June 2024: Coagulation and Literature
by Donna Castellone • June 24, 2024
I love to read, I read 78 books last year and my goal this year is 100 books, I read everywhere now that I can access books on my phone. Standing in a long line is no longer an issue, I can read. I've traveled to places, experienced events, solved murders and looked back on history. And, yes, I have learned things about coagulation disorders, and I am not talking about from textbooks or documentaries, just in novels. It is amazing how disorders are worked into a story.
In case you are wondering, just a few books include "The Andromeda Strain" by Michael Crichton: A thrilling science fiction novel about a team of scientists investigating a deadly extraterrestrial microorganism that causes blood clotting. This included the role of cytokine release and coagulopathy – sound familiar - COVID?1
"The Curse of the Romanovs" by Staton Rabin. It's 1916, the struggling Russian people are tired of war and are blaming their Romanov rulers for it, and some are secretly plotting to murder the young heir and his family. But nobody outside the palace knows that Alexei suffers from a terrible bleeding disease, hemophilia, which threatens to finish him off even before the family¹s enemies can.2 Hemophilia was found throughout the royal families, as seen throughout Queen Victoria's male descendants. This "Royal disease" spread as Victoria's heirs married into royal family across Europe impacting the thrones in Britian, Germany, Russia and Spain. The last carrier of the disease in the royal family was Prince Waldemar of Prussia, who died in 1945. However, when the remains of the Romanov family were found, DNA analysis in 2009 indicated the Royal disease was indeed hemophilia, a rare subtype known as hemophilia B (FIX deficiency) and not hemophilia A (FVIII deficiency).3
Most recently, "Mad Honey" by Jodi Picoult Jennifer Finney Boylan. The story follows the case of 18-year-old Asher Fields, who is charged with the murder of his girlfriend, Lily Campanello. Lily is found bleeding and unconscious at the bottom of the stairs and pronounced dead from a brain bleed as believed caused by blunt trauma. Two clues that are given in the plot are she had a fever for five days prior and is on a hormone cocktail. This leads to revealing she has Acquired thrombotic thrombocytopenic purpura (TTP) and caused neurological symptoms such as dizziness, easy bruising, abnormal bleeding, and fever. Her death was due to tripping and falling.4
I must admit, this book had many twists and turns and I was most surprised at the diagnosis and explanation of acquired TTP including an explanation of ADAMTS13. This leads me to my review of acquired TTP.
Acquired TTP:
This is a microangiopathic hemolytic anemia that presents with a pentad of fever hemolytic anemia, thrombocytopenia and renal and neurologic dysfunction. Patients with acquired TTP have an absence or decrease of the von Willebrand (vW) factor cleaving protease ADAMTS13 which results in microthrombi formation leading to end-organ ischemia and damage. It is caused by autoantibodies targeting ADAMTS13 and can be triggered by anti-platelet drugs, immunosuppressive agents, HIV, estrogen containing birth control or hormone therapy, as well as pregnancy.5
Predominantly affected are the nervous system and kidneys due to the inability of the ADAMTS13 to inactivate the large multimer vWF that is needed to prevent spontaneous coagulation resulting in binding platelets and initiate thrombin formation. A 2006 study looking at autopsies of patients who had died secondary to an acute episode of TTP reported the presence of microvascular thrombi characteristic of TTP in almost all organs. Timely diagnosis is important due to a mortality rate of about 90%, but 80% of patients respond to initial treatment.5
Causes:
Drugs appear to be responsible for < 15% of all TTP cases. Quinine, ticlodipine, trimethoprim, and PEG interferon has been associated with antibody positive TTP. There have been reports of acquired TTP associated with oestrogen-containing hormonal preparations including oral contraceptive, hormone replacement therapy. These medications should be avoided in patients with a previous episode of TTP. Also some chemotherapy agents such as gemcitabine, bleomycin and nitomycin-C can cause HUS but not TTP.6
Treatment:
In 2020 ISTH came up with treatment guidelines for TTP. Below is a summary of their recommendations:
- For initial treatment of TTP, they gave a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (PEX) over PEX alone; however, they did not make any specific recommendation regarding a preferred dosage or type of corticosteroids.7
- For patients with the first acute event, the panel suggested the addition of rituximab to corticosteroids and PEX. The primary documented effect of rituximab in patients with TTP is to prevent relapses, although they noted that the true benefit of rituximab might be masked by the fact that it has only been used in severe cases. They make a conditional recommendation for the use of this therapy based on practitioner judgment, especially if comorbid autoimmune disorders exist.7
- For patients with relapsing TTP, the panel recommended PEX, corticosteroids, and rituximab as recommended for initial treatment, with the addition of caplacizumab.7
- For patients with TTP who are in remission but still have low plasma ADAMTS13 activity without any evidence of clinical signs/symptoms, they recommended using rituximab for prophylaxis.7
- For patients who are pregnant and have decreased plasma ADAMTS13 activity but have no clinical signs/symptoms of TTP, the panel recommended prophylactic treatment with plasma infusion products.7
Laboratory Evaluation:
Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems.
