Splenectomy for the treatment of thrombotic thrombocytopenic purpura.

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.

[A patient with sinus thrombosis associated with paroxysmal nocturnal hemoglobinuria]. / Een patiënte met sinustrombose door paroxismale nachtelijke hemoglobinurie.

A 27-year-old woman with a history of aplastic anaemia complained of poor control of her right arm and hand, unsteady gait, and headache that increased while in a recumbent position. She was diagnosed with cerebral sinus thrombosis. Additional investigation revealed paroxysmal nocturnal haemoglobinuria (PNH). Treatment with heparin was initiated but stopped after the patient developed a brain haemorrhage. The patient recovered with no signs of residual symptoms and began taking oral anticoagulants as maintenance therapy. PNH is a rare acquired clonal disorder due to a defective expression of the glycosylphosphatidyl-inositol anchor membrane protein. It is characterised by haemolytic anaemia, diminished haematopoiesis, increased susceptibility for infections and a hypercoagulable state. Patients with aplastic anaemia have an increased risk of developing PNH. In patients with cerebral sinus thrombosis PNH should be considered as a possible underlying disorder. These patients should be questioned for possible clinical symptoms of PNH, such as acute abdominal pain or dark urine in the morning. For patients with these symptoms and in those with a history of aplastic anaemia or recurrent thrombosis, additional testing for PNH should be conducted.

[Activity loss of Von Willebrand factor cleaving protein (ADAMTS-13) is diagnostic for primary and pregnancy-related thrombotic thrombocytopenic purpura]. / Afwezige activiteit van Von Willebrand-factorsplitsend eiwit (ADAMTS-13) diagnostisch voor primaire en zwangerschapsgerelateerde trombotische trombocytopenische purpura.

OBJECTIVE: To determine whether the measurement of the Von Willebrand factor cleaving protease ADAMTS-13, such as is carried out at the University Medical Centre of Utrecht, The Netherlands, contributes towards the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura (TTP). DESIGN: Descriptive. METHOD: In a group of 98 patients from 21 hospitals, with a Coombs-negative haemolytic anaemia and thrombocytopenia, the ADAMTS-13 activity was measured. Treatment was given irrespective of ADAMTS-13 activity. RESULTS: ADAMTS-13 activity was absent in 27 of 29 patients diagnosed with primary TTP and in all 5 pregnancy-TTP patients. In patients suffering from TTP after bone marrow transplantation (post-BMT) and in all other patients included in this study, ADAMTS-13 activity was normal. Of the 32 patients with absent ADAMTS-13 activity, 28 underwent plasmapheresis. This treatment proved effective as all 28 patients responded well. 17 patients with normal ADAMTS-13 activity also underwent plasmapheresis; 5 (30%) responded well to treatment. In 2 cases a final diagnosis of primary TTP was made, in a further 2, haemolytic uraemic syndrome and in 1 case sepsis was diagnosed. CONCLUSION: In this study, the absence of ADAMTS-13 activity predicted primary TTP and TTP of pregnancy with a sensitivity of 93% and a specificity of 100%. Absence of ADAMTS-13 activity is a strong indication for plasma exchange.

Effective and safe use of recombinant factor VIIa (NovoSeven) in elderly mild haemophilia A patients with high-titre antibodies against factor VIII.

Three patients with mild haemophilia A who developed high-titre antibodies against factor VIII at high age are reported. These patients had only a limited number of exposure days of FVIII concentrates in the past. The patients had to undergo surgery or presented with recurrent bleeding episodes. Treatment with recombinant FVIIa (rFVIIa) was effective and safe. Despite the high age and the presence of coronary heart disease in one of the patients, no adverse events or thrombotic complications occurred. These cases illustrate that the physician should always be alert on the development of inhibitors, also in elderly patients with mild haemophilia, in whom FVIII inhibitors had never been detectable before and that treatment with rFVIIa was effective and well-tolerated.

Hematological long-term results of laparoscopic splenectomy for patients with idiopathic thrombocytopenic purpura: a case control study.

