Genetic disorders of coagulation

Clinical Procedures ◽

Joint Deformity ◽

Prolonged Aptt

Haemophilia is a familial X-linked disorder due to deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), components of the intrinsic enzymatic complex that activates factor X. Clinical features and diagnosis—the main manifestations are bleeding into joints and soft tissues, with haemophilic arthropathy and joint deformity being inevitable complications in untreated patients. Other features include pseudotumours, bleeding into the urinary system, and bleeding following clinical procedures. Laboratory diagnosis is based on a modification of the classic activated partial thromboplastin time (APTT) assay, with inhibitor screening used to exclude other causes of prolonged APTT. Treatment—involves the administration of the deficient factor VIII or factor IX, most commonly ‘on demand’ in response to bleeding, with prophylactic treatment given before surgery. Von Willebrand’s disease is a common autosomal dominant disorder of platelet function caused by a functional deficiency of von Willebrand factor (VWF). VWF, normally synthesized by megakaryocytes, prevents degradation of factor VIII; VWF, also made by endothelial cells, enhances platelet activation and recruitment at sites of tissue damage. Treatment—mild von Willebrand’s disease is treated with desmopressin 1-deamino-8-d-arginine vasopressin (DDAVP), which releases factor VIII and VWF from endothelial cells. Other treatments include ε‎-aminocaproic acid, oestrogens, and factor VIII concentrates. Other hereditary disorders of coagulation, including (1) hereditary deficiency of the plasma metalloproteinase ADAMTS13; (2) combined deficiency of coagulation factors V and VIII; (3) factor XI deficiency; (4) inherited deficiencies of factors II, V, VII, and X; and (5) deficiency of the contact activating factors, factor XIII, and fibrinogen, and hypercoagulable diseases due to deficiencies of anticoagulants or propensity to thrombosis are discussed in this chapter.

HYPOTHYROIDISM AND ACQUIRED VON WILLEBRAND'S DISEASE

10.1055/s-0038-1644115 ◽

1987 ◽

Author(s):

F E Preston ◽

M Greaves ◽

B Sampson ◽

P B A Kernoff ◽

G Savidge ◽

...

Keyword(s):

Factor Viii ◽

Inverse Correlation ◽

Factor Ix ◽

Bleeding Tendency ◽

Thyroxine Therapy ◽

Type Ia ◽

The Relationship ◽

Normal Controls

A diagnosis of type IA von Willebrand's disease was made in three patients presenting with a mild bleeding tendency. Previously unrecognised hypothyroidism was also confirmed in two patients. In the third, hypothyroidism was diagnosed four years after initial presentation. In all three patients, thyroxine therapy was associated with correction of the haemostatic defect and resolution of the bleeding tendency.The association of von Willebrand's disease and hypothyrodism prompted us to examine the relationship between thyrotrophin (TSH), T3, T4 and components of the factor VIII complex in 12 patients with clinical and biochemical hypothyroidism. Factor IX was also studied. Mean VIII:C (measured by 2 stage assay) was 0.90 u/ul (range 0.55 - 1.14); mean vWF:Ag 0-83 u/ul (range 0.44 - 1.64); mean VIII:Rcof 0.75 (range 0.45 - 1.55); mean factor IX 0.72 (range 0.39 - 1.19). Multimeric analysis of vWF:Ag performed in samples from 8 patients was normal. VIII:Rcof levels were significantly lower than those of normal controls. A significant inverse correlation was obtained between TSH and factor IX and T4 and vWF:Ag. Although there is a definite inverse relationship between TSH and factor IX, this is not evident with respect to factor VIII and a different mechanism is probably responsible for the modest reduction of vWF:Ag and the occurrence of clinically-evident von Willebrand's disease which we have demonstrated in a small proportion of hypothyroid patients.

