- Email: [email protected]
An Unusual Presentation of Thrombotic Thrombocytopenic Purpura
DIAGNOSTIC DILEMMA Thomas J. Marrie, MD, Section Editor
An Unusual Presentation of Thrombotic Thrombocytopenic Purpura Yaolin Zhou, MD,a Stephanie D. Reilly, MD,b Radhika Gangaraju, MD,c Vishnu V.B. Reddy, MD,b Marisa B. Marques, MDb a
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City; bDepartment of Pathology, University of Alabama at Birmingham; cDivision of Hematology-Oncology, Department of Medicine, University of Utah, Salt Lake City.
PRESENTATION We describe a patient with sudden and severe postoperative thrombocytopenia whose diagnosis was delayed. The patient was a 58-year-old black man with diabetes mellitus type 2, hypertension, and chronic kidney disease, who presented to our institution with 4 days of abdominal pain. He had a history of remote exploratory laparotomy for an abdominal gunshot wound repair.
ASSESSMENT His physical examination was remarkable for obesity (body mass index of 30.4 Kg/m2), abdominal distension, pain, and rebound tenderness. There were no signs of hemolysis. Vital signs included temperature of 37.4 C, heart rate of 80 beats per minute, respiratory rate of 16 breaths per minute, and blood pressure of 174/99 mm Hg. Laboratory studies showed a hemoglobin of 12.5 g/dL, white blood cell count of 9.4 109/L, platelet count of 211 109/L, blood urea nitrogen of 26 mg/dL, serum creatinine of 2.3 mg/dL, and troponin I of 0.025 ng/mL (reference range: <0.04 ng/mL). A computed tomography scan of the abdomen and pelvis revealed low-grade functional obstruction with segmental Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. IRB/HIPAA: Our institutional policy stipulates that Institutional Review Board approval is not required for case reports of 3 or fewer patients. We notified our institution privacy officer, and as this case study utilizes no Protected Health Information data elements, the Health Insurance Portability and Accountability Act is also not applicable. Note: This case was presented as a poster at the 2012 American Society for Clinical Pathology Annual Meeting, October 31-November 3, 2012 in Boston, Mass. Abstract published in the American Journal of Clinical Pathology. November 2012, Vol. 138, A258. Requests for reprints should be addressed to Yaolin Zhou, MD, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 451, Oklahoma City, OK 73104. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2017.04.022
small bowel thickening and nonspecific mesenteric stranding and adenopathy. The differential diagnosis included Crohn’s disease, lymphoma, and mechanical small bowel obstruction due to postsurgical adhesions. He was admitted for further management, but the location of the obstruction was inaccessible by upper or lower endoscopy. Within 12 hours of admission, the patient underwent laparoscopic resection of a 20-cm segment of ischemic small bowel. He tolerated the procedure well. The following day, the patient was given prophylactic low-molecular-weight heparin and was noted to have mild thrombocytopenia (113 109/L) and a hemoglobin of 11.7 g/dL. Due to a remote possibility of heparin-induced thrombocytopenia, low-molecular-weight heparin was discontinued, and bivalirudin was initiated. His platelet count decreased to 15.7 109/L on postoperative day (POD) 2 and his renal function worsened during the course of hospitalization (Figure 1). One unit of apheresis platelets was transfused on POD 3 but his platelet count did not increase.
DIAGNOSIS On POD 4, the patient was noted to have jaundice, epistaxis, and dark urine, consistent with hemolysis. A hematology consultant reviewed his peripheral blood smear and was schistocytes, and increased reticulocytes. Other laboratory tests showed a D-dimer of 6951 ng/mL (reference range: 110-240 ng/mL), prothrombin time of 17 seconds (reference range: 12.2-14.5 seconds), partial thromboplastin time of 42 seconds (reference range: 23-31 seconds), fibrinogen of 591 mg/dL (reference range: 200-400 mg/dL), and lactate dehydrogenase of 1455 IU/L (reference range: 120-240 IU/L). The differential diagnosis for the thrombocytopenia included consumption, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura. Heparininduced thrombocytopenia was considered unlikely because his platelet count had dropped prior to receiving prophylactic low-molecular-weight heparin, and there was no known previous heparin exposure. Thrombotic
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The American Journal of Medicine, Vol 130, No 8, August 2017
Figure 1 Time course of platelet count and serum creatinine from admission to death. Daily platelet counts and serum creatinine from admission to postoperative day 8 when the patient expired. The purple line represents the platelet count (left y axis), the orange line represents the serum creatinine (right y axis), asterisks mark when platelet transfusions were given, and the vertical lines, when he had therapeutic plasma exchanges.
