Surg Today DOI 10.1007/s00595-013-0823-y
REVIEW ARTICLE
Postoperative thrombotic thrombocytopenic purpura Ahmet Emre Eskazan • Deram Buyuktas Teoman Soysal
•
Received: 18 June 2013 / Accepted: 10 December 2013 Ó Springer Japan 2013
Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia occurring due to platelet and von Willebrand factor deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia. TTP can be idiopathic or secondary, and there are several causes of secondary TTP. There is a clinical syndrome resembling TTP that occurs after surgical procedures, so-called ‘‘postoperative TTP’’ (pTTP). In this review, the differential diagnosis, pathogenesis and clinical and laboratory features of pTTP, together with the treatment modalities and outcomes of the patients, are discussed. The pTTP is a diagnosis of exclusion, and disseminated intravascular coagulation, heparininduced thrombocytopenia and medication-induced effects should be ruled out. As in classical TTP, patients with pTTP should be diagnosed and treated with therapeutic plasma exchange (TPE) as early as possible to reduce their morbidity and mortality. Although rarely seen, surgeons and physicians of all specialties should be alert to the possibility of pTTP, and since pTTP is a life-threatening event that usually can be treated successfully with TPE, especially when diagnosed early in its course, it is critical to recognize and treat pTTP promptly.
A. E. Eskazan (&) T. Soysal Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey e-mail: [email protected] D. Buyuktas Department of Hematology/Oncology, Georg August University, Go¨ttingen, Germany
Keywords Thrombotic thrombocytopenic purpura Postoperative Surgery Therapeutic plasma exchange ADAMTS13
Introduction Thrombotic thrombocytopenic purpura (TTP) or Moschcowitz syndrome is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia (MAHA) due to platelet and von Willebrand factor (vWF) deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia [1]. Molecular defects and antibody-mediated deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13—a vWF cleaving enzyme) provide the central pathophysiological basis for the understanding of this disorder [2]. Without the proper cleavage of vWF by ADAMTS13, unusually large multimers of vWF (ULvWF) are found in the plasma of patients with TTP, and this was the turning point for the understanding of the disease pathophysiology. The presence of the highly platelet-adhesive ULvWF multimers provided a plausible explanation for the platelet- and vWF-rich thrombi observed in the small vessels of patients with TTP. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by auto-antibodies directed against ADAMTS13 [3]. Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Although TTP was first characterized by the classical diagnostic pentad of thrombocytopenia, MAHA, fever, fluctuating neurological manifestations (i.e., hallucinations,
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bizarre behavior, altered mental status, stroke or headaches) and renal insufficiency [4], it can present without all of these findings, and the presence of otherwise unexplained thrombocytopenia, MAHA, and an elevated lactate dehydrogenase (LDH) level strongly suggests TTP [5]. Renal insufficiency and neurological events are the endstage manifestations, and the disease should optimally be recognized well before these manifestations occur. Patients can have either idiopathic or secondary TTP. There are several causes of secondary TTP [6], including pregnancy, infections [including human immunodeficiency virus (HIV)-associated TTP and hemolytic-uremic syndrome (HUS), which can be acquired by the ingestion of enterohemorrhagic bacteria that produce Shiga toxin (e.g., Escherichia coli of serotype 0157:H7)], pancreatitis, collagen vascular disease, cancer, bone marrow or solid organ transplantation and drugs. There is a clinical syndrome resembling TTP occurring after surgical procedures, which is called ‘‘postoperative TTP’’ (pTTP), and there have been a number cases of pTTP reported following cardiac and vascular surgery, renal and liver transplantation and orthopedic, urological and abdominal surgical procedures, as well as cosmetic surgery, published in the literature [7, 8]. The causes of secondary TTP are listed in Table 1. Although rarely seen, or maybe not well recognized, pTTP is a lethal complication of surgery, and surgeons should be aware of this life-threatening disorder. The objective of this review is to provide healthcare professionals (mainly surgeons and clinicians in other specialties) with practical guidance on the management of pTTP, including its differential diagnosis, pathogenesis, clinical and laboratory features, treatment options and outcomes.
