In low resource settings, the diagnosis and treatment of patients with MAHA-associated diseases can be challenging. While some biological tests can help confirm the diagnosis (ADAMTS13, C3b, and factor H), these are often unavailable in low resource settings and can delay patient management . For this reason, healthcare providers rely on the history and clinical presentation to distinguish between these diseases. For example, sudden onset of anemia, thrombocytopenia, and renal insufficiency are in favor of HELLP syndrome. Progressive worsening of the renal lesion is highly suggestive of aHUS while the presence of minimal renal insufficiency, severe thrombocytopenia with signs of neurological involvement pleads in favor of TTP .
Worsening clinical signs of gestational hypertension, preeclampsia, or the aggravation of anemia, thrombocytopenia, and renal function abnormalities (most common target organ damage) after delivery point towards TTP and aHUS. While minimal renal impairment with severe thrombocytopenia and neurological signs suggest TTP and the need for plasma exchange therapy, progressive renal injury (in the absence of an identifiable cause of acute tubular necrosis) suggests aHUS and the need for anti-complement treatment [1, 5].
Unfortunately, this approach is not infallible. For example, thrombocytopenia develops in 5 to 10% of women during pregnancy or the immediate postpartum. A low platelet count is often a fortuitous feature and can, in some instances, be misleading, such as in women with coexisting systemic or gestational disorders. As a result, low platelet count might lead to an indication of a maternal intervention that can harm the fetus .
Given the history and presentation, in this case, there are three possible scenarios we must consider: gestational hypertension or preeclampsia triggering the complications of aHUS; gestational hypertension or preeclampsia evolving to the HELLP syndrome; or aHUS initially presenting as hypertension during pregnancy progressing to overt complications. Gestational hypertension is “hypertension that appears de novo after 20 weeks’ gestation and normalizes after pregnancy”. In comparison, preeclampsia is defined as “de novo hypertension after 20 weeks’ gestation accompanied by at least one of the following: proteinuria, maternal organ dysfunction [renal, hepatic, neurological, and hematological] and uteroplacental dysfunction” . The patient had a history of eclampsia during her first pregnancy, and she presented with bilateral pitting edema and proteinuria. Therefore, she had preeclampsia. At presentation, the patient did not have anemia or low platelets. However, more than 24 h after she had delivered her baby, she had hemorrhages, anemia, declining liver, and renal functions. Standard laboratory findings can help differentiate HELLP syndrome, which is a clinical presentation of severe preeclampsia from aHUS. Women with HELLP syndrome present with LDH (438–782 IU/L) and creatinine (0.7–1.1 mg/dL) levels that are significantly lower than their counterparts with aHUS (LDH 1325–3940 IU/L and creatinine 3.9–7.6 mg/dL). On the other hand, women with HELLP syndrome present higher hemoglobin (7.3–10.4) and platelets (47,000-82,000) .
Our patient had 1398 IU/L LDH, creatinine (6.9 mg/dL), hemoglobin (7.80 g/dL) and platelets (44.000 cells/mm3). Also, HELLP syndrome and preeclampsia tend to resolve once the patient delivers her baby. The elements mentioned above were all in favor of preeclampsia, triggering the complications of aHUS. However, the favorable evolution of the patient after just four hemodialysis sessions is not in favor of preeclampsia, triggering the complications of aHUS.
In the absence of confirmatory genetic test results or kidney biopsy to demonstrate the pathology of thrombotic microangiopathy, the diagnosis of aHUS remains presumptive. We recognize that the clinical and lab criteria are not ideal; however, in most hospitals in developing countries, these are readily available and can help inform clinicians as they make time-sensitive decisions.
aHUS presents as a triad of MAHA, thrombocytopenia, and acute renal failure and can lead to hypertension and extrarenal organ dysfunction [9, 10]. Kidney injury is the result of lesions to endothelial cells by the membrane attack complex, C3a, and C5a. When these lesions affect endothelial cells of preglomerular arterioles, they can lead to the dysfunction of the juxtaglomerular apparatus and subsequently to severe but unstable hypertension.
aHUS, unlike “typical” hemolytic uremic syndrome, is not caused by the Shiga toxin and is not preceded by hemorrhagic diarrhea. The prodomeless aHUS is due to a defect in the alternative complement pathway regulation . The alternative complement pathway is regulated by proteins found in the plasma and on the surface of host cells. Mutations of regulatory proteins predispose pregnant women to develop aHUS and are responsible for the evolution of HELLP syndrome or preeclampsia to aHUS in pregnant women .
The C3a and C5a released in the kidney can equally leak into the general circulation and stimulate the release of histamine by basophils causing lesions of non-renal end organs such as the brain, the retina, the bronchus, the intestine, the pancreas, and serous membranes . MAHA in aHUS results from mechanical injury of erythrocytes as they go through stenotic arterioles and capillaries. The degree of hemolysis depends on the severity of the stenosis in the arterioles and capillaries. Consequently, it is not uncommon for patients with aHUS to present without MAHA when the stenosis is minimal . The last sign of the aHUS triad, thrombotic thrombocytopenia, results from the consumption of platelets.
It is difficult to ascertain the diagnosis of aHUS, and delays in diagnosis and treatment can be life-threatening [2, 9]. The results of molecular tests can take weeks to be available, and they might return false negatives. In practice, patients with TMA are treated with plasma exchange therapy until all non-aHUS causes of TMA have been excluded. As soon as all non-aHUS causes of TMA have been eliminated, aHUS is retained as the diagnosis, and the patient is switched to complement therapy . The reason being that plasma therapy is ineffective in aHUS patients with mutations of complement system regulatory membrane proteins. Additionally, overall dialysis free survival at one year of aHUS patients treated with plasma therapy is only 40% . Unlike plasma therapy, complement therapy is effective in all aHUS cases, indiscriminate of the membrane protein mutations, and failure of the complement therapy should prompt the reevaluation of the diagnosis . Patients are put on eculizumab, a humanized monoclonal antibody of complement C5, once a week for five weeks, then fortnightly subsequently .
Fortunately, the evolution was favorable after hemodialysis in this case. Clinicians must be able to recognize the signs of TMA early on and to narrow down the diagnosis to aHUS. However, governments must invest more in the health system to provide underresourced physicians with the tools to conveniently manage diseases such as aHUS.