Heparin-associated Thrombocytopenia Research Articles

Anticoagulation Management for Veno-Venous ECMO in COVID-19 Patients: Argatroban as Rescue Therapy in Heparin-Associated Thrombocytopenia.

Background/Objectives: Extracorporeal membrane oxygenation (ECMO) has been widely used as a life support technique in COVID-19 acute respiratory distress syndrome (ARDS). The use of anticoagulation during ECMO support remains a topic of debate. The primary aim of this study is to demonstrate the safety and efficacy of using argatroban as an anticoagulant instead of heparin in patients with heparin-associated thrombocytopenia. Methods: 40 patients were enrolled and initially treated with unfractionated heparin for anticoagulation during ECMO, composing the UFH group. Twenty-one of these patients experienced a drop in platelet count to below 100,000 cells/mm3 and, after testing negative for IgG anti-PF4/heparin, the anticoagulation was switched to argatroban, composing the ARG group. Hemorrhagic events were recorded along with blood chemistry parameters. Results: Bleedings were significantly more frequent in the UFH group than in ARG group (58/579 days vs. 21/357 days, p = 0.041). No significant differences were observed in hemorrhagic episodes for each bleeding site, except for tracheal stoma (14 vs. 1, p = 0.011). No differences in activated partial thromboplastin time (aPTT) values were found between the two groups (aPTT 42.65 s vs. 44.70 s, p = 0.443). Linear regression analysis revealed that the platelet count on day 5 was correlated with the initial platelet count but not with the type of anticoagulant used (p = 0.001, CI 0.55, 0.69 and p = 0.078). Linear regression analysis in both groups showed a correlation between the duration of ECMO support and intensive care unit stay for the median aPTT and median platelet count. Furthermore, no major systemic thrombotic events or circuit clotting were observed in this patient cohort. Conclusions: Argatroban seems to be safe in patients with persistent heparin-associated thrombocytopenia undergoing ECMO.

Hemostasis disorders, thrombosis and thrombocytopenia in patients with covid-19 and pneumonia with complicated acute renal injury

«Hemostasis disorders, thrombosis and thrombocytopenia in patients with covid-19 and pneumonia with complicated acute renal injury» Relevance. Thrombosis is one of the most dangerous complications of COVID-19 not only at the peak of the disease, but also in the long term. During the pandemic, the issues of medical prevention of thrombotic complications have been repeatedly reviewed, clarified and supplemented, but the only correct tactics for their prevention and treatment do not yet exist.The purpose of the study. To determine the frequency and nature of the development of venous and arterial thrombosis and thrombocytopenia in severe patients with COVID-19 and pneumonia, complicated by acute renal damage, the course of the disease, including fatal ones.Material and methods. Data on inpatient treatment and diagnosis of 216 COVID-19 patients with viral pneumonia and signs of acute renal injury (AKI) according to KDIGO 2012 criteria. Group 1. Deceased patients with severe COVID-19 and pneumonia, with unreliable signs of AKI, 75 (men 19, women 56), ratio 1:2.9. Age from 29 to 87 years. Ventilation in 56 (74.7 %) Group 2. Deceased patients with COVID-19 and pneumonia with significant signs of AKI, 77 (men 34, women 43), ratio 1:1.3. Age from 41 to 88 years. Ventilation in 53 (70.7 %) Group 3. Recovered patients with AKI or CKD, 64 (men 41, women 23, ratio 1:0.56, age from 43 to 89 years). Ventilation in 1 (1.6 %). The study of hemostasis. Activated partial thromboplastin time according to the modified method of plasma recalcification reaction according to Baluda V. P. et al. (1980). The level of fibrinogen in blood plasma by the ethanol method according to Breen F., Tullis J. (1982). The concentration of D-dimer in the blood by microlatex agglutination with photometric registration of the reaction (immunoturbidimetry).Results. In deceased inpatient patients with Covid-19 and pneumonia, a high incidence of arterial and venous thrombosis of various localization was detected, up to 46–56 %. The thrombotic danger was largely associated with an increased level of D-dimer and the duration of its increase in the blood of patients. Thrombocytopenia was diagnosed in 47–58 % of patients and was a significant risk factor for the development of fatal outcomes. In cases of detection of thrombocytopenia in patients below 20 thousand cells in microl., its character was assessed on a 4Ts scale to identify the syndrome of heparin-associated thrombocytopenia. 92–97 % of patients were prescribed heparins, including such fractionated (low molecular weight) ones as enoxaparin, nadroparin, dalteparin and fundaparinux. Only a small proportion of cases of combination of thrombosis and thrombocytopenia (about 2.3 %) were due to the nature of drug therapy and the development of heparin-associated thrombocytopenia syndrome.Conclusion. The data obtained indicate the high importance of thrombotic mechanisms involving D-dimer in the pathogenesis and outcomes of the disease in groups of deceased patients with covid-19, pneumonia and AKI and the predominant importance of vascular damage in the activation of the thrombotic cascade in them.