different physiological bases. TTP, autoimmune hemolysis/ Evans syndrome, disseminated intravascular coagulation (DIC), pregnancy-associated disorders, such as. hemolysis, elevated liver enzymes and low platelets (HELLP) and eclampsia, drugs, malignant hypertension, infections, autoimmune diseases, vasculitis, HUS, malignancy and catastrophic antiphospholipid syndrome are the main causes of TMA [6]. With regard to pTTP, patients characteristically have a normal complete blood count (CBC) prior to surgery, then develop MAHA with thrombocytopenia about 5–9 days after surgery [7]. Fever, renal insufficiency and neurological manifestations are variably present as in classic TTP. In some patients, the diagnosis of pTTP can be delayed because, due to the recent surgery, these manifestations are often attributed to other causes, such as blood loss, hemodilution, infection, DIC or heparin-induced thrombocytopenia (HIT) [7] (Table 2). DIC is a clinicopathological syndrome which is characterized by systemic activation of pathways leading to and regulating coagulation, which can result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors, which may result in clinical bleeding [9]. Since surgical patients are prone to infections, DIC can be observed as a possible complication of a severe infection in the postoperative patient. HIT is an antibody-mediated adverse effect of heparin, which is caused by the development of IgG antibodies directed against a complex of platelet factor 4 (PF4) and heparin. The IgG/PF4/heparin complexes bind to and activate platelets through their Fc receptors, and may also generate thrombin by other actions, thus resulting in a prothrombotic condition that is associated with venous and
Differential diagnosis TMAs refer to a diverse group of different but related syndromes characterized by MAHA and thrombocytopenia, with
Table 2 The differential diagnosis of postoperative thrombotic thrombocytopenic purpura Blood loss Hemodilution
Table 1 The causes of secondary thrombotic thrombocytopenic purpura
Volume depletion Urinary tract obstruction
Pregnancy Infections (including HIV-associated TTP and HUS)
Infections Seizures
Pancreatitis
Organic lesions in the brain
Collagen vascular disease
Acute stroke
Malignancy (many cancers, especially adenocarcinomas) Bone marrow or solid organ transplantation (transplant-associated microangiopathy)
Drug-induced thrombocytopenia
Drugs Surgery HIV human immunodeficiency virus, HUS hemolytic uremic syndrome
123
Hemolytic uremic syndrome Heparin-induced thrombocytopenia Disseminated intravascular coagulation Post-transfusion thrombocytopenia Malignancy
Surg Today
arterial thrombosis [10]. Heparin and/or low molecular weight heparins (LMWHs) are commonly used in patients undergoing cardiac, vascular, orthopedic and gynecological surgical procedures, which may result in HIT. HIT develops anywhere from 5 to 10 days after the initiation of treatment [10]. Since pTTP usually occurs 5–9 days after surgery, it is sometimes hard to distinguish these two clinical conditions from each other in a postoperative patient who presents with thrombocytopenia. As in classic TTP, pTTP is a diagnosis of exclusion, and DIC and HIT should be excluded from the differential diagnosis. The diagnosis should be based mainly on the clinical history and examination of the patient and the blood films, in addition to some routine and specific laboratory tests. pTTP, DIC and HIT all present with thrombocytopenia. The presence of fragmented red cells (schistocytes) in the blood film, together with non-immune hemolytic anemia (MAHA) distinguishes TMAs from HIT. However, schistocytes are not specific to TTP, as they may also be observed in DIC (but rarely constitute [10 % of the red cells [9]). Moreover, the typical absence of an abundant amount of schistocytes in pTTP (unlike TTP) may make this condition more likely to be missed. In both TTP and DIC, the reticulocyte counts and serum LDH levels are elevated, with a low haptoglobin level, as a result of the ongoing hemolysis. Coagulation tests should be performed, because the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are found to be prolonged, together with the elevation of fibrin degradation products (FDP) and/or D-dimer values, in classical DIC. These laboratory tests are usually normal in patients with TTP and HIT. However, the prolongation of aPTT can be observed in patients with HIT, due to the administration of heparin. Commonly, HIT is seen with the intravenous administration of heparin; however, it is important to be cognizant that any exposure, even to the small amount of heparin used to maintain the patency of intravenous catheters, can cause HIT. Unfractionated heparin (UFH) is the form of the drug most often associated with HIT. LMWH also can cause HIT, although not nearly as frequently as UFH [10]. Medications other than heparins should also be reviewed, to assess their possible contribution to the hematological abnormality. For example, drugs that may cause immune hemolysis and thrombocytopenia [11, 12], as well as medications that may be associated with a TTPlike clinical syndrome, such as ticlopidine [13], and certain drugs including quinine, clopidogrel, mitomycin C and antibiotics [14, 15], should especially raise suspicion. If renal insufficiency develops in a postoperative patient, volume depletion and/or urinary tract obstruction has to be ruled out in the differential diagnosis of pTTP.
