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SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES
AJH Educational Material A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary
Anticoagulation management of left ventricular assist devices Jean M. Connors*
Hematology was consulted to aid in the management of a 56-yearold woman admitted for presumed gastro-intestinal (GI) bleeding. Her history was notable for non-ischemic cardiomyopathy status post placement of a left ventricular assist device (LVAD) as a bridge to transplant 10 months before admission. She had had one episode of guaiac positive stools and a drop in hematocrit requiring transfusion of two units of red cells 3 months after LVAD placement. Thorough GI evaluation at that time demonstrated normal EGD findings and blood in the terminal ilium on colonoscopy. Subsequent video capsule endoscopy however was unrevealing. Anticoagulation was maintained with a target INR of 2.0–3.0 and aspirin 325 mg every day. Two weeks before admission her INR was 1.6, and warfarin dose was increased. Repeat testing a few days later revealed no change in INR and enoxaparin 1 mg/kg twice a day was started. Enoxaparin was stopped after 5 days. She had noted increasing fatigue and dyspnea over these 2 weeks and ultimately presented to the emergency room. She denied any obvious signs of blood loss including epistaxis, melena, hematochezia, or change in stool color. Options for treatment of patients with advanced heart failure have expanded to include the use of mechanical circulatory assist devices for those waiting for heart transplant or as destination devices to improve quality of life for those not eligible for transplant. Despite significant advances both in device technology and anticoagulation protocols, bleeding, and thrombosis are the most significant adverse events accompanying use of these devices. Anticoagulation to protect against the intrinsic pro-thrombotic state resulting from the device must be balanced against bleeding complications that can result in significant morbidity and mortality. Hematologists are increasingly involved in the complex care of these patients. The use of mechanical circulatory support (MCS) devices for patients with advanced heart failure has increased dramatically in the past few years. Improvements and changes in the technology of the devices combined with changes in patient selection have significantly improved outcomes resulting in more widespread use. Left ventricular assist devices (LVAD) are the most frequently used devices. From 2007 to 2012 there was a tenfold increase in the number of LVADs implanted in the United States, from 247 in 2007 to 2,162 in 2012 [1]. The most frequent complications with LVAD use are bleeding and thrombosis. Criteria for selection of patients in whom an LVAD serves as bridge to transplant versus destination device are different. Patients not suitable for heart transplant may be eligible for LVAD implantation. Factors that prohibit heart transplant, such as age, comorbid dis-
ease, and more advanced cardiac or pulmonary disease, may also put these patients at higher risk for hematologic complications. LVADs function by draining blood from the apex of the left ventricle and pumping it through the device to the ascending aorta. Newer devices use a continuous flow rotary pump which has been found to have multiple advantages including improved outcomes, smaller device size, longer durability, and less noise, than earlier models that used volume displacement mechanisms [2,3]. Anticoagulation protocols are both device type and institution specific but rely on a combination of aspirin, from 81 to 325 mg a day, and warfarin, in patients with continuous flow devices. New oral anticoagulants are not used in patients with mechanical circulatory assist devices given that dabigatran was found to be inferior to warfarin for preventing thromboembolic events in patients with mechanical heart valves [4]. Data from a 2009 study of the continuous flow Heartmate II device suggested that immediate post-op bridging anticoagulation with IV unfractionated heparin (UFH) was not required, resulting in less surgical site bleeding. Initiation of warfarin and aspirin without IV UFH has become the standard for HeartMate II LVADs, the most frequently used device in the USA [1]. This study also suggested that the rate of thromboembolic events was extremely low with an INR target of 2.5–3.5; therefore, a lower target INR of 1.5–2.5 was determined to be sufficient to prevent thrombotic events with less bleeding complications [5,6]. The patient had a systolic blood pressure of 76mm HG. Patients with CF-LVADS do not have peripheral pulses therefore no heart rate was recorded. Respiratory rate was 20 breaths per minute. Stool was guaiac positive. Laboratory values were notable for a hemoglobin of 3.4 g/dl and hematocrit 11.2%, decreased from her baseline of approximately 10 g/dl and 30%. LDH was 261 (94–250 U/L) and total bilrubin was normal, suggesting no significant hemolysis which was confirmed by plasma hemoglobin of 3.7 mg/ dl, her baseline value. Platelet count was 206,000/ml. INR was supratherapeutic at 5.9. Additional lab values included a fibrinogen of 490 mg/dl, vWF antigen of 230%, with ristocetin-cofactor activity of 190% and FVIII activity of 280%. Both bleeding and thrombosis occur at very high rates in these patients, present difficult management issues, and can be lifethreatening. An analysis of US registry data of cumulative event rates in 8,644 patients found that 38.9% experience bleeding events and 17.3% develop neurologic dysfunction including thromboembolic stroke and intracranial hemorrhage. Other thrombotic manifestations include a 5.4% rate of VTE, and 1.3% rate of non-stroke arterial embolic events [1]. Review of outcomes over the past 2 years has
Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Conflict of interest: Nothing to report. *Correspondence to: Jean M. Connors, Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. E-mail: [email protected] Received for publication: 7 August 2014; Accepted: 25 August 2014 Am. J. Hematol. 90:175–178, 2015. Published online: 28 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23836 C 2014 Wiley Periodicals, Inc. V
