Thrombocytopenia during pregnancy: from etiologic diagnosis to therapeutic management

Thrombocytopenia complicates 10% of all pregnancies. It has many potential causes, but three are responsible for almost all cases: incidental gestational thrombocytopenia (IGT) (74%), preeclampsia and HELLP (hemolysis, elevated liver function tests, low platelet count) syndrome (21%) and immune thrombocytopenic purpura (ITP) (4%). Although there is no risk of maternal or fetal hemorrhage with IGT, a benign disorder, preeclampsia, HELLP syndrome and ITP expose mother and child to potentially life-threatening complications. Other rare causes are also associated with severe complications: thrombotic thrombocytopenic purpura, hemolytic and uremic syndrome, disseminated intravascular coagulation and von Willebrand disease type IIB. Because risks for mother and child vary so greatly according to the cause of thrombocytopenia, an accurate etiologic diagnosis is essential to ensure optimal therapeutic management.     

Antineutrophil cytoplasmic autoantibody-associated diseases: a rheumatologist's perspective

Autoantibodies against neutrophil cytoplasmic antigens (ANCA) produce two major immunofluorescence (IF) patterns on ethanol-fixed granulocytes: the "classical" (centrally accentuated) C-ANCA, associated with Wegener's granulomatosis (WG), and P-ANCA (perinuclear), which mainly occur in renal vasculitis. Rheumatic manifestations are an important clinical finding in systemic vasculitis, often preceding a fulminant course and sometimes imitating various rheumatic disorders. We analyzed the incidence of ANCA in rheumatic patients and looked for the frequency of rheumatic symptoms in systemic vasculitis. In WG (n = 186), we found rheumatic symptoms in 55% (myalgia, 45%; arthritis, 21%); in 90%, rheumatic complaints were associated with active vasculitis. In 730 patients with various rheumatic conditions (eg, 268 rheumatoid arthritis, 130 systemic lupus erythematosis [SLE], 32 sharp-S, 50 ankylosing spondylitis, 43 systemic sclerosis) no C-ANCA were found. On the contrary, the P-ANCA pattern was seen in seven of 62 giant cell arteritis, five of 27 Felty's/Still's syndrome, and four of 130 SLE patients in addition to renal vasculitis (21/74). We demonstrated that 95% of C-ANCA-positive sera react with proteinase 3 (PR3 or myeloblastin). Using monoclonal antibodies, we showed that PR3 is expressed on the plasma membrane of neutrophil granulocytes and monocytes; thus, PR3 autoantigens are accessible for circulating antibodies. The detection of ANCA in sera from vasculitis and other rheumatic diseases is of immunodiagnostic value and provides new insight in the pathogenesis of systemic vasculitides.     

Hereditary nephritis with macrothrombocytopenia: phenotypic variety and the genotypic defect

A number of patients present to nephrologists with end-stage renal failure of unknown cause and many have small kidneys, making renal biopsy inadvisable. A small number may have clues to the diagnosis of hereditary nephritis, as in the patient we present here. The propositus was a 22-year-old man, who was admitted to our nephrology ward because of recently discovered renal insufficiency. Ultrasound examination revealed bilateral small kidneys. He was severely hypertensive; audiometry and ophthalmic examinations were normal. Thrombocytopenia with giant platelets was observed in peripheral blood smears. Basophilic cytoplasmic inclusions (D?hle-like bodies) were present in neutrophil and basophilic granulocytes. A family history of nephropathy associated with macrothrombocytopenia was obtained. Epstein syndrome was diagnosed, a rare autosomal dominant disorder. He started hemodialysis and subsequently received a living donor kidney transplant (from his mother). Molecular genetics has considerably clarified the field of hereditary nephritis associated with macrothrombocytopenia by demonstrating that these syndromes involve a similar molecular defect. It was first shown that these syndromes were linked to the same locus on chromosome 22q. Then the gene involved--encoding non-muscle myosin heavy chain 9 (MYH9)--was identified. This entity ("MYH9 disease") must be clearly differentiated from Alport syndrome (type IV collagen disease). In conclusion, this case serves to remind us: 1) that in patients presenting late to nephrologists with bilateral small kidneys, the diagnosis can still be made in some instances on the basis of other clinical signs known to be associated with recognized inherited syndromes; 2) that there are various types of inherited thrombocytopenia associated with nephritis; screening for nephritis is mandatory in all of them.     

