted from their nominal anti Xa and anti IIa effects alone.
Blood Coagulation↗
Recurrent reproductive wastage and immunologic factors.
PROBLEM: The causes of recurrent reproductive wastage are varied and complex. The present study was designed to focus on the role of immunologic factors in cases where other causes were not evident. METHOD OF STUDY: Over 20 years, more than 1500 couples were evaluated in our clinic because of recurrent spontaneous abortion. Women were tested for anti-phospholipid antibodies and plasma contact proteins of the intrinsic pathway of blood coagulation after endocrine, organic, infectious and genetic etiologies of miscarriages were excluded. RESULTS: Anti-phosphatidylethanolamine antibodies, anti-annexin antibodies, and factor XII deficiency were more common factors in recurrent spontaneous abortion patients than were anti-cardiolipin antibodies in terms of induction of recurrent pregnancy losses. Paternal leukocyte immunotherapy of patients without such abnormalities was associated with a significantly improved success rate. CONCLUSIONS: Recurrent reproductive wastage can be minimized by individualized therapy based on comprehensive evaluation of immunologic factors, including several anti-phospholipid antibodies.
Abortion, Habitual↗
Induction of disseminated intravascular coagulation in the factor XII-deficient fowl. Morphological effects of liquoid, bacterial endotoxin and tissue thromboplastin in the normal and anticoagulated fowl.
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Animals↗
Congenital deficiency of factor 13: report of a family from Newfoundland with associated mild deficiency of factor XII.
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Adolescent↗
Inherited bleeding disorders.
Congenital bleeding disorders comprise a heterogeneous group of diseases that reflect abnormalities of blood vessels, coagulation proteins and platelets. Studies of these diseases, many of which are rare and several of which result in a mild bleeding diathesis only, have significantly increased our understanding of normal haemostasis. Two lessons have been learned. First, quantitative abnormalities of coagulation proteins and platelets are an important, but not the only, cause of significant haemorrhage; some cases of inherited bleeding disorders reflect synthesis of a dysfunctional coagulation protein or production of abnormal platelets. Diagnostic tests that reflect qualitative abnormalities are therefore important in the evaluation of selected patients with inherited bleeding disorders. Second, in occasional patients the inherited disorder is complex and reflects combined abnormalities of coagulation proteins alone or in association with platelet disorders. In clinical practice it is useful to distinguish disorders that cause significant clinical bleeding from those that cause few or no symptoms. Examples of the former include severe deficiencies of factors VIII and IX, and the homozygous forms of factor II, V, VII, X, XI, XIII, fibrinogen and von Willebrand factor. Comparable platelet disorders include the inherited thrombocytopenias with platelet counts less than 20 x 10(9) litre-1 and the homozygous forms of Bernard-Soulier syndrome and Glanzmann's thrombasthenia. The most frequently encountered mild haemostatic abnormalities include type I von Willebrand's disease, the platelet storage pool deficiency syndromes and the mild and moderate forms of haemophilia A and B; occasionally heterozygous or homozygous forms of the rarer coagulation disorders, e.g. factor XI deficiency, may present with a mild bleeding diathesis. Finally, some disorders are entirely asymptomatic, e.g. factor XII deficiency and deficiencies of other contact coagulation factors. Management of patients with inherited bleeding disorders should reflect knowledge of the specific disorder to be treated plus careful consideration of the clinical circumstance for which therapy is proposed. In all cases, once a decision to treat has been made, the safest efficacious therapy should be given (for example DDAVP in the treatment of patients with mild haemophilia A or type I von Willebrand's disease). Although blood products are now much safer and the risk of blood transmitted viral infections is low, there still remains a risk that transfusion of any blood product may be associated with serious side-effects. As a result, therapy should be given only after careful consideration of the risk: benefit ratio and not merely to treat an abnormal laboratory result.(ABSTRACT TRUNCATED AT 400 WORDS)
Afibrinogenemia↗
Isolation and properties of an abnormal Hageman factor (Factor XII) molecule in a cross-reacting material-positive hageman trait plasma.