VIIIR: Ag in Platelets from Patients with Various Forms of von Willebrand’s Disease

10.1055/s-0038-1656994 ◽

1979 ◽

Vol 42 (03) ◽

pp. 1033-1038 ◽

Cited By ~ 8

Author(s):

L Holmbeg ◽

Inga Marie Nilsson

Keyword(s):

Endothelial Cells ◽

Factor Viii ◽

Recessive Gene ◽

Clinical Severity ◽

Type I ◽

Immunoradiometric Assay ◽

Prolonged Bleeding Time ◽

Severity Of The Disease

SummaryThirty patients with various forms of von Willebrand’s disease were investigated for VIIIR: Ag in their platelets. VIIIR: Ag was extracted from washed platelets and measured both with electroimmunoassay and a sensitive immunoradiometric assay. Six patients had severe von Willebrand’s disease, type I, with very low or no VIIIR: Ag in their plasma. None of these patients had any VIIIR: Ag detectable in their platelets. All 19 patients with mild von Willebrand’s disease had VIIIR: Ag in their platelets but the values often fell below those of normal controls. Five patients with genetic variants of von Willebrand’s disease also had values in their platelets corresponding to those in plasma.Von Willebrand’s disease is a bleeding disorder caused by an inherited defect in so-called factor VIII related antigen (VIIIR: Ag), which is a protein normally occurring in plasma (Zimmerman et al. 1971), endothelial cells (Bloom et al. 1973), platelets (Howard et al. 1974) and megakaryocytes (Piovella et al. 1974). The defect leads to a prolonged bleeding time and as a rule a secondary decrease in factor VIII clotting activity (VIII: C) in plasma. Von Willebrand’s disease is a heterogeneous condition (Holmberg and Nilsson 1972). It varies widely in severity, and a genetic variation causing a qualitative abnormality of VIIIR :Ag is also known (Peake et al. 1974). The disease is, as a rule, transmitted as an autosomal and dominant trait, but some severely affected individuals have been suspected to be homozygous for an autosomal and more or less recessive gene (Italian Working Group 1977, Shoa’i et al. 1977).The clinical severity of the disease varies with the amount of functional VIIIR :Ag (VIIIR: RCF) in plasma (Holmberg and Nilsson 1972, Meyer et al. 1974). Patients with severe von Willebrand’s disease have very little or no VIIIR: Ag in their plasma. They also lack the protein in their endothelial cells (Holmberg et al. 1974 b). There is evidence that also their platelets are devoid of VIIIR :Ag. In the present investigation we studied the platelet content of VIIIR: Ag in a series of patients with various types of von Willebrand’s disease. Both electroimmunoassay (EIA) and a more sensitive immunoradiometric assay (IRMA) for VIIIR: Ag were used.

Factor VIII-Related Activities in Normal, Haemophilic and von Willebrand’s Disease Platelet Fractions

10.1055/s-0038-1648663 ◽

1978 ◽

Vol 40 (02) ◽

pp. 288-301 ◽

Cited By ~ 8

Author(s):

P Meucci ◽

I R Peake ◽

A L Bloom

Keyword(s):

