Endothelial cell damage in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia type II is a severe complication of heparin treatment that may result in thrombosis. When thrombosis occurs it carries a 50% mortality rate. The exact pathophysiology is not fully understood but in the majority of cases it is associated with the production of heparin/platelet factor 4 antibodies. The endothelium provides a protective anticoagulant surface over which blood flows. Perturbation of the endothelial cells causes a reversal of the anticoagulant properties of the cells to that of a procoagulant surface. This is often due to release or down-regulation of the anticoagulant membrane proteins such as thrombomodulin and up-regulation of procoagulant factors such as tissue factor. We studied 10 patients in our cardiothoracic institute with clinically and laboratory-confirmed heparin-induced thrombocytopenia type II for evidence of endothelial cell damage. There was a statistically significant rise in the concentrations of von Willebrand factor (P < 0.0001) and soluble thrombomodulin (P = 0.004) when patients with heparin-induced thrombocytopenia type II were compared with healthy laboratory controls and patients having had cardiopulmonary bypass surgery (von Willebrand factor 324 versus 103 versus 108 U/dl and soluble thrombomodulin 9.5 versus 2.3 versus 1.2 ng/ml, respectively). Our findings suggest that endothelial cell damage is a major factor in the pathophysiology of heparin-induced thrombocytopenia.

Factor XII auto-antibodies present in a patient with a B-cell lymphoma.

A 64-year-old woman was transferred for investigation of a mediastinal mass, biopsy of which showed a diffuse large B-cell lymphoma. She was also found to have an antiphospholipid antibody. The pre-operative coagulation screen showed a prolonged activated partial thromboplastin time, 71.3 s (normal range, 26-36 s), which was not corrected by the addition of normal plasma. The dilute Russell's viper venom time was positive. Anti-cardiolipin assay was strongly positive, immunoglobulin M was 153 AU; immunoglobulin G was normal, 3.1 AU. Assays of factors VIII, IX and XI showed higher concentrations with increasing dilutions in one-stage factor assays from 1: 10 to 1: 80 suggestive of an inhibitor. Factor XII was 9 U/dl and results were unaffected by increasing dilution, suggesting specific antibodies to factor XII. The factor XII antigen was 40 U/dl. The patient had immunoglobulin M auto-antibodies to factor XII.

Teicoplanin-dependent antibodies: detection and characterization.

There are only a few reports of thrombocytopenia associated with clinical doses of teicoplanin, a glycopeptide antibiotic used against Gram-positive bacteria. We investigated 39 patients receiving teicoplanin; 31 were thrombocytopenic with platelet counts between 1-105 x 10(9)/l and 8 were not thrombocytopenic. We identified 14 thrombocytopenic cases (45%) and two (25%) non-thrombocytopenic cases with IgG teicoplanin-dependent platelet-reactive antibodies. Use of glycoprotein (GP) capture enzyme-linked immunosorbent assay with platelets and GPIIb/IIIa transfected Chinese Hamster Ovary cells as well as flow cytometry with GP-deficient platelets indicated that the GPIIb/IIIa complex is a major target antigen of these antibodies.

Correlation between thrombin potential and bleeding after cardiac surgery in adults.

We used a sensitive assay to measure thrombin potential in 20 patients who underwent cardiopulmonary bypass surgery for coronary artery bypass grafts. We measured coagulation factors II, V, VII, VIII and X. Blood loss was measured as the total amount in the mediastinal drains in the first 24 h postoperatively. Thrombin potential was median 107 nmol/l.min (range 62-181) preoperatively and median 46 nmol/l.min (range 19-120) postoperatively. Coagulation factors II, V, VII,VIII and X were within normal limits preoperatively. Factor II fell from 77 IU/dl preoperatively to 37 IU/dl at 120 min postoperatively. Factor V fell from 85 IU/dl preoperatively to 61 IU/dl postoperatively. Factor VII fell from 91 IU/dl to 66 IU/dl postoperatively. Factor VIII was 128 IU/dl preoperatively and 127 IU/dl postoperatively. Factor X fell from 90 IU/dl preoperatively to 50 IU/dl postoperatively. Total blood loss in 24 h in the mediastinal drains postoperatively was mean 673 ml, median 650 ml (range 250-2000). Reduction in thrombin potential correlated inversely with postoperative blood loss, r= -0.75 (Spearman correlation). The fall in the thrombin potential correlated with the prothrombin level (r = 0.75) and factor X (r = 0.47).

Abciximab is rapidly effective in preventing and arresting established platelet aggregation.

BACKGROUND: Abciximab reduces the thrombotic complications of angioplasty. It is also used, as a 'bail out' treatment when angioplasty is complicated by thrombus but its speed of action is not known. This study sought to establish how quickly abciximab blocks the aggregation of both quiescent and activated platelets to explain this rapid efficacy. METHODS: Optical aggregometry (OA) and whole blood electrical impedance platelet aggregometry (WBEA) were performed with blood from 10 healthy volunteers. Abciximab 5 microg/ml was added in each case with saline control 5 minutes before agonist, 10 seconds before agonist and during aggregation. RESULTS: (1) Abciximab administered 5 minutes before agonist, completely inhibited aggregation with OA: (medians and ranges) 0% (all 0), control: 71% (50-95%) p < 0.001. and with WBEA: 0 omega (all 0 omega), control: 7.5 omega (4.8-12.5 omega) p = 0.016. (2) When administered 10 s before agonist with OA a small initial degree of aggregation occurred but this was rapidly reversed (time to reversal: 2 mins (1-4.5 mins) to low levels of aggregation 16.5% (0-22%), control 72.5% (55-95%) p = 0.002. With WBEA aggregation was completely inhibited: 0 omega (all 0 omega), control: 7.5 omega (4.8-12.3 omega) p = 0.016. (3) When administered during aggregation, with OA the rise in the aggregometry tracing was rapidly arrested (time to arrest: 1.5 mins (0.1-3 mins)) with no further aggregation occurring: 42% (30-57%), control: 80% (60-100%) p = 0.002. With WBEA the findings were similar: (time to arrest 1.5 mins (1-2 mins)) 6.3 omega (1.5-11.3 omega), control: 10 omega (3-12 omega) p = 0.031. CONCLUSIONS: These data suggest that when administered during a procedure in which thrombus has occurred, aggregation may be rapidly arrested. This applies to quiescent platelets but also activated platelets undergoing aggregation.