Syndrome hémophagocytaire réactionnel : une cause probablement sous-estimée de thrombopénie en réanimation

Thrombocytopenia is a common feature in ICU patients which occurs usually in case of infection or septic shock. Its mechanisms, which are often unclear, include the haemophagocytic syndrome initially linked with histiocytic proliferation but probably also associated with infectious diseases. This syndrome is characterized by a phagocytosis of medullar blood cells. Reactive haemophagocytic syndrome can probably lead to thrombocytopenia in ICU patients as in this case report of a E. Coli infection.     

Influence of polyclonal ATGs on expression of adhesion molecules: an experimental study

BACKGROUND: The aim of our study was to assess the influence of polyclonal antithymocyte globulins (ATGs) on the expression of adhesion molecules on lymphocytes, neutrophils, and thrombocytes by means of flow cytometry. ATGs are employed in various regimens for solid organ transplantation. Immunosuppression with ATGs may influence the expression of adhesion molecules on thrombocytes, lymphocytes, and neutrophils due to nonspecific antibodies directed against myeloid and nonmyeloid cells. MATERIAL AND METHODS: Depletion, activation, and expression of adhesion molecules on thrombocytes (CD41, CD42, CD62p and CD107a), neutrophils, and lymphocytes (CD11, CD18, CD62L) were studied in vitro in whole blood of healthy volunteers by means of flow cytometry after incubation with different dosages of three ATGs. RESULTS: Our data showed no ATG-mediated cytotoxic activity against platelets. ATGs were able, however, to induce activation of platelets through increased expression of P-selectin and hLAMP-1. ATGs also influenced the expression of adhesion molecules on lymphocytes and neutrophils by reducing the expression of CD62L. Furthermore, the effects of ATG on CD11/CD18 were dependent on the dosage and type of ATG. CONCLUSION: Polyclonal ATGs induced expression of adhesion molecules and activation of unstimulated thrombocytes as well as reduced the expression of adhesion molecules on lymphocytes and neutrophils. Increased adhesion of thrombocytes may be responsible for the undesirable side effects observed in clinical practice such as thrombocytopenia. However, reduction in the expression of adhesion molecules on lymphocytes and neutrophils may decrease the effects of ischemia/reperfusion injury.     

A case of thrombocytopenia associated with the use of hydroxychloroquine following open heart surgery

INTRODUCTION

Thrombocytopenia is a common problem occurring in patients and drug-induced thrombocytopenia is a significant cause of thrombocytopenia.

PRESENTATION OF CASE

We present an unusual case of thrombocytopenia that was considered to be associated with the use of hydroxychloroquine in the late term following open heart surgery.

DISCUSSION

The drug-induced thrombocytopenia, mechanical destruction of the platelets, and hemodilution are common causes of low platelet count. Although drug-induced immune thrombocytopenia has a mild clinical course in most cases (in this case it has severe clinical course), some patients may experience life-threatening hemorrhages. The decision to discontinue the drug that is deemed to be responsible from the drug-induced thrombocytopenia (DITP) relies on the clinical condition of the patient. The diagnosis is mostly established by discontinuation, exclusion, and correlation because the tests performed to detect drug-dependent antibodies (DDAbs) for the diagnosis of DITP are time-consuming, and these tests are also not commonly available. The authors of the current study diagnosed DITP by discontinuation of the drug. We suggest that the use of hydroxychloroquine could be severe thrombocytopenia occurring after open heart surgery.

CONCLUSION

The medication history must be carefully reviewed in patients presenting with thrombocytopenia, and if the medications could cause thrombocytopenia must be discontinued.     

