Medicine:HELLP syndrome

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Short description: Complication of pregnancy associated with severe pre-eclampsia
HELLP syndrome
SpecialtyObstetrics
SymptomsFeeling tired, retaining fluid, headache, nausea, upper abdominal pain, blurry vision, seizures[1]
ComplicationsDisseminated intravascular coagulation (DIC), placental abruption, kidney failure, pulmonary edema[1]
Usual onsetLast 3 months of pregnancy or shortly after childbirth[1]
TypesComplete, incomplete[2]
CausesUnknown[1]
Risk factorsPreeclampsia, eclampsia, previously having HELLP, mother older than 25 years
Diagnostic methodBlood tests[2]
Differential diagnosisViral hepatitis, thrombotic thrombocytopenic purpura, cholangitis, hemolytic uremic syndrome[2]
TreatmentDelivery of the baby as soon as possible, management of blood pressure[1][2]
Prognosis<1% risk of death (mother); 7.3% to 11.9% risk of death (child)[3]
Frequency~0.7% of pregnancies[2]

HELLP syndrome is a complication of pregnancy; the acronym stands for hemolysis, elevated liver enzymes, and low platelet count.[1] It usually begins during the last three months of pregnancy or shortly after childbirth.[1] Symptoms may include feeling tired, retaining fluid, headache, nausea, upper right abdominal pain, blurry vision, nosebleeds, and seizures.[1] Complications may include disseminated intravascular coagulation, placental abruption, and kidney failure.[1]

The cause is unknown.[1] The condition occurs in association with pre-eclampsia or eclampsia.[1] Other risk factors include previously having the syndrome and a mother older than 25 years.[1] The underlying mechanism may involve abnormal placental development.[4] Diagnosis is generally based on blood tests finding signs of red blood cell breakdown (lactate dehydrogenase greater than 600 U/L), an aspartate transaminase greater than 70 U/L, and platelets less than 100×109/l.[2] If not all the criteria are present, the condition is incomplete.[2]

Treatment generally involves delivery of the baby as soon as possible.[1] This is particularly true if the pregnancy is beyond 34 weeks of gestation.[2] Medications may be used to decrease blood pressure and blood transfusions may be required.[1]

HELLP syndrome occurs in about 0.7% of pregnancies and affects about 15% of women with eclampsia or severe pre-eclampsia.[5][2] Death of the mother is uncommon (< 1%).[1][3] Outcomes in the babies are generally related to how premature they are at birth.[1] The syndrome was first named in 1982 by American gynaecologist Louis Weinstein.[2]

Signs and symptoms

The first signs of HELLP usually start appearing midway through the third trimester, though the signs can appear in earlier and later stages.[6] It is highly associated with known pre-eclampsia. Risk factors for pre-eclampsia include older age, uncontrolled hypertension, diabetes mellitus, and obesity. Symptoms for HELLP vary in severity and between individuals and are commonly mistaken with normal pregnancy symptoms, especially if they are not severe.[7]

HELLP syndrome patients experience general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anaemia, and hypertension. Some patients may also have a headache and visual issues. These symptoms may also become more severe at night.[8][9][10][11][12] As the condition progresses and worsens, a spontaneous hematoma occurs following the rupture of the liver capsule, which occurs more frequently in the right lobe. The presence of any combinations of these symptoms, subcapsular liver hematoma in particular, warrants an immediate check-up due to the high morbidity and mortality rates of this condition.[13][14][15]

Risk factors

Elevated body mass index and metabolic disorders, as well as antiphospholipid syndrome, significantly increase the risk of HELLP syndrome in all female patients. Females who have had or are related to a female with previous HELLP syndrome complications tend to be at a higher risk in all their subsequent pregnancies.[16][17][18]

The risk of HELLP syndrome is not conclusively associated with a specific genetic variation, but likely a combination of genetic variations, such as FAS gene, VEGF gene, glucocorticoid receptor gene and the tol-like receptor gene, increase the risk.[17][19][20][21][22]

Pathophysiology

The pathophysiology is still unclear and an exact cause is yet to be found. However, it shares a common mechanism, which is endothelial cell injury, with other conditions, such as acute kidney injury and thrombotic thrombocytopenic purpura.[23][24] Increasing the understanding of HELLP syndrome's pathophysiology will enhance diagnostic accuracy, especially in the early stages. This will lead to advancements in the prevention, management, and treatment of the condition, which will increase the likelihood of both maternal and fetal survival and recovery.[6][25]