Factor Viii ◽

Electrophoretic Mobility ◽

Concanavalin A ◽

Freezing And Thawing ◽

Factor Viii Related Antigen ◽

Normal Plasma ◽

Significant Difference ◽

Ristocetin Cofactor

SummaryFactor VIII-related activities have been studied in platelet fractions in order to try to reconcile the conflicting findings of other workers, and to extend the studies. In platelets from 16 normal subjects procoagulant factor VIII was not detected. The amount of factor VIII-related antigen (FVIIIR: AG) in the cytosol per mg of protein was about twice that in the membrane fraction and about ten times that in the debris fraction. There was no significant difference between the amount of FVIIIR: AG and ristocetin cofactor (RistCof) activity in each fraction. The findings in haemophilic platelets were similar. In von Willebrand’s disease (vWd) one serverely affected patient had no detectable factor VIII related activities in any platelet fraction. In 5 patients with intermediate vWd results were normal. In a further 5, with more prolonged bleeding times, no FVIIIR: RistCof was detected in platelets, despite a normal amount of FVIIIR: AG in the cytosol and debris. The electrophoretic mobility of cytosol FVIIIR: AG was increased in all normals and patients, while that in the membrane and debris fractions had normal mobility. Cytosol FVIIIR: AG eluted later than normal FVIIIR: AG on gel filtration on Sepharose 2B, and also showed reduced antibody binding in an immunoradiometric assay. Precipitation of FVIIIR: AG by concanavalin A was incomplete in all platelet fractions from normals, and even more reduced in vWd platelet fractions. The results suggest the possibility of two types of platelet FVIIIR: AG.A factor VIII-related antigen was shown to be associated with normal washed platelets by immunofluorescence techniques (Bloom et al. 1973). Since then, several studies have been reported on the localisation of factor VIII related antigen (FVIIIR: AG), factor VIII procoagulant activity (FVIII: C) and factor VIII related ristocetin cofactor activity (FVIIIR: RistCof) within the platelets. Initially, Howard et al. (1974) indicated that FVIIIR: AG was firmly bound to the platelet membrane, and noted that in lysed platelets the level of FVIIIR: AG as measured by electroimmunodiffusion was higher than that in whole platelet suspensions. However, further studies by Nachman and Jaffe (1975) showed that FVIIIR: AG was also present to a considerable extent in the granules, and they detected none in the platelet cytosol. Bouma and colleagues (1975) were, however, able to find FVIIIR: AG and FVIIIR: RistCof in the cytosol upon freezing and thawing platelets. This FVIIIR: AG had an electrophoretic mobility comparable to that of normal plasma. They also noted that platelets which were air dried apparently had a granular FVIIIR:AG localisation by immunfluorescence; however, intact platelets in suspension did not stain by this method.Recently Ruggeri et al. (1977) and Sultan et al. (1977) have also found FVIIIR: AG in the cytosol, and the former authors reported it to have increased electrophoretic mobility when compared to normal plasma FVIIIR:AG. Results concerning the localisation of FVIIIR: AG in normal platelets have thus been conflicting. Similarly, in the few reports available concerning platelet FVIIIR: AG in von Willibrand’s disease variable results have also been obtained (Ruggeri et al. 1977, Howard et al. 1974, Shearn et al. 1974 and Bouma et al. 1975).In this study we report on the localisation of factor VIII-related activities in normal, haemophilic and von Willebrand’s disease platelets using available standard techniques as well as precipitation of FVIIIR: AG with the plant lectin concanavalin A, a procedure which has been shown to detect abnormal forms of FVIIIR:AG in certain types of von Willebrand’s disease (Peake and Bloom 1977).

Studies on the Characterization of Factor VIII and a Co-factor VIII

10.1055/s-0038-1649167 ◽

1974 ◽

Vol 31 (02) ◽

pp. 328-338

Author(s):

M. M. P Paulssen ◽

H. L. M. A Vandenbussche-Scheffers ◽

P. B Spaan ◽

T de Jong ◽

M. C Planje

Keyword(s):

Molecular Weight ◽

Factor Viii ◽

The Body ◽

Haemophilia A ◽

Polysaccharide Content ◽

Plasma Factor ◽

Two Factors

SummaryFactor VIII occurs in the body in two different forms. In lymph factor VIII is bound to chylomicra. In plasma, factor VIII is bound to a protein.After delipidation of chylomicra we obtained a glycoprotein with a high polysaccharide content and a molecular weight of approx. 160,000.In plasma, factor VIII is attached to a protein which is present in normal concentrations in plasma of patients with haemophilia A and in serum (co-factor VIII).This factor is deficient in both the plasma and the serum of patients with von Willebrand’s disease.The binding between factor VIII and co-factor VIII is reversible.Some properties of these two factors are described.