Management of Immune Thrombocytopenic Patient Associated with COVID-19 Viral Infection: A Case Series

Severe thrombocytopenia is a cause of morbidity and mortality for patients with COVID-19 infection. The common causes of thrombocytopenia in these patients are; sepsis, drug-associated, disseminated intravascular coagulation (DIC), heparin-associated thrombocytopenia (HIT), microangiopathic hemolytic anemia (MAHA). Recently, cases of COVID-19 infection-associated Immune thrombocytopenic purpura (ITP) have been reported in the literature. In our study, we will present our case series consisting of 10 patients associated with COVID-19

Challenges of Anticoagulation Therapy in Pregnancy.

Thrombotic complications in pregnancy represent a major cause of morbidity and mortality. Pregnancy is a primary hypercoagulable state due to enhanced production of clotting factors, a decrease in protein S activity, and inhibition of fibrinolysis. These physiologic changes will yield a collective rate of venous thromboembolism (VTE) of about 1-2 in 1000 pregnancies for the general obstetric population, which represents a five- to tenfold increased risk in pregnancy compared to age-matched non-pregnant peers. A select group of women, however, will carry a significantly higher rate of thrombosis due to primary thrombophilia, either inherited or acquired. This introduces a population of women who may benefit from prophylactic anticoagulation, either antepartum or postpartum. The coagulation changes that occur in preparation for the hemostatic challenges of delivery endure for several weeks postpartum. In fact, daily risk for pulmonary embolism (PE) is the highest postpartum. Use of anticoagulation in pregnancy introduces particular risk at the time of delivery, where bleeding and clotting risk collide. Altered metabolism rates of anticoagulants in pregnant women often necessitate closer monitoring than is required outside of pregnancy in order to ensure efficacy and safety. Heparin products are the mainstay of treating VTE in pregnancy, chiefly because they do not cross the placenta. In women with mechanical heart valves, the ideal anticoagulation regimen remains controversial as heparin use has shown inferior outcomes for preventing thromboembolic complications compared to warfarin, but warfarin carries risk for fetal embryopathy. Other populations where a heparin alternative is necessary include women with a history of heparin-associated thrombocytopenia (HIT) or other heparin intolerance. Further challenging the management of anticoagulation in pregnancy is the dearth of randomized clinical trials. The evidence governing treatment recommendations is largely based on expert guidelines, observational studies, or extrapolation from non-pregnant cohorts. A careful critique of a woman's history, as well as the available data, is essential for optimal management of anticoagulation in pregnancy. Such decisions should involve a multidisciplinary team involving obstetrics, hematology, cardiology, and anesthesia.

The transfusion‐related acute lung injury controversy: lessons from heparin‐induced thrombocytopenia

The transfusion‐related acute lung injury controversy: lessons from heparin‐induced thrombocytopenia

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry

Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. We assessed the incidence, risk factors and prognosis of heparin-associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25,369 patients with confirmed VTE until February 2009. Among them, 24,401 patients were treated either with UFH or with LMWH, and had available information about the 6-month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150,000 mm(-3) . One hundred and forty-one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6-month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79-2.17) than in the LMWH group (0.54%, 95% CI 0.44-0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58-9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64-3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH-associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non-cancerous patients.