We have previously described two unrelated individuals with homozygous Hageman trait (Factor XII deficiency) whose plasmas contained nonfunctional material immunologically indistinguishable from normal Hageman factor (HF). Abnormal HF from the plasma of one these subjects has now been purified to homogeneity, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, alkaline disc gel electrophoresis, and immunoelectrophoresis. Purified abnormal HF had no clot-promoting activity, but showed the same specific antigenicity as purified normal HF by an immunoassay. The abnormal HF was of a single chain polypeptide with the same molecular weight (80,000) as normal HF and was positively stained by periodic acid-Schiff reagent. Both normal and abnormal HF had similar amino acid compositions and isoelectric points (pI 6.5 approximately 7.1). When 125I-labeled abnormal HF and 131I-labeled normal HF were mixed with normal plasma and exposed to glass, both HF underwent an identical pattern of cleavage, yielding 52,000- and 30,000-mol wt fragments. Similarly, abnormal HF was fragmented by trypsin in the same way as normal HF, but no prekallikrein-activating activity was generated after cleavage. [3H]Diisopropyl phosphorofluoridate was incorporated into a 29,000-mol wt fragment of the trypsin-cleaved normal HF, but not into that of the trypsin-cleaved abnormal HF. These data suggest that the molecular defect in this abnormal HF resides at or near the active site serine residue in the 30,000-mol wt part of the molecule.
Binding Sites↗
Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation.
Factor XII deficiency has been postulated to be a risk factor for thrombosis suggesting that factor XII is an antithrombotic protein. The biochemical mechanism leading to this clinical observation is unknown. We have previously reported high molecular weight kininogen (HK) inhibition of thrombin-induced platelet aggregation by binding to the platelet glycoprotein (GP) Ib-IX-V complex. Although factor XII will bind to the intact platelet through GP Ibalpha (glycocalicin) without activation, we now report that factor XIIa (0. 37 microm), but not factor XII zymogen, is required for the inhibition of thrombin-induced platelet aggregation. Factor XIIa had no significant effect on SFLLRN-induced platelet aggregation. Moreover, an antibody to the thrombin site on protease-activated receptor-1 failed to block factor XII binding to platelets. Inhibition of thrombin-induced platelet aggregation was demonstrated with factor XIIa but not with factor XII zymogen or factor XIIf, indicating that the conformational exposure of the heavy chain following proteolytic activation is required for inhibition. However, inactivation of the catalytic activity of factor XIIa did not affect the inhibition of thrombin-induced platelet aggregation. Factor XII showed displacement of biotin-labeled HK (30 nm) binding to gel-filtered platelets and, at concentrations of 50 nm, was able to block 50% of the HK binding, suggesting involvement of the GP Ib complex. Antibodies to GP Ib and GP IX, which inhibited HK binding to platelets, did not block factor XII binding. However, using a biosensor, which monitors protein-protein interactions, both HK and factor XII bind to GP Ibalpha. Factor XII may serve to regulate thrombin binding to the GP Ib receptor by co-localizing with HK, to control the extent of platelet aggregation in vivo.
Amino Acid Sequence↗
Interactions among Hageman factor (HG, Factor XII), plasma thromboplastin antecedent (PTA, Factor XI), plasma prekallikrein (PK, Fletcher factor) and high molecular weight kininogen (HMW-K, Fitzgerald factor) in blood coagulation.
Studies of plasmas from individuals with Hageman trait (factor XII deficiency), plasma thromboplastin antecedent (PTA, factor XI) deficiency, Fletcher trait (plasma prekallikrein deficiency) and Fitzgerald trait (high molecular weight-kininogen deficiency) have revealed the importance of these proteins in blood coagulation. The interactions among them, however, are not fully elucidated. We have studied these reactions by two different approaches. (1) In a purified system, high molecular weight kininogen was absolutely required for activation of PTA by HF and ellagic acid (EA). The yield of activated PTA was proportional to the amount of HF, HMW-K, and PTA in the mixtures, suggesting that these three proteins may form a complex in the presence of EA. (2) In experiments with whole plasma, we took advantage of the adsorption of EA to Sephadex gels. When normal plasma or plasma deficient in HF, PK, HMW-K or PTA was exposed to Sephadex-EA and was separated by centrifugation, each supernatant plasma except that deficient in HF shortened the prolonged partial thromboplastin time (PTT) of HF-deficient plasma. Plasma simultaneously depleted of HMW-K, PK and PTA also shortened the PTT of HF-deficient plasma and of plasma depleted of HF and PK, but had virtually no procoagulant effect upon the PTT of plasma depleted of HF and MHW-K. Thus, exposure of HF in plasma to Sephadex-EA appeared to generate a clot-promoting form of HF in the absence of other clotting factors, but its expression required the presence of HMW-K.
Blood Coagulation↗
Reaction of blood with artificial surfaces of hemodialyzers. Studies of human blood with platelet defects or coagulation factor deficiencies.
