Romiplostim for the management of perioperative thrombocytopenia

Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single‐centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty‐seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug‐related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 × 10⁹/l (9–120 × 10⁹/l) at romiplostim initiation to 164 × 10⁹/l (28–603 × 10⁹/l) at the time of surgery (P < 0·0001). A dose of 3 μg/kg per week for 2 doses increased the platelet count to >100 × 10⁹/l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population.     

Multicentre,randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia

Eltrombopag, a thrombopoietin receptor agonist, raises platelet counts and reduces bleeding in patients with immune thrombocytopenia (ITP ). In Chinese patients, eltrombopag was evaluated at an initial dose of 25 mg, vs. 50 mg for non‐Asians, because the plasma exposure of eltrombopag is higher in East Asians. A multicentre, double‐blind, randomised, placebo‐controlled, 8‐week, phase III study enrolled 155 patients with chronic, previously treated ITP . Dosage could be adjusted (25–75 mg/day) to maintain platelet counts 50–250 × 10⁹/l. The primary efficacy endpoint was the proportion of patients with a platelet count ≥50 × 10⁹/l after Day 42. Pharmacokinetics and pharmacodynamics of eltrombopag were analysed in an open‐label extension. After Day 42, 57·7% of eltrombopag‐treated and 6·0% of placebo‐treated patients achieved platelet counts ≥50 × 10⁹/l. Odds of achieving a platelet count ≥50 × 10⁹/l were 26·08 times greater with eltrombopag than placebo (P  <  0·001). Compared with placebo, time to response and duration of response were better with eltrombopag (P  <  0·001) and the odds of any bleeding were reduced by 72% (P  =  0·001). Tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics were similar to previous findings in East Asian patients. In conclusion, in Chinese patients with chronic ITP , eltrombopag 25 mg once daily, elevated platelet counts to a safe range and reduced bleeding.     

Effect of pregnancy on the course of immune thrombocytopenia: a retrospective study of 118 pregnancies in 82 women

In women with pre‐existing immune thrombocytopenic purpura (ITP), the effect of pregnancy on the course of the disease is poorly known. We performed a dual‐centre retrospective cohort study of 118 pregnancies in 82 women with primary ITP. In early pregnancy, the platelet count was <100 × 10⁹/l in 35·6% of pregnancies. During pregnancy the median platelet count nadir was 66 × 10⁹/l (25th–75th percentile: 42–117), with platelet count <30 × 10⁹/l for 26 pregnancies (22%). In 49% of pregnancies, a significant decrease of the platelet count required treatment at least transiently in preparation for delivery. At the time of delivery, the median platelet count was 110 × 10⁹/l (77–155). Compared to before pregnancy, at 3 months post‐partum, only 11% of pregnancies [95% confidence interval (95% CI): 6·8–20·2] showed disease worsening. Previous splenectomy was the only factor significantly associated with ITP worsening after pregnancy (53·9% vs. 10·3%, P < 0·001). For 8·3% of the pregnancies (95% CI: 3·8–15·1), neonatal thrombocytopenia required treatment, especially in case of previous maternal splenectomy (adjusted odds ratio 16·7, 95% CI: 2·61–106). The overall risk of exacerbation of ITP and severe thrombocytopenia during pregnancy is acceptable.     

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study

In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05–1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04–1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI₂₄) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI_24. We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.     

How do we approach thrombocytopenia in critically ill patients?

A low platelet count is a frequently encountered haematological abnormality in patients treated in intensive treatment units (ITU s). Although severe thrombocytopenia (platelet count <20 × 10⁹/l) can be associated with bleeding, even moderate‐degree thrombocytopenia is associated with organ failure and adverse prognosis. The aetiology for thrombocytopenia in ITU is often multifactorial and correcting one aetiology may not normalise the low platelet count. The classical view for thrombocytopenia in this setting is consumption associated with thrombin‐mediated platelet activation, but other concepts, including platelet adhesion to endothelial cells and leucocytes, platelet aggregation by increased von Willebrand factor release, red cell damage and histone release, and platelet destruction by the complement system, have recently been described. The management of severe thrombocytopenia is platelet transfusion in the presence of active bleeding or invasive procedure, but the risk‐benefit of prophylactic platelet transfusions in this setting is uncertain. In this review, the incidence and mechanisms of thrombocytopenia in patients with ITU , its prognostic significance and the impact on organ function is discussed. A practical approach based on the authors' experience is described to guide management of a critically ill patient who develops thrombocytopenia.     

