Plasma exchange in thrombotic thrombocytopenic purpura.

Three patients were recently treated for thrombotic thrombocytopenic purpura (TTP). One presented with toxic shock syndrome; TTP developed but promptly responded to a regimen of antiplatelet agents, steroids and plasma exchange. In another the manifestations of TTP developed after presentation with hypertension and abdominal pain. This patient responded to a similar regimen but required extended treatment before remission could be maintained with medications alone. In the third patient the full TTP syndrome appeared after several days of plasma exchange treatment for hemolyticuremic syndrome. He did not respond. It is suggested that TTP may present in many forms initially, that microangiopathic hemolysis may be a late manifestation and that the optimal therapy is not known.     

Plasma exchange therapy for thrombotic microangiopathies

Thrombotic microangiopathies (TMAs) are syndromes associated with thrombocytopenia and multiple organ failure. Plasma exchange is a proven therapy for primary TMA such as thrombotic thrombocytopenic purpura (TTP). There is growing evidence that plasma exchange therapy might also facilitate resolution of organ dysfunction and improve outcomes for secondary TMAs such as disseminated intravascular coagulation (DIC) and systemic inflammation-induced TTP. In this review, we survey the current available evidence and practice of plasma exchange therapy for TMAs.     

Plasma exchange in Canada. The Canadian Apheresis Study Group.

Since 1982 the Canadian Apheresis Study Group (CASG) has collected data on plasma exchange activities in Canada. In 1987, 5907 such procedures were carried out on 700 patients for more than 22 different diseases; this represented an increase of 28% over the figure for 1982. A shift in activity has occurred over the years; originally hematologic disorders accounted for most of the procedures; however, in 1987, 60% of the exchanges were done to treat neurologic disorders, mainly myasthenia gravis and acute and chronic Guillain-Barré syndrome. Several prospective randomized clinical trials have recently been completed by the CASG in the hope of determining the optimal application of plasma exchange. These studies, currently under review, include 168 patients with multiple sclerosis, 100 with thrombotic thrombocytopenic purpura and 43 with rapidly progressive glomerulonephritis. Reactions occur in 12% of cases; they are usually minor and are limited to circumoral paresthesia, mild hypertension or hypotension and hives.     

Use of plasmapheresis in the treatment of thrombotic thrombocytopenic purpura

A course of diagnostic process and treatment of the young female patient with thrombotic thrombocytopenic purpura is discussed. First sign of the imminent disease was significant fragmentation of peripheral blood erythrocytes. Therapy included vincristine and three plasma exchanges with Fenwal CS 3000 separator with substitution of the freshly frozen plasma. It seems that such a management produced significant improvement and recovery. The authors review literature on the role of plasmapheresis in the treatment of this rare but often fatal disease.     

血浆置换及血小板输注治疗特发性血小板减少性紫癜疗效观察

摘要 目的：探究血浆置换及血小板输注治疗特发性血小板减少性紫癜疗效。方法：选择2016年2月至2019年1月于我院接受治疗的60例特发性血小板减少性紫癜患者为研究对象,按照其选择治疗方式的差异将其分为血小板输注组（20例）及血浆置换（Plasma exchange,PE）组（40例）,对比两组患者治疗有效率、治疗前后血细胞计数变化情况以及治疗中各类不良反应发生情况。结果：血小板输注组患者治疗显效数10例,有效数6例,总有效率80.00 %,PE组患者治疗显效数27例,有效数12例,治疗总有效率97.50 %,PE组治疗总有效率高于血小板输注组（P<0.05）。与治疗前比较,PE组患者的PLT、RBC计数和Hb水平出现了明显的升高,WBC计数出现明显的下降（P<0.05）,血小板输注组PLT、RBC计数和Hb水平也出现明显升高,WBC计数水平出现下降（P<0.05）,但组间比较显示治疗后PE组患者上述指标均优于血小板输注组（P<0.05）。血小板输注组患者不良反应总发生人数为4人,不良反应总发生率为20.00 %,PE组总不良反应发生人数3人,不良反应总发生率为7.50 %,PE组不良反应总发生率明显低于血小板输注组（P<0.05）。结论：血血浆置换及血小板输注治疗均对特发性血小板减少性紫癜具有较好的治疗效果,能够显著改善患者血细胞计数异常情况,但血浆置换治疗安全性更高。     

Gastric carcinoma and thrombotic thrombocytopenic purpura: association with plasma immune complex concentrations.

