TRANSPLANTATION IN

THE HIV POPULATION

A Rare Case of Disseminated Intravascular
Coagulation Post Heart Transplantation in an HIV-
Positive recipient

Mrinmayee Mandal
Centennial High School
4300 Centennial Lane
Ellicott City, MD 21042
 Mandal 1

ACKNOWLEDGMENTS

I would like to pay special thankfulness, warmth and appreciation to the persons below who
made my research successful and assisted me at every point to cherish my goal:

Dr. Jennifer Lawton and Dr. Baum Gartner for their vital support and assistance. Their
encouragement made it possible to achieve the goal.

Dr. Alex Suarez, Dr. Xun Zhou and Aravind Krishnan whose help and sympathetic attitude at
every point during my research helped me to work in time.

All the faculty, staff members and lab technicians of the Johns Hopkins Hospital Cardiac
Surgery Division, whose services turned my research a success.

My teacher, Ms. Bagley, whose guidance and strong leadership has always been inspiring.

My Mom and Dad, family members and friends, whose moral support led me through a
wonderful endeavor.
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DISCLAIMERS

Research involving non-human vertebrates or human subjects was conducted under the
supervision of an experienced teacher or researcher and followed state and federal regulatory
guidance applicable to the humane and ethical conduct of such research.
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Table of Contents

INTRODUCTION .......................................................................................................................... 4
METHODOLOGY ......................................................................................................................... 5
CASE REPORT .............................................................................................................................. 6
ANALYSIS ..................................................................................................................................... 8
CONCLUSION ............................................................................................................................. 10
REFERENCES ............................................................................................................................. 11
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INTRODUCTION

The Human Immunodeficiency Virus (HIV) is a retrovirus that attacks the body’s immune
system. First, it binds to the CD4 cell receptors with its glycoproteins. Next, it enters the cell and
initiates reverse transcription. Now, it is able to integrate with cell DNA. Once integrated, it uses
the cell to replicate itself and spread throughout the body to attack other T-cells. The
management of HIV/AIDS normally includes the use of multiple antiretroviral. There are several
classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of
multiple drugs that act on different viral targets is known as highly active antiretroviral
therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of
the immune system, and prevents opportunistic infections that often lead to death. Treatment has
been so successful that in many parts of the world, HIV has become a chronic condition in which
progression to AIDS is increasingly rare.

Dating back to the original discovery of the virus itself, an early belief was instilled that
the HIV infection should prove to be a contraindication, and maybe even an absolute one, to
solid organ transplantation. It was not until after the successful results of HAART, that organ
transplantation was being considered in this community of people. AIDS is no longer the major
concern for HIV infected individuals, and organ failure has replaced its place as the leading
cause of mortality in this population.1

Nonetheless, heart transplantation for patients with HIV remains a rare event, and the
complication profile in this population is not well understood. This research presents a case of a
48-year-old HIV-positive man who underwent orthotopic heart transplantation with a
complicated recovery that involved digital ischemia and jugular vein thrombosis secondary to
disseminated intravascular coagulation (DIC). This is believed to be the first reported case of
DIC as a complication after heart transplantation in an HIV-positive patient.
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METHODOLOGY

In order to investigate transplantation in HIV positive patients, I decided to look into one specific
patient’s course instead of many patients.

First, I read through many published literature and gained a solid background on the
topics of HIV/AIDS and its medical and ethical history, organ transplantation and its medical
and ethical concerns. Looking through similar case reports and case series, I was able to come to
certain conclusions regarding antiretrovirals and how they interact with the human body.

The second task in my research process was to collect and organize data pertaining to the
patient I had chosen to study. With appropriate supervision and permission, I collected and de-
identified the patient information. I specifically focused on the patient’s platelet, CD4, and
fibrinogen counts throughout the hospital course.

Finally, with necessary background information and relevant data, I was able to write up
a research paper detailing the complications and other issues common in the HIV population
when it comes to transplantation.
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CASE REPORT

A 48-year-old man with a history of HIV and familial nonischemic cardiomyopathy was
hospitalized for an acute exacerbation of his end-stage heart failure. His HIV had been well-
controlled since 2015, with a CD4 count of 788/mm3 and undetectable viral load at the time of
admission. His HAART regimen was designed to avoid exacerbating his heart disease and
consisted of raltegravir, tenofovir, and emtricitabine. He was evaluated by the heart transplant
review committee and listed for transplant two months prior to admission. After a 2-month
inpatient course, a heart became available from an HIV-negative donor. He underwent orthotopic
heart transplantation with a bicaval anastomosis. Perioperative immunosuppression comprised of
basiliximab and methylprednisolone. The surgical procedure was uncomplicated.

