Clinical and Experimental Studies on the Bleeding Tendency During Defibrinogenation Therapy

Defibrinogenation with thrombin-like enzyme is expected to be a new type of anticoagulant therapy without serious bleeding complications. However, it appears to be dangerous to perform surgical procedure in defibrinogenated state. In order to investigate the causes of the bleeding tendency which occurs during defibrinogenation therapy, the following clinical and experimental studies were undertaken. Ten mongrel dogs were used, the superior caval vein was replaced by expanded polytetrafluoroethylene graft. 50 to 100 μl/kg of batroxobin was administered 2 days prior to the operation. 5 out of 10 dogs died due to bleeding postoperativelly, and the causes of the bleeding seemed to be the decreased fibrinogen concentration and the reduced platelet function. Fifteen patients suffering from peripheral vascular thrombosis were treated with 30 to 60 μl/kg of batroxobin. In 9 patients, urokinase was administered combined with batroxobin. No bleeding complications were observed in these patients. In another 6 patients, surgical procedure was performed after batroxobin administration. Postoperative bleeding was observed in one out of these 6 patients. This patient was operated on after the initial administration of batroxobin. FDP level was 512 μg/ml and ADP induced platelet aggregation was within normal limits, but fibrinogen concentration was unmeasurable at the time of operation. The cause of the bleeding seemed to be the decreased fibrinogen concentration. From these clinical experiences, it is suggested that platelet adhesion to glass and ADP induced platelet aggregation are not influenced by the decreased fibrinogen concentration nor the increased level of FDP during the defibrinogenation therapy with batroxobin. These results indicate that an adequate level of fibrinogen is needed for certain hemostasis besides normal platelet function.

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Essential Athrombia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647881 ◽

1975 ◽

Vol 33 (02) ◽

pp. 278-285 ◽

Cited By ~ 3

Author(s):

Şeref Inceman ◽

Yücel Tangün

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Bleeding Tendency ◽

Clot Retraction ◽

Platelet Factor ◽

Prolonged Bleeding Time ◽

Normal Platelet ◽

Aggregation Response ◽

Platelet Disorder ◽

Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

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Determination and Treatment of Disorders of Primary Haemostasis

Hämostaseologie ◽

10.1055/s-0038-1660415 ◽

1999 ◽

Vol 19 (04) ◽

pp. 168-175 ◽

Cited By ~ 6

Author(s):

M. Weippert-Kretschmer ◽

V. Kretschmer

Keyword(s):

Platelet Function ◽

Bleeding Risk ◽

Bleeding Complications ◽

Bleeding Tendency ◽

Platelet Counts ◽

Platelet Function Disorders ◽

Perioperative Bleeding ◽

Before And After ◽

Low Sensitivity

SummaryPerioperative bleeding complications due to disorders of primary haemostasis are often underestimated. Routine determination of primary haemostasis is still problematic. The in vivo bleeding time (BT) shows low sensitivity and high variability. In this contribution the results and experiences with the IVBT having been obtained in various studies and during 10 years of routine use are reported. Patients and Methods: Blood donors before and after ASA ingestion, patients with thrombocytopenia as well as congenital and acquired platelet function disorders. Monitoring of desmopressin efficacy. IVBT with Thrombostat 4000 (tests with CaCl2 = TST-CaCl2 and ADP = TST-ADP) and PFA-100 (test cartridges with epinephrine = PFA-EPI and ADP = PFA-ADP). Results and Conclusions: IVBT becomes abnormal with platelet counts <100,000/μl. With platelet counts <50,000/μl the results are mostly outside the methodical range. IVBT proved clearly superior to BT in von Willebrand syndrome (vWS). All 16 patients with vWS were detected by PFA-EPI, whereas with BT 7 of 10 patients with moderate and 1 of 6 patients with mild forms of vWS were spotted. The majority of acquired and congenital platelet function disorders with relevant bleeding tendency were detectable by IVBT. Sometimes diagnostic problems arose in case of storage pool defect. Four to 12 h after ingestion of a single dose of 100 mg ASA the TST-CaCl2 became abnormal in all cases, the PFA-EPI only in 80%. However, the ASA sensitivity of TST-CaCl2 proved even too high when looking for perioperative bleeding complications in an urological study. Therefore, the lower ASS sensitivity of the PFA-100 seems to be rather advantageous for the estimation of a real bleeding risk. The good efficacy of desmopressin in the majority of cases with mild thrombocytopenia, congenital and acquired platelet function disorders and even ASS-induced platelet dysfunction could be proven by means of the IVBT. Thus IVBT may help to increase the reliability of the therapy. However, the IVBT with the PFA-100 is not yet fully developed. Nevertheless, routine use can be recommended when special methodical guidelines are followed.