BACKGROUND: Laparoscopic splenectomy (LS) for idiopathic thrombocytopenic purpura (ITP) appears, when compared to open splenectomy (OS), associated with immediate important advantages. However, in a number of patients splenectomy does not lead to an adequate response, or after initial adequate response a relapse occurs after some time. A relapse may be associated to the presence of accessory spleens and splenosis. The purpose of this study was to compare the operative outcome and the hematological results on the long term of a series of LS with a historic series of OS for the treatment of ITP. METHODS: A retrospective review was done of 50 consecutive patients who underwent LS for ITP. Patient characteristics, outcome of surgery, and hematological results were compared to a historical group of patients who underwent conventional splenectomy for ITP (n = 31). Response to splenectomy was defined in three groups: complete remission, partial remission, and no response. Grouping was based on hematological data. RESULTS: Concerning operative outcome and postoperative complications, there was a significant difference in favor of LS. Moreover, the hematological outcome of both groups showed no differences after a median period of 66 months (OS) and 35 months (LS), respectively. CONCLUSIONS: Hematological results after laparoscopic splenectomy for ITP are comparable to those after open splenectomy in both the short and the long term.

[Intermittent thrombocytopenia as a manifestation of Von Willebrand's disease]. / Intermitterende trombocytopenie als uiting van de ziekte van Von Willebrand.

A 38-year-old man with Von Willebrand's disease type 2 came to us for treatment advice in relation to a trip abroad, and also a 53-year-old woman with bleeding treated as idiopathic thrombocytopenic purpura (ITP). In the man, a trial dose of desmopressin led to severe thrombopenia, and in the woman, treatments, such as splenectomy and prednisone in the past, had been ineffective. In both patients further investigations led to the diagnosis 'Von Willebrand-disease type 2B'. Despite the fact that Von Willebrand's disease type 2B has distinctive laboratory characteristics, such as thrombocytopenia, a positive Ristocetin Induced Platelet Agglutination (RIPA) test at a low ristocetin concentration, and an abnormal multimer pattern, some cases have incomplete or atypical presentations which can be misleading for the diagnosis. A wrong diagnosis can lead to ineffective and potentially dangerous therapeutic interventions. Molecular genetic analysis of type 2B mutations is simple and can help in making the correct diagnosis in cases of familial thrombocytopenia or for a further characterisation of Von Willebrand type 2.

Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy.

Patients with chronic immune thrombocytopenic purpura (ITP) who are unresponsive to corticosteroids require splenectomy, but if this fails, treatment is difficult. We tried to induce durable remissions in ITP patients refractory to corticosteroids before or after splenectomy by applying strong immunosuppression with the combination of cyclosporin A (CyA 5 mg/kg/d) and prednisone (0.4 mg/kg/d). Patients were assigned to one of two groups. Group 1, 10 patients refractory to prednisone; and group 2, 10 patients refractory to at least prednisone and splenectomy. Overall response rate was 55% (50% in group 1 and 60% in group 2 patients). Nine of the 10 patients in group 1 finally had a splenectomy because of relapse, insufficient response or toxicity of CyA. Thirty percent of the patients discontinued CyA because of side-effects; hypertension, severe headache and muscle pain being the most frequent encountered. It is concluded that CyA treatment does not avoid, but only postpones, splenectomy in chronic ITP patients who are refractory to corticosteroids. However, CyA can be useful in a subgroup of patients with corticosteroid- and splenectomy-refractory ITP, but treatment toxicity is high.

Hypercoagulability states in upper-extremity deep venous thrombosis.

Deep venous thrombosis of the upper extremity (DVTUE) is a rare thrombotic disorder that may occur spontaneously but is most often related to predisposing factors, such as an indwelling central venous catheter, malignancy, or exercise. The role of coagulation disorders, i.e., a hypercoagulable state in the pathogenesis of DVTUE is not well known. We have evaluated both genetic and acquired thrombophilia parameters in consecutive patients with DVTUE. A hypercoagulable state was found in 32% of the patients. The most frequent coagulation abnormality was the presence of lupus anticoagulant or anticardiolipin antibodies (27%). Factor V Leiden mutation was detected in two patients, antithrombin deficiency in one, and none of the patients had the prothrombin G20210A gene variant or protein C or S deficiency. The prevalence of coagulation abnormalities was not significantly different in a subgroup of patients with spontaneous DVTUE as compared to those with an obvious predisposing factor, such as an indwelling central venous catheter. We conclude that antiphospholipid antibodies are frequently found in patients with DVTUE. Factor V Leiden mutation, prothrombin 20210A gene variant, protein C deficiency, and protein S deficiency do not seem to play a major pathogenetic role in DVTUE.

Serum thrombopoietin levels in relation to disease status in patients with immune thrombocytopenic purpura.