A reduction in the platelet count or a clear downward trend at subsequent measurements is a sensitive (though not specific) sign of DIC [9]. Thrombocytopenia is a feature in up to 98 % of DIC cases with the platelet count being \50 9 109/L in approximately 50 % of cases [16]. In HIT, the platelet count normally falls by >50 %; the median nadir is 55 9 109/L [17, 18]. Severe thrombocytopenia (platelet count
REVIEW ARTICLE
Postoperative thrombotic thrombocytopenic purpura Ahmet Emre Eskazan • Deram Buyuktas Teoman Soysal
•
Received: 18 June 2013 / Accepted: 10 December 2013 Ó Springer Japan 2013
Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia occurring due to platelet and von Willebrand factor deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia. TTP can be idiopathic or secondary, and there are several causes of secondary TTP. There is a clinical syndrome resembling TTP that occurs after surgical procedures, so-called ‘‘postoperative TTP’’ (pTTP). In this review, the differential diagnosis, pathogenesis and clinical and laboratory features of pTTP, together with the treatment modalities and outcomes of the patients, are discussed. The pTTP is a diagnosis of exclusion, and disseminated intravascular coagulation, heparininduced thrombocytopenia and medication-induced effects should be ruled out. As in classical TTP, patients with pTTP should be diagnosed and treated with therapeutic plasma exchange (TPE) as early as possible to reduce their morbidity and mortality. Although rarely seen, surgeons and physicians of all specialties should be alert to the possibility of pTTP, and since pTTP is a life-threatening event that usually can be treated successfully with TPE, especially when diagnosed early in its course, it is critical to recognize and treat pTTP promptly.
A. E. Eskazan (&) T. Soysal Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey e-mail: [email protected] D. Buyuktas Department of Hematology/Oncology, Georg August University, Go¨ttingen, Germany
Keywords Thrombotic thrombocytopenic purpura Postoperative Surgery Therapeutic plasma exchange ADAMTS13
Introduction Thrombotic thrombocytopenic purpura (TTP) or Moschcowitz syndrome is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia (MAHA) due to platelet and von Willebrand factor (vWF) deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia [1]. Molecular defects and antibody-mediated deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13—a vWF cleaving enzyme) provide the central pathophysiological basis for the understanding of this disorder [2]. Without the proper cleavage of vWF by ADAMTS13, unusually large multimers of vWF (ULvWF) are found in the plasma of patients with TTP, and this was the turning point for the understanding of the disease pathophysiology. The presence of the highly platelet-adhesive ULvWF multimers provided a plausible explanation for the platelet- and vWF-rich thrombi observed in the small vessels of patients with TTP. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by auto-antibodies directed against ADAMTS13 [3]. Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Although TTP was first characterized by the classical diagnostic pentad of thrombocytopenia, MAHA, fever, fluctuating neurological manifestations (i.e., hallucinations,
123
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bizarre behavior, altered mental status, stroke or headaches) and renal insufficiency [4], it can present without all of these findings, and the presence of otherwise unexplained thrombocytopenia, MAHA, and an elevated lactate dehydrogenase (LDH) level strongly suggests TTP [5]. Renal insufficiency and neurological events are the endstage manifestations, and the disease should optimally be recognized well before these manifestations occur. Patients can have either idiopathic or secondary TTP. There are several causes of secondary TTP [6], including pregnancy, infections [including human immunodeficiency virus (HIV)-associated TTP and hemolytic-uremic syndrome (HUS), which can be acquired by the ingestion of enterohemorrhagic bacteria that produce Shiga toxin (e.g., Escherichia coli of serotype 0157:H7)], pancreatitis, collagen vascular disease, cancer, bone marrow or solid organ transplantation and drugs. There is a clinical syndrome resembling TTP occurring after surgical procedures, which is called ‘‘postoperative TTP’’ (pTTP), and there have been a number cases of pTTP reported following cardiac and vascular surgery, renal and liver transplantation and orthopedic, urological and abdominal surgical procedures, as well as cosmetic surgery, published in the literature [7, 8]. The causes of secondary TTP are listed in Table 1. Although rarely seen, or maybe not well recognized, pTTP is a lethal complication of surgery, and surgeons should be aware of this life-threatening disorder. The objective of this review is to provide healthcare professionals (mainly surgeons and clinicians in other specialties) with practical guidance on the management of pTTP, including its differential diagnosis, pathogenesis, clinical and laboratory features, treatment options and outcomes.