Incidence of Thrombocytopenia in Hospitalized Patients with Venous Thromboembolism

Purpose To determine the incidence of heparin-associated thrombocytopenia in patients receiving prophylaxis or treatment for venous thromboembolism. Methods We assessed the database of the National Hospital Discharge Survey from 1979 through 2005 and complemented this with a meta-analysis of published literature. Result Among 10,554,000 patients discharged from short-stay hospitals throughout the US with venous thromboembolism during the 27 years of study, secondary thrombocytopenia was coded in 38,000 patients (0.36%). From 1979 through 1992, secondary thrombocytopenia was coded in only 0.15% of hospitalized patients with venous thromboembolism. The frequency increased sharply to 0.54% from 1993 through 2005. Secondary thrombocytopenia was rarely diagnosed among 1,446,000 patients aged <40 years and among 77,000 women who had venous thromboembolism with deliveries. Meta-analysis of published literature showed a higher incidence among patients who received unfractionated heparin (UFH) for prophylaxis than those who received low-molecular-weight heparin (LMWH) for prophylaxis. Treatment resulted in smaller differences of the incidence between UFH and LMWH. Conclusion Heparin-associated thrombocytopenia is rare among patients aged <40 years and women following delivery. The risk of heparin-associated thrombocytopenia is more duration-related than dose-related, and higher with UFH when used for an extended duration. Our findings and those of the literature suggest that although heparin-associated thrombocytopenia is uncommon, the incidence can be minimized by use of LMWH, particularly if extended prophylaxis or extended treatment is required.

A Clinical Perspective of Venous Thromboembolism

A large number of individuals develop venous thromboembolism (VTE) every year.1 Each patient’s episode of DVT or PE is, naturally, unique. To highlight a variety of aspects about VTE a compilation case is presented that is composed of clinical data and images from several real patients. ### History of Present Illness A 36-year-old woman presents to the Emergency Department with severe shortness of breath and moderately intense anterior chest pain, worse on deep inspiration, which had started suddenly that morning. She also reports a 6-wk history of mild shortness of breath, for which she had been seen 4 wk earlier by her primary care physician who diagnosed her with “asthma.” Bronchodilators and steroids were prescribed but led to no significant improvement in her symptoms. She also gives a history of mild left calf pain that had started about 2 months earlier without preceding trauma, immobilization, or surgery. Her primary care physician had seen her and prescribed Ibuprofen for a “pulled muscle.” However, in the 1 week before her present presentation her leg symptoms worsened, and she had increased diffuse leg pain and swelling and slightly bluish discoloration of the whole leg. Her past medical history is only significant for an appendectomy at age 16. She has never been pregnant. She is on no medications, except for an estrogen and progestin-containing oral contraceptive, started 10 months earlier. She does not smoke. There is no family history of venous thromboembolism, although the patient reports that her paternal grandmother had a “swollen leg for many years” until she died in her 70’s, but no further details are known of the patient. ### Physical Examination The patient’s weight is 86 kg and her height 165 cm, calculating to a body mass index (weight divided by [height in meters]2) of 31.6 kg/m2, ie, she has grade 1 obesity. Her …

No Difference in Risk for Thrombocytopenia During Treatment of Pulmonary Embolism and Deep Venous Thrombosis With Either Low-Molecular-Weight Heparin or Unfractionated Heparin: A Metaanalysis

Low-molecular-weight heparin (LMWH) is a popular alternative to unfractionated heparin (UH) for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), in part based on the perception of a lower risk for heparin-induced thrombocytopenia (HIT). To investigate the evidence supporting this perception, we performed a metaanalysis to compare the incidence of thrombocytopenia between LMWH and UH during PE and/or DVT treatment. Randomized trials comparing LMWH with UH for PE and/or DVT treatment were searched for in the MEDLINE database, bibliographies, and by correspondence with published investigators. Two reviewers independently selected high-quality studies and extracted data regarding heparin-associated thrombocytopenia (HAT), HIT confirmed by laboratory testing, and heparin-induced thrombocytopenia with thrombosis (HITT). Outcome rates between LMWH and UH were compared using a binomial, generalized linear mixed model with a logit link and Gaussian random effects for study. Thirteen studies involving 5,275 patients met inclusion criteria. There were no statistically significant differences in HAT rates between the two treatments (LMWH, 1.2%; UH, 1.5%; p = 0.246). The incidence of documented HIT and HITT was too low to make an adequate comparison between groups. Our review disclosed no statistically significant difference in HAT between LMWH and UH and insufficient evidence to conclude that HIT and HITT rates were different between them. There was no evidence from randomized comparative trials to support the contention that patients receiving treatment for PE or DVT with UH are more prone to these complications than those receiving LMWH.