On POD 7, he underwent another exchange, but had already suffered irreversible brain injury. Clinical examination and nuclear medicine study performed on POD 8 showed brain death. The diagnosis of thrombotic thrombocytopenic purpura was confirmed when the ADAMTS13 activity was later reported as <5% (normal 67%), with an inhibitor level of 1.8 Bethesda units (normal 0.4 inhibitor units). Postmortem examination demonstrated extensive acute neuronal hypoxic injury and microthrombi in several organs. Multiple subepicardial infarctions due to platelet-rich microthrombi were present in the heart (Figure 2). Thrombi were also present in the kidneys and small bowel. Review of the surgically resected intestines showed that the microthrombi were composed of platelets and factor VIII (Figure 3), suggesting thrombotic thrombocytopenic purpura was present at the time of surgery.
DISCUSSION thrombocytopenic purpura also seemed unlikely because of the normal platelet count on admission. On the morning of POD 5, the patient’s platelet count fell to 7.3 109/L. He received another ineffective platelet transfusion. On POD 6, he developed a generalized seizure followed by a pulseless electric activity cardiac arrest. He was successfully resuscitated, intubated, and transferred to the intensive care unit. Given his persistent profound thrombocytopenia and rapid clinical deterioration, thrombotic thrombocytopenic purpura was suspected and the apheresis team was contacted for the first time. A plasma specimen was collected and sent to the Blood Center of Wisconsin for ADAMTS13 activity testing, and emergent therapeutic plasma exchange was performed.
MANAGEMENT Despite therapeutic plasma exchange, our patient continued to experience episodes of cardiac arrest throughout POD 6.
Thrombotic thrombocytopenic purpura is rare, with a yearly incidence of approximately 11 cases per 1 million persons in the US and worldwide.1,2 The currently accepted clinical definition of thrombotic thrombocytopenic purpura is thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation.3,4 Thrombotic thrombocytopenic purpura can be either acquired or inherited.3,5 The inherited form is caused by genetic mutations in the ADAMTS13 gene. More common is the acquired form, mediated by autoantibodies against ADAMTS13. The antibodies cause a deficiency of the A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif 13 (ADAMTS13) enzyme, which cleaves von Willebrand factor into its normal-size multimers. Whether acquired or inherited, deficiency of the ADAMTS13 enzyme leads to widespread formation of aggregates of von Willebrand factor and platelets that block small vessels, leading to end-organ ischemia. Transfusing platelets can intensify the formation of such aggregates in
Figure 2 Pertinent findings at autopsy included (A) the heart showing multiple foci of subepicardial acute infarction (gross image) and (B) platelet fibrin thrombi in the coronary microvasculature (hematoxylin & eosin stain, 400).
Zhou et al
Unusual Presentation of TTP
e325
Figure 3 The surgically resected small bowel showed submucosal hemorrhage and acute inflammation consistent with acute ischemic injury (hematoxylin & eosin stain, 20) and fibrin and platelet thrombi in the microvasculature (inset, hematoxylin & eosin stain, 400).