Effect of induced thrombocytopenia on experimental circulatory shock

Thrombocytopenia (i.e., a circulating platelet count of 20% of normal) was induced in dogs by glass contact perfusion. Splanchnic artery occlusion (SAO) shock was then induced in thrombocytopenic as well as in sham-thrombocytopenic dogs. Thrombocytopenia significantly attenuated the early postrelease increase in SFP, an observation indicative of a reduced formation of platelet aggregates in response to the shock state. However, thrombocytopenia did not significantly alter the heart rate, superior mesenteric artery flow, or portal venous pressure response to SAO shock. Mean arterial blood pressure was transiently higher in the thrombocytopenic dogs (i.e., 5 min after release) but this difference soon disappeared. Plasma accumulation of prostaglandin E and F_2α; the lysosomal protease; cathepsin D; and the toxic factor, MDF, were not modified by thrombocytopenia in shock dogs. These data suggest that neither platelet release of humoral substances nor platelet aggregation are primary mechanisms in the development of the shock state. The data also indicate that removal of a large number of circulating platelets does not confer protection during SAO shock. These findings, however, do not rule out a secondary role of platelets in the pathophysiology of SAO shock.     

Skin changes in rheumatic diseases

The Intruduction includes those eflorescences that might be useful for diagnostics in rheumatology. Further in the text we have described four groups of rheumatic disorders. The first group: rheumatic diseases (lupus erythematosus, dermatomyositis, systemic scleroderma, the mixed connective tissue disease, allergic vasculitis, polyarteritis) which are the most common from the dermatological point of view. The second group: rheumatic diseases (Wegener's granulomatosis, rheumatoid arthritis, Sj?gren, Reiter and Beh?et syndrome and Kawasaki's disease) which are rarely of interest to our dermatologists. In this group there is also psoriatic arthritis, which is not rare in dermatology but its diagnostics and treatment belong to rheumatologists' field of expertise. The third group: infections (rheumatic fever, diseminated gonococcal infection, subacute bacterial endocarditis, Lyme disesease). The fourth group: metabolic disorders (gout). The diseases of the first group are described completely. In the second, third and fourth group of the diseases we have included only skin changes.     

The fate of human platelets perfused through the pig liver: implications for xenotransplantation

Burlak C, Paris LL, Chihara RK, Sidner RA, Reyes LM, Downey SM, Tector AJ. The fate of human platelets perfused through the pig liver: implications for xenotransplantation.
Xenotransplantation 2010; 17: 350–361. © 2010 John Wiley & Sons A/S. Abstract: Background: Pig liver xenotransplantation could offset the shortage of livers available for orthotopic liver transplantation. Studies in pig and baboon liver xenografts revealed the main obstacle to be a lethal thrombocytopenia that occurred within minutes to hours of transplantation. Methods: We have created a model of xenotransplantation‐induced thrombocytopenia using ex vivo pig liver perfusion with human platelets. Thrombocytopenia was examined using fluorescently labeled platelets during the ex vivo perfusion and coculture with primary liver sinusoidal endothelial cells (LSEC). Results: Ex vivo liver perfusion revealed that 93% of human platelets were removed from circulation after 15 min. Endothelial cells and platelets were not activated based on tissue factor release into the perfusate. Biopsies from the ex vivo perfusion at 15 and 30 min and in vitro analysis indicated that human platelets are phagocytosed by pig LSEC and degraded in phagosomes. Sixty to 120 min after the addition of platelets to the ex vivo perfusion system, we observed platelet fragments and degraded platelets in hepatocytes. Platelet phagocytosis was not mediated by opsonization as Fc blocking had no effect on platelet phagocytosis. In vitro uptake of human platelets by primary LSEC cultures peaked at 15 min followed by a greater than 55% decrease in platelet fluorescence after 3 h. Primary pig LSEC phagosomes containing human platelets were colocalized with lysosomes positive for lysosome‐associated membrane protein‐1 (LAMP1), indicating the formation of mature phagosomes within pig LSEC. Conclusions: Our observation of pig LSEC phagocytosis of human platelets describes a novel mechanism of large‐particle uptake in the liver. The creation of a model system to study xenotransplantation‐induced thrombocytopenia makes possible the investigation into mechanisms that mediate platelet loss.     

