Thrombotic Thrombocytopenic Purpura: what was done in the 80s and what is done now: the learning curve.

When I had recently cleared my post graduate examinations and became a consultant I suddenly discovered that I was expected to know everything and when I did not know a thing I had to pretend to to buy time and run to the library or to run to someone who actually had the current knowledge. Often this too was rudimentary. Many of the therapies in current use had not been discovered or invented and we had to do the best we could often learning later that the “best” at that time was all wrong anyway. I have been asked how I managed thrombotic thrombocytopenic purpura in pregnancy. I have kept no records so I cannot give a definite answer but I can try and lay out the different nomenclatures and treatments that were used at that time. I do remember appealing to God a lot of the time as I had a firm belief that at least He had the healing power even if He did not send us the right medicine. The mainstay of treatment was the use of glucocorticoids, immunoglobulins which were rarely available where I practiced, and when available were seldom affordable, and platelet transfusions, for which again, we had to make enormous efforts to obtain. A later addition, specially for TTP was plasmapheresis. This did not work for HELLP.

So let me review how women about to deliver babies were diagnosed if everything was not normal. BP high+proteinuria but still conscious and no fits: pre-eclampsia. Proteinuria +edema + fits +plus loss of consciousness; eclampsia. Hemolysis + elevated liver enzymes + low platelets; HELLP syndrome. Severe thrombocytopenia, severe anemia, and elevated lactate dehydrogenase (LDH) levels occurred late in pregnancy Thrombotic thrombocytopenic purpura. Aspartate aminotransferase and alanine aminotransferase were minimally elevated and the percentage of schistocytes on peripheral smear was often higher in TTP (2 to 5 percent) than in HELLP (less than 1 percent). TTP was often associated with isolated severe platelet consumption, whereas prolongation of the PT and aPTT were typically absent. LDH levels were markedly elevated in TTP (often >1000 IU/L and as high as 2000 or 3000 IU/L) . Acute fatty liver of pregnancy; overlapped with HELLP; there were a lot of non-specific symptoms such as nausea, vomiting, abdominal pain, malaise, headache, and/or anorexia. Hypertension, with or without proteinuria, were there as preeclampsia coexisted; however, hypertension was more common in HELLP than in AFLP.

Time of onset suggested one disorder over the other. The onset of TTP tended to be earlier in gestation than the onset of HELLP: approximately 12 percent of TTP in pregnancy occurred in the first trimester, 56 percent in the second trimester, and 33 percent in the third trimester/postpartum, whereas HELLP does not occur before 20 weeks of gestation and most cases are diagnosed in the third trimester. The presence of proteinuria and hypertension prior to onset of laboratory abnormalities favored the diagnosis of HELLP. TTP may relapse years after pregnancy, whereas HELLP is only associated with pregnancy and the postpartum state.

Thrombotic microangiopathies (TMAs) are a group of distinct disorders in which microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis occur. For many years distinction between these TMAs, especially between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), remained purely clinical and hard to make. Recent discoveries shed light on different pathogenesis of TTP and HUS. Ultra-large von Willebrand factor (UL-VWF) platelet thrombi, resulting from the deficiency of cleavage protease which is now known as ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), were found to cause TTP pathology, while Shiga toxins or abnormalities in regulation of the complement system cause microangiopathy and thrombosis in HUS. TMAs may appear in various conditions such as pregnancy, inflammation, malignancy, or exposure to drugs. These conditions might cause acquired TTP, HUS, or other TMAs, or might be a trigger in individuals with genetic predisposition to ADAMTS-13 or complement factor H deficiency. Differentiation between these TMAs is highly important for urgent initiation of appropriate therapy. Measurement of ADAMTS-13 activity and anti-ADAMTS-13 antibody levels may advance this differentiation resulting in accurate diagnosis. Additionally, assessment of ADAMTS-13 levels can be a tool for monitoring treatment efficacy and relapse risk, allowing consideration of therapy addition or change.

Severe ADAMTS13 deficiency (activity <10 percent) is consistent with a diagnosis of TTP, this testing may take several days, and in patients with a presumptive diagnosis of TTP, urgent therapy with PEX should be initiated. In the past few years, great improvements in ADAMTS-13 assays have been made, and tests with increased sensitivity, specificity, reproducibility, and shorter turnaround time are now available. These new assays enable ADAMTS-13 measurement in routine clinical diagnostic laboratories, which may ultimately result in improvement of TMA management.

Review of TTP.

Thrombotic microangiopathies may result from four types of lesions:

  • ultra-large von Willebrand factor (UL-VWF)-platelet thrombi, as in thrombotic thrombocytopenic purpura (TTP);
  • fibrin-platelet thrombi, as exemplified by disseminated intravascular coagulopathy (DIC) and catastrophic antiphospholipid syndrome;
  • inflammatory or proliferative microangiopathy accompanied by variable fibrin thrombi, as in hemolytic uremic syndrome (HUS);
  • intravascular clusters of cancer cells.