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found a significant increase in LVAD thrombosis within the first 3 months of implantation of the Heartmate II device [7]. Surgical bleeding complications are the most common in the immediate post-implant period, GI bleeding the most frequent non-surgical type of bleeding, and intracranial hemorrhage the most feared. Bleeding rates in LVAD patients are higher than in patients treated with anticoagulation and anti-platelet agents for other indications [8]. Other factors possibly associated with CF-LVAD bleeding, include changes in the vWF multimer pattern, platelet function, and GI tract vasculature. Acquired von Willebrand syndrome (AVWS) has been demonstrated in patients with LVADs similar to that in patients with aortic stenosis and Heyde’s syndrome, in which patients develop an acquired vWD with a phenotype consistent with IIa vWD [9]. Loss of high molecular weight (HMW) vWF multimers is believed to result from high shear stress effects on vWF multimers; this hypothesis is supported by in vitro data [10–14]. High shear stress changes the conformation of the large vWF multimer from a globular mass to a more linear shape, resulting in exposure of ADAMTS13 binding and cleavage sites in the A2 domain [10] Proteolysis of the vWF multimers by ADAMTS13 yields significantly smaller multimers that provide less hemostasis. Multiple investigators have demonstrated loss of HMW vWF multimers in patients with CF-LVADs. A retrospective study of 79 patients revealed that all had decreased or absent HMW vWF multimers while being supported by CF-LVAD but recovered normal vWF multimer pattern after heart transplant. The frequency of bleeding in these patients, however, was not related to the level of vWF antigen or ristocetin-cofactor activity while the LVAD was in place [12]. A prospective study of 37 patients found significant loss of HMW vWF multimers within 30 days after CF-LVAD implantation [13], however, only 27% of these patients had bleeding complications, suggesting that other factors contribute to bleeding risk. Although the increased shear stress associated with CF-LVADs is expected to activate platelets, it may also decrease platelet function and aggregation, although the impact of these functional changes on bleeding rates is not clear. In a small study of LVAD patients, eleven of 16 patients with CF-LVADs had impaired ristocetin-induced platelet activation and both minor and major bleeding [15]. Despite decreased HMW vWF multimers, these patients had vWF ristocetin-cofactor activity in the normal range, suggesting that bleeding events were not due to loss of HMW vWF multimers. It was proposed that vWF fragments inhibited platelet aggregation and that poor platelet reactivity played a role in bleeding. Similar findings were seen by Steinlechner et al. in patients with CF-LVAD with 11 of 12 demonstrating impaired platelet function under high shear stress with impaired ristocetin-induced platelet aggregation not completely attributable to low vWF activity [16]. The most recent analysis found that 30% of patients with CFLVAD experienced GI bleeding with an event rate of 0.45 GI bleeds/ patient-year of support [17]. Anatomic factors, especially the development of small bowel angiodysplasia, may contribute more to bleeding than changes in vWF multimer configuration or decreased platelet activity. One third of patients with CF-LVADs and GI bleeding have documented angiodysplasia that is believed to be the bleeding source [18]. The similarity with Heyde’s syndrome may extend beyond the association with AVWS to include development of angiodysplasia in patients with LVADs as with aortic stenosis [9]. Multiple mechanisms for the development of angiodysplasia have been postulated. First, the congestive vasculopathy with distention of submucosal venous plexus caused by the continuous flow device may lead to an increase in intraluminal pressures in the vessel walls of the GI tract [19]. Second, a decreased pulse pressure from CF-LVADS, as in aortic stenosis, may contribute to mucosal hypoperfusion, leading to hypoxia-induced vascular dilatation and resultant angiodysplasia [20]. Other postulated mechanisms include an impact of vWF on vascular integrity, including the possibility that vWF fragments may be proangiogenic and contrib176
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ute to the development of angiodysplasia [21] or that vWF may be required to aid platelets in maintaining vascular integrity [22]. These factors may be exacerbated by older age. In a recent review of 389 CF-LVAD patients, those over the age of 70 years had six times the rate of GI bleeds compared with those under age 50 [17]. She received IV fluid resuscitation, and was transfused with two bags of FFP and five bags of PRBC over 24 hr as volume status was not a concern. Warfarin and aspirin were held. Despite low hemoglobin, she was felt to be stable and a decision was made not to reverse warfarin with vitamin K. INR dropped to 2.8 after two bags of FFP and then to 2.2 over 3 days without the use of vitamin K. The hematocrit remained relatively stable at 27% with no further need for RBC transfusion. Warfarin was then restarted after 4 days. GI consultation suggested repeat capsule endoscopy, which was again unrevealing. Aspirin was added at a lower dose of 81 mg daily 1 week after presentation. When to restart or increase the intensity of anticoagulation after a bleeding event requires assessment of the individual patient. Severity and duration of bleeding and adverse effects of re-bleeding must be considered. Cautious introduction of an IV anticoagulant, either UFH which can be reversed if bleeding recurs, or an IV DTI with short half life, can be used and the patient closely monitored for signs of immediate re-bleeding. In our bridge to heart transplant candidates, we use an IV direct thrombin inhibitor (bivalirudin) in lieu of UFH given the high potential for development of heparin induced thrombocytopenia (HIT) in these patients, which would make heart transplant and cardiopulmonary bypass more difficult [23]. Once stable on a parenteral agent, warfarin can then be restarted. Aspirin is added back when the patient has no evidence of re-bleeding. Recurrent GI bleeds occur frequently. For patients with more than one bleeding event, the target INR is often subsequently decreased, and aspirin dose is lowered, or dropped completely. Continued re-assessment of anticoagulation and anti-platelet therapy is required. Resumption of full doses of warfarin and aspirin should be considered whenever possible. Target INR was decreased to 2.0–2.5. Future anticoagulation strategy was changed: for INR of 1.5–2.0, warfarin dose would be adjusted; for INR below 1.5 she would be admitted for IV anticoagulation until INR back in the therapeutic range, to avoid overlap of therapeutic INR with LMWH. She was discharged from the hospital in stable condition after 10 days, with no evidence of recurrent GI bleeding at the time of discharge. Seven weeks after discharge she underwent successful orthotopic heart transplant. She had no further indication for anticoagulation and is doing well now 4 months out, without recurrent GI bleeding.
