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Post-cardiac surgery thrombotic thrombocytopenic purpura with digital ischaemia.

SUMMARY

We report a case of thrombotic thrombocytopenic purpura in a woman post mitral valve repair who presented with unexplained thrombocytopenia, intermittent fever, acute renal failure and severe digital ischaemia. The diagnosis of thrombotic thrombocytopenic purpura was confirmed after exclusion of many of the aetiological factors of postoperative digital ischaemia, a positive haemolytic screen and blood film examination which showed schistocytes and fragmented red cells. Plasma ADAMTS-13 activity measured by enzyme-linked immunosorbent assay was reduced. Treatment of thrombotic thrombocytopenic purpura with exchange plasmapheresis and methylprednisolone was of paramount importance and the patient was discharged home on day 30 with complete recovery of haematological, neurological and renal function. In order to increase the awareness of this rare multisystem process, we report our experience in managing this life-threatening condition. Our discussion covers the diagnostic challenges, theories on aetiology, pathogenesis and treatment of this condition in the context of cardiac surgery.

Key Words: thrombotic thrombocytopenic purpura, cardiac surgery

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Thrombotic thrombocytopenic purpura (TTP) after cardiac surgery is a multisystem process characterised by thrombocytopenia, microangiopathic haemolytic anaemia and neurologic dysfunction. In order to increase the awareness of this rare disease process, we report our experience in managing this life-threatening condition. We review the diagnostic challenges, emphasising that early recognition and treatment with exchange plasmapheresis is of paramount importance for a favourable outcome. Our discussion also covers the theorised aetiology and pathogenesis in the context of cardiac surgery.

CASE PRESENTATION

A 71-year-old woman with severe mitral regurgitation underwent redo-sternotomy for mitral valve replacement surgery. Preoperatively she had a mild thrombocytopenia (platelet count 134 x [10.sup.9]/l); the remainder of her biochemical and haematological profiles were normal. The operative procedure was complicated by bleeding from the innominate artery during surgical re-entry. Femoro-femoral cardiopulmonary bypass was achieved swiftly in response and haemodynamic compromise was minimal. The patient underwent an uneventful mitral valve repair. In total, four units of cross-matched red blood cells, three bags of pooled platelets, seven units of cryoprecipitate and 15 ml/kg of flesh frozen plasma were given to provide adequate haemostasis for chest closure. Immediately postoperatively, macroscopic haematuria was noted and she became oliguric. Serum creatinine increased from 61 to 201 [micro]mol/l. On the first postoperative day, the tip of the left thumb appeared ischaemic and several hours later the left index finger appeared mottled (Figure 1). Duplex ultrasound of her left arm showed a non-occlusive thrombus in the left radial artery at the level of arterial catheter insertion site. The left arterial cannula was removed and an intravenous heparin infusion commenced with topical glyceryl trinitrate spray applied over the ischaemic area. The patient became anuric and continuous veno-venous haemofiltration was initiated via a right internal jugular vascular catheter.

On day 2 the right index finger tip also appeared ischaemic. However, no thrombus was found on ultrasound of the right brachial, ulnar and radial arteries. Transthoracic echocardiogram showed the mitral valve repair was satisfactory with no intra-cardiac thrombus. A non-occlusive venous thrombosis developed in both internal jugular veins. The patient became severely thrombocytopenic (platelet count 34 x [10.sup.9]/l). However, there was only a marginal response to a transfusion of ten units of pooled platelets. Neurologically, while predominantly alert and orientated during the first three days, the patient developed intermittent agitation, delirium and an episode of hallucination. No focal neurological deficits were demonstrated. An intermittent fever up to 38[degrees] developed, but a comprehensive septic screen was negative. Heparin induced thrombosis-thrombocytopenia syndrome was considered but screening for heparin-induced antibodies was negative. Coagulation profiles and fibrinogen levels were normal, effectively excluding disseminated intravascular coagulation from the differential diagnosis. The haptoglobin level was less than 0.1 g/1 (normal 0.5-3.3 g/l) and lactate dehydrogenase was raised at 1996 international units/l (normal 98-192 international units/l) suggestive of a haemolytic process. On postoperative day 5, bilirubin increased to 55 [micro]mol/l with an unconjugated bilirubin of 80%. The blood film showed schistocytes and fragmented red cells and a diagnosis of TTP was first considered. Plasma ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin Motifs) activity measured by enzyme-linked immunosorbent assay was reduced at 4% (normal 67-177%) and the working diagnosis of postoperative TTP was established.

Institution of exchange plasmapheresis with flesh frozen plasma was commenced, exchanging 1.5 plasma volumes with each exchange. Six exchanges were performed over eight days of therapy. Intravenous methylprednisolone (1.5 mg/kg) was administered as an adjunct and was changed to oral prednisolone after three days. The thrombocytopenia normalised after five days of treatment. By day 9 complete response to plasma exchange was evident by disappearance of the neurological symptoms, normalisation of haemoglobin, platelet count, lactate dehydrogenase, bilirubin and creatinine levels. Continuous venovenous haemofiltration ceased nine days after starting plasma exchange. The ischaemic left index finger improved; however, the left thumb and right index finger remained necrotic and became demarcated. The patient was discharged home on day 30 on warfarin for bilateral internal jugular vein thrombosis. There was complete recovery of haematological, neurological and renal function with only the necrotic tip of left thumb and right index finger being evidence of irreversible damage.