the microvasculature, which may have contributed to our patient’s rapid clinical deterioration. Because platelet transfusions appear to increase the odds of arterial thrombosis, including acute myocardial infarction and death, they should be avoided unless there is refractory life-threatening hemorrhage attributed to the thrombocytopenia.6,7 Patients with thrombotic thrombocytopenic purpura present with a variety of symptoms, ranging from malaise, altered mental status, and gastrointestinal complaints, to myocardial ischemia and cardiac arrest.2,8 While abdominal pain (presumably due to intestinal ischemia) is common in patients with acquired thrombotic thrombocytopenic purpura,8 our patient’s lack of thrombocytopenia and hemolysis at initial presentation created a diagnostic dilemma. Although he developed severe thrombocytopenia and microangiopathic anemia, the postoperative time course was unusual.9 Without prompt diagnosis and initiation of therapeutic plasma exchange, the mortality rate is 90%.10,11 In retrospect, the magnitude of the thrombocytopenia and the almost normal prothrombin time could have pointed to thrombotic thrombocytopenic purpura (Table).12,13 The presence of schistocytes and reticulocytes were important clues. Similar to disseminated intravascular coagulation, thrombotic thrombocytopenic purpura may increase
D-dimer and lactate dehydrogenase, but prothrombin time and partial thromboplastic time may be only minimally prolonged. The diagnosis of acquired thrombotic thrombocytopenic purpura was confirmed with an ADAMTS13 activity level drawn prior to initiation of therapeutic plasma exchange. Laboratory assays for confirming the diagnosis of thrombotic thrombocytopenic purpura include testing for the ADAMTS13 enzyme activity level and for antibodies (inhibitors) against ADAMTS13.5 One common commercial test is the FRETS-VWF73 assay, which uses a synthetic 73-amino-acid peptide and fluorescence resonance energy transfer to detect ADAMTS13 activity in the patient’s plasma.5 An ADAMTS13 activity <20% has been reported to have a sensitivity of 100% and specificity of 99% for diagnosing thrombotic thrombocytopenic purpura, but most patients will have <10% at presentation.14 Because the test is not available at most institutions, it is often necessary to treat for presumed thrombotic thrombocytopenic purpura while ADAMTS13 levels are pending. A newly developed clinical score (PLASMIC score) combines common laboratory tests with clinical history. It has high sensitivity and specificity to differentiate thrombotic thrombocytopenic purpura from other thrombotic microangiopathies when the ADAMTS13 activity result is not available.12 The score depends on 7 variables represented by each of the letters of the word “PLASMIC” (Platelet count <30 109/L, evidence of hemoLysis, Absence of active cancer or stem cell transplant, Mean corpuscular volume <90 fL, International normalized ratio <1.5, and Creatinine <2 mg/dL). More than 80% of patients with scores above 5 have confirmed thrombotic thrombocytopenic purpura. Our patient’s PLASMIC score was 5 on POD 4 when he first showed evidence of hemolysis; this score is associated with an intermediate risk of thrombotic thrombocytopenic purpura. The PLASMIC score should be interpreted as part of the overall clinical picture. In the context of our patient’s severe thrombocytopenia and microangiopathic hemolytic anemia, initiation of therapeutic plasma exchange was justified. In patients with chronic renal disease, creatinine may be elevated at baseline, which lowers the PLASMIC score by one point. This case highlights the importance of considering thrombotic thrombocytopenic purpura in the differential
Table Laboratory Results in Thrombotic Thrombocytopenic Purpura, Heparin-Induced Thrombocytopenia, and Disseminated Intravascular Coagulation Laboratory Test
Thrombotic Thrombocytopenic Purpura
Heparin-Induced Thrombocytopenia
Disseminated Intravascular Coagulation
Platelet count Peripheral smear PT and PTT Fibrinogen D-dimer LDH
<30 10 /L Schistocytes, reticulocytes Normal or slightly prolonged Normal or high Increased Increased
50-80 10 /L Isolated thrombocytopenia Normal Normal Normal Normal
Variable Schistocytes, reticulocytes Prolonged (especially the PT) Normal, low or high Increased Increased
9
9
LDH ¼ lactate dehydrogenase; PT ¼ prothrombin time; PTT ¼ partial thromboplastin time.
