Propofol-Induced Bleeding Dyscrasia: A Case Report.

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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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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The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648422 ◽

1992 ◽

Vol 67 (02) ◽

pp. 258-263 ◽

Cited By ~ 12

Author(s):

Raffaele De Caterina ◽

Rosa Sicari ◽

An Yan ◽

Walter Bernini ◽

Daniela Giannessi ◽

...

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Plasma Levels ◽

Bleeding Time ◽

Ex Vivo ◽

Random Sequence ◽

Antiplatelet Agent ◽

Antiplatelet Drug ◽

Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

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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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Absence of Pharmacodynamic or Pharmacokinetic Interactions When TAK-442, An Oral, Direct Factor Xa Inhibitor, Is Coadministered with Aspirin or Clopidogrel.

Blood ◽

10.1182/blood.v114.22.4175.4175 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4175-4175 ◽

Cited By ~ 1

Author(s):

Fran Stringer ◽

Graham Scott ◽

Stuart Kupfer ◽

Charlie Cao ◽

Masaki Kawamura

Keyword(s):

Arachidonic Acid ◽

Salicylic Acid ◽

Platelet Aggregation ◽

Bleeding Time ◽

Factor Xa ◽

Direct Factor ◽

Acid Metabolite ◽

Post Dose ◽

Clinically Significant ◽

Global Research

Abstract Abstract 4175 Introduction TAK-442 is a novel orally active, direct Factor Xa (fXa) inhibitor in clinical development for the prevention of venous and arterial thrombotic disorders. Currently, aspirin and clopidogrel are widely used for platelet inhibition in patients with an increased risk of atherothrombotic events, and it is highly likely that TAK-442 may provide incremental anti-thrombotic benefit when used in conjunction with either of these agents. The primary aim of this study was to evaluate the effect of TAK-442 on inhibition of platelet aggregation by aspirin or clopidogrel. Methods Healthy male and female (n=77), subjects were randomly assigned to 1 of 2 treatments groups and received either TAK-442 60 mg or placebo twice daily (BID) for 11 days, with the addition of aspirin 162 mg or clopidogrel 75 mg once daily (QD) from days 5 to 11. Pharmacokinetics were assessed for TAK-442 (days 4 and 11), aspirin/salicylic acid (day 11) and clopidogrel/carboxylic acid metabolite (day 11. Inhibition of fXa (Coatest®) was assessed on day 1 and two hours post dose on days 4 and 11. Platelet aggregation (arachidonic acid-induced for the aspirin group or ADP-induced for the clopidogrel group) was assessed on day -1 and 2 hours post dose on days 4 and 11; bleeding time was assessed on day -1 and 2 hours post dose on day 11. Results Inhibition of arachidonic acid-induced platelet aggregation by aspirin was not affected by TAK-442 (71% for aspirin + TAK-442 and 74% for aspirin + placebo) nor was there any clinically significant effect of TAK-442 treatment on the inhibition of ADP-induced platelet aggregation by clopidogrel (56% for clopidogrel + TAK-442 and 67% for clopidogrel + placebo) at 2 hours post dose on day 11. Likewise, co-administration of TAK-442 did not have a clinically significant effect on the pharmacokinetic profiles of aspirin or clopidogrel. AUC0-24 and Cmax values were increased ≤16% for clopidogrel and ≤13% for the carboxylic acid metabolite. Although aspirin AUC0-24 and Cmax were increased 2- to 3-fold with coadministration (90% confidence intervals were: 76.2% to 741.8% and 90.1% to 825.1%, respectively), the proportional exposure was very low and the variability was high; the values for the active metabolite, salicylic acid, were increased less than 20% with coadministration. TAK-442-mediated inhibition of fXa activity and prolongation of PT, and the PK profile of TAK-442, were unaffected by co-administration with aspirin or clopidogrel. Coadministration of TAK-442 resulted in modest increases in mean bleeding time compared to aspirin with placebo (aspirin + TAK-442: 558 sec vs. aspirin + placebo: 392 sec) and to clopidogrel with placebo (clopidogrel + TAK-442: 893 sec vs. clopidogrel + placebo: 829 sec). TAK-442 was well tolerated, with a low and similar frequency of mild bleeding events with or without aspirin or clopidogrel coadministration. Conclusion This study demonstrated that no clinically meaningful pharmacodynamic or pharmacokinetic interactions were observed when TAK-442 was co-administered with aspirin or clopidogrel. Disclosures: Stringer: Takeda Global Research & Development, Inc.: Employment. Scott:Takeda Global Research & Development, Inc.: Employment. Kupfer:Takeda Global Research & Development, Inc.: Employment. Cao:Takeda Global Research & Development, Inc.: Employment. Kawamura:Takeda Global Research & Development, Inc.: Employment.