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Hemostatic Disorders and Platelet Nucleotide Release in Myeloproliferative Disease

10.1055/s-0039-1684370 ◽

1979 ◽

Author(s):

A.B. Hagedorn ◽

E.J.W. Bowie ◽

C.A. Owen

Keyword(s):

Platelet Aggregation ◽

Postoperative Bleeding ◽

Myeloproliferative Disorders ◽

Myeloproliferative Disease ◽

Myeloid Metaplasia ◽

Normal Platelet ◽

Agnogenic Myeloid Metaplasia ◽

Nucleotide Release ◽

The One ◽

Hemostatic Disorders

Since patients with myeloproliferative disorders may have bleeding tendencies, the surgeon, in particular, is anxious for an hemostatic evaluation if splenectomy is contemplated. It is known that platelet aggregation, particularly with epinephrine, tends to be reduced in these patients. The nucleotide content of their platelets may be deficient. Furthermore, megakaryocytic fine structure is often abnormal. We have studied, In detail, 9 patients with hemostatic disorders. Diagnoses included polycythemia vera, agnogenic myeloid metaplasia, evolving myeloproliferative disease and erythroleukemia. Ages ranged from 36 to 75 years. Bleeding tendencies, including bruising, operative or postoperative bleeding, melena, hematuria, and hemarthrosis, characterized 8 of the 9 patients; the one exception had normal platelet ADP and elevated ATP. All had abnormal platelet aggregation, but the extent of the abnormality could not be related to the ADP and ATP contents of the platelet.ADP (normal 26.7 ± 6.5 nmol/109 platelets) was reduced in 7. ATP (normal 38.6 ± 7.6 nmol/109 platelets) was reduced in 1, elevated in 2 and normal in the other 6. In no patient were both values normal. Nucleotide release induced by collagen activation was measured in 6 of the patients. In all 6 it was deficient whether platelet ADP were normal (1 case) or depressed (5) and whether platelet ADP were elevated (1) or decreased (3).

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Impaired function of platelet membrane glycoprotein IIb-IIIa in end-stage renal disease.

Journal of the American Society of Nephrology ◽

10.1681/asn.v5136 ◽

1994 ◽

Vol 5 (1) ◽

pp. 36-46

Author(s):

M P Gawaz ◽

G Dobos ◽

M Späth ◽

P Schollmeyer ◽

H J Gurland ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Platelet Aggregation ◽