Kidney Transplant Recipients With Rheumatic Diseases: Epidemiological Data From the Polish Transplant Registries 1998–2015

Chronic kidney disease (CKD) is a common complication of rheumatic disorders. We analyzed the incidence of different rheumatic conditions as a primary diagnosis of end-stage renal disease (ESRD) in kidney transplant recipients in Poland.Data were received from the national waiting list for organ transplantation (Poltransplant) registries. Primary diagnosis leading to ESRD were analyzed in 15,984 patients who received kidney transplants between 1998 and 2015. There was no information about primary diagnosis in 4981 cases (31%) and in 1482 cases (9%) the diagnosis was described as unknown.Rheumatic diseases were specified in 566 (5.14%) kidney transplant recipients: lupus erythematosus, (systemic lupus erythematous nephritis) in 211 (1.92%), vasculitis in 176 (1.60%), amyloidosis AA in 82 (0.75%), hemolytic uremic syndrome in 59 (0.54%), secondary glomerulonephritis in 24 (0.22%), scleroderma in 9 (0.08%), rheumatoid arthritis in 4 (0.04%) and Sjögren syndrome in 1 (0.01%). Graft survival at 1 and 5 years were significantly better in the nonrheumatic versus rheumatic group (90 vs 87% and 76 vs 72% respectively, P = .04). Recipient survival at 5 years was significantly better in the nonrheumatic versus the rheumatic group (88 vs 84%, P = .02).Our study showed that systemic lupus erythematosus and systemic vasculitides are the major rheumatic causes of ESRD in the Polish population. Long-term graft and recipient survival were significantly better in the nonrheumatic versus the rheumatic group in the Poltransplant cohort.     

The incidence of thrombocytopenia associated with continuous renal replacement therapy in critically ill patients

Abstract

Introduction: Thrombocytopenia in the intensive care unit (ICU) is a commonly experienced complication; the pathology is not always easily understood. Continuous renal replacement therapy (CRRT) provides a method to dialyze unstable critically ill patients. We hypothesized that CRRT may precipitate a form of thrombocytopenia. In trials thrombocytopenia occurred at rates as high as 70%. The etiology remains unknown and results in additional diagnostic workup, as well as possible drug therapy. The extent, duration and temporal relation of thrombocytopenia remain to be determined. Objectives: Identify a pattern in platelet fluctuations after the initiation of CRRT and its impact on health care. Methods: A retrospective study was conducted in patients receiving CRRT for >24?h with no pre-existing thrombocytopenia. Patients initiated on CRRT had daily platelet counts monitored, and CRRT attributes and therapeutic interventions were collected. Platelets were assessed for time to nadir, degree of decline and time to return to baseline after discontinuation of CRRT. Results: Forty-nine patients met inclusion criteria. Thirty-seven percent of patients receiving heparinoids were tested for heparin-induced thrombocytopenia (HIT), during CRRT, with 39% of these patients having therapy changed to non-heparinoid agents due to suspected HIT; no HIT antibodies were positive. Eleven patients (22%) receiving anticoagulants, prophylactically or therapeutically had them held for a drop in platelets. There was a mean decline in platelets of 48% with a mean of 4.6 days to the nadir. An average 2.48 days were observed until rebound to >150?×?10³/mm³. Statistical analysis failed to identify any patient attributes that correlated with the probability of thrombocytopenia. Conclusion: CRRT appears to be associated with a drop in platelets within the first 5 days of therapy with an average decline of 48%. However, platelets appear to return to >150?×?10³/mm³ after cessation of CRRT. This fluctuation should be considered in the setting of patients developing thrombocytopenia after initiation of CRRT.     

Clindamycin vasculitis in patients with peripheral arterial vascular disease

Clindamycin was first synthesized in 1966. It is a chemical derivative of lincomycin with activity against aerobic gram-positive and gram-negative bacteria. The side effects include diarrhea, pseudomembranous colitis, metallic taste in the mouth, transient elevation of transaminases, granulocytopenia, thrombocytopenia, and rash. The incidence of maculopapular rashes has been reported to be approximately 10%. Leukocytoclastic angitis or vasculitis induced by clindamycin has been reported (Lambert et al., Cutis 30:615–619, 1982) and this is a very serious complication in patients with peripheral arterial vascular diseases which may leads to severe and deep necrotizing vasculitis. We report two cases of necrotizing vasculitis due to clindamycin which was used for the treatment of chronic wounds in patients suffering of peripheral vascular disease.     