Inflammation and coagulation

As a result of endothelial cell injury, a cascade of pathological reactions manifests and become increasingly severe and even fatal as signs and symptoms progress. Following endothelial injury, vasospasms and platelet activation occur alongside the decreased release of the endothelium-derived relaxing factor and increased the release of von Willebrand factor (vWF), leading to general activation of the coagulation cascade and inflammation. Placental components, such as inflammatory cytokines and syncytiotrophoblast particles interact with the maternal immune system and endothelial cells, further promoting coagulation and inflammation.[26][27] These interactions also elevate leukocyte numbers and interleukin concentrations, as well as increase complement activity.[28][29]

Low platelet count

vWF degradation in HELLP syndrome is inhibited due to decreased levels of degrading proteins, leading to an increased exposure of platelets to vWF. As a result, thrombotic microangiopathies develop and lead to thrombocytopenia.[30]

Blood breakdown

As a result of the high number of angiopathies, the erythrocytes fragment as they pass through the blood vessels with damaged endothelium and large fibrin networks, leading to macroangiopathic haemolytic anaemia. As a consequence of hemolysis, lactic acid dehydrogenase (LDH) and hemoglobin are released, with the latter binding to serum bilirubin or haptoglobin.[8][16]

Liver

During the coagulation cascade, fibrin is deposited in the liver and leads to hepatic sinusoidal obstruction and vascular congestion, which increase intrahepatic pressure. Placenta-derived FasL (CD95L), which is toxic to human hepatocytes, leads to hepatocyte apoptosis and necrosis by inducing the expression of TNFα and results in the release of liver enzymes. Hepatic damages are worsened by the disrupted portal and total hepatic blood flow that result as a consequence of the microangiopathies. Collectively, widespread endothelial dysfunction and hepatocellular damage result in global hepatic dysfunction often leading to liver necrosis, haemorrhages, and capsular rupture.[31][32][33]

Diagnosis

Early and accurate diagnosis, which relies on laboratory tests and imaging exams, is essential for treatment and management and significantly reduces the morbidity rate. However, diagnosis of the syndrome is challenging, especially due to the variability in the signs and symptoms and the lack of consensus amongst healthcare professionals. Similarities to other conditions, as well as normal pregnancy features, commonly lead to misdiagnosed cases or more often, delayed diagnosis.[6][25]

There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia and microangiopathic haemolytic anaemia in patients suspected to have preeclampsia. [citation needed]

  • A blood smear will often exhibit abnormalities, such as schistocytes, bur cells, and helmet cells, which indicate erythrocyte damage. [citation needed]
  • Thrombocytopenia, which is the earliest coagulopathy present in all HELLP syndrome patients, is indicated by low platelet count (below 100 x 109 L-1) or by testing the levels of fibrin metabolites and antithrombin III.[citation needed]
  • Elevated serum levels of certain proteins, in particular, LDH, alanine transaminase (ALT) and aspartate transaminase (AST), are indicative of hepatic dysfunction. Extremely high serum levels of these proteins, specifically LDH levels > 1,400 IU/L, AST levels > 150 IU/L and ALT levels > 100 IU/L, significantly elevate the risk of maternal mortality.[31][2][8][9][23][32][34][35][36][37][excessive citations]

A number of other, but less conclusive, clinical diagnostic criteria are also used in diagnosis alongside the main clinical diagnostic criteria for HELLP syndrome.

  • De novo manifestation of hypertension with systolic pressure and diastolic pressure above 160mmHg and 110 mmHg, respectively.
  • Proteinuria, leucocytosis and elevated uric acid concentrations > 7.8 mg.
  • Decreased serum haptoglobin and haemoglobin levels.
  • Increased serum bilirubin levels and visual disturbances.[38][39]

Imaging tests, such as ultrasound, tomography or magnetic resonance imaging (MRI), are instrumental in the correct diagnosis of HELLP syndrome in patients with suspected liver dysfunction. Unurgent cases must undergo MRI, but laboratory tests, such as glucose determination, are more encouraged in mild cases of HELLP syndrome.[31][40]

Classification

A classification system, which was developed in Mississippi, measures the severity of the syndrome using the lowest observed platelet count in the patients alongside the appearance of the other two main clinical criteria. Class I is the most severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.[41]

  • Class I HELLP syndrome is characterised by a platelet count below 50,000/µL.
  • Class II HELLP syndrome is characterised by a platelet count of 50,000-100,000/µL.
  • Class III HELLP syndrome is characterised by a platelet count of 100,000-150,000/µL.

Another classification system, introduced in Memphis, categorises HELLP syndrome based on its expression.