A patient with metastatic adenocarcinoma of the stomach developed microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and fluctuating neurological abnormalities in association with appreciably raised plasma concentrations of immune complexes. This syndrome, similar to thrombotic thrombocytopenic purpura, occurred while the tumour was in sustained objective remission after successful treatment with fluorouracil, doxorubicin, and mitomycin. Reversal of the syndrome was achieved with plasmapheresis, azathioprine, corticosteroids, and antiplatelet treatment; this response was paralleled by a reduction in immune complex concentration, suggesting an immune aetiology for the syndrome. Antibodies eluted from the immune complexes reacted with 50% of cells from the gastric cancer but less than 10% of cells from normal gastric mucosa. There was no reactivity with either carcinoembryonic antigen or mitomycin. A 17S immune complex reacted with a glycoprotein from the patient''s autologous platelets and produced platelet aggregation. It is postulated that reducing the tumour and the pre-existing state of antigen excess by chemotherapy allowed soluble antigen-antibody complexes to form and the syndrome to develop.     

Thrombotic thrombocytopenic purpura--the role of ADAMTS13 assay in clinical practice

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by disseminated thrombotic occlusions of the microcirculation. Identification of ADAMTS13 protease and its place in the pathophysiology of TTP led to better understanding of the disease and better survival for the diseased. Here we show a case report of a patient that had a normal ADAMTS13protease activity and an unusual clinical presentation and utilize that case to highlight how the absence of a severe ADAMTS13 protease deficiency does not preclude a diagnosis of TTP and how early initiation and continuation of plasma exchange therapy can lead to a positive outcome, even in a severely ill patient. Even though ADAMTS13 protease determination has no immediate influence on the decision whether or not to start the plasma exchange therapy, it has great impact on future management of the patient and should be determined whenever possible.     

Prostacyclin and thromboxane A2 in thrombotic thrombocytopenic purpura.

A study was conducted to find whether a deficiency in prostacyclin (prostaglandin I2; PGI2) is implicated in the pathogenesis of thrombotic thrombocytopenic purpura. Plasma samples from two patients with the disease before treatment and from 22 healthy controls were therefore assayed for concentrations of 6-oxo-PGF1 alpha and thromboxane B2, the stable metabolites of PGI2 and thromboxane A2, respectively. Neither of the patients responded to treatment, which in one case included an infusion of PGI2. Both patients had normal concentrations of 6-oxo-PGF1 alpha and thromboxane B2, thus implying that circulating amounts of PGI2 and thromboxane A2 were also normal. These findings suggest that 6-oxo-PGF1 alpha may be detectable in normal amounts in thrombotic thrombocytopenic purpura and that the condition need not be associated with a high concentration of thromboxane A2.     

Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13

ADAMTS13 consists of a reprolysin-type metalloprotease domain followed by a disintegrin domain, a thrombospondin type 1 motif (TSP1), Cys-rich and spacer domains, seven more TSP1 motifs, and two CUB domains. ADAMTS13 limits platelet accumulation in microvascular thrombi by cleaving the Tyr1605-Met1606 bond in von Willebrand factor, and ADAMTS13 deficiency causes a lethal syndrome, thrombotic thrombocytopenic purpura. ADAMTS13 domains required for substrate recognition were localized by the characterization of recombinant deletion mutants. Constructs with C-terminal His6 and V5 epitopes were expressed by transient transfection of COS-7 cells or in a baculovirus system. No association with extracellular matrix or cell surface was detected for any ADAMTS13 variant by immunofluorescence microscopy or chemical modification. Both plasma and recombinant full-length ADAMTS13 cleaved von Willebrand factor subunits into two fragments of 176 kDa and 140 kDa. Recombinant ADAMTS13 was divalent metal ion-dependent and was inhibited by IgG from a patient with idiopathic thrombotic thrombocytopenic purpura. ADAMTS13 that was truncated after the metalloprotease domain, the disintegrin domain, the first TSP1 repeat, or the Cys-rich domain was not able to cleave von Willebrand factor, whereas addition of the spacer region restored protease activity. Therefore, the spacer region is necessary for normal ADAMTS13 activity toward von Willebrand factor, and the more C-terminal TSP1 and CUB domains are dispensable in vitro.     