different physiological bases. TTP, autoimmune hemolysis/ Evans syndrome, disseminated intravascular coagulation (DIC), pregnancy-associated disorders, such as. hemolysis, elevated liver enzymes and low platelets (HELLP) and eclampsia, drugs, malignant hypertension, infections, autoimmune diseases, vasculitis, HUS, malignancy and catastrophic antiphospholipid syndrome are the main causes of TMA [6]. With regard to pTTP, patients characteristically have a normal complete blood count (CBC) prior to surgery, then develop MAHA with thrombocytopenia about 5–9 days after surgery [7]. Fever, renal insufficiency and neurological manifestations are variably present as in classic TTP. In some patients, the diagnosis of pTTP can be delayed because, due to the recent surgery, these manifestations are often attributed to other causes, such as blood loss, hemodilution, infection, DIC or heparin-induced thrombocytopenia (HIT) [7] (Table 2). DIC is a clinicopathological syndrome which is characterized by systemic activation of pathways leading to and regulating coagulation, which can result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors, which may result in clinical bleeding [9]. Since surgical patients are prone to infections, DIC can be observed as a possible complication of a severe infection in the postoperative patient. HIT is an antibody-mediated adverse effect of heparin, which is caused by the development of IgG antibodies directed against a complex of platelet factor 4 (PF4) and heparin. The IgG/PF4/heparin complexes bind to and activate platelets through their Fc receptors, and may also generate thrombin by other actions, thus resulting in a prothrombotic condition that is associated with venous and
Differential diagnosis TMAs refer to a diverse group of different but related syndromes characterized by MAHA and thrombocytopenia, with
Table 2 The differential diagnosis of postoperative thrombotic thrombocytopenic purpura Blood loss Hemodilution
Table 1 The causes of secondary thrombotic thrombocytopenic purpura
Volume depletion Urinary tract obstruction
Pregnancy Infections (including HIV-associated TTP and HUS)
Infections Seizures
Pancreatitis
Organic lesions in the brain
Collagen vascular disease
Acute stroke
Malignancy (many cancers, especially adenocarcinomas) Bone marrow or solid organ transplantation (transplant-associated microangiopathy)
Drug-induced thrombocytopenia
Drugs Surgery HIV human immunodeficiency virus, HUS hemolytic uremic syndrome
123
Hemolytic uremic syndrome Heparin-induced thrombocytopenia Disseminated intravascular coagulation Post-transfusion thrombocytopenia Malignancy
Surg Today
arterial thrombosis [10]. Heparin and/or low molecular weight heparins (LMWHs) are commonly used in patients undergoing cardiac, vascular, orthopedic and gynecological surgical procedures, which may result in HIT. HIT develops anywhere from 5 to 10 days after the initiation of treatment [10]. Since pTTP usually occurs 5–9 days after surgery, it is sometimes hard to distinguish these two clinical conditions from each other in a postoperative patient who presents with thrombocytopenia. As in classic TTP, pTTP is a diagnosis of exclusion, and DIC and HIT should be excluded from the differential diagnosis. The diagnosis should be based mainly on the clinical history and examination of the patient and the blood films, in addition to some routine and specific laboratory tests. pTTP, DIC and HIT all present with thrombocytopenia. The presence of fragmented red cells (schistocytes) in the blood film, together with non-immune hemolytic anemia (MAHA) distinguishes TMAs from HIT. However, schistocytes are not specific to TTP, as they may also be observed in DIC (but rarely constitute [10 % of the red cells [9]). Moreover, the typical absence of an abundant amount of schistocytes in pTTP (unlike TTP) may make this condition more likely to be missed. In both TTP and DIC, the reticulocyte counts and serum LDH levels are elevated, with a low haptoglobin level, as a result of the ongoing hemolysis. Coagulation tests should be performed, because the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are found to be prolonged, together with the elevation of fibrin degradation products (FDP) and/or D-dimer values, in classical DIC. These laboratory tests are usually normal in patients with TTP and HIT. However, the prolongation of aPTT can be observed in patients with HIT, due to the administration of heparin. Commonly, HIT is seen with the intravenous administration of heparin; however, it is important to be cognizant that any exposure, even to the small amount of heparin used to maintain the patency of intravenous catheters, can cause HIT. Unfractionated heparin (UFH) is the form of the drug most often associated with HIT. LMWH also can cause HIT, although not nearly as frequently as UFH [10]. Medications other than heparins should also be reviewed, to assess their possible contribution to the hematological abnormality. For example, drugs that may cause immune hemolysis and thrombocytopenia [11, 12], as well as medications that may be associated with a TTPlike clinical syndrome, such as ticlopidine [13], and certain drugs including quinine, clopidogrel, mitomycin C and antibiotics [14, 15], should especially raise suspicion. If renal insufficiency develops in a postoperative patient, volume depletion and/or urinary tract obstruction has to be ruled out in the differential diagnosis of pTTP.
A reduction in the platelet count or a clear downward trend at subsequent measurements is a sensitive (though not specific) sign of DIC [9]. Thrombocytopenia is a feature in up to 98 % of DIC cases with the platelet count being \50 9 109/L in approximately 50 % of cases [16]. In HIT, the platelet count normally falls by >50 %; the median nadir is 55 9 109/L [17, 18]. Severe thrombocytopenia (platelet count