  • Partial expression of the condition is characterised by the manifestation of one or two of the main diagnostic criteria.
  • The complete expression of the condition is characterised by the manifestation of all three main diagnostic criteria.[42]

Treatment

The only current recommended and most effective treatment is delivery of the baby, as the signs and symptoms diminish and gradually disappear following the delivery of the placenta. Prompt delivery is the only viable option in cases with multiorgan dysfunction or multiorgan failure, haemorrhage and considerable danger to the fetus. Certain medications are also used to target and alleviate specific symptoms.[31][2][43][44]

Corticosteroids are of unclear benefit, though there is tentative evidence that they can increase the mother's platelet count.[45][46]

Prognosis

With treatment, maternal mortality is about 1 percent, although complications such as placental abruption, acute kidney injury, subcapsular liver hematoma, permanent liver damage, and retinal detachment occur in about 25% of women. Perinatal mortality (stillbirths plus death in infancy) is between 73 and 119 per 1000 babies of woman with HELLP, while up to 40% are small for gestational age.[47] In general, however, factors such as gestational age are more important than the severity of HELLP in determining the outcome in the baby.[48]

Epidemiology

HELLP syndrome affects 10-20% of pre-eclampsia patients and is a complication in 0.5-0.9% of all pregnancies.[6][49] Caucasian women over 25 years of age comprise most of the diagnosed HELLP syndrome cases.[50] In 70% of cases before childbirth, the condition manifests in the third trimester, but 10% and 20% of the cases exhibit symptoms before and after the third trimester, respectively. Postpartum occurrences are also observed in 30% of all HELLP syndrome cases.[51]