Heparinized human blood was exposed to the dialysis membranes of commercially available pediatric size hemodialyzers in an in vitro flow circuit. Bloods from normal subjects and from patients with various blood coagulation and platelet function deficiencies were tested in this model system. In most cases, there was a heavy linear deposit of leukocytes on the dialysis membrane overlying support structures. In other areas, the cellular deposit was less uniform and consisted of single platelets, platelet aggregates, leukocytes, and occasional fibrocellular microthrombi. The number of adherent platelets was smaller in tests with blood from patients with congenital afibrinogenemia, factor XII deficiency, severe von Willebrand's disease, and thrombasthenia then in tests with blood from normal subjects or hemophilic patients. Hence, fibrinogen, factor XII, the von Willebrand factor, and a normal platelet plasma membrane appear necessary for adhesion of platelets to dialysis membranes.
Afibrinogenemia↗
Inherited bleeding disorders in Indian women with menorrhagia.
In order to define the prevalence of haemostatic defects in women presenting with menorrhagia in our region, the coagulation data on women bleeders investigated in the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200 menorrhagic women investigated were characterized to have an inherited bleeding disorder; 221 of these 337 women presented with menorrhagia alone while 116 also had other associated bleeding manifestations as prolonged bleeding from injury site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and major bleeds like intracerebral bleeding. The tests performed included bleeding time (BT), platelet count, prothrombin time (PT), prothrombin consumption index (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin. Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor assay and electron microscopy were performed wherever necessary. Inherited platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these, isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and Bernard-Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the platelet function defect could not be classified into any specific subtypes. Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst these, von Willebrand disease (vWD) was the most frequent being seen in 40 (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII deficiency in one (0.3%) of the patients. It is concluded that although hereditary platelet function defects constitute a large majority of women bleeders in India but among the coagulation defects, vWD is the commonest as reported from the caucasian population. It is thus suggested that in women presenting with menorrhagia, screening tests for haemostasis especially for vWD and inherited platelet function defects must be performed.
Adolescent↗
Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass.
During cardiopulmonary bypass, thrombin is generated, which is thought to be initiated by activation of factor XII on the surface of the bypass equipment. We present a patient with severe factor XII deficiency who underwent cardiac surgery. As much thrombin was formed during cardiopulmonary bypass (measured by the prothrombin activation fragment F1 + 2 and thrombin-antithrombin complexes) as in normal patients, showing that factor XII was not necessary for thrombin generation. Factor X, but not factor IX, was activated (as measured by their activation peptides), and this activation correlated with F1 + 2 and thrombin-antithrombin complexes, suggesting that the tissue-factor/factor-VIIa pathway is the trigger for thrombin formation.
Antithrombin III↗
Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID).
We describe two members of a single family, father and son, with mild factor XII deficiency associated to von Willebrand disease (vWD) with aberrant structure in whom distinct multimeric abnormalities and an abnormal proteolytic processing of von Willebrand factor (vWF) after desmopressin (DDAVP) administration were present. They had a mild bleeding history, low levels of vWF-related activities, and a prolonged bleeding time. Low-resolution agarose gel electrophoresis showed a vWF with all size multimers in plasma and platelets. Higher-resolution agarose gels demonstrated that the main band was present, but the relative proportion of the satellite bands was markedly reduced. The smallest oligomer was not increased. After the infusion of DDAVP to the father, a transient increase in the relative proportion of the satellite bands was seen, as described in normal individuals. No difference in the structure of vWF was observed when blood was collected with proteinase inhibitors. The analysis of native subunits of vWF and their proteolytic derived fragments, after DDAVP administration, showed a temporary augmentation of the 176 kDa fragment, as seen in normal subjects, as well as an increase of the 189 kDa fragment. This finding had not been reported previously either in normal individuals or in patients with vWD.
Adult↗
Two different incubation times for the activated partial thromboplastin time (APTT): a new criterion for diagnosis of lupus anticoagulant.
We describe a test for LA based on the specific APTT behaviour of LA plasmas when the incubation time with the APTT reagent is increased from 1 to 20 min. "1-10 APTT" test was defined as the difference (s) between results of the APTT performed with 1 and the one performed with 10 min incubation. A test value > 11 s (upper normal limit determined on 134 normal plasmas) was considered positive for a LA. The test distinguished all the LA patients studied (n = 40) from patients with factor VIIIc inhibitors, patients receiving heparin or warfarin therapy and also patients with congenital factor deficiencies, except those with prekallikrein and factor XII deficiencies. The test detected LA in warfarin (n = 3) and in heparin (n = 2) LA anticoagulated patients. Among 195 patients referred for LA screening, the test detected LA in 5 patients with normal standard APTT. This simple test, using a single reagent for screening and confirmatory procedures is sensitive and fairly specific for LA when combined with mixing studies. However, since the test was defined using one APTT reagent, the performances of other reagents have to be assessed.