䊏 Discussion Patients with LVADs should be assessed for severity of bleeding as one would do for any anti-coagulated patient presenting with bleeding. Standard supportive care, including fluid resuscitation, should be initiated, with appropriate involvement of gastroenterologists, neurosurgeons, and other consultants. Further treatment requires weighing the persistent thrombotic risk of the LVAD against the severity and acuity of bleeding. Newly published data, however, demonstrate that since 2011, there has been an increase in early device thrombosis in the first 3 months after implantation [7]; anticoagulation strategies are therefore currently undergoing intense re-evaluation [24]. There are concerns that holding anticoagulation for bleeding events may increase the risk of device thrombosis.
Life-threatening major hemorrhage Life-threatening bleeding requires immediate cessation of anticoagulant and anti-platelet drugs and requires reversal of warfarin as well as platelet transfusion to overcome the platelet aspirin defect. In patients with life-threatening bleeding, four factor prothrombin complex concentrate (PCC) is preferred over fresh frozen plasma (FFP)
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SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES for warfarin reversal due to smaller volume, faster administration time, and faster restoration of coagulant factor activity [25], especially for patients with intracranial hemorrhage. Evacuation of sub-dural hematomas may be required. For major GI bleeding, transfusion support with red cells is often necessary despite concern of alloimmunization, which can have a negative effect on cardiac transplant. Measures including endoscopy and treatment of bleeding sites, radiologic imaging of vessels with interventions such as embolization, and even surgery may be required. Vitamin K may be necessary, especially in cases of severe bleeding when extended time off anticoagulation is expected, however, patients will eventually need to return to warfarin anticoagulation when stable, which can be made more difficult by excess vitamin K levels. Patients with LVADs have a persistent inflammatory state and will usually have significantly elevated levels of fibrinogen and vWF antigen, including FVIII and ristocetin co-factor activity. Although there is evidence of loss of HMW vWF multimers in CF-LVAD patients, there are few data regarding efficacy of DDAVP or vWF concentrates in reversing bleeding. Registry data of AVWS patients suggest that only 10% of patients with a cardiac etiology respond to DDAVP, compared with 33–44% of those with underlying auto-immune or lymphoproliferative disorders [26]. One case report discusses the use of vWF concentrate in a patient with an LVAD. This patient had a diagnosis of amyloid heart requiring both RVAD and LVAD support. GI bleeding was eventually brought under control after use of multiple strategies including a prolonged course of vWF concentrate infusions. Despite documentation of extremely high levels of vWF antigen and ristocetin-cofactor activity during infusions, HMW vWF multimers remained absent from the circulation [27]. Native and infused vWF multimers likely have equally short circulation time before shear stress induced cleavage occurs, suggesting that there is little or no role for DDAVP or vWF concentrate to try to increase HMW vWF multimers to decrease bleeding, especially in patients with baseline normal or elevated vWF antigen and ristocetin-cofactor activity.