e326 diagnosis of postoperative patients with severe thrombocytopenia and microangiopathic hemolytic anemia. Thrombotic thrombocytopenic purpura has been rarely described in the postoperative setting and may be related to surgically induced endothelial damage. Our patient’s thrombocytopenia manifested after his surgery, but it is unlikely he had true “postoperative thrombotic thrombocytopenic purpura,” which typically occurs 5-9 days after surgery.9,15 Regardless of the precipitating factors, thrombotic thrombocytopenic purpura is a life-threatening emergency with a clearly defined treatment. In order to maximize their chances of survival, these patients require emergent therapeutic plasma exchange with donor plasma as replacement fluid.10-12 The mortality of patients with untreated thrombotic thrombocytopenic purpura is close to 90%, but early diagnosis and therapeutic plasma exchange increase survival to 80%-90%.10,12,16
References 1. Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost. 2005;3(7):1432-1436. 2. Shatzel JJ, Taylor JA. Syndromes of thrombotic microangiopathy. Med Clin North Am. 2017;101(2):395-415. 3. Scully M, Cataland S, Coppo P, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017;15(2): 312-322. 4. Williams LA, Marques MB. Education Committee of the Academy of Clinical Laboratory Physicians and Scientists. Pathology consultation on the diagnosis and treatment of thrombotic microangiopathies (TMAs). Am J Clin Pathol. 2016;145(2):158-165. 5. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211-225.
The American Journal of Medicine, Vol 130, No 8, August 2017 6. Benhamou Y, Baudel JL, Wynckel A, et al. Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center. Am J Hematol. 2015;90(6):E127-E129. 7. Goel R, Ness PM, Takemoto CM, Krishnamurti L, King KE, Tobian AA. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood. 2015;125(9):1470-1476. 8. Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion. 2013;53(1):235-237. 9. Eskazan AE, Buyuktas D, Soysal T. Postoperative thrombotic thrombocytopenic purpura. Surg Today. 2015;45(1):8-16. 10. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393-397. 11. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the seventh special issue. J Clin Apher. 2016;31(3):149-162. 12. Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4(4):e157-e164. 13. Park YA, Waldrum MR, Marques MB. Platelet count and prothrombin time help distinguish thrombotic thrombocytopenic purpura-hemolytic uremic syndrome from disseminated intravascular coagulation in adults. Am J Clin Pathol. 2010;133(3):460-465. 14. Barrows BD, Teruya J. Use of the ADAMTS13 activity assay improved the accuracy and efficiency of the diagnosis and treatment of suspected acquired thrombotic thrombocytopenic purpura. Arch Pathol Lab Med. 2014;138(4):546-549. 15. Chang JC, El-Tarabily M, Gupta S. Acute thrombotic thrombocytopenic purpura following abdominal surgeries: a report of three cases. Arch Pathol Lab Med. 2014;138(4):546-549. 16. Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol. 2008;1:23.
An Unusual Presentation of Thrombotic Thrombocytopenic Purpura Yaolin Zhou, MD,a Stephanie D. Reilly, MD,b Radhika Gangaraju, MD,c Vishnu V.B. Reddy, MD,b Marisa B. Marques, MDb a
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City; bDepartment of Pathology, University of Alabama at Birmingham; cDivision of Hematology-Oncology, Department of Medicine, University of Utah, Salt Lake City.
PRESENTATION We describe a patient with sudden and severe postoperative thrombocytopenia whose diagnosis was delayed. The patient was a 58-year-old black man with diabetes mellitus type 2, hypertension, and chronic kidney disease, who presented to our institution with 4 days of abdominal pain. He had a history of remote exploratory laparotomy for an abdominal gunshot wound repair.
ASSESSMENT His physical examination was remarkable for obesity (body mass index of 30.4 Kg/m2), abdominal distension, pain, and rebound tenderness. There were no signs of hemolysis. Vital signs included temperature of 37.4 C, heart rate of 80 beats per minute, respiratory rate of 16 breaths per minute, and blood pressure of 174/99 mm Hg. Laboratory studies showed a hemoglobin of 12.5 g/dL, white blood cell count of 9.4 109/L, platelet count of 211 109/L, blood urea nitrogen of 26 mg/dL, serum creatinine of 2.3 mg/dL, and troponin I of 0.025 ng/mL (reference range: <0.04 ng/mL). A computed tomography scan of the abdomen and pelvis revealed low-grade functional obstruction with segmental Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. IRB/HIPAA: Our institutional policy stipulates that Institutional Review Board approval is not required for case reports of 3 or fewer patients. We notified our institution privacy officer, and as this case study utilizes no Protected Health Information data elements, the Health Insurance Portability and Accountability Act is also not applicable. Note: This case was presented as a poster at the 2012 American Society for Clinical Pathology Annual Meeting, October 31-November 3, 2012 in Boston, Mass. Abstract published in the American Journal of Clinical Pathology. November 2012, Vol. 138, A258. Requests for reprints should be addressed to Yaolin Zhou, MD, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 451, Oklahoma City, OK 73104. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2017.04.022
small bowel thickening and nonspecific mesenteric stranding and adenopathy. The differential diagnosis included Crohn’s disease, lymphoma, and mechanical small bowel obstruction due to postsurgical adhesions. He was admitted for further management, but the location of the obstruction was inaccessible by upper or lower endoscopy. Within 12 hours of admission, the patient underwent laparoscopic resection of a 20-cm segment of ischemic small bowel. He tolerated the procedure well. The following day, the patient was given prophylactic low-molecular-weight heparin and was noted to have mild thrombocytopenia (113 109/L) and a hemoglobin of 11.7 g/dL. Due to a remote possibility of heparin-induced thrombocytopenia, low-molecular-weight heparin was discontinued, and bivalirudin was initiated. His platelet count decreased to 15.7 109/L on postoperative day (POD) 2 and his renal function worsened during the course of hospitalization (Figure 1). One unit of apheresis platelets was transfused on POD 3 but his platelet count did not increase.
