Reasons For Thrombocytopenia Research Articles

Heparin induced thrombocytopenia in critically ill: Diagnostic dilemmas and management conundrums.

Thrombocytopenia is often noted in critically ill patients. While there are many reasons for thrombocytopenia, the use of heparin and its derivatives is increasingly noted to be associated with thrombocytopenia. Heparin induced thrombocytopenia syndrome (HITS) is a distinct entity that is characterised by the occurrence of thrombocytopenia in conjunction with thrombotic manifestations after exposure to unfractionated heparin or low molecular weight heparin. HITS is an immunologic disorder mediated by antibodies to heparin-platelet factor 4 (PF4) complex. HITS is an uncommon cause of thrombocytopenia. Reported incidence of HITS in patients exposed to heparin varies from 0.2% to up to 5%. HITS is rare in ICU populations, with estimates varying from 0.39%-0.48%. It is a complex problem which may cause diagnostic dilemmas and management conundrum. The diagnosis of HITS centers around detection of antibodies against PF4-heparin complexes. Immunoassays performed by most pathology laboratories detect the presence of antibodies, but do not reveal whether the antibodies are pathological. Platelet activation assays demonstrate the presence of clinically relevant antibodies, but only a minority of laboratories conduct them. Several anticoagulants are used in management of HITS. In this review we discuss the incidence, pathogenesis, diagnosis and management of HITS.

The Paradoxical Beneficial Effect on Thrombocytopenia in Refractory Immune Thrombocytopaenic Purpura by Leishmaniasis

The phenomenon of platelet recovery in untreated patients with severe chronic refractory immune thrombocytopenic purpura (ITP) has never been described. A 44 year old lady presented with pyrexia. The blood count was Hb 9.8 g/l WBC 6.5 × 109/l Platelets 125 × 109/l. A bone marrow aspirate revealed macrophage hyperplasia with heavy infiltration by Leishman Donovani. The patient had a twenty year history of severe ITP responsive only to high doses of prednisolone. She had undergone two splenectomies and failed to respond to the sequential administration of dapsone, azathiaprine and cyclosporine. The minimum daily dose of prednisolone required to maintain the platelet count was 30 mg and she was on this maintenance dose for most of the duration of the disease. Intensive treatment with liposomal amphotericin and sodium stibogluconate failed to clear the parasites and for the rest of her life (14 months) she remained a carrier of leishmania requiring maintainance monthly doses of Leishmaniacides. During this period the platelet count remained normal even though the steroids were tapered to zero. The normalisation of the platelet count without steroids was unexpected and had never been observed before in her case. It was noted that she maintained a normal platelet count spontaneously even though she had developed transfusion dependent anaemia. Moreover, by then she had developed severe neutropenia partially corrected with granulocyte colony stimulating factor. Both cytopenic effects were a consequence of the ongoing sepsis. The patient eventually succumbed to renal failure secondary to a diabetic nephropathy. Kala-azar in normal subjects characteristically causes thrombocytopenia partly because of hypersplenism and partly because of consumption by the diffuse macrophage hyperplasia within the reticuloendothelial system. Also, in HIV infection where ITP is common, visceral leishmaniasis has been shown to worsen the thrombocytopenia. The main reason for thrombocytopenia in ITP is macrophage mediated phagocytosis of the antibody coated platelets. Two highly effective therapeutic agents are directed against this macrophage activity. Intravenous immunoglobulin saturates the macrophage receptor sites, thereby sparing the sensitised platelets by competitive inhibition [1]. Anti–D transiently diverts macrophages from destruction of platelets by focusing their activity against the sensitised erythrocytes [2]. Using the similar paradigm of these immunemodulatory agents, I postulate that the continual saturation of macrophages with the Leishmania parasites likewise had a platelet sparing effect. This observation may be of interest for pharmaceutical companies in their drug development research.