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Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion

Blood ◽

10.1182/blood-2007-03-080184 ◽

2007 ◽

Vol 110 (9) ◽

pp. 3183-3191 ◽

Cited By ~ 119

Author(s):

Catherine Léon ◽

Anita Eckly ◽

Béatrice Hechler ◽

Boris Aleil ◽

Monique Freund ◽

...

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Strong Increase ◽

Clot Retraction ◽

Gene Encoding ◽

Normal Platelet ◽

Coated Surface ◽

Platelet Functions

Abstract Mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain IIA result in bleeding disorders characterized by a macrothrombocytopenia. To understand the role of myosin in normal platelet functions and in pathology, we generated mice with disruption of MYH9 in megakaryocytes. MYH9Δ mice displayed macrothrombocytopenia with a strong increase in bleeding time and absence of clot retraction. However, platelet aggregation and secretion in response to any agonist were near normal despite absence of initial platelet contraction. By contrast, integrin outside-in signaling was impaired, as observed by a decrease in integrin β3 phosphorylation and PtdIns(3,4)P2 accumulation following stimulation. Upon adhesion on a fibrinogen-coated surface, MYH9Δ platelets were still able to extend lamellipodia but without stress fiber–like formation. As a consequence, thrombus growth and organization, investigated under flow by perfusing whole blood over collagen, were strongly impaired. Thrombus stability was also decreased in vivo in a model of FeCl3-induced injury of carotid arteries. Overall, these results demonstrate that while myosin seems dispensable for aggregation and secretion in suspension, it plays a key role in platelet contractile phenomena and outside-in signaling. These roles of myosin in platelet functions, in addition to thrombocytopenia, account for the strong hemostatic defects observed in MYH9Δ mice.

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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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Inhibition of Human Platelet Function Induced by Sulphinpyrazone

10.1055/s-0038-1665778 ◽

1979 ◽

Author(s):

E Maguire ◽

G Pay ◽

J Turney ◽

R Wallis ◽

M Weston ◽

...

Keyword(s):

Arachidonic Acid ◽

Platelet Count ◽

Platelet Aggregation ◽

Bleeding Time ◽

Human Platelet ◽

Ex Vivo ◽

Term Treatment ◽

Second Phase ◽

Maximum Plasma ◽

At Iii

A single 400 mg dose of sulphinpyrazone (S) administered orally to 5 volunteers inhibited arachidonic acid (AA)-induced platelet aggregation and platelet MDA production ex vivo biphasically. The initial inhibitory phase coincided with the maximum plasma concentration of S but the second phase occurred 24 h after dosing when no plasma S was detectable. At 2 h the concentration of AA inducing half-maximal aggregation was increased 1.95 times and at 24 h by 1.61 times. Dosing 7 volunteers with 200 mg q.d.s. for 7 days and 5 volunteers with 400 mg b.d.s. for 5 days also led to inhibitory activity against AA-induced platelet aggregation and MDA production which declined to zero 48 h after the last dose. Platelet count, fibrinogen, F VIII, β-TG and AT III were not influenced by the longer term treatment but bleeding time was slightly extended in all but one subject.

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Abnormal Ristocetin-Aggregation of Platelets in Uraemia and on Haemodialysis Therapy

10.1055/s-0038-1665834 ◽

1979 ◽

Author(s):

H. F. Woods ◽

J. Turney ◽

M. J. Weston

Keyword(s):

Platelet Aggregation ◽

Factor Viii ◽

Bleeding Time ◽

Dialysis Patients ◽

Normal Platelet ◽

Crossover Studies ◽

Coagulant Activity ◽

Aggregation Of Platelets ◽

Ristocetin Cofactor ◽

Membrane Defect

Impaired platelet aggregation to ADP and collagen is recognised in uraemia and the loss of normal platelet function contributes to the prolonged capillary bleeding time observed in uraemia. in von Willebrand’s disease prolongation of capillary bleeding time is associated with impaired platelet aggregation to ristocetin because of a relative or absolute deficiency of the Factor VIII-Ristocetin Cofactor. We have studied platelet aggregation to ristocetin and Factor VIII coagulant activity (CA) and related antigen (RA) in 14 uraemic and 28 dialysed patients. Ristocetin aggregation (delta-0.D/min) was significantly less in uraemia (50 ± 21: m ± S.D) and in dialysis patients (38 ± 18) than in controls (78 ± 20). Factor VIII CA and RA were significantly higher in uraemic and dialysed patients than in controls.In crossover studies plasma from uraemic patients either enhanced or did not change ristocetin aggregation of normal platelets but plasma from dialysed patients impaired ristocetin aggregation of normal platelets. Plasma from dialysed patients was not contaminated by heparin. Thus in uraemia impaired platelet aggregation to ristocetin is unlikely to be due to a Factor VIII deficiency and may be due to a membrane defect as in Bernard-Soulier disease. in dialysed patients’ plasma there appears to be an additional circulating inhibitor of platelet-ristocetin interaction.