Platelet Function ◽

Uremic Toxin ◽

Bleeding Tendency ◽

Fibrinogen Receptor ◽

Fibrinogen Binding ◽

Uremic Patients ◽

Stage Renal Disease

Impaired platelet function and a bleeding tendency are well-recognized complications of chronic renal failure. Because the fibrinogen receptor GPIIb-IIIa plays a central role in platelet aggregation and adhesion to the subendothelium, it was reasoned that a defect in this receptor may underlie the impaired platelet function in uremia. To test this hypothesis, the function of this receptor in the platelets of 11 uremic patients was studied. Aggregation studies were performed with flow cytometric techniques with anti-GPIIb-IIIa conformation-specific monoclonal antibodies (mAb) (anti-LIBS1 and anti-PMI-1). Antifibrinogen and antithrombospondin mAb were used to characterize fibrinogen binding to GPIIb-IIIa and the release of alpha-granules, respectively. Platelets from patients with chronic renal failure showed significantly decreased binding of conformation-dependent anti-LIBS1 mAb after ADP, phorbol myristate acetate, or RGD-peptide stimulation compared with normal controls, suggesting a defect related to the ability of the fibrinogen receptor to undergo a conformational change. Moreover, antifibrinogen and antithrombospondin binding to activated platelets were reduced in uremic patients, implying impairment of both ligand-binding and alpha-granule release. Hemodialysis partially restored GPIIb-IIIa function, which may account for the observed effects of this therapy in restoring platelet aggregation. These findings indicate that platelets of patients with chronic renal failure reveal an aggregation defect at least partially due to an intrinsic GPIIb-IIIa dysfunction and the presence of a putative uremic toxin that inhibits fibrinogen binding to GPIIb-IIIa.

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Platelet Function in Various Haemorrhagic Disorders

10.1055/s-0039-1689499 ◽

1975 ◽

Author(s):

T. Mandalaki ◽

C. Dimitriadou

Keyword(s):

Platelet Aggregation ◽

Density Gradient ◽

Platelet Function ◽

Factor Xiii ◽

Platelet Rich Plasma ◽

Bleeding Tendency ◽

Factor Xiii Deficiency ◽

Haemorrhagic Diathesis

Platelet aggregation by ADP, collagen, thrombin and ristocetin was studied systematically both in citrate platelet rich plasma and isolated platelets by density gradient using albumine (according to Nicholls and Hampton) in various cases of congenital haemorrhagic diathesis, namely v. Willebrand disease, Glanzmann disease (thrombasthenia), Thrombopathy (PF3, defect), Factor XIII deficiency and in unclassified hereditary haemorrhagic disorders as well as in acquired bleeding tendency. According to the platelet abnormalities found during this study a classification of “Thrombopathies” observed in Greece is attempted.

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"Impotent" Platelets in Albinos With Prolonged Bleeding Times

Blood ◽

10.1182/blood.v39.4.490.490 ◽

1972 ◽

Vol 39 (4) ◽

pp. 490-499 ◽

Cited By ~ 18

Author(s):

Harold M. Maurer ◽

James A. Wolff ◽

Sue Buckingham ◽

Arthur R. Spielvogel

Keyword(s):

Platelet Aggregation ◽

Adenosine Diphosphate ◽

Bleeding Tendency ◽

Prolonged Bleeding ◽

Prolonged Bleeding Time ◽

Normal Platelet ◽

Tryptophan Metabolites ◽

History Of

Abstract Functional, biochemical, and morphologic platelet abnormalities are reported in four children with the syndrome of albinism, mild bleeding tendency, prolonged bleeding time, and normal platelet count. In these children, primary platelet aggregation with adenosine diphosphate occurred normally, but secondary aggregation was impaired. Collagen and norepinephrine produced almost no platelet aggregation. Platelet content of serotonin (5-HT) was markedly reduced, and uptake and retention of 5-HT by the platelets in vivo and in vitro was poor. In one child who was given a tryptophan load, urinary tryptophan metabolites were normal, suggesting that there was no evidence of a block in the 5-HT synthetic pathway in the gastrointestinal tract. Electron microscopy revealed an absence of densely osmophilic granules in 5-HT poor platelets. Platelets from other albinos with no history of bleeding contained normal amounts of 5-HT and densely osmophilic granules.