The Incidence of Heparin-Induced Thrombocytopenia (HIT) After Prophylactic Heparin Exposure in Pediatric Intensive Care and Congenital Cardiology Patients: A Single Center, Prospective and Phase-IV Study: Turkish Experience

AbstractAbstract 4365Heparin is the standard therapy for the prevention and the treatment of venous thromboembolism in children. Heparin-induced thrombocytopenia (HIT) is a well-known serious adverse effect related with heparin therapy or prophylaxis. HIT affects up to %5 of patients treated with unfractionated heparin (UFH). However, prospective studies are so rare in children for technical and ethical reasons.Aim of this study was to determine the incidence of HIT in UFH-exposed children for prohylaxis. Patients who used treatment doses of UFH were excluded. Only ICU and cardiology patients were included. We performed a prospective single center phase-IV study in Ege University Children’s Hospital after approved by Ethics Commitee and Ministry of Health. Children who exposed to UFH for any time were eligible for study. Study group consists of intensive care (ICU) patients (n=28) and congenital heart disorders who will undergo catheter operation (n=25). Mean age was 52 mo (range:1–204). Thirty of patients were female and others were male. All ICU patients used diluted UFH for flushing to maintain patency of central lines. All cardiology cases received only one bolus dose of UFH (50 IU/kg) for prophylaxis. In all patients (n=53) blood samples were collected for platelet counts (CELL DYN 3700 counter, Abbott), anti-Heparin/PF4 antibody (ELISA)(Asserachrom HPIA-Ig G, Diagnostica Stago) and heparin-induced platelet agregation tests (APACT-4004, Tokra) prior to and after 10 days (median) (range: 7–15) of first UFH exposure.After 2 years of observation, we have not found any single patient diagnosed as HIT by clinical findings and confirmed by laboratory analysis. Significant dropping (>50%) of platelet count was observed in only 4 ICU patients. Only one patient had below <150.000/mm3. However, ELISA and agregation tests were negative for these patients. Reasons for thrombocytopenia were evaluated as underlying medical conditions (trauma, pneumonia and sepsis) not for HIT. In only one ICU case, ELISA test was found border-line positive (O.D: 1.374)(positive controls: 1.35±0.34). However, no thrombocytopenia and no activation in agregation related heparin studies were found. This result was evaluated as false-positivity for ELISA. However, mean OD values for ELISA test was found significantly elevated after heparin exposure (before heparin: 0.119±0.061 versus after heparin: 0.258±0.262)(Wilcoxon test; p<0.0001). Elevated heparin-induced agregation response (more than >20% after heparin exposure) was found only in three cardiology patients (diagnosed as ASD, VSD and PDA). However, there was no thrombocytopenia and ELISA seropositivity in these patients. This hyperactivity was evaluated as “non-specific” heparin-induced agregation.In literature, infants with congenital heart disease or children requiring admission to ICU are particularly at risk of venous thromboembolism and likely to be exposed to heparins for prevention and treatment. However, in this single center phase-IV study, we have not found prospectively any HIT patients among 53 risky patients. Reasons may be prophylaxis versus treatment doses, short exposure time versus long-term exposures and medical versus surgical interventions and lower count of patients for low incidence. However significant ELISA activity after heparin exposure was noted as interesting finding. This point might supported for mild heparin activity in patient group who has lower immunogenicity of heparin. Disclosures:No relevant conflicts of interest to declare.