Kawasaki disease--a cause of vasculitis in children

Two cases of Kawasaki disease (mucocutaneous lymph node syndrome) with peripheral vasculitis of the extremities are described. Ischemia began 2-3 weeks after the onset of symptoms and was present for greater than 24 h before hospitalization. Despite supportive therapy, gangrene of the extremities resulted in amputation. The vasculitis causes inflammation and occlusion of vessels, and therefore therapy aimed at arterial dilatation may not be beneficial. Early recognition of ischemia and treatment with correction of hypovolemia, anticoagulation, and hyperbaric therapy may be useful. Steroids may decrease peripheral vasculitis, but there is also an associated increased risk of coronary aneurysms.     

In vitro assessment of dose-dependent platelet activation by polyclonal antithymocyte globulins: a flow-cytometric analysis

Polyclonal antithymocyte globulins (ATGs) are immunosuppressive drugs widely used in transplantation and hematologic disorders. Treatment with ATGs can induce side effects such as neutropenia and thrombocytopenia because of unspecific antibodies directed against nonmyeloid cells present in these preparations. Depletion, activation, and expression of adhesion molecules on platelets in vitro were studied in the whole blood of healthy volunteers by means of flow cytometry after incubation with different doses of three polyclonal ATGs. Our data show no ATG-mediated cytotoxic activity against platelets. ATGs are able to induce activation of platelets through increased expression of P-selectin and hLAMP-1 and higher percentages of gated thrombocytes expressing these molecules. Furthermore, increased expression of hLAMP-1 presented a dose-dependent pattern. ATGs induced activation and enhanced expression of adhesion molecules in unstimulated platelets. Increased adhesion may be responsible for undesirable side effects such as thrombocytopenia and reticulopenia.     

Clinical analysis of thrombocytopenia in chronic dialysis patients

Thrombopoietic status in dialysis patients is controversial. This study addressed this issue by analyzing factors associated with thrombopoiesis. One hundred and fifty-one dialysis patients(119 HD and 32 CAPD) and 41 age-matched control subjects were studied. Thrombocytopenia was defined as a platelet count less than 150 x 10(9)/l. Reticulated platelets(RET), a marker for marrow megakaryopoiesis, were measured using thiazole orange dye by flowcytometry. Serum thrombopoietin (TPO) level was measured by ELISA. Hepatitis C virus(HCV) antibody, platelet-associated IgG(PAIgG), and other clinical parameters were examined in the patients. The platelet counts in the HD patients were significantly lower than those in the CAPD or controls. The incidence of thrombocytopenia was 30.0% in the HD patients. Thrombocytopenia was more prominent in the HCV-infected HD patients in whom PAIgG was mostly positive(81.8%) and its titer was remarkably high(102.9 +/- 92.7 pg/ml). There were significant differences in the RET counts between patients with and without thrombocytopenia. None of the other parameters, such as iPTH, beta 2 microglobulin, and Kt/V, nor any prescribed drugs were related to thrombocytopenia. Serum TPO was significantly higher in HD patients(135.9 +/- 60.1 pg/ml) than in the controls(97.0 +/- 53.4 pg/ml). In conclusion, thrombocytopenia is frequent in HD patients, especially in HCV-infected HD patients. Reduced marrow magakaryopoiesis is mostly responsible for thrombocytopenia and peripheral destruction of platelets could be, in part, involved. Mild elevation of serum TPO possibly indicates a counter-response to decreased mass of megakaryocyte in bone marrow.     

Intravenous immunoglobulin therapy in rheumatic diseases

Prepared from the collective plasma of several thousand people, therapeutic intravenous immunoglobulin (IVIg) consists mostly of human polyspecific IgG. In addition to its use in primary and secondary immune deficiencies, IVIg is used in the treatment of several rheumatic conditions, including Kawasaki disease, dermatomyositis and antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. In these diseases, IVIg therapy generally involves the use of 2 g/kg administered over either 2 or 5 consecutive days. However, dosage regimens have not been thoroughly explored, and indications for IVIg in most rheumatic diseases, such as systemic lupus erythematosus, polymyositis and catastrophic antiphospholipid syndrome, derive from its off-label usage. Randomized clinical trials are warranted to support the evidence-based use of IVIg, and to identify the ideal administration protocols to maximize the benefits of what is a limited resource. Further research to improve the therapeutic application of IVIg relies essentially on the conception of next-generation immunoglobulin preparations and optimization of combined therapies with immunomodulatory drugs and biologic agents.     