Mild to moderate bleeding In patients with mild to moderate bleeding, an individualized assessment may be required to identify the best strategy to minimize bleeding while maintaining anticoagulation. While some past algorithms have recommended holding anticoagulation for 2–4 weeks after a GI bleed [28] recent data reveal that a decrease in the level of anticoagulation in response to GI bleeding may lead to increased thrombotic events at a later time. In this analysis, patients with a previous GI bleed were 7.4-fold more likely to have a thromboembolic event [17], suggesting that stopping anticoagulation in response to mild or moderate GI bleeds may not be appropriate. For patients with mild mucosal bleeding, such as epistaxis or mild GI bleeding, holding aspirin may be sufficient to achieve hemostasis. Dropping the target INR to a lower range of 1.5–2.0 instead of 2.0–3.0 can aid in resolution of mild to moderate bleeding of any type and can be accomplished by allowing the INR to drift down, or with the judicious use of low doses of PCC or vitamin K for supratherapeutic INRs. Other adjunctive therapies are often employed, especially in the cases of GI bleeding, including standard of care proton pump inhibitors, and octreotide. The somatostatin analog octreotide has been used in non-VAD patients with upper GI bleeding from both varices and non-varices with some success [29]. Octreotide is also used in patients with LVADs, although its efficacy has not been firmly established. In one study the use of octreotide did not affect red cell transfusion number or rebleeding rates, suggesting that it has little or no impact on outcomes [30]. The use of thalidomide has been suggested based on some success in patients with HHT [31,32], however, the associated thrombotic risk of the drug is concerning for use in patients with LVADs and is not recommended at this time. doi:10.1002/ajh.23836
Anticoagulation management of LVAD
Thrombosis Although thrombotic events occur much less frequently than bleeding complications, the impact of stroke and device thrombosis can be devastating, with significant morbidity and death. Thrombosis occurs for many reasons in LVAD patients. The artificial surfaces of the device directly activate coagulation though contact mechanisms, high flow rates and high shear stress can result in activation of many blood components including vascular endothelial cells, platelets, and white cells. Red cell hemolysis and the procoagulant effects of red cell debris also likely contribute to thrombosis. Patients with LVADs have an increased level of inflammation, as evidenced by increased inflammatory markers such as ESR and C reactive protein, which also may contribute to the pro-thrombotic state. Thrombotic manifestations are usually a result of device thrombosis, including thromboembolic stroke, although thrombosis in the left ventricle, aortic arch, and carotid bulb, believed to be due to low flow state have been reported [33–35]. Anticoagulation and anti-platelet protocols have evolved over time. Early protocols started anticoagulation quickly after device implantation and aimed to achieve high levels of anticoagulation, with significant resultant bleeding and intracranial hemorrhage. With the demonstration of low thromboembolic rates in the immediate postoperative period, there had been a trend toward decreasing the intensity of anticoagulation, and even delaying initiation of anticoagulation, immediately following surgery [5,36,37]. As noted above, however, review of the data since March 2011 has shown an increase in device thrombosis rates from 2.2% to 8.4% within the first 3 months following implantation [7]. It is unclear whether this reflects a change in the risk related to change in device components, changes in antithrombotic therapy, or is intrinsic to the procedure. Following LVAD implantation, patients are started on standard anticoagulation with warfarin to maintain an INR of 2.0–3.0 without IV UFH bridge and aspirin 325 mg a day. Thrombotic complications often occur in the setting of lowering anticoagulation for a bleeding event [19]. Patients with a history of DVT or PE prior to LVAD implantation have demonstrated increased risk for events in our center, especially those with known inherited thrombophilia, such as factor V Leiden or antiphospholipid syndrome. In these patients a higher INR range of 2.5-3.5 is targeted and, attempts are made not to stop anticoagulation or anti-platelet treatments for mild or moderate bleeding. For patients with peripheral thromboembolic events such as embolic stroke, both aspirin dose and target INR are increased, although over-anticoagulation and hemorrhagic evolution of ischemic infarcts is a concern. The target INR in patients with a history of atrial fibrillation and past stroke will be increased to 2.5–3. Higher INRs are also targeted if the patient has a history of antiphospholipid syndrome with past thrombotic events, despite extremely limited data to support this approach [38].
Device thrombosis Device thrombosis is the biggest challenge to manage. Detecting device thrombosis is difficult, as the internal chamber of the device cannot be visualized with any radiologic imaging technique. D-dimer measurements are uniformly elevated in these patients at baseline and are not helpful. Cardiologists use a combination of indicators to determine the presence of LVAD thrombosis. Evidence of increased red cell hemolysis based on an increase in the LDH of greater than 2.5 times the upper limit of normal and increased plasma hemoglobin above typical elevated baseline can point to early device thrombosis [7]. Power spikes can indicate rotor thrombosis but characteristic findings on ramp transthoracic echocardiogram are the mainstay of diagnosing LVAD thrombosis. American Journal of Hematology, Vol. 90, No. 2, February 2015
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Ramp echocardiogram involves increasing the LVAD pump speed; unloading or decompression of the LV should occur with increased speed as more blood is drained from the native left ventricle and pumped through the device, with minimal to no aortic valve opening. If the LV remains distended and the AV opens frequently, LVAD thrombosis is suspected [39]. Initial medical management of suspected device thrombosis involves rapidly increasing the level of anticoagulation, often by admitting the patient and starting IV UFH until a higher target INR is achieved. In our bridge to heart transplant candidates, we use an IV direct thrombin inhibitor (bivalirudin) as discussed above [23]. Use of systemic thrombolytic therapy with TPA and use of the IIb/IIIa inhibitor eptifibatide, alone or in combination with each other and UFH, have demonstrated efficacy in case reports and small studies. Although these agents would seem to address the underlying pathophysiology and either lead to thrombolysis or prevent clot prop-
䊏 References
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agation, larger studies have demonstrated higher morbidity and mortality with these strategies, suggesting that urgent or elective surgical exchange for a new device may be the better treatment [40–42]. The recently reported findings of a sharp increase in CF-LVAD thrombosis in the first 3 months post-implantation, however, are resulting in re-evaluation of timing of initiation and intensity of anticoagulation and anti-platelet protocols [24,25]. Management of the simultaneous high bleeding and thrombotic risk of patients with CF-LVADs can be challenging. Inherent patient specific factors can alter the baseline balance of procoagulant and anticoagulant activity, which are exacerbated by the multiple changes in physiology that accompany the use of CF-LVAD. The ideal levels of anticoagulant and anti-platelet intensity have yet to be determined and protocols are continuing to evolve. A multi-disciplinary approach involving hematologists is integral to manage the balance between bleeding and thrombosis to achieve the optimal outcome for patients with LVADs.