DIAGNOSIS On POD 4, the patient was noted to have jaundice, epistaxis, and dark urine, consistent with hemolysis. A hematology consultant reviewed his peripheral blood smear and was schistocytes, and increased reticulocytes. Other laboratory tests showed a D-dimer of 6951 ng/mL (reference range: 110-240 ng/mL), prothrombin time of 17 seconds (reference range: 12.2-14.5 seconds), partial thromboplastin time of 42 seconds (reference range: 23-31 seconds), fibrinogen of 591 mg/dL (reference range: 200-400 mg/dL), and lactate dehydrogenase of 1455 IU/L (reference range: 120-240 IU/L). The differential diagnosis for the thrombocytopenia included consumption, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura. Heparininduced thrombocytopenia was considered unlikely because his platelet count had dropped prior to receiving prophylactic low-molecular-weight heparin, and there was no known previous heparin exposure. Thrombotic
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The American Journal of Medicine, Vol 130, No 8, August 2017
Figure 1 Time course of platelet count and serum creatinine from admission to death. Daily platelet counts and serum creatinine from admission to postoperative day 8 when the patient expired. The purple line represents the platelet count (left y axis), the orange line represents the serum creatinine (right y axis), asterisks mark when platelet transfusions were given, and the vertical lines, when he had therapeutic plasma exchanges.
On POD 7, he underwent another exchange, but had already suffered irreversible brain injury. Clinical examination and nuclear medicine study performed on POD 8 showed brain death. The diagnosis of thrombotic thrombocytopenic purpura was confirmed when the ADAMTS13 activity was later reported as <5% (normal 67%), with an inhibitor level of 1.8 Bethesda units (normal 0.4 inhibitor units). Postmortem examination demonstrated extensive acute neuronal hypoxic injury and microthrombi in several organs. Multiple subepicardial infarctions due to platelet-rich microthrombi were present in the heart (Figure 2). Thrombi were also present in the kidneys and small bowel. Review of the surgically resected intestines showed that the microthrombi were composed of platelets and factor VIII (Figure 3), suggesting thrombotic thrombocytopenic purpura was present at the time of surgery.
DISCUSSION thrombocytopenic purpura also seemed unlikely because of the normal platelet count on admission. On the morning of POD 5, the patient’s platelet count fell to 7.3 109/L. He received another ineffective platelet transfusion. On POD 6, he developed a generalized seizure followed by a pulseless electric activity cardiac arrest. He was successfully resuscitated, intubated, and transferred to the intensive care unit. Given his persistent profound thrombocytopenia and rapid clinical deterioration, thrombotic thrombocytopenic purpura was suspected and the apheresis team was contacted for the first time. A plasma specimen was collected and sent to the Blood Center of Wisconsin for ADAMTS13 activity testing, and emergent therapeutic plasma exchange was performed.
MANAGEMENT Despite therapeutic plasma exchange, our patient continued to experience episodes of cardiac arrest throughout POD 6.