血栓性血小板减少性紫癜37例临床分析

目的:总结分析血栓性血小板减少性紫癜(TTP)患者临床表现,实验室特点及治疗反应,以提高TTP诊断水平和治疗效果。方法:对我院1998年1月～2009年4月期间诊断为TTP的37例患者进行临床特征和治疗转归分析,对所有病例的外周血涂片进行破碎红细胞计数,计数5000个红细胞中所含裂红细胞进行定量。结果:37例患者仅7例(18.9%)出现典型TTP五联征(发热、血小板减少、微血管病性溶血性贫血、神经系统症状和肾脏损害);30例TTP患者(81.1%)出现三联征(血小板减少、微血管病性溶血性贫血、神经系统症状)。本组病例中主要的致病因素为自身免疫性疾患,特发性TTP占56.76%。本组病例外周血涂片100%存在破碎红细胞,均值为4.4%,范围为0.3%～13.4%。本组病例的治疗以血浆置换和输注血浆为主,治疗有效率88.46%;接受血浆输注治疗的患者缓解率仅为18%,而死亡率为82%。结论:TTP诊断仍然依赖临床表现特点,破碎红细胞计数是非常有价值的诊断指标。血浆置换联用血浆输注仍是治疗TTP的首先方法。     

Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure, mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case

Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (>5 μg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case.     

Chronic immune thrombocytopenic purpura in hemophilia A.

Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding.     

Immunoglobulin Responses in Rubella and its Complications

Normal responses of rubella-specific IgG and IgM antibody were assessed in eight patient by immunofluorescence. A prolonged rubella-specific IgM response was shown in three patients with complications of rubella infection. Two patients had thrombocytopenic purpura and one had carpal-tunnel compression.     

预防性应用抗生素对糖皮质激素治疗老年ITP并发感染的影响

目的:探讨预防性应用抗生素对糖皮质激素治疗老年特发性血小板减少性紫癜并发感染的影响。方法:将哈尔滨医科大学附属第二医院血液科2012年3月~2015年3月的收治的72例老年特发性血小板减少性紫癜患者随机分为两组,自应用糖皮质激素第一天开始观察15天,观察组自应用糖皮质激素开始即使用抗生素,对照组不常规应用抗生素,以出现感染症状即开始应用抗生素,同时定为观察终止。比较两组患者感染发生率的差异。结果:观察组感染发生率为38.89%,对照组为69.44%,较观察组显著升高,差异有统计学意义(P0.05)。两组患者感染发生部分的分布情况比较无统计学差异(P0.05),以呼吸系统感染发生率最高,其次是尿路感染。结论:预防性的使用抗生素可以降低糖皮质激素治疗老年特发性血小板减少性紫癜患者过程中感染的发生率。     

Plasma exchange for removal of anti-A and anti-B group antibodies in AB0 major-incompatible bone marrow transplantation

Between 1980-1986 seven patients underwent AB0-major incompatible bone marrow transplantation. Incompatible anti-A and anti-B antibodies could be decreased by the plasma exchange from titers 8-256 down to 0-8. Our practice combined with additional depletion of erythrocytes from marrow allowed to transplant all patients successfully, however, one patient demonstrated an acute haemolytic reaction during infusion of marrow. Plasma exchange was fairly well tolerated, however, 4 patients developed slight urticarial reactions. Both thrombocytopenic patients overcompensated the platelet loss caused by the exchange.     

Severe thrombocytopenia in Epstein-Barr virus-induced mononucleosis.