4Ts HIT Scoring in the Medical-Surgical ICU

Abstract 4669 Background:Thrombocytopenia occurs in 20–45% of critically-ill medical-surgical patients. The ‘4Ts' HIT score (with 4 domains: Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and oTher reason for thrombocytopenia) might reliably identify patients at low risk of HIT. Agreement on 4Ts scoring is uncertain in this setting. Objective:To compare 4Ts HIT scores among research coordinators (who scored real-time), and 2 adjudicators (who scored retrospectively, independently) during an international heparin thromboprophylaxis trial. Methods:763 of 3746 medical-surgical ICU patients in PROTECT met enrolment criteria in this HIT substudy, if any of the following occurred: platelets <50×109/L, platelets decreased to 50% of ICU admission value, venous thrombosis, or if HIT was otherwise clinically suspected. Persons independently completed 4Ts scores blinded to all laboratory HIT results and each others’ scores. 475 of these patients had a central or local laboratory HIT test performed and had 4Ts scoring by adjudicators; 432 were scored by research coordinators. Results:Most patients (410, 86.3%) had a 4Ts score ≤3 conferring a low pretest probability (PTP) of HIT whereas 57 (12.0%) had a moderate PTP, and 8 (1.7%) had a high PTP, as determined by adjudicator consensus. Raw agreement on the 4Ts score was good for central adjudicators overall; however, agreement between adjudicated consensus scores and real time research coordinator scores was not as high. 4Ts agreement (raw and chance-corrected) is presented below.Adjudicator A vs B (N = 475)Adjudicator Consensus vs Research Coordinator (N=432)RawKappaWeighted kappaRawKappaWeighted kappaQ1. Thrombocytopenia92.0%0.860.9376.9%0.600.78Q2. Timing82.3%0.600.6871.1%0.390.47Q3. Thrombosis92.8%0.860.9184.0%0.700.78Q4. Other73.9%0.250.3160.6%0.100.13Total (low/ intermed/high)80.8%0.330.4171.5%0.190.23 Conclusions:Real time 4Ts scoring by research coordinators was reasonably close to that obtained by calibrated central adjudicators, suggesting the 4Ts score is somewhat reliable at the bedside when performed by trained personnel. The fourth domain of 4Ts (oTher causes of thrombocytopenia) generated the most disagreement. Further studies of 4Ts scoring by bedside clinicians is needed. Funding:Heart and Stroke Foundation of Canada Disclosures:Crowther:Pfizer: Consultancy, Honoraria; Leo Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BI: Honoraria; CSL Behring: Consultancy; Octaphram: Consultancy; Artisan: Consultancy. Off Label Use: Dalterparin is not indicated for prolonged prophylaxis in critically ill medical patients. Zytaruk:Pfizer: donated study drug dalteparin for PROTECT. Cook:Pfizer: donated study drug dalteparin for PROTECT. Warkentin:Sanofi-Aventis: Speakers Bureau; Pfizer Canada: Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding; GTI Diagnostics: Consultancy, Research Funding; Canyon Pharma: Consultancy, Speakers Bureau; Informa: Patents & Royalties.

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

Heparin-induced thrombocytopenia (HIT) is a fairly common and potentially catastrophic complication of heparin therapy. Diagnosing HIT remains a challenge, as the patients at risk often have other reasons for thrombocytopenia and/or thrombosis. HIT is considered a clinicopathologic disorder whose diagnosis is generally made on the basis of both clinical criteria and the presence of "HIT antibodies" in the patient's serum or plasma. There are two basic laboratory approaches to detect HIT antibodies. The immunoassays detect antibodies based on their binding properties, whereas the functional assays detect antibodies based on their platelet-activating properties. Prompt and accurate diagnosis of HIT is imperative, as overdiagnosis exposes patients to alternative anticoagulants and their associated bleeding risks, whereas under- or delayed diagnosis leaves patients vulnerable to the thromboembolic sequelae of HIT, which can be life threatening. A critical interpretation of laboratory results by the clinician is an essential component of diagnosing HIT. This requires a keen understanding of the current concepts in the pathophysiologic mechanisms of the disease, and the application of these concepts when interpreting the results of both the functional and immunoassays. Equally important is an awareness of the strengths and weaknesses, as well as the current lack of standardization and proficiency testing, of these assays.

Heparin-Induced Thrombosis without Thrombocytopenia Causing Fulminant Pulmonary Embolism after Off-pump Coronary Artery Bypass Grafting

Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated complication of heparin administration. A potentially life-threatening complication, HIT is difficult to diagnose in patients in the intensive care unit after cardiac surgery because there can be multiple reasons for thrombocytopenia. Moreover, immune-mediated platelet consumption may be masked by reactive thrombocytosis, which is common in the typical postoperative course after cardiac surgery. We report the case of a 57-year-old male patient who developed fulminant pulmonary embolism following heparin-induced thrombosis without thrombocytopenia after off-pump coronary artery bypass surgery.

Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction caused by heparin. As thrombocytopenia is common in hospitalized patients receiving heparin, it would be useful to have a clinical scoring system that could differentiate patients with HIT from those with other reasons for thrombocytopenia. To compare prospectively the diagnostic utility of a clinical score for HIT in two different clinical settings. The pretest clinical scoring system, the '4 T's', was used to classify 100 consecutive patients referred for possible HIT in one hospital (Hamilton General Hospital, HGH) into high, intermediate, and low probability groups. This system was also used to classify likewise 236 patients by clinicians in Germany referring blood for diagnostic testing for HIT in Greifswald (GW). The clinical scores were correlated with the results of laboratory testing for HIT antibodies using the serologic criteria for HIT with high diagnostic specificity. In both centers, patients with low scores were unlikely to test positive for HIT antibodies [HGH: 1/64 (1.6%), GW: 0/55 (0%)]. Patients with intermediate [HGH: 8/28 (28.6%), GW: 11/139 (7.9%)] or high scores [HGH: 8/8 (100%), GW: 9/42 (21.4%)] were more likely to test positive for clinically significant HIT antibodies. The positive predictive value of an intermediate or high clinical score for clinically significant HIT antibodies was higher at one center (HGH). A low pretest clinical score for HIT seems to be suitable for ruling out HIT in most situations (high-negative predictive value). The implications of an intermediate or high score vary in different clinical settings.

Prevalance of Heparin-Dependent Platelet-Activating Antibodies in Preterm Newborns After Exposure to Unfractionated Heparin

Heparin is frequently used in preterm infants to prolong the patency of intravascular catheters. The aim of this study was to evaluate the prevalence of heparin-dependent platelet-activating antibodies in newborns. A cross-section of all preterm newborn infants expected to require heparin to maintain patency of a central venous access line were enrolled. A blood sample was obtained soon after birth before heparin exposure to exclude the possibility of placental transfer of maternal heparin-dependent platelet-activating antibodies. A second sample was obtained at termination of heparin use (mean duration of heparin exposure was 23 +/- 13 days; range, 6-67). Paired samples, at birth and after heparin use, were available for 42 infants with a mean gestational age of 27.8 +/- 2.2 weeks and birth weight of 1036 +/- 267 g. Thrombocytopenia developed in 57% (24/42) of the infants. None of these infants had clinical suspicion of thrombosis during the study period. The etiology of thrombocytopenia was confirmed sepsis in six, presumed sepsis in three, necrotizing enterocolitis in one, and unclear in 14 infants. Anti-heparin/platelet factor 4 antibodies measured using the standard assays for heparin-induced thrombocytopenia (two commercially available enzyme-linked immunosorbent assay tests and the functional platelet serotonin release assay) were negative on all infants. Although it could be related to the poor ability of these infants to mount an immunologic response, further research is necessary to fully understand this lack of response to heparin and to elucidate further the reasons for thrombocytopenia in very-low-birth-weight infants.

Therapy and Monitoring of Heparin-Induced Thrombocytopenia Type II in Critically Ill Patients During Continuous Venovenous Hemodiafiltration: Comparison of aPTT and Ecarin Clotting Time for Monitoring of r-Hirudin Therapy

We conducted a survey of therapy, complications, and monitoring of heparin-induced thrombocytopenia (HIT) type II in critically ill patients during continuous venovenous hemodiafiltration (CVVHDF). We also compared activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) for monitoring recombinant (r)-hirudin therapy. Six patients with HIT type II were treated with r-hirudin and were on CVVHDF due to acute renal failure (blood flow rate 90 ml/hr, dialysate flow rate 1 L/hr, substitution 1 L/hr predilution, acrylonitrile membrane 0.9 m2). The mean duration of CVVHDF was 6.2 ± 3.6 days (range 3-17 days). Diagnosis of HIT was established 5.0 ± 1.5 days (range 3-8 days) after a decrease in the platelet count. Three of six patients had other possible reasons for thrombocytopenia apart from HIT, such as massive transfusion, sepsis, or liver cirrhosis. Three thromboembolic events occurred before the diagnosis of HIT was established, none of them during treatment of HIT with r-hirudin. In all patients the platelet count doubled or increased up to 100/nl within 2.5 ± 0.5 days. The dose-response relationship of r-hirudin and aPTT was not satisfactory ( r = 0.371). In patients receiving CVVHDF with one of two different doses of r-hirudin (1 mg/hr versus 2 mg/hr), there was no difference in aPTT ( p &lt; 0.77) but a significant difference in ECT ( p &lt; 0.001). The correlation between r-hirudin dose and ECT was r = 0.654 ( p &lt; 0.0001). r-Hirudin was safe and effective in the treatment of HIT type II in critically ill patients during CVVHDF. ECT seems to be superior to aPTT for monitoring r-hirudin therapy because it correlates better with the concentrations of r-hirudin.