Platelet function tests predict bleeding in patients with acute myeloid leukemia and thrombocytopenia

Bleeding is frequent among patients with thrombocytopenia. We studied whether in vitro platelet function predicts future bleeding in patients with acute myeloid leukemia (AML), and thrombocytopenia. Adult AML patients with platelet count <5.0 × 10¹⁰/L were included. Detailed bleeding history and blood samples were collected at inclusion and every 7 days. We analyzed hematology and coagulation parameters. With flow cytometry we evaluated platelet activation (activated GPIIb/IIIa, P-selectin, and CD63 expression), and platelet aggregation. Agonists were thrombin-receptor activating peptide (TRAP) and collagen-related peptide (CRP-XL). During 18 months, sixty participants were enrolled and followed for a total of 114 weeks. Bleeding occurred in 52 weeks, and was not associated with clinical, hematology or coagulation parameters. Predictors of bleeding were assessed using multivariate logistic regression, adjusted for platelet count, sex, and age. Bleeding history and receiver operating curves were compared using c-index. Reduced TRAP-induced platelet aggregation had Odds ratio 3.00 (95% confidence interval [CI] 1.38-6.60). Reduced CRP-XL-induced platelet aggregation had Odds ratio 4.00 (95%-CI 1.70-9.20) for bleeding. Overall, C-index was 0.71 for the models including platelet aggregation results, 0.72 for activated GPIIb/IIIa-positive platelets after stimulation with TRAP, 0.68 for percent P-selectin positive platelets with TRAP and 0.63 for the platelet count. Among patients receiving no platelet transfusion, C-index was 0.83–0.91 for bleeding; highest for models using platelet aggregation. Change in platelet aggregation did not correlate with the number of platelet concentrates administered. In conclusion, platelet aggregation and platelet activation results predict bleeding better than platelet count alone, among AML patients with thrombocytopenia.     

The PFA‐100® does not predict delta‐granule platelet storage pool deficiencies

Summary.  There are no published reports investigating the ability of the platelet function analyzer (PFA‐100^®) to detect the presence of delta‐granule platelet storage pool deficiencies (δ‐PSPD), a common mild bleeding disorder. Prior studies of the PFA‐100^® and congenital platelet disorders have been limited by small numbers of patients with a variety of disorders. We examined PFA‐100^® results in a large paediatric patient population diagnosed specifically with δ‐PSPD, and determined the relationship between PFA‐100^® and platelet electron microscopy (the gold standard for diagnosis). This study is a retrospective review of patients <19 years of age diagnosed with δ‐PSPD at Nationwide Children’s Hospital from 2008 to 2010. To examine the correlation between PFA‐100^® and average number of granules per platelet we used Spearman’s Rho as a non‐parametric measure of dependence. A total of 105 patients diagnosed with δ‐PSPD were included, of which 99 patients underwent PFA‐100^® testing. Of those tested 46% had at least one abnormal closure time, whereas 16% had abnormal results for both cartridges. We found no statistical correlation between C‐EPI closure time and average number of granules per platelet (ρ= ?0.0095, P‐value = 0.9328), nor between C‐ADP closure time and the average number of granules (ρ = 0.0315, P‐value = 0.7798). The PFA‐100^®, a widely used screening test for suspected bleeding disorders, did not correlate with presence or severity of δ‐PSPD as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA‐100^® alone cannot be used to rule out the presence of a δ‐PSPD.     

