Heparin-associated Thrombocytopenia Research Articles

Platelets of patients with peripheral arterial disease are hypersensitive to heparin

We sought to verify earlier reports of increased platelet reactivity in patients with peripheral arterial disease (PAD) during perioperative heparin administration, and to test the hypothesis of platelet hypersensitivity to heparin in these patients. Before and after incubation of platelet rich plasma with unfractionated (UH), low molecular weight heparin (LMWH), and a low molecular weight heparinoid, real-time quantitative assessment of platelet function was performed by stagnation point flow adhesio-aggregometry (SPAA) in 21 patients with PAD and 14 healthy volunteers. With SPAA the occurrence of spontaneous aggregation is pathological. In the 15 patients requiring operation, platelet function and count were measured at regular intervals. To detect heparin dependent antibodies, the heparin induced platelet activation assay (HIPA) was performed preoperatively and after 10 days of heparin therapy. Mean baseline platelet adhesion in patients was double that observed in controls (p < 0.001). Spontaneous aggregation was seen in 9 (43%) patients and no controls (p < 0.001). In controls heparinoid reduced, whereas UH and LMWH slightly increased adhesion. Spontaneous aggregation was observed once with UH. Platelets from patients showed significantly enhanced adhesiveness and aggregability (p < 0.05) with UH and LMWH when compared to controls. Effects with the heparinoid were less pronounced and non-significant. In patients requiring operation, postoperative increases in platelet function and reductions in count were significant (p < 0.001). Ten (67%) experienced a fall in platelet count of > 50%. Preoperatively the HIPA assay showed no evidence of antibodies, whereas after heparin administration antibodies were verified in 4 (32%) patients and could not be ruled out in 6 (40%). Three developed postoperative thrombosis, in one case fatal. A hypersensitive in vitro and in vivo platelet response to heparin was verified in patients with PAD and a large number developed the immunological type of heparin-associated thrombocytopenia. Our findings suggest that a thrombin antagonist which does not interact with platelets may give the best perioperative protection in these patients.

Temporary cava filter: effective prophylaxis of pulmonary embolism in venous thrombosis in the region of the pelvic vascular system and the inferior vena cava?

To assess the temporary Günther filter system concerning handling, complication rate and efficacy in respect to prophylaxis of pulmonary embolism. 45 temporary Günther filters were placed in 44 patients (mean age 46 years) with deep venous thrombosis of the iliac and/or inferior vena cava. The mean time until filter retrieval was 6.1 +/- 4.1 days (maximum 14 days) dependent on the success of either thrombolytic therapy or thrombus consolidation. 27 patients underwent systemic thrombolytic therapy (61%), three patients (7%) received local thrombolysis. 14 patients (32%) were treated with heparin in a therapeutic dosage (PTT > 60 sec). We observed four complications (8.8%): one accidental arterial puncture (carotid artery on attempting an internal jugular vein approach), one infection located at the puncture site and one caval vein thrombosis in a patient with known heparin-associated thrombocytopenia. One patient died of pulmonary embolism despite correct filter positioning. Percutaneous placement of inferior vena cava filters is therefore an easy, safe and effective prophylaxis in respect of pulmonary embolism if combined with thrombolytic therapy or therapeutic heparinisation.

Lupus anticoagulant, heparin use, and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: A preliminary report