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The Role of Platelets in the Pathogenesis of Thrombosis and Hemorrhage in Patients with Thrombocytosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651925 ◽

1977 ◽

Vol 38 (04) ◽

pp. 1085-1096 ◽

Cited By ~ 40

Author(s):

Peter N. Walsh ◽

Scott Murphy ◽

William E. Barry

Keyword(s):

Platelet Function ◽

Bleeding Complications ◽

Platelet Counts ◽

Normal Platelet ◽

Coagulant Activity ◽

Hemorrhagic Complications ◽

Myeloproliferative Diseases ◽

Thrombotic Complications ◽

Preliminary Study

SummarySome patients with thrombocytosis due to myeloproliferative diseases or other etiologies experience thromboembolic complications and others may bleed excessively. It seems unlikely that elevations in platelet count per se are a direct cause either of thrombosis or of hemorrhage. In an effort to ascertain whether variations in platelet function might determine whether an individual patient experiences thrombotic or hemorrhagic complications we have evaluated platelet function in 22patients with thrombocytosis due to a variety of etiologies. The results of platelet counts, bleeding time determinations, and studies of platelet aggregation were similar in patients with thrombosis, in patients with bleeding and in patients with neither complication. Therefore, detailed studies of platelet coagulant activities were carried out in 8patients. The results of platelet coagulant activity assays were normal in all 3patients with thrombocytosis and neither thrombotic nor bleeding complications and an additional 3patients with myeloproliferative diseases, normal platelet counts and no thrombohemorrhagic complications. In 2patients with thrombotic complications significant elevation of platelet coagulant activities concerned with the early phases of intrinsic coagulation were observed whereas in 2patients with severe hemorrhagic complications deficiences of either contact forming activity or collagen-induced coagulant activities were evident. This preliminary study suggests the possibility that variations in platelet coagulant activities concerned with the early stages of intrinsic coagulation may determine whether patients with thrombocytosis will experience bleeding or thrombotic complications.

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Propofol-Induced Bleeding Dyscrasia: A Case Report.

Blood ◽

10.1182/blood.v104.11.3894.3894 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3894-3894

Author(s):

Rabih C. Fahed ◽

Thomas K. Schulz2

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Bleeding Time ◽

Postoperative Bleeding ◽

Sigmoid Resection ◽

Von Willebrand Disease ◽

Prior History ◽

Normal Platelet ◽

Anesthetic Drugs ◽

Relative Safety

Abstract Propofol is one of the most commonly used anesthetic drugs, with rapid induction, maintenance and recovery times. Its relative safety has resulted in it becoming a popular choice for general anesthesia. A 56 y o woman with no prior history of bleeding underwent laparoscopic cholecystectomy. Postoperatively she experienced bleeding to the degree that open laparotomy was required to achieve hemostasis.Two years later, she underwent open sigmoid resection under propofol anesthesia for refractory diverticulitis. Severe postoperative bleeding ensued, necessitating IV fluid resuscitation and transfusion of packed red blood cells.Template bleeding time was repeatedly greater than 20 minutes on the first postoperative day. Platelet count, coagulation studies, von Willebrand disease assays, fibrinogen level and fibrinolytic system assays were found to be normal. Platelet aggregation in response to arachidonic acid was decreased at 9% (reference 60 - 120 %). The patient received platelet transfusions; hemostasis was achieved and the template bleeding time returned to normal on the second postoperative day and remained normal on repeat testing several weeks later. A few reports have shown an increased bleeding with propofol, which is thought to be related to inhibition of thromboxane A2 synthesis and increased synthesis of leucocyte nitric oxide. Some studies show increased bleeding even without any change in the template bleeding time. In summary, we report a case of a propofol-induced life threatening bleeding dyscrasia associated with a prolonged template bleeding time and platelet aggregation studies consistent with decreased response to arachidonic acid. This rarely reported complication should always be in the differential diagnosis of postoperative bleeding given the widespread usage of propofol anesthesia in major surgeries.

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A New Dysfibrinogenemia: Fibrinogen Oslo IV

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657335 ◽

1983 ◽

Vol 49 (02) ◽

pp. 120-122 ◽

Cited By ~ 2

Author(s):

H Stormorken ◽

F Brosstad ◽

H Seim

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Bleeding Tendency ◽

Normal Value ◽

Normal Platelet ◽

Fibrinogen Binding ◽

Successive Generations

SummaryA family with dysfibrinogenemia is described. The abnormal fibrinogen occurred in three successive generations indicating a dominant hereditary pattern. Thrombin and reptilase times were about twice the normal value. This was shown to be caused by a polymerization defect, fibrinopeptide release being normal. Platelet aggregation was undisturbed, indicating normal platelet-fibrinogen binding. The bleeding time was normal and there was no bleeding tendency. However, an obscure recurrent pulmonary ailment may, or may not, be related to the dysfibrinogenemia. The abnormal fibrinogen was tentatively termed Oslo IV.