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AJH Educational Material A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary
Anticoagulation management of left ventricular assist devices Jean M. Connors*
Hematology was consulted to aid in the management of a 56-yearold woman admitted for presumed gastro-intestinal (GI) bleeding. Her history was notable for non-ischemic cardiomyopathy status post placement of a left ventricular assist device (LVAD) as a bridge to transplant 10 months before admission. She had had one episode of guaiac positive stools and a drop in hematocrit requiring transfusion of two units of red cells 3 months after LVAD placement. Thorough GI evaluation at that time demonstrated normal EGD findings and blood in the terminal ilium on colonoscopy. Subsequent video capsule endoscopy however was unrevealing. Anticoagulation was maintained with a target INR of 2.0–3.0 and aspirin 325 mg every day. Two weeks before admission her INR was 1.6, and warfarin dose was increased. Repeat testing a few days later revealed no change in INR and enoxaparin 1 mg/kg twice a day was started. Enoxaparin was stopped after 5 days. She had noted increasing fatigue and dyspnea over these 2 weeks and ultimately presented to the emergency room. She denied any obvious signs of blood loss including epistaxis, melena, hematochezia, or change in stool color. Options for treatment of patients with advanced heart failure have expanded to include the use of mechanical circulatory assist devices for those waiting for heart transplant or as destination devices to improve quality of life for those not eligible for transplant. Despite significant advances both in device technology and anticoagulation protocols, bleeding, and thrombosis are the most significant adverse events accompanying use of these devices. Anticoagulation to protect against the intrinsic pro-thrombotic state resulting from the device must be balanced against bleeding complications that can result in significant morbidity and mortality. Hematologists are increasingly involved in the complex care of these patients. The use of mechanical circulatory support (MCS) devices for patients with advanced heart failure has increased dramatically in the past few years. Improvements and changes in the technology of the devices combined with changes in patient selection have significantly improved outcomes resulting in more widespread use. Left ventricular assist devices (LVAD) are the most frequently used devices. From 2007 to 2012 there was a tenfold increase in the number of LVADs implanted in the United States, from 247 in 2007 to 2,162 in 2012 [1]. The most frequent complications with LVAD use are bleeding and thrombosis. Criteria for selection of patients in whom an LVAD serves as bridge to transplant versus destination device are different. Patients not suitable for heart transplant may be eligible for LVAD implantation. Factors that prohibit heart transplant, such as age, comorbid dis-
ease, and more advanced cardiac or pulmonary disease, may also put these patients at higher risk for hematologic complications. LVADs function by draining blood from the apex of the left ventricle and pumping it through the device to the ascending aorta. Newer devices use a continuous flow rotary pump which has been found to have multiple advantages including improved outcomes, smaller device size, longer durability, and less noise, than earlier models that used volume displacement mechanisms [2,3]. Anticoagulation protocols are both device type and institution specific but rely on a combination of aspirin, from 81 to 325 mg a day, and warfarin, in patients with continuous flow devices. New oral anticoagulants are not used in patients with mechanical circulatory assist devices given that dabigatran was found to be inferior to warfarin for preventing thromboembolic events in patients with mechanical heart valves [4]. Data from a 2009 study of the continuous flow Heartmate II device suggested that immediate post-op bridging anticoagulation with IV unfractionated heparin (UFH) was not required, resulting in less surgical site bleeding. Initiation of warfarin and aspirin without IV UFH has become the standard for HeartMate II LVADs, the most frequently used device in the USA [1]. This study also suggested that the rate of thromboembolic events was extremely low with an INR target of 2.5–3.5; therefore, a lower target INR of 1.5–2.5 was determined to be sufficient to prevent thrombotic events with less bleeding complications [5,6]. The patient had a systolic blood pressure of 76mm HG. Patients with CF-LVADS do not have peripheral pulses therefore no heart rate was recorded. Respiratory rate was 20 breaths per minute. Stool was guaiac positive. Laboratory values were notable for a hemoglobin of 3.4 g/dl and hematocrit 11.2%, decreased from her baseline of approximately 10 g/dl and 30%. LDH was 261 (94–250 U/L) and total bilrubin was normal, suggesting no significant hemolysis which was confirmed by plasma hemoglobin of 3.7 mg/ dl, her baseline value. Platelet count was 206,000/ml. INR was supratherapeutic at 5.9. Additional lab values included a fibrinogen of 490 mg/dl, vWF antigen of 230%, with ristocetin-cofactor activity of 190% and FVIII activity of 280%. Both bleeding and thrombosis occur at very high rates in these patients, present difficult management issues, and can be lifethreatening. An analysis of US registry data of cumulative event rates in 8,644 patients found that 38.9% experience bleeding events and 17.3% develop neurologic dysfunction including thromboembolic stroke and intracranial hemorrhage. Other thrombotic manifestations include a 5.4% rate of VTE, and 1.3% rate of non-stroke arterial embolic events [1]. Review of outcomes over the past 2 years has
Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Conflict of interest: Nothing to report. *Correspondence to: Jean M. Connors, Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. E-mail: [email protected] Received for publication: 7 August 2014; Accepted: 25 August 2014 Am. J. Hematol. 90:175–178, 2015. Published online: 28 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23836 C 2014 Wiley Periodicals, Inc. V