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Hemophilia in a Chromosomal Female - An Extreme Example of Lyonization?

10.1055/s-0039-1682603 ◽

1977 ◽

Author(s):

J.M. Lusher ◽

J.A. Penner ◽

I. Warrier ◽

R.K. Evans

Keyword(s):

Platelet Aggregation ◽

X Chromosome ◽

Glass Bead ◽

Bleeding Time ◽

Hemophilia A ◽

Spontaneous Mutation ◽

Normal Platelet ◽

Extreme Degree ◽

Low Levels ◽

Antigen Quantitation

Severe Factor (F.) VIII deficiency is rare in females. We have previously reported two (unrelated) females with 1-3% F. VIII activity (Jour. Pediatr. 74:265-271, 1969). This report concerns a third Michigan female with Hemophilia A. Although this 12 year old girl’s F. VIII activity has ranged from 1-3% she has had only occasional hemarthroses. Her bleeding time is normal, her platelets aggregate normally with ristocetin and F. VIII antigen quantitation has varied from 1.02-1.40 μ/ml. In addition, platelet retention in a glass bead column has been normal. Her father has classical hemophilia A (F. VIII activity <1%, F. VIII antigen 1.61 μ/ml., normal bleeding time and normal platelet aggregation with ristocetin), while her mother appears to be normal (F. VIII activity 90-105% with corresponding values for F. VIII antigen, normal bleeding time and normal platelet aggregation with ristocetin). The child’s only sibling, a 9 year old sister has a F. VIII activity of 40-46%, F. VIII antigen of 1.40 μ/ml., normal bleeding time and normal platelet aggregation with ristocetin. While both girls are obligate carriers, one can only speculate on the reasons for the very low levels of F. VIII activity in the propositus. Although it is possible that there was a spontaneous mutation in the propositus’ maternal X chromosome, it seems likely that her 1-3% F. VIII activity reflects an extreme degree of lyonization.

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Is a Standardized Preoperative Questionnaire a Good Tool To Detected Coagulation Disorders In Children

Blood ◽

10.1182/blood.v122.21.4786.4786 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4786-4786

Author(s):

Susan Halimeh ◽

Hannelore Rott ◽

Guenther Kappert ◽

Manuela Siebert

Keyword(s):

Bleeding Time ◽

Postoperative Bleeding ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

Coagulation Disorders ◽

Good Tool ◽

Prolonged Bleeding Time ◽

Prolonged Aptt ◽

Von Willebrand ◽

Preoperative Examination

Introduction In our study 144 children were send to our coagulation centre with a positive anamnesis (such as haematomas or nose bleeding’s) a positive family anamnesis (p.e. Mother with Menorrhagie) or a prolonged aPTT during a standardized preoperative examination. Samples and Methods We analyzed samples of 144 children by conduction the following tests: Blood count, VWF:RCo, VWF:Ag, VWF:CB, Fibrinogen (Clauss), activities of FII, FV, FVII, FVIII (clotting and chromogenic), FIX, FX, FXI, FXII, FXIII. Results In 107 of 144 children (74.3%) a bleeding disorder could be detected. In those with a bleeding disorder the distribution was as followed: 23.6% had a von Willebrand disease, 27.8% had a prolonged bleeding time and 5.6% a factor XIII-deficiency. The remaining 43% hat other bleeding. disorders (e.g. FVIII-deficiency, FVII-deficiency and other mild factor deficiencies). Discussion A standardized preoperative questionnaire can be useful in clinical practice. In our study 74.3% children with one or more positive evidence in the anamnesis suffer from a bleeding disorder. It is specifically noticeable that we found in 68% of the children which mother has a menorrhagia a bleeding disorder. In 31.8% of the children we found a von Willebrand disease. In our more coagulation disorders could be detected if a standardized preoperative questionnaire would be used and if we pay more attention to children with would a mothers with menorrhagia. Conclusions Children from mothers with menorrhagia suffer more frequently from a bleeding disorder. In our patients in 75% of the children with a mother with menorrhagia a bleeding disorder was found. To avoid an unexpected bleeding during a planned surgery or a postoperative bleeding a standardized preoperative questionnaire should be performed. Disclosures: Halimeh: Octapharma AG: Investigator Other, Research Funding.

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