Thrombotic thrombocytopenic purpura is rare, with a yearly incidence of approximately 11 cases per 1 million persons in the US and worldwide.1,2 The currently accepted clinical definition of thrombotic thrombocytopenic purpura is thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation.3,4 Thrombotic thrombocytopenic purpura can be either acquired or inherited.3,5 The inherited form is caused by genetic mutations in the ADAMTS13 gene. More common is the acquired form, mediated by autoantibodies against ADAMTS13. The antibodies cause a deficiency of the A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif 13 (ADAMTS13) enzyme, which cleaves von Willebrand factor into its normal-size multimers. Whether acquired or inherited, deficiency of the ADAMTS13 enzyme leads to widespread formation of aggregates of von Willebrand factor and platelets that block small vessels, leading to end-organ ischemia. Transfusing platelets can intensify the formation of such aggregates in
Figure 2 Pertinent findings at autopsy included (A) the heart showing multiple foci of subepicardial acute infarction (gross image) and (B) platelet fibrin thrombi in the coronary microvasculature (hematoxylin & eosin stain, 400).
Zhou et al
Unusual Presentation of TTP
e325
Figure 3 The surgically resected small bowel showed submucosal hemorrhage and acute inflammation consistent with acute ischemic injury (hematoxylin & eosin stain, 20) and fibrin and platelet thrombi in the microvasculature (inset, hematoxylin & eosin stain, 400).
the microvasculature, which may have contributed to our patient’s rapid clinical deterioration. Because platelet transfusions appear to increase the odds of arterial thrombosis, including acute myocardial infarction and death, they should be avoided unless there is refractory life-threatening hemorrhage attributed to the thrombocytopenia.6,7 Patients with thrombotic thrombocytopenic purpura present with a variety of symptoms, ranging from malaise, altered mental status, and gastrointestinal complaints, to myocardial ischemia and cardiac arrest.2,8 While abdominal pain (presumably due to intestinal ischemia) is common in patients with acquired thrombotic thrombocytopenic purpura,8 our patient’s lack of thrombocytopenia and hemolysis at initial presentation created a diagnostic dilemma. Although he developed severe thrombocytopenia and microangiopathic anemia, the postoperative time course was unusual.9 Without prompt diagnosis and initiation of therapeutic plasma exchange, the mortality rate is 90%.10,11 In retrospect, the magnitude of the thrombocytopenia and the almost normal prothrombin time could have pointed to thrombotic thrombocytopenic purpura (Table).12,13 The presence of schistocytes and reticulocytes were important clues. Similar to disseminated intravascular coagulation, thrombotic thrombocytopenic purpura may increase
D-dimer and lactate dehydrogenase, but prothrombin time and partial thromboplastic time may be only minimally prolonged. The diagnosis of acquired thrombotic thrombocytopenic purpura was confirmed with an ADAMTS13 activity level drawn prior to initiation of therapeutic plasma exchange. Laboratory assays for confirming the diagnosis of thrombotic thrombocytopenic purpura include testing for the ADAMTS13 enzyme activity level and for antibodies (inhibitors) against ADAMTS13.5 One common commercial test is the FRETS-VWF73 assay, which uses a synthetic 73-amino-acid peptide and fluorescence resonance energy transfer to detect ADAMTS13 activity in the patient’s plasma.5 An ADAMTS13 activity <20% has been reported to have a sensitivity of 100% and specificity of 99% for diagnosing thrombotic thrombocytopenic purpura, but most patients will have <10% at presentation.14 Because the test is not available at most institutions, it is often necessary to treat for presumed thrombotic thrombocytopenic purpura while ADAMTS13 levels are pending. A newly developed clinical score (PLASMIC score) combines common laboratory tests with clinical history. It has high sensitivity and specificity to differentiate thrombotic thrombocytopenic purpura from other thrombotic microangiopathies when the ADAMTS13 activity result is not available.12 The score depends on 7 variables represented by each of the letters of the word “PLASMIC” (Platelet count <30 109/L, evidence of hemoLysis, Absence of active cancer or stem cell transplant, Mean corpuscular volume <90 fL, International normalized ratio <1.5, and Creatinine <2 mg/dL). More