Guido Luzzatto

Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura

Sixty‐one consecutive patients undergoing splenectomy for chronic immune thrombocytopenia were retrospectively evaluated. Platelet response was considered as complete (CR) when platelet count rose to > 100 × 109/l, partial (PR) when 30–100 × 109/l or absent (NR) if otherwise. Follow‐up (mean time 7·6 years) was possible in 54 patients. Forty‐eight patients (88%) had an immediate response to splenectomy (39 CR, 9 PR) whereas six (12%) were NR. Thirty‐six responders (67%) had sustained remission (31 CR; 5 PR) without further treatment; thrombocytopenia recurred in 12 patients (33%). The probability curve of continued remission showed a constant relapse‐rate during the first 36 months; a further step of relapse was observed beginning 70 months after surgery. The only positive predictive factor for the long‐term response to splenectomy was age < 40 (P < 0·005). Neither duration of thrombocytopenia nor previous response to medical treatment (steroids and/or intravenous immunoglobulins) were related to splenectomy response.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia

Abstract. Fabris F, Luzzatto G, Soini B, Ramon R, Scandellari R, Randi ML, Girolami A (University of Padua Medical School, Padova, Italy). Risk factors for thrombosis in patients with immune mediated heparin‐induced thrombocytopenia. J Intern Med 2002; 252: 149–154.

Platelet Count, Anti-Heparin/Platelet Factor 4 Antibodies and Tissue Factor Pathway Inhibitor Plasma Antigen Level in Chronic Dialysis

We studied 50 chronic dialysis patients with end-stage renal disease. Mean platelet count was within normal limits. An inverse linear correlation was observed between pre-dialysis platelet count and serum creatinine (r=0.304, p=0.038). Dialysis caused a decrease in platelet count (216+/-80x10(9)/L, pre; 198+/-68, post; p=0.0001), and the higher the pre-dialysis platelet count, the greater the decrease (r=0.623, p=0.0001). Post-dialysis triglyceride decreased (1.67+/-1.27 mmol/L, pre; 1.23+/-0.96, post; p=0.0001). Tissue factor pathway inhibitor (TFPI) antigen plasma level was higher in uremic patients than in controls (114+/-42 ng/ml vs. 64+/-12, p=0.0001). TFPI increased 2.3 times following dialysis and such an increase was directly correlated with post-dialysis plasma heparin concentration (r=0.571, p=0.0002) and inversely correlated with post-dialysis triglyceride variation (r=0.407, p=0.005). Six of fifty patients (12%) had anti-heparin/platelet factor 4 antibodies (Hab), 3 IgG, and 3 IgM. Female sex and the use of cuprophane membranes were more frequent among Hab-positive patients (p=0.0001), while a lower percentage of them were on anti-aggregating drugs as compared to Hab-negative patients (p=0.002). Only one Hab-positive patient was slightly thrombocytopenic and none showed bleeding or thrombotic manifestations. Serum albumin and y globulin decreased following dialysis in Hab-positive patients, while the opposite was seen in those Hab-negative (-2.47+/-1.72 g/L, vs. 0.21+/-1.77, p=0.001 and -0.48+/-0.60 g/L vs. 0.64+/-0.97, p=0.007, respectively). In vivo factors other than Hab are involved in the development of heparin-induced thrombocytopenia. Besides a blunted immunological response, increased levels of TFPI, the use of anti-aggregating drugs, and the observed behavior of serum proteins might play a role in this regard.