Upregulation of CD40/CD40L system in rheumatic mitral stenosis with or without atrial fibrillation

Thrombelastography (TEG) analyses the status of blood coagulation including abnormalities associated with low platelet count. The aim of this study was to investigate the changes in TEG parameters in idiopathic thrombocytopenic purpura (ITP) patients. Thirty nine patients with ITP (platelet count?<?100?×?103 µl^?1) were included in the study. Age-matched 17 patients with thrombocytopenia due to chemotherapy were selected as a control group. Platelet count was positively correlated with maximum clot formation (MCF) in INTEM (r?=?0.716, p?<?0.001) and MCF in EXTEM (r?=?0.679, p?<?0.001); negatively correlated with clot formation time (CFT) in INTEM (r?=??0.755, p?<?0.001) and CFT in EXTEM (r?=??0.585, p?<?0.001) in ITP patients. Platelet count was positively correlated with MCF in INTEM (r?=?0.776, p?<?0.001) and MCF in EXTEM (r?=?0.878, p?<?0.001); negatively correlated with CFT in INTEM (r?=??0.627, p?<?0.001) in control group. Receiver operating characteristic curves to describe the critical platelet count and fibrinogen level that affect MCF revealed 31?×?103?µl^?1 and 375 mg?dl^?1 as cut-off values, respectively. In conclusion, ROTEM determines the contribution of fibrinogen and platelets to clot strength in patients with ITP. MCF appears to be the most important TEG parameter in predicting bleeding in ITP patients that makes TEG superior to other hemostatic tests.     

Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations

Lenalidomide is an effective drug in low‐risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide‐treated patients with del(5q) MDS, conventional G‐banding cytogenetics (CC), single nucleotide polymorphism array (SNP‐A), and genomic sequencing methods were used. SNP‐A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 10⁹/l) were associated with the achievement of haematological response (P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response (P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 10⁹/l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.     

Delayed Haematological recovery after autologous stem cell transplantation is associated with favourable outcome in acute myeloid leukaemia

Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 10⁹/l] and platelets (platelet count >20·0 × 10⁹/l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3‐internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.     

A cross‐sectional study of bleeding phenotype in haemophilia A carriers

Haemophilia A carriers have historically been thought to exhibit normal haemostasis. However, recent data demonstrates that, despite normal factor VIII (FVIII), haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers exhibit an increase in clinically relevant bleeding. A cross‐sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM‐1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity (FVIII:C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser‐100^TM and ABO blood type. Forty‐four haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII:C (82·5 vs. 134%, P < 0·001). Carriers reported a higher number of bleeding events, and both condensed MCMDM‐1 VWD bleeding scores (5 vs. 1, P < 0·001) and PBAC scores (423 vs. 182·5, P = 0·018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management.     

Assessment of romiplostim immunogenicity in adult patients in clinical trials and in a global postmarketing registry

Antibodies to first-generation recombinant thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second-generation TPO receptor agonist romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti-romiplostim-binding antibodies post-baseline. The first positive binding antibody was detected 14 weeks (median) after starting romiplostim, at median romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 10⁹/l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to romiplostim developed in 0·4% of patients, but were unrelated to romiplostim dose and did not affect platelet count. Thirty-three patients (3·4%) developed anti-TPO-binding antibodies; none developed anti-TPO-neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti-romiplostim-neutralising antibodies (negative at follow-up). Collectively, anti-romiplostim-binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to romiplostim, there was no cross-reactivity with TPO and no associated loss of platelet response.     

The haematological features and transfusion management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based study

