Heparin-associated Thrombocytopenia Research Articles

A Rapid and Sensitive Test for Diagnosing Heparin-Associated Thrombocytopenia

Heparin-associated thrombocytopenia (HAT) is a severe complication of heparin therapy. Its diagnosis is difficult. Conventional assays employ platelet aggregometry (PAA) and/or 14C-serotonin release (SRA) which are either insensitive (PAA) or require radioactive tracers (SRA). We here describe a newly developed sensitive and rapid assay based on visual evaluation of heparin-induced platelet activation (HIPA) in microtiter wells. Using sera of 34 patients with clinically suspected HAT we found the HIPA assay to be as sensitive as the SRA and superior to PAA. The HIPA assay allows investigation of crossreactivity with different types of heparins, low molecular weight (LMW) heparins and heparinoids. Three patients who required further parenteral anticoagulation and in whom the HIPA assay was negative before treatment with the LMW heparinoid Org 10172, were treated with this new heparinoid without adverse reactions. We conclude that the HIPA assay may be a useful tool for differential diagnosis and therapy in patients with HAT.

Perfusion Techniques of Profound Hypothermia and Circulatory Arrest for Pulmonary Thromboendarterectomy

One hundred ninety-five patients with the diagnosis of chronic pulmonary thromboembolic pulmonary hypertension have been operated on utilizing a standardized protocol involving profound hypothermia and circulatory arrest. A small subgroup, nine, were identified preoperatively as having heparinassociated thrombocytopenia (HAT). This challenging subgroup of patients was treated during heparin exposure with an investigational, “platelet disaggregating” agent, Iloprost. The surgical procedure of pulmonary thromboendarterectomy requires multiple periods of circulatory arrest under profound hypothermia. Perfusion management of this procedure involves cerebral and myocardial protection, cooling, reperfusion at hypothermia, and rewarming; treatment with Iloprost when appropriate; and methods of hemodilution.

Adrenal insufficiency secondary to adrenal hemorrhage. Two case reports and a review of cases confirmed by computed tomography

We report two cases of adrenal hemorrhage and review 17 others that were confirmed by hormone measurements and computed tomography. Precipitating factors included heparin therapy, surgery, hypotension, and sepsis. Heparin-associated thrombocytopenia may be an underappreciated cause of adrenal hemorrhage. Despite the availability of computed tomography, adrenal hemorrhage mimics many other diseases, and an early diagnosis remains difficult.

Heparin-Associated Thrombocytopenia and Immunoglobulin Therapy

Excerpt To the Editor:The by Frame and associates (1) claims to report the first case of severe heparin-associated thrombocytopenia complicated by intestinal bleeding and progressive thromb...

Fellowship award in cardiovascular perfusion: Perfusion Techniques of Profound Hypothermia and Circulatory Arrest for Pulmonary Thromboendarterectomy

One hundred ninety-five patients with the diagnosis of chronic pulmonary thromboembolic pulmonary hypertension have been operated on utilizing a standardized protocol involving profound hypothermia and circulatory arrest. A small subgroup, nine, were identified preoperatively as having heparin-associated thrombocytopenia (HAT). This challenging subgroup of patients was treated during heparin exposure with an investigational, “platelet disaggregating” agent, Iloprost. The surgical procedure of pulmonary thromboendarterectomy requires multiple periods of circulatory arrest under profound hypothermia. Perfusion management of this procedure involves cerebral and myocardial protection, cooling, reperfusion at hypothermia and rewarming, treatment with Iloprost when appropriate, and methods of hemodilution.