Pre- and post-treatment serum thrombopoietin (TPO) concentration was measured in 35 patients with immune thrombocytopenic purpura (ITP). Mean post-treatment levels were significantly lower (P = 0.02) than pretreatment and not different for treatment modality. No significant correlation between pre- or post-treatment TPO and platelet counts was demonstrable (R = -0.325, P = 0.056 and R = -0.227, P = 0.190 respectively). In patients with very low platelet counts (< or =20 x 10(9)/l), pretreatment serum TPO was significantly higher than in patients with higher counts (P = 0.033). The logarithm of the platelet turnover rate, measured in 15 patients, correlated with pretreatment TPO levels (R = 0.64). These findings suggest a contributory role for TPO in the mechanism of ITP.

[Deep venous thrombosis of the arm: etiology, diagnosis and treatment]. / Diepe veneuze trombose van de arm: oorzaak, diagnostiek en behandeling.

Thrombosis of the upper extremity is frequently (30-52%) related to the use of an indwelling venous catheter, but it can also occur in healthy individuals after exercise. In the past it was considered a relatively benign thrombotic event, which was treated conservatively, sometimes even without anticoagulant therapy. Recent studies have shown that complications of deep venous thrombosis of the upper extremity occur frequently: pulmonary embolism (8-36%), recurrence thrombosis after cessation of anticoagulant treatment (2-15%) and post-thrombotic syndrome (up to 50%). Therefore when thrombosis of the upper extremity is clinically suspected, it should be objectively diagnosed by compression echography followed if negative by phlebography, with anticoagulant treatment directly afterward, preferably with low-molecular heparin and then acenocoumarol or phenprocoumon.

[Laparoscopic splenectomy for hematological diseases; results in 28 patients]. / Laparoscopische splenectomie voor hematologische aandoeningen; resultaten bij 28 patiënten.

OBJECTIVE: To evaluate the first results of laparoscopic splenectomy for haematological diseases and the learning curve. DESIGN: Retrospective. PATIENTS AND METHODS: Data of all patients who underwent a laparoscopic splenectomy in October 1994-July 1998 in the University Hospital Rotterdam, Department of surgery, the Netherlands, were collected from electronic databases. Data on postoperative complications were collected from medical records. Patients with splenomegaly (> 15 cm) were not eligible for the procedure. RESULTS: 28 patients were eligible for a laparoscopic splenectomy. The male:female ratio was 1:4. The mean age was 35 years. The indications for surgery were idiopathic thrombocytopenic purpura (ITP; n = 24), Gilbert syndrome (n = 1), spherocytosis (n = 1), thalassaemia (n = 1) and haemolytic anaemia with ITP (n = 1). Conversion to an open procedure was necessary in 5 of 28 laparoscopic splenectomies (18%). The median operating time was 172 minutes. Complications occurred in four patients: pneumonia (n = 2), bleeding (n = 1) and urosepsis (n = 1). The median hospital stay was 5 days (range: 1-18). The first 14 laparoscopic splenectomies differed from the following 14 by a higher conversion rate (p = 0.01), a longer operation time (p = 0.002) and a longer hospital stay (p = 0.004). In 23 out of 25 patients with ITP the thrombocyte count became normal. CONCLUSION: Laparoscopic splenectomy is associated with a learning curve, with a high incidence of conversion in the early procedures. It appears to be a safe and effective operation.

[Thrombotic thrombocytopenic purpura in 13 Dutch centres: treatment and longterm follow-up]. / Trombotische trombocytopenische purpura in 13 Nederlandse centra: behandeling en beloop.

OBJECTIVE: Analysis of the incidence, treatment modalities and disease course of thrombotic thrombocytopenic purpura (TTP) in the Netherlands. DESIGN: Retrospective follow-up study. SETTING: 13 centres in the Netherlands. METHODS: Regarding all patients admitted between 1-1-1979 and 1-1-1992 to one of 13 Dutch haematological centres, in whom the diagnosis of TTP was made for the first time, information was gathered from the medical records and from the patients own physicians on patient characteristics at presentation and the occurrence of relapse or death. The follow-up period tended on 1-4-1995. RESULTS: A total of 65 patients with newly diagnosed TTP were identified: 0.34 per 1,000,000 persons a year (95% confidence interval (95%-CI): 0.26-0.45), increasing to 0.83 in the last year of the study. Forty-six (95%) patients were treated with fresh frozen plasma: 18 (28%) by plasma infusion and 44 (68%) by plasma exchange; 48 (74%) (additionally) received corticosteroids. All 52 patients (80%) who survived the first four weeks after admission reached complete remission. Twelve patients with relapsing TTP underwent splenectomy in remission. The 5-year survival rate was 77% (95% CI: 66-87) and the 5-year relapse-free survival rate 38% (95% CI: 25-52). Cardiac symptoms, severe thrombocytopenia and a high serum LDH were risk factors for acute mortality, but no risk factors for relapse or late-occurring death could be identified. CONCLUSION: TTP is a rare disease which is increasingly being recognized. Plasma exchange and corticosteroids are the most frequently used therapies. The disease has a high mortality rate in the acute phase of the disease.

Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases.

Heparin-induced thrombocytopenia and/or thrombosis (HITT) are serious complications of heparin treatment. The incidence, as previously reported, varies widely and, in consequence, is not precisely known. Moreover, most reports only concern clinically defined heparin-induced thrombocytopenia. Therefore we carried out a prospective study of the incidence of serologically confirmed HITT. All patients admitted to the Departments of Cardiology and Neurology of our institution with an indication for treatment with therapeutic-dose intravenous unfractionated heparin were enrolled in the study. The patients were examined daily for the occurrence of thromboembolic complications. Regular platelet counts and tests for the presence of heparin-dependent antibodies were carried out using two different tests: a quantitative platelet factor 4/ heparin (PF4/hep) Elisa, and a functional test, the heparin-induced platelet activation assay (HIPAA). HITT was defined as a rapidly occurring (within 5 d) decrease of the platelet count from normal values of > 120 x 10(9)/l to < 60 x 10(9)/l or to < 100 x 10(9)/l if there was a rapid fall of >50% of starting value or >30% with concomitant acute thrombosis. The observed incidence of HITT was 1/358 patients (0.3%, 95% confidence limits 0.01-1.5%). However, Elisa PF4/hep specific IgG antibodies were demonstrated in nine (2.5%) and IgM antibodies in seven (2.0%) of 358 patients. 30/358 patients (8.4%) had platelet activating antibodies in the HIPAA. We conclude that the incidence of serologically confirmed HITT in this study is very low (0.3%) in patients with cardiac and neurologic diseases treated with intravenous unfractionated heparin. The frequency of heparin-dependent antibodies without concomitant occurrence of thrombocytopenia is much higher.

Heparin-induced thrombocytopenia with multiple cerebral infarctions simulating thrombotic thrombocytopenic purpura. A case report.

The authors describe a patient with stroke, treated with heparin for unstable angina, whose clinical features mimicked those of thrombotic thrombocytopenic purpura (TTP). His condition eventually proved to be caused by heparin-induced thrombocytopenia (HIT), complicated by thrombosis (HITT). The absence of microangiopathic hemolytic anemia should question the diagnosis in a presumed TTP patient. Early diagnosis of HITT is possible since recently two highly sensitive and specific tests have become available. Heparin treatment has to be stopped immediately if HITT is diagnosed. First-choice antithrombotic treatment in HITT patients is danaparoid.

Parvovirus B19 infection and idiopathic thrombocytopenic purpura.

The potential association of human parvovirus B19 infection with idiopathic thrombocytopenic purpura (ITP) was studied. All 60 adult patients presenting with ITP at the University Hospital Rotterdam - Dijkzigt during a 12-year period (41 with acute ITP, 19 with chronic ITP) were included. Patient files were retrospectively analyzed. Stored serum samples were tested for parvovirus B19-specific IgG and IgM anti-bodies, and for parvovirus B19 DNA. In only one patient (1.7%) was evidence of recent B19 infection found. Parvovirus B19 is not a frequent cause of adult ITP and should be tested for only when there are other indications of possible parvovirus B19 involvement.

Heparin-induced thrombocytopenia and thrombosis: a potential fatal complication in a routine treatment.

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. Life-threatening thromboembolism (HITT) may occur in a large number of patients with HIT. In this article diagnostic problems and the clinical course of 4 typical patients are described. Diagnosis was based on the occurrence of thrombocytopenia during heparin therapy and was confirmed in vitro by an ELISA to heparin-platelet factor 4 antibodies, heparin-induced platelet activation assay (HIPAA) or the platelet aggregation assay (PAA). Thrombotic complications developed in 2 patients, one of whom suffered a fatal embolism after accidentally rechallenging with low-dose heparin which was used to maintain the patency of an intravascular catheter. After discontinuation of heparin the thrombocyte count rapidly increased to normal values during treatment with the heparinoid danaparoid (Orgaran) without complications.