Understanding the coagulopathy of major‐obstetric‐haemorrhage (MOH) that leads to massive‐transfusion (MT) is fundamental to improving outcomes. This study reports on the haematological features and transfusion management of women experiencing MT [defined as transfusion of ≥8 units of red blood cells (RBC) within 24 h of delivery]. One hundred and eighty‐one cases [median (interquartile range; IQR) age 33 years (29–36)] were identified from all UK hospitals, using the UK Obstetric Surveillance System between July 2012 and June 2013. The median (IQR) estimated blood loss was 6 l (4·5–8). At presentation, the median platelet count was lowest for placenta accreta, compared with other causes, while the median prothrombin time and fibrinogen were <1·5 × mean normal and <3 g/l, respectively for all aetiologies. Median platelet count and fibrinogen fell to <75 × 10⁹/l and <2 g/l, respectively for all causes during bleeding, except for trauma. The median (IQR) units of RBC, fresh‐frozen‐plasma (FFP) and cryoprecipitate transfused were 10 (8–14), 6 (4–8) and 2 (2–4), respectively. The median time from the onset of bleeding to delivery of the first RBC unit was significantly shorter for women who delivered via elective caesarean section, compared with others. The coagulopathy of MT during MOH differs significantly depending on its cause, suggesting that more targeted transfusion strategies are required.     

Enhanced ex vivo inhibition of platelet function following addition of dipyridamole to aspirin after transient ischaemic attack or ischaemic stroke: first results from the TRinity AntiPlatelet responsiveness (TrAP) study

Ex vivo dipyridamole ‘non‐responsiveness’ has not been extensively studied in ischaemic cerebrovascular disease. Platelet surface marker expression, leucocyte‐platelet complex formation and inhibition of platelet function at high shear stress as detected by the PFA‐100^® Collagen‐Adenosine‐diphosphate (C‐ADP) and Collagen‐Epinephrine cartridges was assessed in 52 patients within 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke on aspirin, and then 14 d (14 d) and >90 d (90 d) after adding dipyridamole. A novel definition of ‘Dipyridamole non‐responsiveness’ was used. The median C‐ADP closure time increased following addition of dipyridamole, remained elevated at 90 d (P ≤ 0·03), and was unaffected by aspirin dose. 59% at 14 d and 56% at 90 d were ‘dipyridamole non‐responders’ on the PFA‐100. The proportion of non‐responders at 14 and 90 d was similar (P = 0·9). Compared with baseline (4·6%), median monocyte‐platelet complexes increased at 14 d (5·0%, P = 0·03) and 90 d (4·9%, P = 0·04). Low C‐ADP closure times were associated with increased monocyte‐platelet complexes at 14 d (r = ?0·32, P = 0·02) and 90 d (r = ?0·33, P = 0·02). Monocyte‐platelet complexes increased in the subgroup of dipyridamole non‐responders on the PFA‐100 (P ≤ 0·045), but not in responders (P ≥ 0·5), at 14 and 90 d versus baseline. Additional inhibition of platelet function has been detected with the PFA‐100 when dipyridamole is added to aspirin. Elevated monocyte‐platelet complexes may contribute to ex vivo dipyridamole non‐responsiveness.     

Treatment efficacy for adult persistent immune thrombocytopenia: a systematic review and network meta-analysis

Persistent immune thrombocytopenia (ITP) patients require second-line treatments, for which information on clinical outcomes are lacking. A systematic review and network meta-analysis (NMA) were conducted. Only randomised controlled trials (RCT) of second-line drugs in adult persistent ITP patients with platelet response, platelet count, any bleeding or serious adverse events (SAE) outcome were eligible. Twelve RCTs (n = 1313) were included in NMA. For platelet response outcome, eltrombopag and romiplostin were the best relative to placebo; the former had a non-significant advantage [risk ratio (RR) = 1·10 (95% confidence interval: 0·46, 2·67)]. Both treatments were superior to rituximab and recombinant human thrombopoietin (rhTPO)+rituximab, with corresponding RRs of 4·56 (1·89, 10·96) and 4·18 (1·21, 14·49) for eltrombopag; 4·13 (1·56, 10·94) and 3·79 (1·02, 14·09) for romiplostim. For platelet count, romiplostim ranked highest, followed by eltrombopag, rhTPO+rituximab, and rituximab. For bleeding, rituximab had lowest risk, followed by eltrombopag and romiplostim. For SAEs, rhTPO+rituximab had highest risk, followed by rituximab, eltrombopag and romiplostim. From clustered ranking, romiplostim had the best balance between short-term efficacy and SAEs, followed by eltrombopag. In conclusion, romiplostim and eltrombopag may yield high efficacy and safety. Rituximab may not be beneficial due to lower efficacy and higher complications compared with the thrombopoietin receptor agonists. RCTs with long-term clinical outcomes are required.     