Don't miss HIT (heparin induced thrombocytopenia)

Thrombocytopenia following a burn injury can cause serious complications. There are several possible causes including the burn itself, drugs, sepsis and disseminated intravascular coagulation (DIC). A case report of a patient who developed heparin induced thrombocytopenia (HIT) whilst on haemofiltration for acute renal failure is presented. The aetiology of thrombocytopenia in a burns patient and its management is discussed. The key to effective treatment of thrombocytopenia is identification of the cause. HIT is an important diagnosis to include in the differential.     

Hemolytic uremic syndrome associated with glomerular disease

Secondary hemolytic uremic syndrome (HUS) is uncommon. When it occurs, it is usually in association with pregnancy, malignancy, severe hypertension, drugs, or collagen vascular diseases. It has rarely been reported in patients with glomerular disease. Two such patients with secondary HUS are described. A 17-month-old girl with hematuria and the nephrotic syndrome, negative antistreptolycin O (ASO) titer, and low serum levels of C3 and C4 developed oliguria, progressive azotemia, thrombocytopenia, and microangiopathic hemolytic anemia. A kidney biopsy showed fibrin in glomerular capillaries and cresentic membranoproliferative glomerulonephritis. A 22-year-old man with a 16-year history of relapsing minimal change nephrotic syndrome had been in remission for 5 years when he experienced nephrotic syndrome relapse and developed thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. A kidney biopsy revealed foot process fusion and obstruction of glomerular capillaries with fibrin and platelets. These cases illustrate that HUS can occur in association with other glomerular diseases and should be considered when thrombocytopenia and hemolytic anemia occur in a nephritic or nephrotic patient.     

Hyper-IgE syndrome and autoimmunity in Mexican children

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent skin abscesses, recurrent pneumonia with pneumatocele formation, eczema, eosinophilia, and elevated levels of serum IgE. Patients with the autosomal recessive (AR) form of HIES appear to be prone to developing autoimmune diseases. We present two cases of HIES with autoimmune complications; one case was a product of a consanguineous marriage, the other one was a sporadic case. The first patient presented with recurrent episodes of erythema nodosum, warts, bronchiolitis obliterans and thrombocytopenia. The second patient developed glomerulonephritis resulting in endstage renal failure. She later developed malar rash, oral ulcers, cerebral infarcts with vasculitis and positive ANA, anti-dsDNA, and antiphospholipid antibodies. We discuss the dilemma in treating patients who present with both primary immunodeficiency and autoimmunity.     

Platelets: active players in the pathogenesis of arthritis and SLE

Nearly one trillion platelets circulate in the blood to monitor and preserve the integrity of the vasculature. However, haemostasis is not their only function. Platelets are also potent immune cells capable of a range of effector responses. Studies have shown that platelets can have unexpected roles in rheumatic diseases. In patients with rheumatoid arthritis (RA), IL-1-containing platelet-derived vesicles called microparticles are abundant in arthritic joint fluid. These microparticles can elicit production of inflammatory mediators from resident synovial fibroblasts, which have an integral role in the development of arthritis. Platelets also serve as a source of prostaglandins that contribute to synovial inflammation. Furthermore, serotonin released by platelets helps drive the persistent vascular permeability that characterizes the microvasculature of the inflamed synovium, an unexpected function for a cell that more typically serves as a guardian of vascular integrity. Beyond RA, platelet activation has been observed in systemic lupus erythematosus, mediated at least in part through the interaction of circulating immune complexes with platelet Fc receptors and by promotion of interferon release from plasmacytoid dendritic cells. These findings point to a distinct role for platelets in autoimmunity and support the possibility that platelets are an attractive target in rheumatic disease.