Correction of Severe Heparin-Associated Thrombocytopenia with Intravenous Immunoglobulin

Brief Reports1 December 1989Correction of Severe Heparin-Associated Thrombocytopenia with Intravenous ImmunoglobulinJames N. Frame, MD, Kevin P. Mulvey, MD, John C. Phares, MD, Michael J. Anderson, MDJames N. Frame, MDSearch for more papers by this author, Kevin P. Mulvey, MDSearch for more papers by this author, John C. Phares, MDSearch for more papers by this author, Michael J. Anderson, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-111-11-946 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptHeparin-associated thrombocytopenia develops in approximately 5% of patients treated with heparin (1) and generally occurs after 2 to 10 days of therapy (2). While platelets usually increase to over 100 X 109/L within 2 to 19 days after heparin discontinuation (3), this disorder rarely causes clinical bleeding or warrants platelet transfusion. We report the first case of severe heparin-associated thrombocytopenia complicated by intestinal bleeding and progressive thrombocytopenia that had intestinal bleeding stopped and normal platelet counts restored shortly after the administration of intravenous immunoglobulin.Case ReportA 62-year-old woman was referred to us with a 5-day history of deep venous...

Heparin-associated thrombocytopenia and thrombosis syndrome in a rehabilitation patient

Heparin-associated thrombocytopenia and thrombosis (HATT) syndrome is a severe complication of heparin therapy. Since patients admitted for rehabilitation are at high risk for deep-vein thrombosis and pulmonary embolism, prophylactic doses of subcutaneous heparin are frequently used. We report the case of a 73-year-old woman with a history of heparin exposure, admitted to a comprehensive rehabilitation program for management of severe back pain. The patient was started on subcutaneous heparin. After 18 days of hospitalization, she developed marked thrombocytopenia and a massive venous thrombosis in the right lower extremity. On intravenous heparin therapy, the platelet count continued to decline. The thrombocytopenia resolved with discontinuation of heparin. This case illustrates a devastating complication of heparin therapy and emphasizes that physiatrists should be aware of this acute and preventable drug reaction.

Disorders associated with antibodies to endothelial cells.

Antibodies that bind to endothelial cells have been identified in patients with diverse forms of vasculitis and thrombosis. Sera from patients with systemic lupus erythematosus contain both complement-fixing antibodies and immune complexes that bind to cultured endothelial cells. Sera from patients with heparin-associated thrombocytopenia and thrombosis contain antibodies that react with heparin bound to the endothelium and cross-react with heparan sulfate synthesized by endothelial cells. Children with Kawasaki syndrome may develop cytolytic IgM antibodies that recognize surface antigens induced on endothelial cells by interferon-gamma, interleukin 1, and tumor necrosis factor. The presence of alloantibodies to tissue-restricted polymorphic antigens expressed by endothelial cells is frequently associated with thrombotic microvascular injury and hyperacute allograft rejection. Binding of antibodies and immune complexes to endothelial cells in vitro initiates platelet adherence, production of tissue factor, and secretion of plasminogen activator inhibitor. Antibody-mediated endothelial cell injury may play a role in other vascular disorders of unknown cause.

Heparin-associated Thrombocytopenia: A Complication of Low-dose Heparin Prophylaxis

The authors describe a 61-year-old white female who received low-dose heparin prophylaxis in conjunction with a radical vulvectomy with abdomino-perineal resection for stage III Bartholin gland carcinoma and subsequently developed heparin-associated thrombocytopenia with thrombosis. This phenomenon occurs in 0.1% of patients exposed to heparin therapy and has been reported as having a mortality rate of 29% and a 21% rate of limb loss. It is thought to be caused by a heparin-dependent IgG platelet-aggregating antibody. Because of the widespread use of heparin prophylaxis in surgery, the clinician needs to be aware of this complication.

Heparin-associated Thrombocytopenia

Heparin-associated Thrombocytopenia

Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis: specific diagnostic test for a rare side effect