History

HELLP syndrome was identified as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982.[31] In a 2005 article, Weinstein wrote that the unexplained postpartum death of a woman who had haemolysis, abnormal liver function, thrombocytopenia, and hypoglycemia motivated him to review the medical literature and to compile information on similar women.[10] He noted that cases with features of HELLP had been reported as early as 1954.[10][52]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 "HELLP syndrome" (in en). 2018. https://rarediseases.info.nih.gov/diseases/8528/hellp-syndrome. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "The HELLP syndrome: clinical issues and management. A Review". BMC Pregnancy Childbirth 9: 8. February 2009. doi:10.1186/1471-2393-9-8. PMID 19245695. 
  3. ↑ 3.0 3.1 Odze, Robert D.; Goldblum, John R. (2009) (in en). Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Elsevier Health Sciences. p. 1240. ISBN 9781416040590. https://books.google.com/books?id=8ITX093f1j0C&pg=PA1240. 
  4. ↑ Cohen, Hannah; O'Brien, Patrick (2015) (in en). Disorders of Thrombosis and Hemostasis in Pregnancy: A Guide to Management. Springer. p. 305. ISBN 9783319151205. https://books.google.com/books?id=XdvyCQAAQBAJ&pg=PA305. 
  5. ↑ "Preeclampsia and Eclampsia". March 2018. https://www.merckmanuals.com/home/women-s-health-issues/complications-of-pregnancy/preeclampsia-and-eclampsia#v813330. 
  6. ↑ 6.0 6.1 6.2 6.3 "Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia". J Perinat Med 155 (3): 501–9. September 1986. doi:10.1016/0002-9378(86)90266-8. PMID 3529964. 
  7. ↑ "Temporising management of severe pre-eclampsia with and without the HELLP syndrome". Br J Obstet Gynaecol 102 (2): 111–7. February 1995. doi:10.1111/j.1471-0528.1995.tb09062.x. PMID 7756201. 
  8. ↑ 8.0 8.1 8.2 "Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count". Obstet Gynecol 103 (5 Pt 1): 981–91. May 2004. doi:10.1097/01.AOG.0000126245.35811.2a. PMID 15121574. 
  9. ↑ 9.0 9.1 "he HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?". Am J Obstet Gynecol 162 (2): 311–6. February 1990. doi:10.1016/0002-9378(90)90376-i. PMID 2309811. 
  10. ↑ 10.0 10.1 10.2 "It has been a great ride: The history of HELLP syndrome". Am J Obstet Gynecol 193 (3 Pt 1): 860–3. September 2005. doi:10.1016/j.ajog.2005.06.058. PMID 16150288. 
  11. ↑ "A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study". Br J Obstet Gynaecol 93 (2): 145–55. February 1986. doi:10.1111/j.1471-0528.1986.tb07879.x. PMID 3511956. 
  12. ↑ "Characteristics and treatment of hepatic rupture caused by HELLP syndrome". Am J Obstet Gynecol 1995 (1): 129–33. July 2006. doi:10.1016/j.ajog.2006.01.016. PMID 16579935. 
  13. ↑ "Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome". Gastroenterology 126 (3): 849–58. March 2004. doi:10.1053/j.gastro.2003.11.054. PMID 14988839. 
  14. ↑ "Preeclampsia-associated hepatic hemorrhage and rupture: mode of management related to maternal and perinatal outcome". Obstet Gynecol Surv 54 (3): 196–202. March 1996. doi:10.1097/00006254-199903000-00024. PMID 10071839. 
  15. ↑ "Subcapsular liver hematoma in HELLP syndrome: Evaluation of diagnostic and therapeutic options--a unicenter study". Am J Obstet Gynecol 190 (1): 106–12. January 2004. doi:10.1016/j.ajog.2003.08.029. PMID 14749644. 
  16. ↑ 16.0 16.1 "A genome-wide scan for preeclampsia in the Netherlands". Eur J Hum Genet 9 (10): 758–64. October 2001. doi:10.1038/sj.ejhg.5200706. PMID 11781687. 
  17. ↑ 17.0 17.1 "Long-term maternal and subsequent pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome". Am J Obstet Gynecol 201 (4): 385 e1–5. October 2009. doi:10.1016/j.ajog.2009.06.033. PMID 19716544. 
  18. ↑ "Follow-up analysis of pregnancies complicated by HELLP syndrome". Fetal Diagn Ther 21 (6): 519–22. 2006. doi:10.1159/000095665. PMID 16969007. 
  19. ↑ "Fas (TNFRSF6) gene polymorphism in pregnant women with hemolysis, elevated liver enzymes, and low platelets and in their neonates". Obstet Gynecol 107 (3): 582–7. March 2009. doi:10.1097/01.AOG.0000195824.51919.81. PMID 16507928. 
  20. ↑ "Vascular endothelial growth factor (VEGF) polymorphisms in HELLP syndrome patients determined by quantitative real-time PCR and melting curve analyses". Clin Chim Acta 389 (1–2): 126–31. 2006. doi:10.1016/j.cca.2007.12.003. PMID 18167313. 
  21. ↑ "Overrepresentation of BclI polymorphism of the glucocorticoid receptor gene in pregnant women with HELLP syndrome". Clin Chim Acta 405 (1–2): 148–52. July 2009. doi:10.1016/j.cca.2009.03.046. PMID 19336230. 
  22. ↑ "Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome". PLOS ONE 3 (4): e1865. April 2008. doi:10.1371/journal.pone.0001865. PMID 18382655. Bibcode: 2008PLoSO...3.1865V. 
  23. ↑ 23.0 23.1 "The HELLP syndrome". Br J Obstet Gynaecol 104 (8): 877–91. August 1997. doi:10.1111/j.1471-0528.1997.tb14346.x. PMID 9255078. 
  24. ↑ "DCurrent understanding of severe preeclampsia, pregnancy-associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemolysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute renal failure: different clinical syndromes or just different names?". Curr Opin Nephrol Hypertens 3 (4): 436–45. July 1994. doi:10.1097/00041552-199407000-00010. PMID 8076148. 