An increased occurrence of thrombotic events has been described in patients exhibiting a lupus anticoagulant (LA). In patients with chronic, major vessel thromboembolic pulmonary hypertension, not only has there been a relatively high frequency of the LA, but also an unexpected association with heparin-related thrombocytopenia. This retrospective report emphasizes the frequency of this association. We retrospectively reviewed the medical records of 216 patients admitted to the University of California, San Diego, Medical Center who were being considered for surgical correction of their chronic thromboembolic pulmonary hypertension. For each patient, the following information was sought: presence of an LA, variation in platelet numbers during the preoperative evaluation, and determination of whether an observed thrombocytopenia was related to heparin use. An LA was found in 23 of the 216 patients (10.6%). Of the remaining patients, sufficient platelet data for comparison were available for 68 patients. These 68 patients constituted the control group. Within the LA group, platelet counts during the preoperative evaluation declined to 51.6% +/- 16.7% of baseline counts, a highly significant difference (P < 0.0001) compared with the non-LA control group, who underwent a comparable evaluation with similar heparin exposure. In addition, heparin-associated thrombocytopenia developed in 13 of the 23 LA patients (56.5%) and in none of the control patients. Heparin-induced arterial thrombosis was implicated as the cause of a myocardial infarction in 1 of the patients with heparin-associated thrombocytopenia. In patients with chronic thromboembolic pulmonary hypertension, a high incidence of the LA and an accompanying association with heparin-related thrombocytopenia have been observed. Although further prospective studies of this relationship are needed, physicians should be alert to the possibility of thrombocytopenia when using heparin for patients exhibiting an LA.

Heparin-associated thrombocytopenia treated with hirulog

Heparin-associated thrombocytopenia treated with hirulog

Pseudomyxoma of the right atrium in a patient with heparin-associated thrombocytopenia and antiphospholipid antibodies

NACTIVATION of the hemostatic mechanism must be achieved before starting cardlopulmonary bypass (CPB). This is currently obtained with heparln, a highly effective anticoagulant with few side effects and with an antidote available. Although its action on coagulant proteins is well defined, its interaction with platelets is complex: A mild thrombocytopenia after heparln administration is a wellknown phenomenon,I but eciually well-known is the possibility that severe thrombocytopenla and thrombosis can occur after contact with heparin. The former effect is of trivial importance and is secondary to a platelet agglutination, but the latter is a potentially lethal complication mediated by an immune mechanism. 2 However, this is not the only clinical condition characterized by the coexistence of thrombocytopenia and thrombosis; an acquired circulating factor also called lupus anticoagulant 3 can induce the same syndrome. The biologic action of this immunoglobulin is directed against anionic phosphollpids; hence it is also called antiphospholipid antibody. This is mainly found in the serum of patients affected by systemic lupus erythematosus (prevalence of about 10%) but can also be idiopathic, secondary to treatment with some drugs (procainamlde, phenothiazines), or to some autoimmune disorders. A case is reported of a patient with both heparin-dependent and antiphosphohpid antibodies who required cardiac surgery.

Erfolgreiche Therapie einer heparinassoziierten Thrombozytopenie mit einem niedrig-sulfatierten Heparinoid

Heparin-associated thrombocytopenia (HAT) is a relative frequent complication of thromboembolic prophylaxis and therapy. There is good evidence that the more severe HAT Type II is caused by an antibody dependent on polysulfated oligosaccharide epitopes. At present, low molecular weight heparins are used with varying success in patients with HAT that require further anticoagulation, although there are several known cases of cross reactivity between standard and low molecular weight heparins. Using our present case as an example, we show that the In-vitro- diagnostic of cross-reactivity is an indispensable precondition for any sufficient therapy. Additionally, we give support to previous findings that the low-grade sulfated heparinoid Org 10,172 shows no (or less) cross reactivity with standard or low molecular weight heparins. Thus, it might be the most appropriate choice if an anticoagulation is necessary before the results of In-vitro-diagnostics are available.

Absence of In Vitro Cross-Reaction of Pentasaccharide with the Plasma Heparin-Dependent Factor of Twenty-Five Patients with Heparin-Associated Thrombocytopenia

Absence of In Vitro Cross-Reaction of Pentasaccharide with the Plasma Heparin-Dependent Factor of Twenty-Five Patients with Heparin-Associated Thrombocytopenia

Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis.

Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis.

Heparin-associated thrombocytopenia: an update.