Acquired haemostatic defects in the ill newborn

Summary . The kinetics and function of platelets and fibrinogen were studied in 22 ill newborns. Overall ⁵¹Cr-platelet survival was considerably shortened (patients 2·6 d ± 1·7, adult normal 9·5 d ± 0·6, P < 0·001) while ¹²⁵I-fibrinogen surival was less severely decreased (patients 2·1 d ± 0·8, adult normal 5·1 d ± 0·4, P < 0·05). Three patients with bacterial sepsis and one with disseminated herpes simplex had the most severely reduced platelet survival times (1·3 d ± 0·9), causing thrombocytopenia (62 ±32 × 10⁹/l) despite production rates averaging 2 1/2 times normal. Although fibrinogen survival times were comparably reduced in these patients to 1·4 d ± 0·4, fibrinogen concentrations were normal because of compensatory increased production. In three patients with necrotizing enterocolitis platelet and fibrinogen survival times were similarly reduced (platelets 1·6 d ± 0·6, fibrinogen 1·6 d ± 0·6) with platelet counts of 69 ± 27 × 10⁹/l and platelet production rates of twice normal. Since their fibrinogen production was not increased, they had decreased fibrinogen concentration (1·0 ± 0·19 g/l). In six patients with respiratory distress syndrome the kinetic results were more variable. Platelet survival was less severely affected than in the other groups and production was approximately twice normal; hence, the platelet count was maintained (177 ± 107 × 10⁹/l). Fibrinogen in this group was slightly reduced because of decreased production in the presence of mildly decreased survival (2·7 d ± 0·7). The two patients with cytomegalovirus infection had severe thrombocytopenia (23 × 10⁹/l) due to a combination of decreased platelet survival (3·6 d), increased splenic pooling and no compensatory increase in marrow platelet production. Fibrinogen production was normal but its plasma concentration was moderately reduced because of a decrease in fibrinogen survival. In many of these patients, fibrinogen dysfunction was suggested by a prolonged thrombin time and a discrepancy between fibrinogen concentration as determined by a time dependent assay and an equilibrium total clottable protein assay. Likewise, platelet dysfunction, evidenced as a prolonged bleeding time, was found in patients with RDS; some of these infants had otherwise unexplained bleeding.     

Heparin-induced thrombocytopenia: A prospective study

Thrombocytopenia is a well-described complication of heparin therapy. Few studies describe the incidence of thrombocytopenia when low-dose heparin (10,000–15,000 units/day) is used for prophylaxis of deep venous thrombosis. In our study, ten of 66 courses (15%) of heparin prophylaxis in coronary care unit patients were accompanied by a mild thrombocytopenia with platelet counts below 150 ± 10³/mm³. In all cases the platelet count returned to normal despite continued heparin therapy. Patients who became thrombocytopenic had significantly lower initial platelet counts. No cases of severe thrombocytopenia were seen (platelet count below 100 ± 10³/mm³). No patient developed thrombosis, bleeding or elevated fibrin split products. Mild thrombocytopenia occuring after 2–5 days of low-dose heparin is common, but clinically insignificant.     

Combination of recombinant factor VIIa and fibrinogen corrects clot formation in primary immune thrombocytopenia at very low platelet counts