  25. ↑ 25.0 25.1 "Biochemistry of HELLP syndrome". Adv Clin Chem. Advances in Clinical Chemistry 53: 85–104. 2011. doi:10.1016/B978-0-12-385855-9.00004-7. ISBN 9780123858559. PMID 21404915. 
  26. ↑ "Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity". PLOS ONE 6 (10): e26313. 2011. doi:10.1371/journal.pone.0026313. PMID 22022598. Bibcode: 2011PLoSO...626313G. 
  27. ↑ "Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome". PLOS ONE 4 (12): 2569–75. December 2006. doi:10.1111/j.1538-7836.2006.02205.x. PMID 16968329. 
  28. ↑ "SLeukocytosis is proportional to HELLP syndrome severity: evidence for an inflammatory form of preeclampsia". South Med J 93 (8): 768–71. August 2000. doi:10.1097/00007611-200093080-00005. PMID 10963506. 
  29. ↑ "Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count". Obstet Gynecol 79 (1): 19–26. January 1992. PMID 1727579. 
  30. ↑ "Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome". Haematologica 88 (9): 1029–34. September 2003. PMID 12969811. 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 "Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy". Am J Obstet Gynecol 142 (2): 159–67. January 1982. doi:10.1016/s0002-9378(16)32330-4. PMID 7055180. 
  32. ↑ 32.0 32.1 "Acute complications of preeclampsia". Clin Obstet Gynecol 45 (2): 308–29. June 2002. doi:10.1097/00003081-200206000-00004. PMID 12048392. 
  33. ↑ "Hepatic hemorrhage and the HELLP syndrome: a surgeon's perspective". Am Surg 61 (9): 756–60. September 1995. PMID 7661469. 
  34. ↑ "The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification". Am J Obstet Gynecol 180 (6 Pt 1): 1373–84. June 1999. doi:10.1016/s0002-9378(99)70022-0. PMID 10368474. 
  35. ↑ "Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child". Am J Obstet Gynecol 195 (4): 914–34. October 2006. doi:10.1016/j.ajog.2005.08.044. PMID 16631593. 
  36. ↑ "The natural history of HELLP syndrome: patterns of disease progression and regression". Am J Obstet Gynecol 164 (6 Pt 1): 1500–9; discussion 1509–13. June 1992. doi:10.1016/0002-9378(91)91429-z. PMID 2048596. 
  37. ↑ "Severe preeclampsia with fulminant and extreme elevation of aspartate aminotransferase and lactate dehydrogenase levels: high risk for maternal death". Am J Perinatol 12 (5): 310–3. September 1995. doi:10.1055/s-2007-994482. PMID 8540929. 
  38. ↑ "Preeclampsia: an endothelial cell disorder". Am J Obstet Gynecol 161 (5): 1200–4. November 1989. doi:10.1016/0002-9378(89)90665-0. PMID 2589440. 
  39. ↑ "Treatment of hypertension in pregnant women". N Engl J Med 335 (45): 257–65. July 1996. doi:10.1056/NEJM199607253350407. PMID 8657243. 
  40. ↑ "Preeclampsia/eclampsia with hemolysis, elevated liver enzymes, and thrombocytopenia". Obstet Gynecol 66 (5): 657–60. November 1985. PMID 4058824. 
  41. ↑ "Pregnancy complicated by preeclampsia-eclampsia with the syndrome of hemolysis, elevated liver enzymes, and low platelet count: how rapid is postpartum recovery?". Obstet Gynecol 76 (5 Pt 1): 737–41. November 1990. doi:10.1097/00006250-199011000-00001. PMID 2216215. 
  42. ↑ "Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome". Am J Obstet Gynecol 175 (2): 460–4. August 1996. doi:10.1016/s0002-9378(96)70162-x. PMID 8765269. 
  43. ↑ "Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome". Am J Obstet Gynecol 183 (2): 444–8. August 2000. doi:10.1067/mob.2000.105915. PMID 10942484. 
  44. ↑ "The importance of early laboratory screening methods for maternal and fetal outcome in cases of HELLP syndrome". Eur J Obstet Gynecol Reprod Biol 36 (1–2): 43–51. August 1990. doi:10.1016/0028-2243(90)90048-6. PMID 2365128. 
  45. ↑ Woudstra, DM; Chandra, S; Hofmeyr, GJ; Dowswell, T (8 September 2010). "Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy.". The Cochrane Database of Systematic Reviews (9): CD008148. doi:10.1002/14651858.CD008148.pub2. PMID 20824872. 
  46. ↑ "HELLP syndrome: understanding and management of a pregnancy-specific disease". J Obstet Gynaecol 33 (4): 331–7. May 2013. doi:10.3109/01443615.2013.775231. PMID 23654309. 
  47. ↑ Belfort, Michael A.; Steven Thornton; George R. Saade (2002). Hypertension in Pregnancy. CRC Press. pp. 159–60. ISBN 9780824708276. https://books.google.com/books?id=OD3nK6HUIUEC&pg=PA159. Retrieved 2012-04-13. 
  48. ↑ Stevenson, David Kendal; William E. Benītz (2003). Fetal and Neonatal Brain Injury. Cambridge University Press. p. 260. ISBN 9780521806916. https://books.google.com/books?id=RuekFAj_tIAC&pg=PA260. Retrieved 2012-04-13. 
  49. ↑ "Hypertensive disorders in twin pregnancy". Eur J Obstet Gynecol Reprod Biol 58 (1): 13–9. January 1995. doi:10.1016/0028-2243(94)01982-d. PMID 7758654. http://repub.eur.nl/pub/61934. 
  50. ↑ "HELLP syndrome: recognition and perinatal management". American Family Physician 60 (3): 829–36, 839. September 1999. PMID 10498110. 
  51. ↑ "Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome". Clin Perinatol 31 (4): 807–33. December 2004. doi:10.1016/j.clp.2004.06.008. PMID 15519429. 
  52. ↑ "Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy". N Engl J Med 250 (3): 89–98. Jan 1954. doi:10.1056/NEJM195401212500301. PMID 13119851. 

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