Abortion, Habitual↗
Cardiopulmonary bypass in patients with pre-existing coagulopathy.
Patients with pre-existing coagulopathies who undergo surgical interventions are at increased risk for bleeding complications. This risk is especially true in cardiac surgical procedures with cardiopulmonary bypass (CPB) because of the necessity for heparinization and the use of the extracorporeal circuits, which have destructive effects on most of the blood components. In this review, cases of cardiac surgeries in patients with certain pre-existing coagulopathies are summarized, which could shed a light on future managements of such patients undergoing cardiac procedures with CPB. Pre-existing coagulopathies include antithrombin III deficiency, heparin-induced thrombocytopenia, cancer, factor XII deficiency, hemophilia, idiopathic thrombocytopenic purpura, protein S deficiency, and drug-induced platelet inhibition. In summary, pre-existing coagulopathy in patients undergoing open-heart surgeries, if not recognized and appropriately managed, can cause serious complications. Management of patients undergoing cardiac procedures should include a routine coagulation work-up and a thorough past medical history examination. If any of the foregoing is abnormal, further evaluation is warranted. Proper diagnosis and management of the pre-existing coagulopathy disorders is of crucial importance to the surgical outcome and long-term morbidity.
Blood Coagulation Disorders↗
So-called "vascular headache of the migraine type": one or more nosological entities?
The dispute about whether migraine and cluster headache are one disorder--the "unified theory"--or two facets of a spectrum of "vascular headache" has not yet been settled. The author discusses various clinical features that unite or divide migraine and cluster headache in this respect: so-called "mixed forms" of vascular headache, corneal indentation pulse amplitudes, partial Horner's syndrome and possible aberrations in histamine metabolism. Evidence is presented showing that there may exist subunits of cluster headache, such as chronic paroxysmal hemicrania (C.P.H.) and a hitherto unreported type that co-exists with recurring bouts of retrobulbar neuritis and a partial factor XII deficiency.
Adult↗
Issues in the etiology of recurrent spontaneous abortion.
Recurrent spontaneous abortion is seen often. Although many causes of this condition have been identified, there is still a large proportion in which no cause can be found. This review highlights some of the newly described proposed causes. Several reports have linked reproductive inefficiency to hypersecretion of luteinizing hormone (LH) in the follicular phase. It is apparent that the presence of inappropriate elevation of LH, and not the ultrasonographic appearance of polycystic ovaries, is the critical factor in determining the risk of abortion. Consequently, by lowering the LH levels one can expect a better reproductive outcome. This hypothesis awaits testing through clinical trials. The role of ultrasonography in evaluating the luteal phase, by assessing the image of the endometrium, has been studied by many investigators. This non-invasive technique is not yet able to replace the endometrial biopsy. The association between antisperm antibodies in the female serum and recurrent spontaneous abortion requires re-evaluation in light of more recent evidence; however, the role of semen abnormalities, especially severe oligospermia in this disorder, points towards a factor in the male partner that should be identified. Oligomenorrhea has been identified by mathematical modeling as a potential risk factor for recurrent abortion, although the mechanism has not been clearly elucidated. Chromosome heteromorphisms, particularly inv (9)(p11 q12), appear to be associated, more frequently, with recurrent abortion. Similarly, associations were observed with factor-XII deficiency and high titers of immunoglobulin G (IgG) antibody to Chlamydia trachomatis.(ABSTRACT TRUNCATED AT 250 WORDS)
Abortion, Habitual↗
Low factor XII level in an individual with Sotos syndrome.
Sotos syndrome is an overgrowth disorder that manifests characteristic dysmorphic features, neurological problems, and an increased risk for cancers and heart defects. Alterations of NSD1 are responsible for this disease. A subset of cases arise from deletions, which is of interest as the factor XII locus lies in close proximity to NSD1. This case report describes an individual with Sotos syndrome and factor XII deficiency, providing a potential link between these two genes and, consequently, expanding the clinical phenotype of Sotos syndrome.
Abnormalities, Multiple↗