The use of heparin may be complicated by two types of thrombocytopenia (HAT): type I occurs early, is transient, and has no clinical relevance, while type II may lead to very severe manifestations (arterial or venous thromboses and more rarely bleedings), that are still underestimated by some clinicians. HAT-type II most frequently develops after use of therapeutic doses of unfractionated heparin (UH) but has also been described less frequently after use of very low doses of UH, of low molecular weight heparins (LMWH), and even of polysulfated glycosaminoglycosans devoid of anticoagulant action. The estimation of the incidence of HAT-type II and of related thromboses is a very difficult matter. Recent observations suggest that thromboses (notably venous) may be more frequent than previously estimated. HAT-type II pathophysiology includes the formation of immune complexes at the surface of platelets; the antigen has been shown to be most often platelet factor 4 bound to heparin while the antibody is recognized by platelet Fc gamma RII receptors. Thromboses result most probably from activation of both platelets (leading to the formation of microparticles) and endothelial cells. Several biological tests are presently available for diagnosing HAT-type II but none of them has been shown to be ideal. The prevention of HAT-type II requires history taking preference of LMWH to UH, early start of oral anticoagulation, and platelet monitoring from the fifth day of heparin therapy. The therapy of HAT-type II implies immediate discontinuation of heparin and avoidance of platelet transfusions, unless severe bleeding occurs. If further antithrombotic treatment is deemed necessary (probably in all cases), several options are possible but presently, the most recommended ones are Org 10172 or Ancrod; embolectomy or thrombolysis may also be required if a new thrombotic event has developed. A very difficult dilemma concerns patients previously sensitized to heparin and who present a clinical situation that theoretically mandates re-exposure to UH, such as by-pass surgery; prostacyclin analogues may be successfully used in such cases. Recent developments in the therapy of HAT-type II include recombinant hirudin or synthetic analogs, or use of some intravenous immunoglobulin preparations. Possible candidates are the heparin synthetic pentasaccharide and recombinant tissue factor pathway inhibitor.

Characterization of the Structural Requirements for a Carbohydrate Based Anticoagulant with a Reduced Risk of Inducing the Immunological Type of Heparin-associated Thrombocytopenia

HAT is the most frequent drug induced immune-thrombocytopenia. We recently identified multimolecular PF4/heparin complexes as the major antigen. In order to evaluate the structural requirements for formation of the antigenic complex, we chemically synthesized 13 glucan sulfates and used 5 heparin fractions (2.4-4.8 kD) and a synthesized pentasaccharide, representing the antithrombin III binding sequence of heparin, for further characterize the HAT antigen. In the presence of glucan sulfates and heparin, HAT antibodies caused platelet activation typically at low but not at high concentrations, as measured by 14C-5HT release. The concentration range giving the activation pattern depended on the degree of sulfation (DS) and molecular weight (MW) of the glucan sulfates but not on the type of glycosidic linkage of a polysaccharide. With linear glucan sulfates with a chain length of 35 monosaccharides, the critical DS to form the HAT antigen ranged between 0.60 and 1.20. Glycosidic branched glucan sulfates were able to form the HAT antigen at a lower DS and a lower MW than linear glucan sulfates. Platelet activation by HAT-antibodies in the presence of linear curdlan sulfate fractions was dependent on their MW. At a low concentration (0.01 microM) medium-size fractions (60 kD) caused platelet activation but neither small (12 kD) nor large fractions ( > 150 kD) did. At higher concentrations (2 microM) the opposite reaction pattern was observed. In the case of heparin, the optimal chain length for forming the HAT antigen is a hexadecasaccharide (4.8 kD). Antigen generation decreased with larger and smaller fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet response to vascular surgery—A preliminary study on the effect of aspirin and heparin