On postoperative day 2, he developed progressively painful duskiness of his fingers and

toes bilaterally, which gradually evolved into dry gangrene. These symptoms were attributed to
peripheral hypoperfusion and he was weaned off vasopressors. The digital ischemia persisted,
and laboratory testing revealed thrombocytopenia with a nadir platelet count of 16,000/mm3 and
fibrinogen levels of 44 mg/dL by postoperative day 6, concerning for disseminated intravascular
coagulation. The possibility of heparin-induced thrombocytopenia as an etiology of his low
platelet count was excluded by a negative heparin-platelet factor 4 enzyme-linked
immunosorbent assay. Given the suspicion for DIC, noninvasive Doppler ultrasonography was
performed of his upper and lower extremities, revealing bilateral non-occlusive thrombi of the
internal jugular, left subclavian, and brachiocephalic veins. He was initiated on systemic
anticoagulation with a heparin infusion. On postoperative day 13, he was noted to have a
downtrending hemoglobin, and computed tomography was obtained of his chest, abdomen, and
pelvis. This revealed a retroperitoneal hematoma, for which his anticoagulation was held. His
fibrinogen and platelet count gradually increased over the remainder of his hospital course to 316
mg/dL and 179,000/mm3 respectively by the time of discharge.

His postoperative course was otherwise notable for isolated right ventricular dysfunction
that developed on postoperative day 5, leading to hypoxemic respiratory failure from volume
overload and acute renal failure. Although he did temporarily require an intra-aortic balloon
pump, mechanical ventilation, and hemodialysis, by the time of discharge, his cardiac,
pulmonary, and renal function had returned to baseline. Additional post-operative course
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consisted of isolated 2R rejection on week 3 biopsy treated with pulse corticosteroids. The
patient was discharged home on postoperative day 41 on an immunosuppression regimen
consisting of mycophenolate mofetil, tacrolimus, and prednisone. No other rejection episodes
occurred during his subsequent follow up. His HIV remained well-controlled on his pre-
transplant antiretroviral regimen, with undetectable viral load and CD4 count of 410/mm3.
 Mandal 8

ANALYSIS

Since the United Network for Organ Sharing first proposed removing HIV as a contraindication
for organ transplantation in 2001, interest in this patient population has dramatically increased.
Although no heart transplants in HIV-positive patients have yet been reported in the Scientific
Registry of Transplant Recipients,2 a review of the literature reveals that a total of at least 11
heart transplants in HIV-positive patients have been performed, both in the United States and
abroad.3 With appropriate patient selection, heart transplantation in HIV positive patients has
been shown to result in promising results at five years.4
However, long-term outcomes remain unknown, particularly with regards to finding the
optimal balance of immunosuppressive and antiretroviral regimens that prevent cardiac allograft
dysfunction while maintaining control of the human immunodeficiency virus. Understanding this
relationship will become crucial to patient management as the HIV population gains more access
to transplantation. Experience from liver and kidney transplant in HIV-positive patients has
demonstrated that this cohort may be at increased risk of acute allograft rejection,5 and several
antiretroviral medications are known to affect the metabolism of tacrolimus and other calcineurin
inhibitors.6
The ethics of organ donation to HIV-positive patients remain complex. Patients with HIV
have been shown to have worse outcomes while awaiting organ transplantation, 7 but the
transplant of HIV-negative organs into HIV-positive recipients also raises questions regarding
the appropriate allocation of a limited resource.8 The balance between beneficence and equity
will likely shift as outcomes and the donor pool evolve. The HIV Organ Policy Equity (HOPE)
Act passed in 2013 authorized the transplantation of organs from HIV-positive donors into HIV-
positive recipients, potentially expanding the supply of donor organs for patients with HIV.9
Nonetheless, the use of HIV-positive donors also raises new concerns, such as the possibility of
super-infection with multiple strains of HIV. Overall, the HOPE Act has opened a new avenue
for research in order to fully understand the complication profile of this population.
Disseminated intravascular coagulation is a rare complication in both organ
transplantation and HIV. It is a serious disorder characterized by derangements in the
coagulation cascade leading to concomitant small vessel thrombosis and bleeding diathesis, as
coagulation factors and platelets are consumed. Low platelet count and fibrinogen concentration,
purpura, and prolonged bleeding are all common signs and symptoms. Recognized precipitating
 Mandal 9