DISCUSSION

Postoperative TTP is a unique syndrome not formally recognised as a disease entity in the literature. In the case described here, the diagnosis of TTP was delayed despite the patient presenting with the classical pentad of TTP symptoms including fever, thrombocytopenia, central nervous system abnormalities, haemolytic anaemia and renal impairment. Initially we considered many differential diagnoses to explain the indeterminate presentation. The postoperative kidney injury was attributed to a combination of pre-renal and renal mechanisms secondary to cardiopulmonary bypass. Similarly delirium, hallucinations and neurocognitive changes were considered not uncommon after cardiac surgery. The occurrence of digital ischaemia was initially considered embolic in nature, the source originating from the arterial cannula. This complication is reported to occur in approximately 20% of patients after arterial cannulation; however, the incidence of permanent thrombosis or ischaemia is rare with a reported incidence of only 0.09% (1,2). A duplex ultrasound showed thrombus in the left radial artery at the insertion site of the radial arterial cannula, although it was non-occlusive and echocardiography showed no cardiac source for emboli. Therefore, we initially suspected that the mechanism of the digital embolic was thrombotic in nature, secondary to the radial arterial catheter.

We initially considered heparin-induced thrombosis-thrombocytopenia syndrome as the cause of digital ischaemia. However, in heparin induced thrombosis-thrombocytopenia syndrome there is gradual extension of ischaemia toward the proximal part of the extremity and identifiable thrombi can usually be demonstrated by sonogram or at thrombectomy. In the case presented here, digital ischaemia was localised to the peripheral digit and did not extend to the proximity of the extremity. Furthermore, we were unable to demonstrate gross thrombi, an observation reported by other investigators (3). The causes of digital ischaemia following cardiac surgery are summarised in Table 1. Our patient displayed thromboembolic events associated with all four intravascular cannulae--bilateral radial arterial cannulae and thrombosis associated with both internal jugular venous lines. It is possible that the prothrombotic effect of coagulation factor therapy used to manage the post-bypass coagulopathy may be a contributing factor to these events.

Post-cardiac surgery decreases of ADAMTS-13 activity have been described in patients without TTP, which can further confound the diagnosis (4-9). ADAMTS-13 is a plasma metalloprotease that cleaves von Willebrand factor (vWF). Platelets adhere to uncleaved ultra-large vWF multimers and form microvascular aggregates on endothelial cells, resulting in platelet-rich microvascular occlusions and organ dysfunction. It has been postulated that cardiopulmonary bypass activates endothelial cells leading to the release of ultra-large multimers of vWF that in turn induces platelet aggregation and thrombus formation in the microcirculation (10). Furthermore, during cardiac surgery ADAMTS-13 can be reduced or dysfunctional and thus unable to dispose of the increased burden of ultra-large multimers (11). Our observation of TTP occurring postcardiac surgery supports this cause-effect relationship. However, as demonstrated in this case, compared to classical TTP, our patient presented with the florid pentad of classical signs. In comparison, only 20-40% of classical TTP cases present with all five typical criteria (12).

Postoperative TTP responds to plasma exchange faster than classical TTP, but also progresses more rapidly and usually fatally if untreated or if treatment is commenced late. A high index of suspicion is recommended in evaluating post-cardiac surgery patients with thrombocytopenia, and plasma exchange should be commenced as early as possible if TTP is suspected for a more favourable outcome. Therapy with plasma exchange should be initiated as soon as possible because the mortality of untreated TTP is as high as 85-100%, whereas plasma exchange has reduced the mortality to between 10 and 30% (13,14). Plasma exchange is efficacious because it replenishes ADAMTS-13, removes ADAMTS-13 inhibitors and removes thrombogenic uncleaved ultra-large multimers of vWE rather than removing antibodies (15). Corticosteroids are frequently administered as an adjunct to plasma exchange and responses to this alone have been documented. For patients refractory to plasma exchange, the use of cryo-poor plasma (or cryosupernatant, which is deplete of high-molecular weight vWB multimers that have a pathogenic role in TTP) may lead to a response. Other alternatives to refractory treatments include the chemotherapeutic agent vincristine, the staphylococcal protein A column Prosorba, which acts by removing immune complexes, and the anti-CD20 monoclonal antibody rituximab (16,17). Early identification is paramount and aggressive intervention with fresh frozen plasma exchange is indicated if significant morbidity and mortality is to be prevented (10,18).

TTP is a rare clinical-pathological entity following cardiac surgery with a high mortality if left untreated. Postoperative TTP syndrome should be one of the differential diagnoses for any postsurgical patient who presents with unexplained anaemia, thrombocytopenia and a new neurological finding.