The Spectrum of von Willebrand’s Disease

10.1055/s-0038-1655015 ◽

1967 ◽

Vol 18 (01/02) ◽

pp. 040-056 ◽

Cited By ~ 13

Author(s):

E. J Walter Bowie ◽

P Didisheim ◽

J. H Thompson ◽

C. A Owen

Keyword(s):

Factor Viii ◽

Bleeding Time ◽

Severe Bleeding ◽

Platelet Adhesiveness ◽

Platelet Activity ◽

The Third ◽

Generation Test

SummaryPatients (from 5 kindreds) with variants of von Willebrand’s disease are described. In one kindred the depression of factor VIII was moderate (20 to 40% of normal) and transfusion of 500 ml of normal plasma led to an increase higher than anticipated and to an almost normal level of factor VIII 17 to 24 hrs later. This represents the usual type of von Willebrand’s disease.In the second kindred the concentration of factor VIII was less than 2 % of normal in the son and daughter, who had severe bleeding and hemarthroses.The third kindred was characterized by reduction of factor VIII and a long bleeding time as well as by a serum defect in the thromboplastin-generation test comparable to that seen in patients with hemophilia B, yet with normal levels of factors IX, X, and VII. The severity of the serum defect, the positive result with the Rumpel-Leede test, and the reduced platelet activity in the thromboplastin-generation test are all compatible with the diagnosis of thrombopathy or ‘‘thrombopathic hemophilia.” In two other kindreds, one patient had a long bleeding time and normal levels of factor VIII and another had a normal bleeding time and decrease of factor VIII. The last patient had the type of response to transfusion usually seen in von Willebrand’s disease.In four kindreds, platelet adhesiveness in vivo was found to be strikingly abnormal (virtually absent).It would appear, therefore, that von Willebrand’s disease forms a spectrum, and whether the kindreds reported simply reflect variations of a single genetic disease state or represent separate entities will be answered only by clarification of the underlying etiology of that disease.

A Simple Enzyme-Immunoassay (EIA) Test for Factor VIII-Related Antigen (VIIIAGN)

10.1055/s-0038-1666933 ◽

1979 ◽

Vol 42 (03) ◽

pp. 848-854 ◽

Cited By ~ 22

Author(s):

Paul M Ness ◽

Herbert A Perkins

Keyword(s):

Factor Viii ◽

Enzyme Immunoassay ◽

Hemophilia A ◽

Single Sample ◽

Healthy Controls ◽

Factor Viii Related Antigen ◽

Increased Sensitivity

SummaryAn enzyme immunoassay (EIA) system has been developed to measure factor VIII- related antigen (VIIIAGN). This assay gives similar results to the commonly used Laurell electroimmunodiffusion (EID) assay for VIIIAGN as shown by comparison of both techniques with samples from healthy controls, patients with hemophilia A, and patients with von Willebrand’s disease. The assay also has a greater precision than the EID technique as demonstrated by multiple assays of aliquots of a single sample. The use of this EIA test for VIIIAGN is simple and employs inexpensive reagents and equipment. The use of expensive antisera is minimized. EIA for VIIIAGN has the advantage of increased sensitivity compared to Laurell EIA.

Studies on the pathophysiology and treatment of von Willebrand's disease. V. Properties of factor VIII after DDAVP infusion in variant von Willebrand's disease

Thrombosis Research ◽

10.1016/0049-3848(81)90136-5 ◽

1981 ◽

Vol 21 (4-5) ◽

pp. 357-365 ◽

Cited By ~ 11

Author(s):

Hoyu Takahashi

Keyword(s):

Factor Viii ◽

Von Willebrand’S Disease

Factor VIII Antigen in the Vessel Walls in Von Willebrand's Disease and Haemophilia A

Scandinavian Journal of Haematology ◽

10.1111/j.1600-0609.1974.tb00232.x ◽

2009 ◽

Vol 13 (1) ◽

pp. 33-38 ◽

Cited By ~ 41

Author(s):

L. Holmberg ◽

P. M. Mannucci ◽

I. Turesson ◽

Z. M. Ruggeri ◽

I. M. Nilsson

Keyword(s):