Patients with peripheral arterial disease (PAD) demonstrate high cardiovascular mortality, which is further increased after arterial reconstruction. Enhanced platelet reactivity has been postulated for these patients. The effect of surgery and of periprocedural aspirin and heparin therapy on platelet reactivity was assessed with the Stagnation Point Flow Adhesio-Aggregometer (SPAA). The platelet adhesivity and aggregability of 44 PAD patients was quantitated perioperatively. Aspirin was administered during the entire course, low molecular weight heparin (LMWH) preoperatively and as of the fourth postoperative (pOP) day and unfractionated heparin (UH) upon surgery and three days thereafter. A group of 15 aspirin-free general surgical patients receiving LMWH and with no evidence of PAD served as controls. Plasma fibrinogen levels and platelet count were determined. The heparin-induced platelet activation (HIPA) assay for detection of heparin-associated thrombocytopenia (HAT) antibodies was also performed. Baseline values of SPAA-measured platelet reactivity (p < 0.001) and plasma fibrinogen (p < 0.01) were higher for patients as compared to controls and increased markedly after surgery. In the PAD group maximum platelet activation and fibrinogen levels coincided with a marked drop in platelet count and were concomitant to administration of unfractionated heparin. Thereby, a drop in platelet count of > 30% was observed in 25 patients (57%). The HIPA test verified HAT antibodies in 3 (12%) of these patients, two of which suffered postoperative thrombosis. In the control group significant pOP increases were noted only for plasma fibrinogen. Changes in platelet count and reactivity were minimal and nonsignificant. No thrombosis occurred and no HAT antibodies were detected. In PAD patients, concurrent to pathologically enhanced baseline platelet function, surgical intervention resulted in a further increase in platelet reactivity in spite of aspirin therapy. UH may have promoted this hyperreactivity, as indicated by the concomitant decrease in platelet count with the coincidence of postoperative thrombosis and the presence of HAT antibodies. In the absence of PAD platelets participate insignificantly in the pOP acute phase reaction hallmarked by an increase in plasma fibrinogen.

Fatal Thrombocytopenic Coagulopathy After Cardiopulmonary Bypass: Clinicopathologic Correlations Implicating Heparin

Heparin-associated thrombotic thrombocytopenia after cardiopulmonary bypass is frequently lethal. The propensity for this syndrome generally goes unrecognized because thrombocytopenia is common in the early postoperative period and because testing for heparin-induced platelet antibody may not distinguish between patients with thrombocytopenia alone and those in whom associated thrombi (the white clot syndrome) may develop. Moreover, differentiation between heparin-associated thrombotic thrombocytopenia and a consumptive coagulopathy may be difficult, and intervention may be inappropriate because of diametrically opposite treatments. Our experience with three cases and the necropsy findings in two of them demonstrate that postbypass thrombocytopenic coagulopathy may be a clinical and pathologic spectrum of consumptive coagulopathy, with heparin as the major premorbid factor. This report further emphasizes the need for vigilance in assessing certain patients preoperatively to lessen the high risk of morbidity and mortality associated with this syndrome.

Successful treatment of massive pulmonary embolism after coronary artery bypass grafting due to heparin-induced thrombocytopenia

Massive pulmonary embolism is a rare complication in patients undergoing coronary artery bypass grafting. Frequently patients have had exposure to heparin before the operation. In this article we report a patient who 6 days after a cardiac operation suffered a massive pulmonary embolism. The patient was later discovered to have heparin-associated thrombocytopenia with serum heparin antibody. We recommend patients receiving heparin have frequent platelet counts and those with induced thrombocytopenia undergo sensitivity testing.

Normal Activated Clotting Time Despite Adequate Anticoagulation with Ancrod in a Patient with Heparin-associated Thrombocytopenia and Thrombosis Undergoing Cardiopulmonary Bypass

Normal Activated Clotting Time Despite Adequate Anticoagulation with Ancrod in a Patient with Heparin-associated Thrombocytopenia and Thrombosis Undergoing Cardiopulmonary Bypass

Heparin-Associated Thrombocytopenia: The Effects of Various Intravenous lgG Preparations on Antibody Mediated Platelet Activation - A Possible New Indication for High Dose i.v. IgG