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found a significant increase in LVAD thrombosis within the first 3 months of implantation of the Heartmate II device [7]. Surgical bleeding complications are the most common in the immediate post-implant period, GI bleeding the most frequent non-surgical type of bleeding, and intracranial hemorrhage the most feared. Bleeding rates in LVAD patients are higher than in patients treated with anticoagulation and anti-platelet agents for other indications [8]. Other factors possibly associated with CF-LVAD bleeding, include changes in the vWF multimer pattern, platelet function, and GI tract vasculature. Acquired von Willebrand syndrome (AVWS) has been demonstrated in patients with LVADs similar to that in patients with aortic stenosis and Heyde’s syndrome, in which patients develop an acquired vWD with a phenotype consistent with IIa vWD [9]. Loss of high molecular weight (HMW) vWF multimers is believed to result from high shear stress effects on vWF multimers; this hypothesis is supported by in vitro data [10–14]. High shear stress changes the conformation of the large vWF multimer from a globular mass to a more linear shape, resulting in exposure of ADAMTS13 binding and cleavage sites in the A2 domain [10] Proteolysis of the vWF multimers by ADAMTS13 yields significantly smaller multimers that provide less hemostasis. Multiple investigators have demonstrated loss of HMW vWF multimers in patients with CF-LVADs. A retrospective study of 79 patients revealed that all had decreased or absent HMW vWF multimers while being supported by CF-LVAD but recovered normal vWF multimer pattern after heart transplant. The frequency of bleeding in these patients, however, was not related to the level of vWF antigen or ristocetin-cofactor activity while the LVAD was in place [12]. A prospective study of 37 patients found significant loss of HMW vWF multimers within 30 days after CF-LVAD implantation [13], however, only 27% of these patients had bleeding complications, suggesting that other factors contribute to bleeding risk. Although the increased shear stress associated with CF-LVADs is expected to activate platelets, it may also decrease platelet function and aggregation, although the impact of these functional changes on bleeding rates is not clear. In a small study of LVAD patients, eleven of 16 patients with CF-LVADs had impaired ristocetin-induced platelet activation and both minor and major bleeding [15]. Despite decreased HMW vWF multimers, these patients had vWF ristocetin-cofactor activity in the normal range, suggesting that bleeding events were not due to loss of HMW vWF multimers. It was proposed that vWF fragments inhibited platelet aggregation and that poor platelet reactivity played a role in bleeding. Similar findings were seen by Steinlechner et al. in patients with CF-LVAD with 11 of 12 demonstrating impaired platelet function under high shear stress with impaired ristocetin-induced platelet aggregation not completely attributable to low vWF activity [16]. The most recent analysis found that 30% of patients with CFLVAD experienced GI bleeding with an event rate of 0.45 GI bleeds/ patient-year of support [17]. Anatomic factors, especially the development of small bowel angiodysplasia, may contribute more to bleeding than changes in vWF multimer configuration or decreased platelet activity. One third of patients with CF-LVADs and GI bleeding have documented angiodysplasia that is believed to be the bleeding source [18]. The similarity with Heyde’s syndrome may extend beyond the association with AVWS to include development of angiodysplasia in patients with LVADs as with aortic stenosis [9]. Multiple mechanisms for the development of angiodysplasia have been postulated. First, the congestive vasculopathy with distention of submucosal venous plexus caused by the continuous flow device may lead to an increase in intraluminal pressures in the vessel walls of the GI tract [19]. Second, a decreased pulse pressure from CF-LVADS, as in aortic stenosis, may contribute to mucosal hypoperfusion, leading to hypoxia-induced vascular dilatation and resultant angiodysplasia [20]. Other postulated mechanisms include an impact of vWF on vascular integrity, including the possibility that vWF fragments may be proangiogenic and contrib176
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ute to the development of angiodysplasia [21] or that vWF may be required to aid platelets in maintaining vascular integrity [22]. These factors may be exacerbated by older age. In a recent review of 389 CF-LVAD patients, those over the age of 70 years had six times the rate of GI bleeds compared with those under age 50 [17]. She received IV fluid resuscitation, and was transfused with two bags of FFP and five bags of PRBC over 24 hr as volume status was not a concern. Warfarin and aspirin were held. Despite low hemoglobin, she was felt to be stable and a decision was made not to reverse warfarin with vitamin K. INR dropped to 2.8 after two bags of FFP and then to 2.2 over 3 days without the use of vitamin K. The hematocrit remained relatively stable at 27% with no further need for RBC transfusion. Warfarin was then restarted after 4 days. GI consultation suggested repeat capsule endoscopy, which was again unrevealing. Aspirin was added at a lower dose of 81 mg daily 1 week after presentation. When to restart or increase the intensity of anticoagulation after a bleeding event requires assessment of the individual patient. Severity and duration of bleeding and adverse effects of re-bleeding must be considered. Cautious introduction of an IV anticoagulant, either UFH which can be reversed if bleeding recurs, or an IV DTI with short half life, can be used and the patient closely monitored for signs of immediate re-bleeding. In our bridge to heart transplant candidates, we use an IV direct thrombin inhibitor (bivalirudin) in lieu of UFH given the high potential for development of heparin induced thrombocytopenia (HIT) in these patients, which would make heart transplant and cardiopulmonary bypass more difficult [23]. Once stable on a parenteral agent, warfarin can then be restarted. Aspirin is added back when the patient has no evidence of re-bleeding. Recurrent GI bleeds occur frequently. For patients with more than one bleeding event, the target INR is often subsequently decreased, and aspirin dose is lowered, or dropped completely. Continued re-assessment of anticoagulation and anti-platelet therapy is required. Resumption of full doses of warfarin and aspirin should be considered whenever possible. Target INR was decreased to 2.0–2.5. Future anticoagulation strategy was changed: for INR of 1.5–2.0, warfarin dose would be adjusted; for INR below 1.5 she would be admitted for IV anticoagulation until INR back in the therapeutic range, to avoid overlap of therapeutic INR with LMWH. She was discharged from the hospital in stable condition after 10 days, with no evidence of recurrent GI bleeding at the time of discharge. Seven weeks after discharge she underwent successful orthotopic heart transplant. She had no further indication for anticoagulation and is doing well now 4 months out, without recurrent GI bleeding.