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Evaluation of Children with Suspected Bleeding Disorder Applying the Impact-R [Cone and Plate(let) Analyzer].

Blood ◽

10.1182/blood.v110.11.3962.3962 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3962-3962 ◽

Cited By ~ 1

Author(s):

Shoshana Revel-Vilk ◽

Esther Hyam ◽

Tali Zelikowitz ◽

Ela Shai ◽

David Varon

Keyword(s):

Platelet Aggregation ◽

Factor Viii ◽

Platelet Function ◽

Predictive Value ◽

Bleeding Disorder ◽

Measurement Sensitivity ◽

Normal Platelet ◽

Function Defect ◽

Bleeding History ◽

The Impact

Abstract Background: von Willebrand’s disease (VWD) is the most common bleeding disorder, affecting between 1–10% of the general population. There is a need for a simple test to screen patients with bleeding symptoms before more labor-intensive diagnostic steps are taken. The Impact-R [Cone and Plate(let) Analyzer (CPA)] (DiaMed Switzerland), was designed in an attempt to test platelet function under close to physiological conditions. Citrated whole blood is applied on polystyrene surface, under controlled shear conditions using a cone and plate device, followed by a quantitative analysis of platelet deposition to immobilized plasma von Willebrand’s factor (VWF) and fibrinogen. Results of the test are presented for adhesion as % surface coverage (SC) and for aggregation as average size (μm2, AS). In this study we report the use of CPA test in evaluation of children with suspected bleeding disorder. Methods: Fifty-four consecutive children with bleeding symptoms and normal platelet count and coagulation tests were evaluated between August 1st, 2006 and July 31, 2007. In addition to the CPA test, all children were tested for VWF: antigen plasma level, VWF: ristocetin activity, factor VIII: C plasma level, platelet aggregation test using turbidometric aggregometer (Helena, USA) and blood type. The study was approved by the local Helsinki committee. Statistical analysis was done by SPSS. Results: Of 54 children, 10 (18.9%) were diagnosed with VWD and 6 (11.1%) children were diagnosed with platelet function defect according to bleeding history, family history, aggregation and factor VIII/VWF tests. To test the validity of the CPA as a screening test for diagnosis of VWD and platelet function defects a ROC curve was formulated for both SC and AS measurements. The best cutting point for a positive test was equal or less then 6.5% for SC measurement (sensitivity 60%, specificity 65%), and equal or lest then 26.5μm2 for AS measurement (sensitivity 67%, specificity 81.6%). The predictive value of a normal CPA test (negative predictive value), i.e. SC > 6.5% and AS > 26.5μm2, was 92%. Of the 26 normal CPA tests, one child was diagnosed with mild type I VWD and one child was diagnosed with mild platelet defect in response to epinephrine (40%). The predictive value of an abnormal CPA test (positive predictive value) was 50%. Of the 28 abnormal CPA test, 9 children were diagnosed with VWD, 4 children with platelet defect in response to epinephrine (<30%) and one child with platelet defect in response to collagen (10%). Significant bleeding symptoms (bleeding score 3 or more) were reported in 4 of 14 children with abnormal CPA test but with normal VWF, normal factor VIII and normal platelet aggregation. Conclusions: The CPA test was found to be a useful tool for excluding VWD and platelet function defect in children suspected for bleeding disorder. Yet, in case of an abnormal CPA test, further testing are needed. Interestingly, abnormal CPA test was the only finding in some children with a significant bleeding history, suggesting other underlying adhesion defects yet to be described.

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