THE HISTORY OF TMA PATHOGENESIS DISCOVERY—FROM BEDSIDE TO BENCH

(I have given the reference below)

The history of the TMA discovery (between 1924 and 1960) is associated with very talented clinicians who had the ability and the vision to recognize the pathophysiology of the diseases, although they lacked the technology to demonstrate and prove it. Not until the 1980s was evidence for the proposed mechanisms discovered.

In 1924, Eli Moschcowitz was the first to report on a 16-year-old girl with a sudden onset of fever and hemolytic anemia, followed rapidly by paralysis, coma, and death. Moschcowitz suspected that microvascular platelet-rich thrombi which were found in the microcirculation were the cause for this disease. This was probably the first description of TTP.

In 1955, Gasser et al. described five childhood cases of HUS, which were clinically defined by thrombocytopenia, non-immune microangiopathic hemolytic anemia, and acute kidney failure followed by death from renal cortical necrosis.

In 1960, Schulman et al. described the case of an 8-year-old girl who exhibited relapsing episodes of thrombocytopenia. This patient responded well to plasma infusion, and the authors suggested that the disorder was due to the deficiency of a platelet-stimulating factor. Upshaw later reported comparable findings in a 29-year-old woman whose first episode occurred at the age of 6 months. The author suggested as the underlying pathogenic mechanism the deficiency of a plasma factor that promotes platelet and red blood cell destruction. It is now clear that the disorder described by Schulman and Upshaw, which now bears their name—the Upshaw–Schulman syndrome—represents a congenital form of TTP.

In 1982, Moake et al. found ultra-large molecular forms of von Willebrand Factor (UL-VWF) in patients with TTP and proposed that this played a pathogenic role in the formation of microvascular platelet-rich thrombi in patients with acute TTP.

In 1985, Karmali et al. discovered the link between the HUS and enteric infections with Escherichia coli that produce Shiga toxin (Stx).

In 1996, simultaneously, Furlan et al. in Switzerland and Tsai in New York reported independently the isolation and identification of a VWF-cleaving protease from human plasma.

In 2001, several groups (Fujikawa et al., Gerritsen et al., and Levy et al.) identified the VWF-cleaving protease as ADAMTS-13.

The majority of patients with TTP show severe deficiency in the VWF-cleaving activity of ADAMTS-13, either caused by missense or frame-shift mutations or due to ADAMTS-13 neutralizing autoantibodies.

THROMBOTIC MICROANGIOPATHY

Thrombotic microangiopathy (TMA) refers to a group of pathological disorders that are characterized by hemolytic anemia, thrombocytopenia, and widespread microvasculopathy, with or without thrombi.

Clinical manifestations of TMA reflect ischemic injury of the affected organs. In some patients neurological deficits predominate; in others, renal failure is severe. This clustering provided a convenient basis for defining thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS). However, this classification has been misleading, since some patients have both neurological deficits and renal failure, and others may have predominant neurological deficits or renal failure on different occasions.

Thrombotic microangiopathy may appear in a variety of conditions such as pregnancy, inflammation, malignancy, or exposure to such drugs as thienopyridines or calcineurin inhibitors. These conditions might be the cause of acquired TTP, HUS, or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), or the trigger in individuals with a genetic predisposition to ADAMTS-13 or complement factor H deficiency.

While patients with congenital TTP and acquired immune TTP attributed to low ADAMTS-13 activity demonstrate a good response to plasma infusion or plasma exchange (PEX), other clinical forms of TMA occur in the absence of severe ADAMTS-13 deficiency, and this may be the reason why patients with the other clinical forms of TTP do not respond to plasma therapy.

The diagnosis of TMA can be very difficult, as there is a clinical overlap between various TMAs. Since in untreated cases mortality may approach 90%, the availability of ADAMTS-13 activity and anti-ADAMTS-13 antibody assays is crucial for the differentiation between the TMAs, accurate diagnosis, and urgent initiation of the appropriate treatment.

Acquired Thrombotic Thrombocytopenic Purpura

Acquired TTP is a rare, autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS-13, with an annual incidence of 0.2–1 per 100,000. In its most common, characteristic form, TTP begins abruptly and virulently, occasionally after a febrile, viral-like prodrome; a minor infection or pregnancy may be the trigger. Thrombocytopenia and fragmentation hemolysis are severe, and central neurologic signs exist at presentation or supervene quickly, out of proportion to renal signs. Dialysis-requiring renal failure is rare. Without immediate recognition and intervention, death, often precipitated by seizures and arrhythmias, may come rapidly and suddenly. Before the advent of modern therapy, mortality was about 90%. One-third of TTP survivors experience relapses over the course of years, especially soon after initial presentation. Some have persistent cognitive and central neurologic impairments, other chronic health problems, or die prematurely even when TTP is inactive. About 5%–10% of patients later in their course manifest systemic lupus erythematosus.

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS) is a TMA defined by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with elevated serum creatinine levels, low glomerular filtration rates, microscopic hematuria, and subnephrotic proteinuria. The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (Shiga-HUS). Atypical form of HUS (aHUS) is associated with defects in the immunological complement pathway.