SPECIFIC ANTIPLATELET AUTOANTIBODIES IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES AND THROMBOCYTOPENIA

By means of immunoblotting and monoclonal antibody immobilization of platelet antigens (MAIPA) we have studied the specificity of antiplatelet antibodies in patients with antiphospholipid antibodies and thrombocytopenia defined as presence of anticardiolipin IgG and a platelet count below 100 × 109/l. The study group consisted of 10 patients with systemic lupus erythematosus (SLE), 8 patients with primary anti‐phospholipid syndrome (PAPS) and 16 patients with idiopathic thrombocytopenic purpura (ITP). The comparison group was formed by 17 patients with classical chronic ITP without anticardiolipin IgG. We identified the 80–100, 130–150 and 150–170 KD surface proteins that comigrate with GPIIIa, GPIIb and GPIb and a 50–70 KD cytoplasm band by immunoblot. In patients with classical chronic ITP, the prevalence of the antiplatelet antibodies against GPIIIa was 53% on immunoblot assay and 47% on MAIPA. In ITP patients who had also anti‐phospholipid antibodies in serum, the percentage of reactivity to GPIIIa declined to 37% on immunoblot and 21 % on MAIPA but it was not statistically different from the percentage observed in patients with classical ITP. Autoantibodies to platelet surface glycoproteins were almost absent in SLE and PAPS patients, who showed a significant prevalence (78%) of IgG reactivity to the 50–70 KD internal platelet protein which was frequently encountered also in patients with ITP and aPL (56%). Our study provides additional evidence that platelet antigens in patients with phospholipid‐associated secondary immune thrombocytopenia are different from those of primary ITP, and that surface glycoproteins were not involved.

Main clinical manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical history taking

Summary.  A suitable clinical evaluation of a bleeding diathesis is often forgone. The young doctor is often unprepared to describe in an accurate way the different types of bleeding. An adequate classification and adequate clinical information about a bleeding diathesis are instead of paramount importance. Bleeding may be cutaneous, mucous, articular, muscular, parenchymal, intracavitary, orificial. Each of these sites and forms may have diagnostic implications. An accurate description of the several forms of cutaneous bleeding (petechiae, purpuric spots, ecchymosis, haematomas, etc.) is needed for referrals and for controls. The correct evaluation of cutaneous bleeding manifestations of children (battered child syndrome) is absolutely important for clinical and medico‐legal purposes. The same is true for the battering syndrome seen in women abused by their spouses. The grading of haemarthrosis in haemophilia patients is important for the follow‐up. A proper description of haematuria is essential in suggesting the probable site of bleeding (kidney or bladder or urethra). A proper evaluation of bleeding may give also useful information on the general health status of the patients (presence of anaemia, poor nutrition, renal insufficiency, etc.). The combination of bleeding and thrombosis in the same patient is also a clinical challenge. The relationship between haemorrhage and thrombosis may be sequential or concomitant. Sequential thrombosis may occur in a patient confined in bed for a brain haemorrhage. Concomitant thrombosis and bleeding occur in DIC and in patients with thrombosis being treated with anticoagulants. Finally, it should be kept in mind that a proper evaluation of the bleeding diathesis of a given patient may help the caring doctor in ordering appropriate laboratory tests (e.g. a platelet count for petechiae, a PTT for a patient with haemarthrosis, etc.).

Response to Splenectomy in Idiopathic Thrombocytopenic Purpura: Prognostic Value of the Clinical and Laboratory Evaluation

Sixteen patients with chronic idiopathic thrombocytopenic purpura underwent splenectomy after failure of steroid therapy. The average time of follow-up was 69 months. Immediately after splenectomy, complete response (platelets above 150 x 10(9)/l) was obtained by 68% of patients while 25% had partial response (platelets from 50 to 150 x 10(9)/l) and only in 1 patient splenectomy failed. During the long-term follow-up, 2 patients relapsed 9 and 20 years, respectively, after splenectomy (20% of non-responders). Partial recurrence of thrombocytopenia (partial response) was observed in 33% of the patients. The persistent complete response rate was then 47%. The young patient age appears to be the only positive predictive factor both for short-term and long-term response to splenectomy. The platelet recovery rate and postsplenectomy thrombocytosis are also early features of lasting response. Positive serum and platelet-associated immunoglobulins became negative after splenectomy, but there is no correlation with clinical response.

Clinical and laboratory factors that affect the post-transfusion platelet increment.