Bilateral Lower Extremity Gangrene Requiring Amputation Associated With Heparin-Induced Thrombocytopenia

Heparin is a common cause of thrombocytopenia in hospitalized patients. Between 10% and 15% of patients receiving therapeutic doses of heparin develop thrombocytopenia. Heparin-induced thrombocytopenia (HIT) can cause severe bleeding and thrombosis owing to intravascular platelet aggregation. HIT must be distinguished from other causes of thrombocytopenia. Importantly, heparin use is often associated with an early fall in the platelet count that usually occurs within the first 4 days of initiation and recovers without cessation of heparin treatment. This nonimmune heparin-associated thrombocytopenia has not been found to be associated with thrombosis and does not necessitate discontinuation of heparin. The authors present a case report of a 70-year-old man who received heparin therapy following aortic tissue valve replacement and aortic root repair with graft and developed bilateral lower extremity arterial clots 6 days postoperatively in the setting of positive heparin antibody titers. Ultimately the patient required bilateral above-knee amputations.

18F-Fluorodeoxy glucose (FDG) uptake in nontraumatic bilateral adrenal hemorrhage secondary to heparin-associated thrombocytopenia syndrome (HATS)—a case report

(18)F-Fluorodeoxy glucose (FDG) activity reflects tissue glucose metabolism; malignancies, metastases, and acute infections have relatively increased FDG activity reflecting increased glucose metabolism. Benign adrenal disease demonstrating mild FDG uptake can be worrisome for metastasis in patients with a history of malignancy. Our patient with breast and colon cancer developed gastrointestinal bleeding on heparin therapy, enlarged adrenals with heterogeneous attenuation consistent with hemorrhage and blood clots as seen on abdominal computed tomography scan, and as abnormal intense FDG activity in the bilateral adrenal glands on positron emission tomography scan.

A New Role for FcγRIIA in the Potentiation of Human Platelet Activation Induced by Weak Stimulation.

The low affinity receptor for immunoglobulin G, FcγRIIA, is expressed in human platelets, mediates heparin-associated thrombocytopenia, and participates in platelet activation induced by von Willebrand factor. Activation of FcγRIIA occurs upon clustering of the receptor induced by immunocomplexes, and consists in the phosphorylation of two tyrosine residues within the ITAM, typically promoted by an associated Src kinase. The phosphorylated receptor acts as a docking site for SH2 domain-containing signaling proteins, including the tyrosine kinase Syk. This event initiates an intracellular tyrosine kinase-based signaling cascade that eventually leads to phosphorylation and activation of phospholipase C (PLC) γ2, and elicits cellular responses. To date, very little is known on the possible involvement of FcγRIIA in platelet activation induced by soluble agonists. We have found that stimulation of platelets with agonists acting on G-protein-coupled receptors resulted in Src-kinase-mediated tyrosine phosphorylation of FcγRIIA. Treatment of platelets with the blocking monoclonal antibody IV.3 against FcγRIIA, but not with control IgG, inhibited platelet aggregation induced by TRAP1, TRAP4, the thromboxane A2 analogue U46619, and low concentrations of thrombin. By contrast, platelet aggregation induced by high doses of thrombin was unaffected by blockade of FcγRIIA. We also found that the anti-FcγRIIA monoclonal antibody IV.3 inhibited pleckstrin phosphorylation and calcium mobilization induced by low, but not high, concentrations of thrombin. Thrombin- and U46619-induced tyrosine phosphorylation of Syk and PLCγ2, which represent substrates typically involved in FcγRIIA-mediated signaling, was clearly reduced by incubation with anti-FcγRIIA antibody IV.3. Morever, we were able to demonstrated that platelet stimulation by thrombin induced the association of FcγRIIA with Syk. Signaling through immunoreceptor typically takes places in characteristic membrane microdomains called lipid rafts. Upon stimulation with thrombin, FcγRIIA relocated in lipid rafts, and thrombin-induced tyrosine phosphorylation of FcγRIIA occurred within these membrane domains. Controlled disruption of lipid rafts by depleting membrane cholesterol prevented tyrosine phosphorylation of FcγRIIA, and impaired platelet aggregation induced by U46619 or by low, but not high, concentrations of thrombin. These results indicate that FcγRIIA can be activated in human platelets downstream G-protein-coupled receptors, and initiates a tyrosine kinase-based signaling pathway that significantly contributes to platelet activation and aggregation in response to weak stimulation.