Shiga Toxin-induced HUS

About 10%–20% of symptomatic infections lead to HUS. Shiga toxin-induced HUS (Shiga-HUS) is the commonest TMA, most prevalent in children under the age of 5 years, with an annual incidence of 6 per 100,000. Severe thrombocytopenia, fragmentation hemolysis, renal failure, and hyper-tension are characteristic.

The diagnosis of Shiga-HUS depends on the detection of E. coli O157:H7 and other Stx-producing bacteria and their products in stool cultures.

In extreme cases, the brain and other organs may be involved. The condition is a medical emergency with a short-term mortality of about 5%–10% without urgent therapy. Renal function recovers in 70% to over 90% of cases.

Approximately 5% of HUS cases in children are not associated with Stx-producing bacteria and result from infection by neuraminidase-producing Streptococcus pneumoniae.

Atypical HUS is the result of excessive alternative complement pathway activation. Prominent causes of aHUS are a heterozygous mutation of the complement factor H gene, or homozygous deletion in genes for the factor H-related proteins or autoantibody-mediated inhibition of factor H deficiency. Lately, treatment with eculizumab has been approved for aHUS. Eculizumab is a humanized monoclonal antibody to terminal complement protein C5 that prevents activation of the terminal complement pathway by binding C5 and inhibiting generation of pro-inflammatory C5a and the lytic C5b-9 membrane attack complex. Before administering eculizumab therapy for an acute episode of aHUS, there is a need to rule out TTP which is proved by normal levels of ADAMTS-13 activity (>30%), without the presence of anti-ADAMTS-13 antibodies.

Pregnancy-associated TMA

Pre-eclampsia and HELLP syndrome are serious TMA complications in pregnancy. In these events, the hypoxic placenta releases receptors for angiogenic factors, like soluble VEGF receptor-1. These circulating soluble angiogenic receptors contribute to the progressive renal dysfunction and hepatic necrosis in pregnancy TMAs.

Nevertheless, pregnancy is a hypercoagulation state with very high levels of VWF and UL-VWF released from endothelial cells and the placenta, and can trigger TTP (acquired or congenital), aHUS, or other TMAs.

Pregnancy is the initiating event for approximately 5%–25% of TTP cases, which are late-onset adult congenital TTP or acute idiopathic TTP.

Thrombosis occurs in the placenta in untreated TTP pregnancies, resulting in fetal growth restriction, intrauterine fetal death, and pre-eclampsia. There is a continued risk of relapse during subsequent pregnancies.

TMA Due to Drugs

Thienopyridines (ticlopidine and clopidogrel) are the most frequent TMA-causing drugs reported to the United States Food and Drug Administration.  Other drug causes are the calcineurin inhibitors (cyclosporine and tacrolimus), the mTOR inhibitors (sirolimus and everolimus), anti-neoplastic agents (mitomycin and gemcitabine, both in a cumulative, dose-dependent manner), and quinine

Ref: 1. Rambam Maimonides Med J. 2014 Oct; 5(4): e0026.Published online 2014 Oct 29. doi: 10.5041/RMMJ.10160

Ref: 2. Br J Haematol. 2012 Aug;158(3):323-35. doi: 10.1111/j.1365-2141.2012.09167.x. Epub 2012 May 25.

Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.

Scully M1Hunt BJBenjamin SLiesner RRose PPeyvandi FCheung BMachin SJBritish Committee for Standards in Haematology.

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

3 thoughts on “Thrombotic Thrombocytopenic Purpura: what was done in the 80s and what is done now: the learning curve.”

  1. Thanks a lot madam.You have given a very nice detailed explanation of everything. Is eculizumab easily available.Actually a few days back I received a young unbooked 20 years old CNE patient at 32 weeks gestation with atypical haemolytic uraemic syndrome.After termination of her pregnancy and transfusion of FFPs and platelets her haemodialysis was done the very next day. I requested the nephrologist for plasmaphoresis but I don’t know why it was delayed. (Probably the reason was that her clinical features and labs did not fit her in typical HUS category).The lady became very critical and went on ventilator .Several multidisciplinary team meetings were held between haematologist,nephrologist ,intensivist and me .Finally plasmaphoresis was started. The young lady survived Alhamdulillah. I plan to screen her for SLE and antiphospholipid syndrome.Even if its negative she is a candidate for low molecular weight heparin and low dose aspirin throughout her next pregnancy.Clexane is very short in market these days.Is erixtra a good alternative for it.Is ADAMTS 3 essay facility available? .All these investigations and treatments are so costly and most of the patients are non affording. 😞

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    1. I am glad I was able to help. Romiplastin is another drug which is a thrombopoetin which can help to raise the platelet levels. Drugs like icluzimab which are not available in the commercial outlets can sometimes be bought by applying to the pharmaceutical company concerned. they can get permission from the Ministry of Health to import on a “named patient” basis. GHQ can usually help to speed up the process. I used to get OKT3 and thymoglobulin this way for my transplant patients. Shaheen Moin

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