Severe thrombocytopenia is a rare complication of Epstein-Barr virus-induced infectious mononucleosis. We evaluated the clinical and laboratory data from seven patients seen between 1976 and 1985 whose lowest platelet counts varied from 3 to 25 x 10(9) per liter. Five of the seven patients were initially thought to have either acute leukemia or idiopathic thrombocytopenic purpura; eventually, however, primary Epstein-Barr virus infections were confirmed in all patients. Two of six patients tested had antiplatelet antibodies during the acute phase of their illnesses. Eight additional patients with acute disease who had only mild thrombocytopenia (94 to 144 x 10(9) per liter) were also tested for platelet antibodies with negative results. Steroid therapy was administered to three patients and platelet transfusions to one. All seven patients recovered with no serious hemorrhagic sequelae.     

Streptokinase in central retinal vein occlusion: a controlled clinical trial.

Forty patients with central retinal vein occlusion were allocated at random either to a treatment group given streptokinase followed by anticoagulatns or to a control group given no specific treatment. The two groups, which were each of 20 patients, were broadly similar in respect of clinical and laboratory values and similar in their initial visual acuity. At follow-up ("final" vision) the visual acuity in the treated group was significantly better than in the untreated group. Only one treated patient developed thrombotic glaucoma compared with four controls. Streptokinase may, however, have been responsible for vitreous haemorrhage (and permanent loss of vision) in three patients and hence probably has only a limited role in the treatment of central retinal vein occlusion.     

ADAMTS13, von Willebrand factor specific cleaving protease

ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats) is the specific von Willebrand factor (VWF)-cleaving protease. ADAMTS13 was partially purified from human plasma in 1996 and its gene was cloned in 2001. In case of vascular injury, multimeric VWF is the mediator of both platelet adhesion to the sub-endothelium and platelet aggregation within the microvessels at high shear rates of blood flow. ADAMTS13 regulates VWF adhesive capacity by reducing the size of VWF multimers. A severe functional deficiency of ADAMTS13 (activity lower than 10%) is associated with most cases of thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy characterized by the spontaneous formation, within the microcirculation, of VWF-rich platelet thrombi responsible for a mechanical hemolytic anemia, a consumption thrombocytopenia and a multivisceral ishemia. TTP is a rare disease (4 cases/10(6)/year) with a life-threatening prognosis in the absence of an appropriate treatment in emergency (plasmatherapy). In 90% of cases, TTP is acquired and related to the development of auto-antibodies to ADAMTS13. In the other cases, TTP is inherited via bi-allelic autosomic recessive mutations of ADAMTS13 gene (Upshaw-Schulman syndrome). A better characterization of ADAMTS13 structure/function combined to clinical trials led in TTP patients is crucial to evaluate the relevance of either a -plasma-purified or a -recombinant ADAMTS13 as a therapeutic agent.     

Plasma exchange and human factor VIII concentrate in managing haemophilia A with factor VIII inhibitors.

Plasma exchanges were combined with human factor VIII concentrate therapy in the treatment of major bleeding episodes in five patients with haemophilia A and factor VIII inhibitors. All patients had a good clinical response to combined treatment. Inhibitor levels showed satisfactory falls before rapid secondary increases of inhibitor levels took place. A sixth patient with von Willebrand''s disease and a factor VIII clotting activity inhibitor was successfully prepared for operation using plasma exchange. Postoperative haemostasis and healing were normal. In two patients the plasma exchanges were relatively more effective than the administered human factor VIII in reducing the levels of factor VIII inhibitor. Combined plasma exchange and human factor VIII treatment may offer a rapidly effective means of reducing factor VIII inhibitor levels in this group of patients, together with significant saving of costs.     

Thrombotic thrombocytopenic purpura: a syndrome of intravascular platelet consumption.

In four of five patients with thrombotic thrombocytopenic purpura (TTP) in whom serial tests of hemostatic function were performed, severe thrombocytopenia, normal plasma fibrinogen concentrations and mildly increased concentrations of fibrinogen/fibrin degradation products were observed. Widespread platelet thrombi were found in arterioles and capillaries. Fibrin could be seen around some of the platelet clumps and was the main component in a small number of the thrombi in two patients. The observations show that TTP is a disorder in which intravascular platelet consumption results in disseminated platelet thrombosis. The coagulation system is apparently activated secondarily to platelet aggregation and variable quantities of fibrin are incorporated into the thrombi. Clinical improvement resulted from combined therapy with corticosteroids, heparin and drugs that suppress platelet function.