䊏 Discussion Patients with LVADs should be assessed for severity of bleeding as one would do for any anti-coagulated patient presenting with bleeding. Standard supportive care, including fluid resuscitation, should be initiated, with appropriate involvement of gastroenterologists, neurosurgeons, and other consultants. Further treatment requires weighing the persistent thrombotic risk of the LVAD against the severity and acuity of bleeding. Newly published data, however, demonstrate that since 2011, there has been an increase in early device thrombosis in the first 3 months after implantation [7]; anticoagulation strategies are therefore currently undergoing intense re-evaluation [24]. There are concerns that holding anticoagulation for bleeding events may increase the risk of device thrombosis.
Life-threatening major hemorrhage Life-threatening bleeding requires immediate cessation of anticoagulant and anti-platelet drugs and requires reversal of warfarin as well as platelet transfusion to overcome the platelet aspirin defect. In patients with life-threatening bleeding, four factor prothrombin complex concentrate (PCC) is preferred over fresh frozen plasma (FFP)
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SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES for warfarin reversal due to smaller volume, faster administration time, and faster restoration of coagulant factor activity [25], especially for patients with intracranial hemorrhage. Evacuation of sub-dural hematomas may be required. For major GI bleeding, transfusion support with red cells is often necessary despite concern of alloimmunization, which can have a negative effect on cardiac transplant. Measures including endoscopy and treatment of bleeding sites, radiologic imaging of vessels with interventions such as embolization, and even surgery may be required. Vitamin K may be necessary, especially in cases of severe bleeding when extended time off anticoagulation is expected, however, patients will eventually need to return to warfarin anticoagulation when stable, which can be made more difficult by excess vitamin K levels. Patients with LVADs have a persistent inflammatory state and will usually have significantly elevated levels of fibrinogen and vWF antigen, including FVIII and ristocetin co-factor activity. Although there is evidence of loss of HMW vWF multimers in CF-LVAD patients, there are few data regarding efficacy of DDAVP or vWF concentrates in reversing bleeding. Registry data of AVWS patients suggest that only 10% of patients with a cardiac etiology respond to DDAVP, compared with 33–44% of those with underlying auto-immune or lymphoproliferative disorders [26]. One case report discusses the use of vWF concentrate in a patient with an LVAD. This patient had a diagnosis of amyloid heart requiring both RVAD and LVAD support. GI bleeding was eventually brought under control after use of multiple strategies including a prolonged course of vWF concentrate infusions. Despite documentation of extremely high levels of vWF antigen and ristocetin-cofactor activity during infusions, HMW vWF multimers remained absent from the circulation [27]. Native and infused vWF multimers likely have equally short circulation time before shear stress induced cleavage occurs, suggesting that there is little or no role for DDAVP or vWF concentrate to try to increase HMW vWF multimers to decrease bleeding, especially in patients with baseline normal or elevated vWF antigen and ristocetin-cofactor activity.