The Emergency Use of Recombinant Hirudin in Cardiopulmonary Bypass

The most common anticoagulant used for cardiopumonary bypass is heparin. An alternate form of anticoagulant therapy is needed for patients who have immune-mediated heparin-associated thrombocytopenia (HIT). Thrombocytopenia causes bleeding and may lead to serious arterial and venous thrombosis. HIT or heparin-induced thrombocytopenia with thrombosis type II (HITT) are both described as adverse reactions to heparin. They are diagnosed with a platelet count less than a 100,000/mcl for 2 consecutive days. HITT, the severe form, is characterized with the thrombocytopenia in combination with thromboembolic complications, such as strokes, myocardial infarctions, and limb ischemia. Two cases are presented in which r-hirudin was used for anticoagulation for aortocoronary bypass surgery and mitral valve replacement. The activated partial prothrombin time (aPTT) was used to monitor coagulation. In the first case, the aPTT was maintained greater than 100 seconds, and at the termination of cardiopulmonary bypass, some clot was noted in the cardiopulmonary bypass circuit. In the second case, a longer cardiopulmonary bypass run was anticipated, the hirudin bolus and infusion rate were increased, and the aPTT was maintained at greater than 200 sec. Adequate coagulation resulted, and, at the end of bypass, no clot was noted. These case studies seem to suggest a higher dosage of r-hirudin may be required for the use of cardiopulmonary bypass and a need to maintain aPTT values greater than 200 sec to help monitor anticoagulation.

When Heparins Promote Thrombosis

Heparin-induced thrombocytopenia (HIT; sometimes known as HIT type II) is a serious, immune system–mediated complication of heparin therapy often resulting in devastating thromboembolic outcomes. Although nomenclature distinctions have been made historically between this condition and the non–immune system–mediated, asymptomatic transient drop in platelet count in some patients receiving heparin (sometimes known as HIT type I), the term “HIT” is now preferably reserved for the immune system–mediated condition.1 An estimated 1 in 100 patients who receive unfractionated heparin for at least 5 days will develop HIT-associated thrombosis.2 The pervasive use of heparins makes HIT one of the most important adverse drug reactions confronting physicians. Heparin is routinely used for thromboprophylaxis or treatment in many clinical settings, including cardiovascular surgery and interventional procedures, acute coronary syndromes, venous thromboembolism, atrial fibrillation, peripheral occlusive disease, dialysis, and extracorporeal circulation. It is among the most frequently prescribed medications in the United States, with >1 trillion units used3 and 12 million patients treated4 annually. Because thrombocytopenia is common in hospitalized patients, occurring in up to 58% of critically ill patients, and can be caused by a variety of factors,5 HIT unfortunately often remains unrecognized. However, consistent with standard clinical practice for life-threatening conditions, HIT should be suspected in a heparin-treated patient who has thrombocytopenia with or without thrombosis. Increased awareness and a high degree of suspicion for HIT are critical to ensure its prompt recognition, diagnosis, and treatment. Advances in understanding the pathophysiology of HIT and its natural history have led to current treatment recommendations—specifically, that heparin must be discontinued immediately and alternative anticoagulation must be initiated.6 Herein we review the pathogenesis, frequency, natural history, diagnosis, and treatment of HIT. Unfractionated heparin is a heterogeneous group of negatively charged, sulfated glycosaminoglycans (molecular weight 3000 to 30 000 Da) from animal …