Caption: Figure 1: Ischaemic left distal thumb with mottled ischaemic changes affecting the distal index finger.

REFERENCES

(1.) Scheer B, Perel A, Pfeiffer UJ. Clinical review: complications and risk factors of peripheral arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care medicine. Crit Care 2002; 6:199-204.

(2.) Chang JC, Ikhlaque N. Peripheral digit ischemic syndrome can be a manifestation of postoperative thrombotic thrombocytopenic purpura. Ther Apher Dial 2004; 8:413-418.

(3.) Chang JC. Coronary Artery Bypass Graft Thrombocytopenia: Differential Diagnosis of HITT and TTR From www.medscape.com/viewarticle/408467_5. Accessed March 2012.

(4.) Mannucci PM, Parolari A, Canciani MT, Alemanni F, Camera M. Opposite changes of ADAMTS-13 and von Willebrand factor after cardiac surgery. J Thromb Haemost 2005; 3:397-399.

(5.) Schmidt T, Tsakiris DA, Grapow M, Siegemund M. Thrombotic microangiopathy after extracorporeal circulation: important differential diagnosis. Anaesthesist 2011; 60:451-456.

(6.) Saltzman DJ, Chang JC, Jimenez JC, Carson JG, Abolhoda A, Newman RS et al. Postoperative thrombotic thrombocytopenic purpura after open heart operations. Ann Thorac Surg 2010; 89:119-123.

(7.) Chang JC, Shipstone A, Llenado-Lee MA. Postoperative thrombotic thrombocytopenic purpura following cardiovascular surgeries. Am J Hematol 1996; 53:11-17.

(8.) Bernardo A, Bali C, Nolasco L, Moake JE Dong JE Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104:100-106.

(9.) Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Losche W et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 2008; 93:137-140.

(10.) Nguyen TC, Han YY, Kiss JE, Hall MW, Hassett AC, Jaffe R et al. Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 2008; 36:2878-2887.

(11.) Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998; 339:1578-1584.

(12.) Pavlovsky M, Weinstein R. Thrombotic thrombocytopenic purpura following coronary artery bypass graft surgery: prospective observations of an emerging syndrome. J Clin Apher 1997; 12:159-164.

(13.) Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991; 325:398-403.

(14.) George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354:1927-1935.

(15.) Moake JL Thrombotic microangiopathies. N Engl J Med 2002; 347:589-600.

(16.) Jhaveri KD, Scheuer A, Cohen J, Gordon B. Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine. Transfus Apher Sci 2009; 41:19-22.

(17.) Scully M, McDonald V, Cavenagh J, Hunt BJ, Longair I, Cohen H et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011; 118:1746-1753.

(18.) Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC 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; 325:393-397.

L. WEINBERG *, J. CHANG ([dagger]), P. HAYWARD ([double dagger]), M. REYNOLDS ([section]), J. FERNANDES **

Department of Anaesthesia, Austin Hospital, Heidelberg, Victoria, Australia

* BSc, MB, BCh, MRCP, FANZCA, Dip Crit Care Echo, Anaesthetist, Department of Anaesthesia, Austin Hospital and Senior Fellow, Department of Surgery, University of Melbourne.

([dagger]) BSc, MB, BS, Registrar.

([double dagger]) BSc, MB, BCh, MRCP, FRCS, Cardiac Surgeon, Department of Cardiac Surgery, Austin Hospital and Senior Fellow, Department of Surgery, University of Melbourne.

([section]) MB, BS, Resident Medical Officer.

** MB, BS, FANZCA, Dip Crit Care Echo, Anaesthetist.

Address for correspondence: Dr L. Weinberg, Department of Anaesthesia, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. Email: Laurence.Weinberg@austin.org.au

Accepted for publication on October 23, 2012.

Table 1
Differential diagnosis of digital ischaemia post-cardiac surgery

Aetiology         Pathology and clinical examples

Vessel wall       Atherosclerosis

                  Vasculitis: drug induced, cryoglobulinaemia,
                  Takayasu's arteritis, Wegener's
                  granulomatosis, Reynaud's syndrome,
                  systemic sclerosis, mixed connective tissue
                  disease

Embolism          Cardiac source

                  Proximal arterial aneurysm

Thrombosis        Atherosclerosis

                  Arterial reconstruction

                  Arterial catheter injury

                  Arterial dissection

                  Antiphospholipid syndrome

                  Thrombosic thrombocytopenia purpura

                  HITTS

                  Disseminated intravascular coagulation

Trauma/physical   Drugs, e.g. high dose vasoconstrictors
                  (adrenaline, noradrenaline)

                  Severe hypothermia

HITTS = heparin induced thrombosis-thrombocytopenia syndrome.
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Title Annotation:Case Reports
Author:Weinberg, L.; Chang, J.; Hayward, P.; Reynolds, M.; Fernandes, J.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Date:May 1, 2013
Words:2331
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