Therapy and Monitoring of Heparin-Induced Thrombocytopenia Type II in Critically Ill Patients During Continuous Venovenous Hemodiafiltration: Comparison of aPTT and Ecarin Clotting Time for Monitoring of r-Hirudin Therapy

We conducted a survey of therapy, complications, and monitoring of heparin-induced thrombocytopenia (HIT) type II in critically ill patients during continuous venovenous hemodiafiltration (CVVHDF). We also compared activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) for monitoring recombinant (r)-hirudin therapy. Six patients with HIT type II were treated with r-hirudin and were on CVVHDF due to acute renal failure (blood flow rate 90 ml/hr, dialysate flow rate 1 L/hr, substitution 1 L/hr predilution, acrylonitrile membrane 0.9 m2). The mean duration of CVVHDF was 6.2 ± 3.6 days (range 3-17 days). Diagnosis of HIT was established 5.0 ± 1.5 days (range 3-8 days) after a decrease in the platelet count. Three of six patients had other possible reasons for thrombocytopenia apart from HIT, such as massive transfusion, sepsis, or liver cirrhosis. Three thromboembolic events occurred before the diagnosis of HIT was established, none of them during treatment of HIT with r-hirudin. In all patients the platelet count doubled or increased up to 100/nl within 2.5 ± 0.5 days. The dose-response relationship of r-hirudin and aPTT was not satisfactory (r = 0.371). In patients receiving CVVHDF with one of two different doses of r-hirudin (1 mg/hr versus 2 mg/hr), there was no difference in aPTT (p < 0.77) but a significant difference in ECT (p < 0.001). The correlation between r-hirudin dose and ECT was r = 0.654 (p < 0.0001). r-Hirudin was safe and effective in the treatment of HIT type II in critically ill patients during CVVHDF. ECT seems to be superior to aPTT for monitoring r-hirudin therapy because it correlates better with the concentrations of r-hirudin.

Humoral regulation of erythropoiesis and thrombopoiesis in appropriate and small for gestational age infants.

Fourteen infants with birth weight appropriate for gestational age (AGA) and 16 small for gestational age (SGA) infants were investigated for haemoglobin concentration, haematocrit level and thrombocyte count on the first day of life. Cord serum was tested for erythropoietin (ESF) and thrombopoietin (TSF) activity. The same investigations were performed on venous blood and serum from 18 healthy adult individuals. SGA infants had higher haemoglobin concentration and haematocrit level (p less than 0.05), and lower platelet count (p less than 0.001) than AGA infants. Significant ESF activity was present in cord serum, but was not detectable in serum from adults. Significant TSF activity was present in cord serum as well as in serum from adults, with higher levels in the newborn infants (p less than 0.05). An inverse relationship was found between serum TSF activity and the number of platelets in adults, which was not demonstrable in newborn infants. Long-term intrauterine hypoxia because of placental dysfunction may be the reason for polycythemia and thrombocytopenia in SGA infants. Thrombocytopenia may be caused by competitive mechanisms on common stem cells for erythropoiesis and thrombopoiesis, shunting stem cells in direction of erythropoiesis during hypoxic exposure. Normal serum TSF activity in SGA infants indicates that lack of the humoral factor for platelet production is not the reason for the thrombocytopenia in these infants. A negative feed-back mechanism may exist between platelet number and TSF production.