Lepirudin: a bivalent direct thrombin inhibitor for anticoagulation therapy

Lepirudin (Refludan®, Berlex Laboratories, USA and Canada; Pharmion®, all other countries), a recombinant derivative of the naturally occurring leech anticoagulant hirudin, was the first direct thrombin inhibitor to be approved by the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration for the treatment of heparin-induced thrombocytopenia. Since its introduction into Europe and the USA, it has been studied in over 7000 patients requiring anticoagulation in conditions including acute coronary syndromes, percutaneous coronary intervention, cardiopulmonary bypass and heparin-induced thrombocytopenia. Three European clinical trials, designated Heparin-Associated Thrombocytopenia (HAT)-1, -2 and -3, demonstrated the efficacy and safety of lepirudin in the prevention and treatment of thrombosis in patients with antibody-confirmed heparin-induced thrombocytopenia. A postmarketing, observational study, termed the Drug-Monitoring Program, evaluated lepirudin in over 1000 patients with heparin-induced thrombocytopenia in the setting of routine clinical practice. In the Drug-Monitoring Program, adverse events were substantially reduced compared with clinical trials, while clinical efficacy was maintained; suggesting that insight gained through clinical experience was translated into improved safety. Here, pharmacotherapy using lepirudin is reviewed, with particular reference to clinical studies in heparin-induced thrombocytopenia, and some recommendations based on this extensive clinical experience with lepirudin are provided. Although only approved for the treatment of heparin-induced thrombocytopenia, the use of lepirudin in acute coronary syndromes, percutaneous coronary intervention, vascular surgery and coronary artery bypass grafting is also discussed. The review concludes with a discussion of pharmacokinetic and clinical data supporting the potential for subcutaneous administration of lepirudin.

Delayed-Onset Heparin-Induced Thrombocytopenia

Letters4 November 2003Delayed-Onset Heparin-Induced ThrombocytopeniaLawrence Rice, MD, Walid K. Attisha, MD, and John L. Francis, PhDLawrence Rice, MDFrom Baylor College of Medicine; Houston, TX 77030; and Florida Hospital Center for Hemostasis and Thrombosis; Orlando, FL 32804-4603.Search for more papers by this author, Walid K. Attisha, MDFrom Baylor College of Medicine; Houston, TX 77030; and Florida Hospital Center for Hemostasis and Thrombosis; Orlando, FL 32804-4603.Search for more papers by this author, and John L. Francis, PhDFrom Baylor College of Medicine; Houston, TX 77030; and Florida Hospital Center for Hemostasis and Thrombosis; Orlando, FL 32804-4603.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-139-9-200311040-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We deserve no credit for the muddied waters of heparin-induced thrombocytopenia terminology. The concept of early, mild, nonimmune, clinically inconsequential heparin-induced thrombocytopenia was advanced years ago as heparin-induced thrombocytopenia type 1 (1). In fact, low platelet counts in some hospitalized patients may often be unrelated to heparin and may be due instead to infection, surgery, other drugs, and stresses. The recommendation to designate this as heparin-associated thrombocytopenia to distinguish it from serious heparin-induced thrombocytopenia (2) has not gained wide favor. Furthermore, separating heparin-induced thrombocytopenia from heparin-induced thrombocytopenia with thrombosis syndrome is artificial and misleading, since isolated heparin-induced thrombocytopenia ...

A critical role of lipid rafts in the organization of a key FcγRIIa-mediated signaling pathway in human platelets

The involvement of platelet FcgammaRIIa in heparin-associated thrombocytopenia (HIT) is now well established. However, the precise sequence of molecular events initiated by FcgammaRIIa cross-linking in platelets remains partly characterized. We investigated here the role of lipid rafts in the spatio-temporal organization of the FcgammaRIIa-dependent signaling events. Upon cross-linking, FcgammaRIIa relocated in rafts where the kinase Lyn and the adapter LAT were among the major phosphotyrosyl proteins. Upon stimulation by HIT sera, the second messenger phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) accumulated in rafts in a P(2)Y(12) adenosine diphosphate (ADP) receptor-dependent manner. PtdIns(3,4,5)P(3) was then essential to specifically recruit phospholipase Cgamma2 (PLCgamma2) to these membrane microdomains. Controlled disruption of rafts by methyl beta-cyclodextrin reversibly abolished PtdIns(3,4,5)P(3) production, PLC activation and platelet responses induced by FcgammaRIIa cross-linking without affecting the tyrosine phosphorylation events. This work demonstrates that platelet rafts are essential for the integration of a key signaling complex leading to the rapid production of PtdIns(3,4,5)P(3) and in turn PLCgamma2 activation during HIT.