Haemostatic treatment modalities alternative to platelet transfusion are desirable to control serious acute bleeds in primary immune thrombocytopenia (ITP). This study challenged the hypothesis that recombinant activated factor VII (rFVIIa) combined with fibrinogen concentrate may correct whole blood (WB) clot formation in ITP. Blood from ITP patients (n = 12) was drawn into tubes containing 3·2% citrate and corn trypsin inhibitor 18·3 μg/ml. WB [mean platelet count 22 × 10⁹/l (range 0–42)] was spiked in vitro with buffer, donor platelets (+40 × 10⁹/l), rFVIIa (1 or 4 μg/ml), fibrinogen (1 or 3 mg/ml), or combinations of rFVIIa and fibrinogen. Coagulation profiles were recorded by tissue factor (0·03 pmol/l) activated thromboelastometry. Coagulation in ITP was characterized by a prolonged clotting time (CT, 1490 s (mean)) and a low maximum velocity (MaxVel, 3·4 mm × 100/s) and maximum clot firmness (MCF , 38·2 mm). Fibrinogen showed no haemostatic effect, whereas rFVIIa reduced the CT and increased the MaxVel. The combination of fibrinogen and rFVIIa revealed a significant synergistic effect, improving all parameters (CT 794 s, MaxVel 7·9 mm × 100/s, MCF 50·7 mm) even at very low platelet counts. These data suggest that rFVIIa combined with fibrinogen corrects the coagulopathy of ITP even at very low platelet counts, and may represent an alternative to platelet transfusion.     

Thrombocytopenia at birth in neonates with red cell alloimmune haemolytic disease

Objective To evaluate the incidence and severity of and risk factors for thrombocytopenia at birth in neonates with red cell alloimmunization. Study design All neonates with haemolytic disease of the foetus/newborn (HDFN) due to red cell alloimmunization admitted to our centre between January 2000 and September 2010 were included in this retrospective study. We measured platelet counts at birth and determined the incidence of thrombocytopenia (platelet count < 150 × 10⁹/l) and severe thrombocytopenia (platelet count < 50 × 10⁹/l). Risk factors for thrombocytopenia at birth were evaluated. Results Thrombocytopenia was present in 26% (94/362) of included neonates with HDFN at birth. Severe thrombocytopenia was found in 6% (20/362) of neonates. Three risk factors were found to be independently associated with thrombocytopenia at birth: treatment with intrauterine red cell transfusion (IUT) (OR 3·32, 95% CI 1·67–6·60, P = 0·001), small for gestational age (SGA) below the 10th percentile (OR 3·32, 95% CI 1·25–8·80, P = 0·016) and lower gestational age at birth (OR 1·22/week, 95% CI 1·02–1·44, P = 0·025). Conclusions Thrombocytopenia at birth occurs in 26% of neonates with HDFN due to red cell alloimmunization and is independently associated with IUT treatment, SGA and lower gestational age at birth.     

Feasibility and usefulness of self-assessment of bleeding in patients with haematological malignancies, and the association between platelet count and bleeding

Background and Objectives The aim of this study was to evaluate the collection of daily prospective information about bleeding outcomes in patients with thrombocytopenia, including information obtained by patient self‐assessment. Materials and Methods Consecutive patients with haematological malignancies were enrolled in a study of bleeding data collection during the period of thrombocytopenia. A short educational session and information sheet was designed for self‐assessment. Platelet counts and all transfusions were recorded daily. Bleeding scores were translated into World Health Organization (WHO) bleeding grades. Results Nineteen patients were included in the study. Four‐hundred and ten days of thrombocytopenia were eligible for assessment of bleeds. Self‐assessment was feasible, as defined by the total proportion of days on which self‐assessment was completed (70%, 288 thrombocytopenic days). There was 86% agreement between bleeding data collected by self‐assessment and by medical examination using a structured assessment form. Examples of discrepancies included the duration of petechiae/bruises and the reporting of minor bleeding. There was no evidence for an association between patients’ morning platelet count and daily WHO bleeding grade. The incidences of WHO grade 1 and grade 2 bleeding on days with platelet counts ≤ 10 × 10⁹/l, 11–20 × 10⁹/l, and > 20 × 10⁹/l were similar and did not reveal higher rates of bleeding at lower counts. Conclusions Patient self‐assessment can help to support comprehensive daily prospective monitoring of bleeding, specifically facilitating data collection following hospital discharge. The discrepancies between self‐assessment and medical examination highlight the need to develop a validated international assessment tool. The association among platelet count, risk of bleeding and role of prophylactic platelet transfusions needs further evaluation in larger prospective trials.