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CHAPTER 51 Although initially known as edema-proteinuria-hypertension gestosis
type B, a catchier phrase, HELLP syndrome (H for hemolysis, EL for ele-
3
FRAGMENTATION vated liver function tests, and LP for low platelet counts), was later applied
by Louis Weinstein in 1982.
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HEMOLYTIC ANEMIA EPIDEMIOLOGY

HELLP syndrome occurs in approximately 0.5 percent of pregnan-
5
Kelty R. Baker and Joel Moake cies overall, in 4 to 12 percent of those complicated by preeclampsia
(hypertension + proteinuria), and in 30 to 50 percent of those compli-
cated by eclampsia (hypertension + proteinuria + seizures); however,
approximately 15 percent of patients ultimately diagnosed with HELLP
SUMMARY syndrome present with neither hypertension nor proteinuria. Two-
6
thirds of HELLP patients are diagnosed antepartum, usually between
Erythrocyte fragmentation and hemolysis occur when red cells are forced at 27 and 37 weeks. The remaining one-third are diagnosed in the post-
high shear stress through partial vascular occlusions or over abnormal vas- partum period, from a few to 48 hours following delivery (occasion-
cular surfaces. “Split” red cells, or schistocytes, are prominent on blood films ally as long as 6 days). Risk factors for HELLP syndrome include
7,8
under these conditions, and considerable quantities of lactate dehydroge- European ancestry, multiparity, older maternal age (older than age
5
nase are released into the blood from traumatized red cells. In the high-flow 34 years), and a personal or familial history of the disorder. Although
(high-shear) microvascular (arteriolar/capillary) or arterial circulation, par- the presence of homozygosity for the 677 (C→T) polymorphism of the
tial vascular obstructions are caused by platelet aggregates in the systemic methylenetetrahydrofolate reductase gene may be a modest risk fac-
microvasculature during episodes of thrombotic thrombocytopenic purpura by tor for the development of preeclampsia, this weak association does
9
platelet-fibrin thrombi in the renal microvasculature in the hemolytic uremic not exist for HELLP syndrome. Whether or not the factor V Leiden
or prothrombin 20210 gene mutations are risk factors for HELLP syn-
syndrome; and by malfunction of a cardiac prosthetic valve in valve-related drome remains controversial. 10–12
hemolysis. Less-extensive red cell fragmentation, hemolysis, and schistocyto-
sis occur under conditions of more moderate vascular occlusion or endothe-
lial surface abnormalities, sometimes under conditions of lower shear stress. ETIOLOGY AND PATHOGENESIS
These latter entities include excessive platelet aggregation, fibrin polymer A developing embryo must acquire a supply of maternal blood to
formation, and secondary fibrinolysis in the arterial or venous microcircula- survive. During a normal pregnancy, the first wave of trophoblastic
tion (disseminated intravascular coagulation); in the placental vasculature invasion into the decidua occurs at 10 to 12 days. This is followed by
in preeclampsia/eclampsia and the syndrome of hemolysis, elevated liver a second wave at 16 to 22 weeks, when these specialized placental epi-
enzymes and low platelets (HELLP) in march hemoglobinuria; and in giant thelial cells replace the endothelium of the uterine spiral arteries and
cavernous hemangiomas (the Kasabach-Merritt phenomenon). intercalate within the muscular tunica, increasing the vessels’ diame-
ters and decreasing their resistance. As a result, the spiral arteries are
remodeled into unique hybrid vessels composed of fetal and maternal
cells, and the vasculature is converted into a high-flow–low-resistance
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PREECLAMPSIA/ECLAMPSIA AND system resistant to vasoconstrictors circulating in the maternal blood.
In a preeclamptic pregnancy, the second wave fails to penetrate ade-
HELLP SYNDROME quately the spiral arteries of the uterus, perhaps as a result of reduced
placental expression of syncytin and subsequent altered cell fusion pro-
DEFINITION AND HISTORY cesses during placentogenesis. The resultant poorly perfused, hypoxic
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A life-threatening condition of pregnancy denoted by eclampsia, hemoly- placenta then releases the extracellular domain (soluble) form of fms-
sis, and thrombocytopenia was first noted in the German literature by Sta- like tyrosine kinase 1 (sFLT-1), also known as soluble vascular endo-
hnke in 1922. Subsequently, Pritchard and coworkers described three cases thelial growth factor receptor-1 (sVEGF receptor-1, or sVEGFR-1).
1
in English and suggested that an immunologic process might account for sVEGFR-1 functions as an antiangiogenic protein because it binds to
both the preeclampsia or eclampsia and the hematologic abnormalities. vascular endothelial growth factor (VEGF) and placental growth factor
2
(PGF), and prevents their interaction with endothelial cell receptors.
The result is glomerular endothelial cell and placental dysfunction. 15–17
Direct and indirect sequelae include increased vascular tone, hyper-
Acronyms and Abbreviations: ADAMTS13, a disintegrin and metalloproteinase tension, proteinuria, enhanced platelet activation and aggregation, and
with thrombospondin domain 13; ALT, alanine transaminase; aPTT, activated partial decreased levels of the vasodilators prostaglandin I (PGI ) and nitrous
2
2
5,17
thromboplastin time; AST, aspartic acid transaminase; AT, antithrombin; DIC, dis- oxide (NO). Concurrent activation of the coagulation cascade results
seminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes, and in platelet-fibrin deposition in the capillaries, multiorgan microvascu-
low platelet count; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic lar injury, microangiopathic hemolytic anemia, elevated liver enzymes
anemia; NO, nitrous oxide; PGF, placental growth factor; PGI , prostaglandin I ; PT, because of hepatic necrosis, and thrombocytopenia because of periph-
2
2
prothrombin time; PTT, partial thromboplastin time; sEng, soluble endoglin; sFlt-1, eral consumption of platelets. 5
soluble form of fms-like tyrosine kinase 1; sVEGFR-1, soluble vascular endothelial Another antiangiogenic molecule, a soluble form of endog-
growth factor receptor-1; TGF-β, transforming growth factor-β; TTP, thrombotic lin (sEng), also increases in patient serum during early and severe
thrombocytopenic purpura; VEGF, vascular endothelial growth factor; VWF, von preeclampsia. Endoglin is part of the transforming growth factor-β
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Willebrand factor. (TGF-β) complex, and is expressed on vascular endothelial cells and syn-
cytiotrophoblasts. The shed extracellular domain of endoglin, sEng, is

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