Routine laboratory evaluations are not able to provide results specific for TTP but they are used to calculate clinical scores. Features include evidence of hemolytic anemia, schistocytes, thrombocytopenia, reticulocytosis and an undetectable haptoglobin level. Additionally, there may be a high LDH and cardiac troponin. A coagulation profile is usually normal. In acquired TTP a Coombs test is negative. There may be proteinuria, hematuria and possibly elevated serum creatinine and urea levels.8
A clinical score developed in 2017 PLASMIC uses a combination of clinical and laboratory parameters to predict severe ADAMTS-13 deficiency by looking at seven parameters to predict TTP. It has a high clinical sensitivity and specificity in predicting TTP.8
The reference test for the diagnosis of TTP is the ADAMTS-13 activity level of < 10%. The test is based on measuring the quantity of degraded VWF substrate in the plasma or serum of patients. Two commonly used functional assays are collagen-binding activity and fluorescence resonance energy transfer assay using a truncated, VWF synthetic 73-amino-acid peptide-based assays. An advantage of functional assays is the accurate detection of autoantibodies. However, they require high technical demands and are time-consuming. Serum anti-ADAMTS13 antibodies can be detected in patients also by using immunochemical assays and are simple and rapid and useful in emergency situations. Genetic testing would be performed if congenital TTP was suspected.8
Conclusion:
Ernest Hemingway said: "There is nothing to writing. All you do is sit down at a typewriter and bleed." –
Not to be taken out of context, that is figuratively not literally. So, yes I do read to escape, but many times reality creeps in and there is a coagulation puzzle to solve. I always learn something in anything that I read, but sometimes a good mindless book is required. Think of the advantages, decreased acute phase reactants, increased serotonin and adding a glass of wine and chocolate will decrease platelet reactivity. I guess it is in my blood!
References:
- Crichton, M. "The Andromeda" StrainMass Market Paperback, September 1, 1969.
- Rabin, S., "The Curse of the Romanovs", by Margaret K. McElderry Books July 10, 2007
- Case Closed: Famous Royals Suffered From Hemophilia, Russian bones solve centuries-old mystery, 8 OCT 2009 https://www.science.org/content/article/case-closed-famous-royals-suffered-hemophilia
- Picoult, J., Boylan, JF., Mad Honey, October 4, 2022 by Ballantine.
- Michael Stanley; Robert B. Killeen; Joel M. Michalski. Thrombotic Thrombocytopenic Purpura https://www.ncbi.nlm.nih.gov/books/NBK430721/
- Scully, M., Yarranton, H., Liesner, R., Cavenagh, J., Hunt, B., Benjamin, S., Bevan, D., Mackie, I. and Machin, S. (2008), Regional UK TTP Registry: correlation with laboratory ADAMTS 13 analysis and clinical features. British Journal of Haematology, 142: 819-826. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07276.x
- X. Long Zheng, Sara K. Vesely, Spero R. Cataland, Paul Coppo, Brian Geldziler, Alfonso Iorio, Masanori Matsumoto, Reem A. Mustafa, Menaka Pai, Gail Rock, Lene Russell,Rawan Tarawneh, Julie Valdes, and Flora Peyvandi, ISTH guidelines for treatment of thrombotic thrombocytopenic purpura, J Thromb Haemost. 2020 Oct; 18(10): 2496–2502. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091490/
- Murtadha Al-Khabori, corresponding author,* Faisal Alsayegh, Hasan Al Yaseen, Sabir Hussien, Amar Lal, Muna Al Rasheed, Mohammad Al Bader, Salam Al Kindi, and Mahmoud Marashi, The Challenges in Diagnosis and Management of Acquired Thrombotic Thrombocytopenic Purpura: Consensus Report from Three Gulf Countries, Oman Med J. 2022 Jul; 37(4): e407.