Heparin-Induced Thrombocytopenia and Thrombosis: A Review of Pharmacologic Therapy

Objective: To review pharmacological therapy in heparin-induced thrombocytopenia and thrombosis (HITT). Data Sources: Articles and abstracts in English published from 1966 to January 2000 were identified by MEDLINE and International Pharmaceutical Abstracts searches using the terms HIT, Hill, heparin-associated thrombocytopenia, thrombocytopenia, hirudin, lepirudin, argatroban, ancrod, heparinoids, orgaran, danaparoid, and org 10172. Additional articles were identified from the bibliographies of retrieved literature. Data Synthesis: HITT is a devastating drug-induced immunologic complication that occurs in 2–5% of patients on heparin. Often, HITT results in life- or limb-threatening complications. HITT is frequently diagnosed by clinical presentation, and there is no optimal drug treatment approach. The first step of treatment is to discontinue all forms of heparin. If anticoagulation is indicated, several agents have been evaluated. Lepirudin, argatroban, and danaparoid are agents available for use in HITT. Lepirudin is a recombinant hirudin that directly complexes with thrombin. Danaparoid is a heparinoid moiety that works by inactivation factor Xa. Argatroban, a direct semisynthetic thrombin inhibitor, is the newest agent available. Ancrod is derived from pit viper venom and acts as a fibrinolytic agent; its use is not recommended. No studies have evaluated the comparative efficacy and safety of these agents. Conclusions: Argatroban, danaparoid, and lepirudin have shown efficacy and safety in treatment of HITT. Each agent exerts differences in pharmacologic and pharmacokinetic parameters and has advantages and disadvantages in particular patient populations. Therapy must be guided on an individual basis. Further investigation is needed to ascertain an optimal treatment approach.

FcγRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation

FcγRIIA, the only Fcγ receptor present in platelets, is involved in heparin-associated thrombocytopenia (HIT). Recently, adenosine diphosphate (ADP) has been shown to play a major role in platelet activation and aggregation induced by FcγRIIA cross-linking or by sera from HIT patients. Herein, we investigated the mechanism of action of ADP as a cofactor in FcγRIIA-dependent platelet activation, which is classically known to involve tyrosine kinases. We first got pharmacologic evidence that the ADP receptor coupled to Gi was required for HIT sera or FcγRIIA clustering-induced platelet secretion and aggregation. Interestingly, the signaling from this ADP receptor could be replaced by triggering another Gi-coupled receptor, the α2A-adrenergic receptor. ADP scavengers did not significantly affect the tyrosine phosphorylation cascade initiated by FcγRIIA cross-linking. Conversely, the Gi-dependent signaling pathway, initiated either by ADP or epinephrine, was required for FcγRIIA-mediated phospholipase C activation and calcium mobilization. Indeed, concomitant signaling from Gi and FcγRIIA itself was necessary for an efficient synthesis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase Cγ2 activation. Altogether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induced by FcγRIIA.

FcγRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation

AbstractFcγRIIA, the only Fcγ receptor present in platelets, is involved in heparin-associated thrombocytopenia (HIT). Recently, adenosine diphosphate (ADP) has been shown to play a major role in platelet activation and aggregation induced by FcγRIIA cross-linking or by sera from HIT patients. Herein, we investigated the mechanism of action of ADP as a cofactor in FcγRIIA-dependent platelet activation, which is classically known to involve tyrosine kinases. We first got pharmacologic evidence that the ADP receptor coupled to Gi was required for HIT sera or FcγRIIA clustering-induced platelet secretion and aggregation. Interestingly, the signaling from this ADP receptor could be replaced by triggering another Gi-coupled receptor, the α2A-adrenergic receptor. ADP scavengers did not significantly affect the tyrosine phosphorylation cascade initiated by FcγRIIA cross-linking. Conversely, the Gi-dependent signaling pathway, initiated either by ADP or epinephrine, was required for FcγRIIA-mediated phospholipase C activation and calcium mobilization. Indeed, concomitant signaling from Gi and FcγRIIA itself was necessary for an efficient synthesis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase Cγ2 activation. Altogether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induced by FcγRIIA.