Factor Viii ◽

Haemophilia A ◽

Factor Viii Antigen ◽

Vessel Walls

Characterization of the defect of the factor VIII/von Willebrand factor protein in von Willebrand's disease

Blood ◽

10.1182/blood.v59.3.542.542 ◽

1982 ◽

Vol 59 (3) ◽

pp. 542-548 ◽

Cited By ~ 14

Author(s):

HR Gralnick ◽

MC Cregger ◽

SB Williams

Keyword(s):

Sialic Acid ◽

Factor Viii ◽

Von Willebrand Factor ◽

Platelet Rich Plasma ◽

Molecular Forms ◽

Platelet Receptor ◽

Von Willebrand ◽

Willebrand Factor

Abstract The factor VIII/von Willebrand factor (f.VIII/vWf) protein was purified from the plasma of a patient with von Willebrand's disease (vWd). The patient had all of the classic laboratory findings of vWd except for the ristocetin-induced platelet aggregation of his own platelet-rich plasma. The disease has been documented in three generations. Comparison of the purified normal and vWd f.VIIi/vWf protein revealed several abnormalities, including decreased concentration of f.VIII/vWf antigen; decreased specific vWf activity; absence of the larger molecular forms of the f.VIII/vWf protein; carbohydrate deficiencies affecting the sialic acid, penultimate galactose and N- acetylglucosamine moieties; and decreased binding of the f.VIII/vWf protein to its platelet receptor. These studies indicate the multiplicity of biochemical and functional abnormalities associated with the f.VIII/vWf protein in vWd. f.VIII/vWf protein to normal f.VIII/vWf protein that had been treated with 2-mercaptoethanol (2-ME) to reduce the multimer size and then treated with specific exoglycosidases to remove the sialic acid and penultimate galactose residues revealed similar biologic properties.

Effect Of DDAVP In Patients With Von Willebrand’s Disease And Hemophilia A

10.1055/s-0038-1652989 ◽

1981 ◽

Author(s):

A I Warrier ◽

C Hillman ◽

J M Lusher

Keyword(s):

Side Effects ◽

Factor Viii ◽

Hemophilia A ◽

Blood Components ◽

Excessive Bleeding ◽

Crossed Immunoelectrophoresis ◽

Transient Improvement ◽

The U.S

European investigators have reported on the efficacy of l-deamino-9-D-arginine vasopressin (DDAVP) in von Willebrand’s disease (vWD) and mild hemophilia A. We have thus evaluated the effects of a single intranasal dose of DDAVP (200ugm of the more dilute form available in the U.S.), in 12 individuals with vWD and in 4 with moderate hemophilia A. Crossed immunoelectrophoresis of VIII: RAg demonstrated normal electrophoretic mobility in each of the vWD subjects. Components of the factor VIII system (VIII: C, VIII: RAg, VIII: R Cof.) were assayed pre - and 90 and 180 minutes post- DDAVP. Each of 11 subjects with mild or moderate vWD had an increase in VIII: C activity (avg. 2X increase), 8 of 11 had an increase in VIII: R Cof, and 9 of 11 had an increase in VIII: RAg. The twelfth vWD subject, who had severe vWD, had no rise in any of these components. Of 4 vWD subjects who had pre- and post-DDAVP template bleeding times (BT) performed, the only one who had a prolonged baseline BT showed a normal BT 90 minutes post-DDAVP. One vWD subject, in whom we had documented an increase in all F. VIII components after DDAVP, later underwent dental extractions 90 minutes after DDAVP. No excessive bleeding was noted. Four individuals with moderate hemophilia A (baseline VIII: C values of 0.02-0.10 u/ml) were also studied. Three had a rise in all components of the factor VIII system post-DDAVP while the fourth did not. No undesirable side effects were noted in any of the 16 subjects who received DDAVP. We conclude that even the more dilute form of DDAVP available in the U.S., when given intranasally, results in transient improvement in selected individuals with vWD or moderate hemophilia A. This drug thus warrants further study as an alternative to blood components in the management of vWD, as well as in mild and moderate hemophilia A.