H eparin-induced skin necrosis, first described by O'Toole [1] in 1973 has since been recognized as a rare side effect of heparin therapy. This phenomenon may accompany the more frequently occurring heparin-associated thrombocytopenia and thrombosis syndrome (HATT) [2] and seems to be independent from dose [3,4]. In most reported cases, heparin-induced skin necrosis occurred after subcutaneous heparin administration, but in a few instances it has also been observed with intravenous use of the drug [5]. Bovine heparin was found to bear a greater potential of causing H A T T than do porcine mucosal dr low-molecularweight heparins [3,6,7]. Heparin-associated thrombocytopenia presents in two distinct forms [8]: the first is a mild, transient thrombocytopenia beginning within two to five days after starting heparinization; the pat ient remains asymptomatic. The second, severe form occurs after an interval of at least six days from initiating heparin administration and is accompanied in more than half of the cases by thromboembolic complications. Unlike the former, this late-onset heparinassociated thrombocytopenia does not resolve unless the drug is discontinued. Pathogenetically, an IgG antibody causing heparin-dependent platelet aggregation has been found in plasma from patients with lateonset thrombocytopenia [8]. Intravascular platelet aggregation in the presence of therapeut ic heparin concentrations may be responsible for the frequently fatal thromboembolic complications seen with continued heparinization [4]. We describe a patient with heparin-associated skin necrosis, thrombocytopenia, and deep vein thrombosis. The patient's plasma consistently induced fast and pronounced heparin-dependent aggregation of normal platelets from several donors. In order to assess the specificity of this in vitro test, 159 control plasma samples were examined.

Surgical management of heparin-associated thrombocytopenia: Strategies in the treatment of venous and arterial thromboembolism

We report the vascular surgical strategies and results in 13 patients with heparin-associated thrombocytopenia and describe useful in vitro techniques for the evaluation of anticoagulant therapy. Thirteen of 40 patients with heparin-associated thrombocytopenia had 18 cardiovascular procedures done to save life or limb. Greenfield filters were placed in eight patients to prevent pulmonary embolism. Eight patients had 10 arterial procedures, with alternative anticoagulation that used dextran or warfarin in five cases. In three cases iloprost, a derivative of prostacyclin and a potent platelet inhibitor, was infused intraoperatively and heparin was given. Both the use of alternative anticoagulants and platelet suppression by iloprost were clinically effective strategies. The concurrent measurement of plasma levels of β-thromboglobulin and fibrinopeptide A in two patients confirmed that both approaches can successfully prevent activation of platelets and plasma coagulation during arterial surgery. One operative death occurred; all vascular reconstructions remained patent at 3 to 6 months. In two patients who received heparin alone for arterial surgery, both procedures resulted in thrombosis and limb loss. When major venous thromboembolism is complicated by heparin-associated thrombocytopenia, insertion of a Greenfield vena cava filter should be considered if there is significant risk of pulmonary embolism. When necessary, arterial surgery is feasible in patients with heparin-associated thrombocytopenia if alternative anticoagulation or adequate suppression of platelet reactivity can be achieved.

Surgical management of heparin-associated thrombocytopenia

Surgical management of heparin-associated thrombocytopenia

Plasmapheresis in the management of heparin‐associated thrombocytopenia with thrombosis

Heparin-associated thrombocytopenia with thrombosis (HATT) is fatal in 29% and leads to limb amputation in another 21% of patients. Patients with arterial thrombosis do worse than do those with venous thrombosis alone. Heparin-associated thrombocytopenia is mediated through IgG or IgM immunoglobulin fractions and is believed to be an immune phenomenon, with heparin acting as a hapten. In addition, endothelial injury may be responsible for the development of thrombosis. Heparin-induced platelet aggregation persists for weeks to months after its withdrawal in these patients. Acute management of HATT includes surgical thrombectomy, thrombolytic therapy, dextran, ancrod, low-molecular-weight heparin, and antiplatelet agents, but overall results remain unsatisfactory. We report the use of plasmapheresis, along with aspirin and dextran, in a patient with HATT. The patient experienced pain relief in 1 day; the heparin-associated platelet aggregation test became negative in 5 days, and there was functional salvage of the affected limb. We suggest that plasmapheresis may be an effective therapy in the management of HATT.

Immune endothelial-cell injury in heparin-associated thrombocytopenia: Cines DB, Tomaski A, Tannenbaum S. N Engl J Med 1987;316:581-9

Immune endothelial-cell injury in heparin-associated thrombocytopenia: Cines DB, Tomaski A, Tannenbaum S. N Engl J Med 1987;316:581-9

Heparin-associated Thrombocytopenia in Maintenance Hemodialysis Patients

Thrombocytopenia associated with the presence of a heparin-dependent platelet aggregating factor developed in two patients after hemodialysis with heparin. It resolved in one patient after heparin was stopped; but persisted in the other during a two-week heparin-free period and intermittently thereafter. We suggest that when heparin causes thrombocytopenia in dialysis patients the heparin should be stopped whenever possible, but this may not be necessary in all patients.