Transfusion of platelet concentrates (PC) reduced the incidence of fatal hemorrhages in several thrombocytopenic conditions. Unfortunately, long-term platelet supportive care may be complicated by the development of a state of refractoriness, resulting in inadequate recovery of functional platelets. PC handling, clinical conditions of the patients and alloimmunization are the main factors affecting refractoriness. We evaluated the post-transfusion platelet increase in 25 patients (M=6, F=19) with hypomegakaryocytic thrombocytopenia receiving random ABO-compatible PC within 24 h after collection. Quality of PC was assessed by platelet count, pH measuring, LDH release, glycocalicin levels, CD-62 and CD-42b expression. Besides history, clinical status and therapy, we searched for the presence of anti-HLA class 1 and anti-HPA 1-4-5 antibodies. Only six patients (24%) were refractory to PC transfusion, as assessed by a corrected count increment (CCI)<5000. Four of such six patients (67%) had anti-HLA antibodies, as compared to zero of 19 responders (P<0.02). No other investigated clinical or laboratory feature was significantly different in refractory and responsive patients. Although post-transfusion bleeding time was shorter in responders than in refractory patients (297.33+/-249.95 versus 673.33+/-409.96; P<0.02), it did not significantly change even in patients with adequate correct count increment. Our data confirm the importance of anti-HLA antibodies in determining adequate post-transfusion recovery or refractoriness.

Toxicity and side effects of hydroxyurea used for primary thrombocythemia

Over the last 20 years a vast array of data has been accumulated on the efficacy of hydroxyurea (HU) in patients with Philadelphia-negative myeloproliferative disorders (MPD). However, several side effects have been described as well. Besides many anecdotal reports, no evaluation of their prevalence and type exists in large series of treated patients. We report here the side effects of HU in a retrospective, single institution, cohort study of 152 patients suffering from MPD with thrombocytosis (median follow-up 8.13 years). In 6.5% of patients drug failure was registered. Unwanted side-effects (five symptomatic macrocytic anemia, two fever reactions, two allergic reactions, four cases each of leg painful ulcers, three acute leukemia or myelodysplasia) induced to withdraw therapy in 16 patients. Three cases of nail pigmentation were observed. In our experience, HU showed to be an effective and safe drug in most patients with MPD. Prompt recognition of side effects, which have been mostly minor and rapidly subsiding on drug withdrawal, is in any case crucial to avoid more severe complications.

Interaction between Histidine-Rich Glycoprotein and Platelet Factor 4 with Dermatan Sulfate and Low-Molecular-Weight Dermatan Sulfate

There is a controversy about whether or not histidine-rich glycoprotein (HRG), the most abundant plasma protein with glycosaminoglycans-neutralizing capacity, is able to prevent the inhibition of human thrombin by heparin cofactor II (HC II) in the presence of dermatan sulfate (DS). The authors studied the interaction of DS and low molecular weight DS, in a purified system with HRG, platelet factor 4 (PF 4), and with HC II. Their results show that HRG, like PF 4, has an affinity, not only for heparin, but also for DS. However, this affinity seems very weak. In fact, HRG is 10 times less effective than PF 4 in neutralizing the 50% antithrombin activity of HC II in the presence of DS.

Leg ulcers in elderly on hydroxyurea: a single center experience in Ph− myeloproliferative disorders and review of literature

Hydroxyurea (HU) is effective in controlling thrombocytosis while reducing the risk of thrombosis in essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). However, HU may carry more or less severe side-effects. Rare cases of patients with painful leg ulcers have been published. We report our experience on such a side-effect in a large cohort of patients with ET and PV treated with HU and review the literature on the topic. Five (4%) out of our 124 patients (69 ET, 51 PV, 4 MF; 49 males, 75 females; mean age at diagnosis 59.1±11.8 years) treated with HU developed painful leg ulcers. Sixty-one other patients affected with Ph− myeloproliferative disorders (Ph− MPD) developing HU-related painful leg ulcers are described in the English literature. All our five patients were women and developed leg ulcers over the age of 75. Sixty-five percent of all described cases are women; 59% were over 65 years of age and 45% over 70. Most cases received over 1 gr HU per day for at least 1 year. The pathogenesis of HU-induced skin ulcers remains elusive. Treatment is difficult and requires prompt cessation of HU therapy.