than 80% of patients with scores above 5 have confirmed thrombotic thrombocytopenic purpura. Our patient’s PLASMIC score was 5 on POD 4 when he first showed evidence of hemolysis; this score is associated with an intermediate risk of thrombotic thrombocytopenic purpura. The PLASMIC score should be interpreted as part of the overall clinical picture. In the context of our patient’s severe thrombocytopenia and microangiopathic hemolytic anemia, initiation of therapeutic plasma exchange was justified. In patients with chronic renal disease, creatinine may be elevated at baseline, which lowers the PLASMIC score by one point. This case highlights the importance of considering thrombotic thrombocytopenic purpura in the differential
Table Laboratory Results in Thrombotic Thrombocytopenic Purpura, Heparin-Induced Thrombocytopenia, and Disseminated Intravascular Coagulation Laboratory Test
Thrombotic Thrombocytopenic Purpura
Heparin-Induced Thrombocytopenia
Disseminated Intravascular Coagulation
Platelet count Peripheral smear PT and PTT Fibrinogen D-dimer LDH
<30 10 /L Schistocytes, reticulocytes Normal or slightly prolonged Normal or high Increased Increased
50-80 10 /L Isolated thrombocytopenia Normal Normal Normal Normal
Variable Schistocytes, reticulocytes Prolonged (especially the PT) Normal, low or high Increased Increased
9
9
LDH ¼ lactate dehydrogenase; PT ¼ prothrombin time; PTT ¼ partial thromboplastin time.
e326 diagnosis of postoperative patients with severe thrombocytopenia and microangiopathic hemolytic anemia. Thrombotic thrombocytopenic purpura has been rarely described in the postoperative setting and may be related to surgically induced endothelial damage. Our patient’s thrombocytopenia manifested after his surgery, but it is unlikely he had true “postoperative thrombotic thrombocytopenic purpura,” which typically occurs 5-9 days after surgery.9,15 Regardless of the precipitating factors, thrombotic thrombocytopenic purpura is a life-threatening emergency with a clearly defined treatment. In order to maximize their chances of survival, these patients require emergent therapeutic plasma exchange with donor plasma as replacement fluid.10-12 The mortality of patients with untreated thrombotic thrombocytopenic purpura is close to 90%, but early diagnosis and therapeutic plasma exchange increase survival to 80%-90%.10,12,16
References 1. Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost. 2005;3(7):1432-1436. 2. Shatzel JJ, Taylor JA. Syndromes of thrombotic microangiopathy. Med Clin North Am. 2017;101(2):395-415. 3. Scully M, Cataland S, Coppo P, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017;15(2): 312-322. 4. Williams LA, Marques MB. Education Committee of the Academy of Clinical Laboratory Physicians and Scientists. Pathology consultation on the diagnosis and treatment of thrombotic microangiopathies (TMAs). Am J Clin Pathol. 2016;145(2):158-165. 5. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211-225.
The American Journal of Medicine, Vol 130, No 8, August 2017 6. Benhamou Y, Baudel JL, Wynckel A, et al. Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center. Am J Hematol. 2015;90(6):E127-E129. 7. Goel R, Ness PM, Takemoto CM, Krishnamurti L, King KE, Tobian AA. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood. 2015;125(9):1470-1476. 8. Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion. 2013;53(1):235-237. 9. Eskazan AE, Buyuktas D, Soysal T. Postoperative thrombotic thrombocytopenic purpura. Surg Today. 2015;45(1):8-16. 10. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393-397. 11. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the seventh special issue. J Clin Apher. 2016;31(3):149-162. 12. Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4(4):e157-e164. 13. Park YA, Waldrum MR, Marques MB. Platelet count and prothrombin time help distinguish thrombotic thrombocytopenic purpura-hemolytic uremic syndrome from disseminated intravascular coagulation in adults. Am J Clin Pathol. 2010;133(3):460-465. 14. Barrows BD, Teruya J. Use of the ADAMTS13 activity assay improved the accuracy and efficiency of the diagnosis and treatment of suspected acquired thrombotic thrombocytopenic purpura. Arch Pathol Lab Med. 2014;138(4):546-549. 15. Chang JC, El-Tarabily M, Gupta S. Acute thrombotic thrombocytopenic purpura following abdominal surgeries: a report of three cases. Arch Pathol Lab Med. 2014;138(4):546-549. 16. Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol. 2008;1:23.