The immunologic type of heparin-associated thrombocytopenia (HAT) is caused by antibodies which activate platelets via the Fc-receptor in the presence of polysulfated oligosaccharides. The antigen is formed by a releasable platelet protein (in many cases PF4) complexed to heparin. Since the role of GP IIb/IIIa in platelet activation by HAT antibodies is controversial, we investigated platelet activation by antibodies related to HAT. We used normal platelets and platelets from a patient with Glanzmann's thrombasthenia (GT) lacking GP IIb/IIIa. Heparin and sera from patients with HAT stimulated GT platelets in the same manner as determined by 14C-serotonin release and the changes in phosphorylation of p20 and p47. Platelet activation could be inhibited by an anti FcRII monoclonal antibody (IV. 3, Fab-fragments), and by Fc-fragments, but not by F(ab')2-fragments of human IgG. The effect of four different, commercially available preparations of intact i.v. IgG on the platelet activation by six HAT sera was investigated by 14C-serotonin release. The inhibitory effect was strongly dependent upon the manufacturing process. At a concentration of 20 mg/ml only IgG that had been subjected to low pH and traces of pepsin sufficiently inhibited platelet activation. IgG treated with polyethylenglycol or sulfitolysis was less effective, whereas beta-propiolactone-treated IgG almost completely lost the ability to inhibit platelet activation by antibodies related to HAT. We conclude that inhibition of GP IIb/IIIa-fibrinogen interaction is insufficient for preventing platelet activation in HAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Crossreactivity Studies between Sera of Patients with Heparin Associated Thrombocytopenia and a New Low Molecular Weight Heparin, Reviparin

Crossreactivity Studies between Sera of Patients with Heparin Associated Thrombocytopenia and a New Low Molecular Weight Heparin, Reviparin

A diagnostic and therapeutic approach to heparin-associated thrombocytopenia (HAT)

A diagnostic and therapeutic approach to heparin-associated thrombocytopenia (HAT)

White clot syndrome associated with renal failure.

In a minority of patients, heparin administration is associated with thrombocytopenia and this thrombocytopenia may be associated with thromboembolic events. Heparin-associated thromboembolism is described as heparin-associated thrombocytopenia and thrombosis or white clot syndrome. White clot syndrome is caused by antibodies to a heparin-platelet membrane complex. The diagnosis carries a high mortality and morbidity from limb thromboembolism. Treatment includes discontinuation of heparin, use of alternate anticoagulants, and aggressive treatment of thromboses. A case in which acute renal failure occurred in the setting of heparin treatment and thrombocytopenia is described, and evidence that renal failure was a result of white clot syndrome is provided.

Heparin-associated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulphated oligosaccharides.

The interaction of sulphated oligosaccharides (SO) with platelets and the antibody of heparin-associated thrombocytopenia (HAT type II) was investigated. 3H-heparin binding to platelets was inhibited by different SO, depending on their grade of sulphation. Dextran sulphate, pentosan polysulphate, and heparin were more effective than were LMW heparins. De-N-sulphated heparin and a LMW heparinoid (Org 10172) had no effect. Platelets preincubated with high-grade SO and washed, released serotonin in the presence of HAT sera without additional heparin. Platelets preincubated with HAT sera and then washed were not activated when heparin was added. Only high-grade SO which inhibited heparin binding to platelets caused platelet activation with HAT sera. However, low- and high-grade SO in high concentrations (0.11 g/l) inhibited serotonin release induced by HAT sera and heparin. 32P-phosphorylation of platelet proteins was enhanced by HAT-IgG and heparin and by heat-aggregated IgG, and was inhibited by the moab IV.3. High SO concentrations inhibited only the effect of HAT-IgG and not that of aggregated IgG. We assume that the antigen in HAT involves a releasable platelet protein with a binding site for SO. This was corroborated by studies with an anti-platelet factor 4 antibody causing Fc-receptor dependent platelet activation inhibitable by high SO concentrations.

Heparin-associated thrombocytopenia: no association of immune response with HLA.

Heparin-associated thrombocytopenia (HAT) is a severe adverse reaction of heparin therapy. Patients with the immunologic type of HAT are at risk of developing arterial and venous thromboembolic complications caused by an antibody which activates platelets in the presence of heparin. Yet, there are no means to identify patients at risk of developing HAT before heparin administration. We investigated the frequency of HLA class-I and class-II antigens in 47 patients with the immunologic type of HAT verified by a positive two-point heparin-induced platelet activation assay. Compared to a control group of 629 healthy individuals HLA antigens B8 and DR3 were less frequent, whereas DR4 and DR53 had a higher frequency. However, none of these antigens proved to be statistically significant. This is another example of an immunologically mediated disease showing no discernible association with the HLA system.