Management of Patients with Heparin-Associated Thrombocytopenia and Thrombosis Requiring Cardiac Surgery

Heparin-associated thrombocytopenia and thrombosis (HATT) is a serious complication of heparin therapy that results in intravascular platelet aggregation with arterial or venous thrombosis. Platelet aggregation to heparin in vitro is used to confirm the diagnosis. Cessation of heparin therapy with avoidance of reexposure to heparin is an important principle in the management of HATT. However, certain patients with HATT may require reexposure to heparin for emergency cardiac operations requiring cardiopulmonary bypass while still demonstrating positive in vitro platelet aggregation with heparin. The present report describes the management of 2 such patients. In each patient aspirin was shown to inhibit platelet aggregation to heparin in vitro; therefore, aspirin and dipyridamole were administered to each patient before heparin reexposure and continued throughout the perioperative period. Cardiopulmonary bypass with full heparinization was achieved without thrombotic or hemorrhagic complications in both patients. Despite the presence of a heparin-dependent platelet-aggregating factor in the plasma of these 2 patients, inhibition of platelet aggregation with aspirin and dipyridamole allowed uneventful reexposure to heparin.

Drug-mediated thrombocytopenia

Thrombocytopenia due to drug-dependent antibodies most frequently occurs with quinine/quinidine and with heparin. Considerable evidence has accumulated about the mechanism of action of quinine/quinidine-induced antibodies but less is known about the effect of heparin. Although there is controversy, it is likely that the action of quinine/quinidine-induced antibodies follows a loose association between drug and platelet with antibodies acting independently of the Fc receptor. There is strong evidence that the complex of glycoprotein Ib and glycoprotein IX, absent in the Bernard-Soulier syndrome, provides the binding site for quinine/quinidine-dependent antibodies. It also appears that the two glycoproteins must be present in complex form for antibody binding to occur. There is some heterogeneity of quinine/quinidine-dependent antibodies since there are reports of a proportion of patient antibodies reacting with other membrane determinants or acting independently of the drug. Heparin-induced thrombocytopenia may be the consequence of a direct effect, or a more serious condition associated with thrombosis may occur when heparin-dependent antibodies are formed. The mode of action of these antibodies and the nature of their antigenic determinants remain unclear. Recognition of heparin-associated thrombocytopenia is important so that serious bleeding or thrombotic sequelae can be forestalled.

Heparin-associated antibody with pregnancy: Discussion of two cases

Heparin-associated thrombocytopenia may be a potentially devastating event when linked with thrombosis. Two cases of heparin-associated thrombocytopenia are presented, one with thrombosis that culminated in maternal death. Heparin-associated platelet antibody was seen in both patients. The incidence and management of heparin-associated thrombocytopenia are discussed.

Immune Endothelial-Cell Injury in Heparin-Associated Thrombocytopenia

We studied the possibility that immune injury to endothelial cells may have a role in the development of thrombosis in some patients with heparin-associated thrombocytopenia. Serum samples from each of 27 patients who had this clinical diagnosis contained heparin-dependent platelet antibodies and deposited more than normal amounts of IgG, IgA, or IgM on endothelial cells, stimulating the production of tissue factor. Binding of immunoglobulins to endothelial cells was no longer detected when the patients were studied after heparin was withdrawn, but reappeared within several days upon reexposure to heparin in a patient who experienced a clinical recurrence. Binding of immunoglobulin to endothelial cells was partially reduced by the preadsorption of serum samples with heparin or heparan sulfate bound to Sepharose or by enzymatic cleavage of cell-bound heparan sulfate, and was augmented by the addition of heparan sulfate. Thus, serum from some patients with heparin-associated thrombocytopenia may contain antibodies that react with heparin bound to endothelial cells or with heparan sulfate synthesized by endothelial cells. Immune injury to both platelets and endothelial cells may play a part in the development of thrombosis in some patients after heparin therapy.