Mild to moderate bleeding In patients with mild to moderate bleeding, an individualized assessment may be required to identify the best strategy to minimize bleeding while maintaining anticoagulation. While some past algorithms have recommended holding anticoagulation for 2–4 weeks after a GI bleed [28] recent data reveal that a decrease in the level of anticoagulation in response to GI bleeding may lead to increased thrombotic events at a later time. In this analysis, patients with a previous GI bleed were 7.4-fold more likely to have a thromboembolic event [17], suggesting that stopping anticoagulation in response to mild or moderate GI bleeds may not be appropriate. For patients with mild mucosal bleeding, such as epistaxis or mild GI bleeding, holding aspirin may be sufficient to achieve hemostasis. Dropping the target INR to a lower range of 1.5–2.0 instead of 2.0–3.0 can aid in resolution of mild to moderate bleeding of any type and can be accomplished by allowing the INR to drift down, or with the judicious use of low doses of PCC or vitamin K for supratherapeutic INRs. Other adjunctive therapies are often employed, especially in the cases of GI bleeding, including standard of care proton pump inhibitors, and octreotide. The somatostatin analog octreotide has been used in non-VAD patients with upper GI bleeding from both varices and non-varices with some success [29]. Octreotide is also used in patients with LVADs, although its efficacy has not been firmly established. In one study the use of octreotide did not affect red cell transfusion number or rebleeding rates, suggesting that it has little or no impact on outcomes [30]. The use of thalidomide has been suggested based on some success in patients with HHT [31,32], however, the associated thrombotic risk of the drug is concerning for use in patients with LVADs and is not recommended at this time. doi:10.1002/ajh.23836
Anticoagulation management of LVAD
Thrombosis Although thrombotic events occur much less frequently than bleeding complications, the impact of stroke and device thrombosis can be devastating, with significant morbidity and death. Thrombosis occurs for many reasons in LVAD patients. The artificial surfaces of the device directly activate coagulation though contact mechanisms, high flow rates and high shear stress can result in activation of many blood components including vascular endothelial cells, platelets, and white cells. Red cell hemolysis and the procoagulant effects of red cell debris also likely contribute to thrombosis. Patients with LVADs have an increased level of inflammation, as evidenced by increased inflammatory markers such as ESR and C reactive protein, which also may contribute to the pro-thrombotic state. Thrombotic manifestations are usually a result of device thrombosis, including thromboembolic stroke, although thrombosis in the left ventricle, aortic arch, and carotid bulb, believed to be due to low flow state have been reported [33–35]. Anticoagulation and anti-platelet protocols have evolved over time. Early protocols started anticoagulation quickly after device implantation and aimed to achieve high levels of anticoagulation, with significant resultant bleeding and intracranial hemorrhage. With the demonstration of low thromboembolic rates in the immediate postoperative period, there had been a trend toward decreasing the intensity of anticoagulation, and even delaying initiation of anticoagulation, immediately following surgery [5,36,37]. As noted above, however, review of the data since March 2011 has shown an increase in device thrombosis rates from 2.2% to 8.4% within the first 3 months following implantation [7]. It is unclear whether this reflects a change in the risk related to change in device components, changes in antithrombotic therapy, or is intrinsic to the procedure. Following LVAD implantation, patients are started on standard anticoagulation with warfarin to maintain an INR of 2.0–3.0 without IV UFH bridge and aspirin 325 mg a day. Thrombotic complications often occur in the setting of lowering anticoagulation for a bleeding event [19]. Patients with a history of DVT or PE prior to LVAD implantation have demonstrated increased risk for events in our center, especially those with known inherited thrombophilia, such as factor V Leiden or antiphospholipid syndrome. In these patients a higher INR range of 2.5-3.5 is targeted and, attempts are made not to stop anticoagulation or anti-platelet treatments for mild or moderate bleeding. For patients with peripheral thromboembolic events such as embolic stroke, both aspirin dose and target INR are increased, although over-anticoagulation and hemorrhagic evolution of ischemic infarcts is a concern. The target INR in patients with a history of atrial fibrillation and past stroke will be increased to 2.5–3. Higher INRs are also targeted if the patient has a history of antiphospholipid syndrome with past thrombotic events, despite extremely limited data to support this approach [38].
Device thrombosis Device thrombosis is the biggest challenge to manage. Detecting device thrombosis is difficult, as the internal chamber of the device cannot be visualized with any radiologic imaging technique. D-dimer measurements are uniformly elevated in these patients at baseline and are not helpful. Cardiologists use a combination of indicators to determine the presence of LVAD thrombosis. Evidence of increased red cell hemolysis based on an increase in the LDH of greater than 2.5 times the upper limit of normal and increased plasma hemoglobin above typical elevated baseline can point to early device thrombosis [7]. Power spikes can indicate rotor thrombosis but characteristic findings on ramp transthoracic echocardiogram are the mainstay of diagnosing LVAD thrombosis. American Journal of Hematology, Vol. 90, No. 2, February 2015
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Ramp echocardiogram involves increasing the LVAD pump speed; unloading or decompression of the LV should occur with increased speed as more blood is drained from the native left ventricle and pumped through the device, with minimal to no aortic valve opening. If the LV remains distended and the AV opens frequently, LVAD thrombosis is suspected [39]. Initial medical management of suspected device thrombosis involves rapidly increasing the level of anticoagulation, often by admitting the patient and starting IV UFH until a higher target INR is achieved. In our bridge to heart transplant candidates, we use an IV direct thrombin inhibitor (bivalirudin) as discussed above [23]. Use of systemic thrombolytic therapy with TPA and use of the IIb/IIIa inhibitor eptifibatide, alone or in combination with each other and UFH, have demonstrated efficacy in case reports and small studies. Although these agents would seem to address the underlying pathophysiology and either lead to thrombolysis or prevent clot prop-
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agation, larger studies have demonstrated higher morbidity and mortality with these strategies, suggesting that urgent or elective surgical exchange for a new device may be the better treatment [40–42]. The recently reported findings of a sharp increase in CF-LVAD thrombosis in the first 3 months post-implantation, however, are resulting in re-evaluation of timing of initiation and intensity of anticoagulation and anti-platelet protocols [24,25]. Management of the simultaneous high bleeding and thrombotic risk of patients with CF-LVADs can be challenging. Inherent patient specific factors can alter the baseline balance of procoagulant and anticoagulant activity, which are exacerbated by the multiple changes in physiology that accompany the use of CF-LVAD. The ideal levels of anticoagulant and anti-platelet intensity have yet to be determined and protocols are continuing to evolve. A multi-disciplinary approach involving hematologists is integral to manage the balance between bleeding and thrombosis to achieve the optimal outcome for patients with LVADs.
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