factors for DIC include sepsis, trauma, and obstetrical complications, but a causal relationship
has not been found with either HIV or organ transplantation. Frank DIC in patients with well-
controlled HIV is an unusual phenomenon, although patients with CD4 count <400 may develop
sepsis from opportunistic infections, which can then lead to DIC.10 Infection with the virus has
been shown to lead to a pro-thrombotic state.11 Feffer and colleagues postulated that this
increased risk of thrombosis may be caused by a baseline degree of chronic DIC in patients with
HIV.12 It is possible that the combination of HIV with transplant surgery or the
immunosuppression regimen represented “two hits” which interacted to increase the risk of DIC
in this patient, as severe immunodeficiency has been implicated as an instigating factor.13
 Mandal 10

CONCLUSION

Heart transplantation in HIV-positive individuals is likely to become an increasingly common

phenomenon, with important implications for clinical and public health. Because the human
immunodeficiency virus and organ transplant immunosuppression affect physiology and
biochemistry in complex and interrelated ways, it is possible for de novo risks and unusual
complications to arise from their interaction. Given the limitations in the current understanding,
further study is required to investigate and characterize the risks unique to this patient population
and develop strategies to prevent them.
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REFERENCES

1. Agüero F, Castel MA, Cocchi S, et al. An Update on Heart Transplantation in Human

Immunodeficiency Virus-Infected Patients. Am J Transplant. 2016;16(1):21-28.
doi:10.1111/ajt.13496.
2. Kotton CN, Huprikar S, Kumar D. Transplant Infectious Diseases: A Review of the
Scientific Registry of Transplant Recipients Published Data. Am J Transplant.
2017;17(6):1439-1446. doi:10.1111/ajt.14195.
3. Jahangiri B, Haddad H. Cardiac transplantation in HIV-positive patients: are we there yet?
J Heart Lung Transplant. 2007;26(2):103-107. doi:10.1016/j.healun.2006.11.007.
4. Uriel N, Jorde UP, Cotarlan V, et al. Heart transplantation in human immunodeficiency
virus-positive patients. J Heart Lung Transplant. 2009;28(7):667-669.
doi:10.1016/j.healun.2009.04.005.
5. Blumberg EA, Rogers CC. Human immunodeficiency virus in solid organ transplantation.
Am J Transplant. 2013;13(SUPPL.4):169-178. doi:10.1111/ajt.12109.
6. Tricot L, Teicher E, Peytavin G, et al. Safety and efficacy of raltegravir in hiv-infected
transplant patients cotreated with immunosuppressive drugs. Am J Transplant.
2009;9(8):1946-1952. doi:10.1111/j.1600-6143.2009.02684.x.
7. Ragni M V., Eghtesad B, Schlesinger KW, Dvorchik I, Fung JJ. Pretransplant survival is
shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver
Transplant. 2005;11(11):1425-1430. doi:10.1002/lt.20534.
8. Mgbako O, Glazier A, Blumberg E, Reese PP. Allowing HIV-positive organ donation:
Ethical, legal and operational considerations. Am J Transplant. 2013;13(7):1636-1642.
doi:10.1111/ajt.12311.
9. Richterman A, Blumberg E. The Challenges and Promise of HIV-Infected Donors for
Solid Organ Transplantation. Curr Infect Dis Rep. 2015;17(4). doi:10.1007/s11908-015-
0471-z.
10. Fera G, Semeraro N, De Mitrio V, Schiraldi O. Disseminated intravascular coagulation
associated with disseminated cryptococcosis in a patient with acquired immunodeficiency
syndrome. Infection. 21(3):171-173. http://www.ncbi.nlm.nih.gov/pubmed/8365814.
Accessed July 7, 2017.
11. Opie J. Haematological complications of HIV infection. S Afr Med J. 2012;102(6):465-
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468. http://www.ncbi.nlm.nih.gov/pubmed/22668938. Accessed July 7, 2017.

12. Feffer SE, Fox RL, Orsen MM, Harjai KJ, Glatt AE. Thrombotic tendencies and
correlation with clinical status in patients infected with HIV. South Med J.
1995;88(11):1126-1130. http://www.ncbi.nlm.nih.gov/pubmed/7481983. Accessed July 7,
2017.
13. Rheingold SR, Burnham JM, Rutstein R, Manno CS. HIV infection presenting as severe
autoimmune hemolytic anemia with disseminated intravascular coagulation in an infant. J
Pediatr Hematol Oncol. 2004;26(1):9-12.
https://insights.ovid.com/pubmed?pmid=14707703. Accessed July 7, 2017.