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2012 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2013

and placental syncytiotrophoblasts, functioning as a coreceptor for the in anticipation of a spontaneous recovery. If thrombocytopenia and
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potent angiogenic factor transforming growth factor-β. Expression of hemolysis (as assessed by serum lactate dehydrogenase levels) con-
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its messenger RNA is increased in preeclamptic placenta. The levels tinue to worsen beyond this time, intervention with plasma exchange
of the soluble extracellular domain, produced by proteolysis, are ele- is appropriate for the presumed diagnosis of TTP-HUS (Chap. 133).
vated in the blood of preeclamptic patients. In pregnant rats, soluble At this point, TTP-HUS cannot be distinguished from atypical preec-
endoglin works synergistically with sFlt1 to produce vascular damage lampsia/HELLP syndrome, for which plasma exchange treatment may
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and a HELLP-like syndrome. These findings strongly suggest that a be beneficial. Earlier intervention with plasma exchange is indicated
tonic level of VEGF-like angiogenic factors is required to maintain the for more severe clinical problems, such as neurologic abnormalities or
normal function of vascular endothelial cells and that this process is acute, anuric renal failure. In patients with AFLP, however, liver insuf-
dysregulated during preeclampsia/eclampsia. ficiency, encephalopathy and coagulopathy may not improve despite
The connection between preeclampsia and thrombocytopenia is immediate delivery and intensive supportive care. These patients may
not clear, although many cases have evidence of activation of blood require liver transplantation. 352
coagulation detected by elevated levels of fibrin-degradation products
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and thrombin–antithrombin complexes. Low levels of the VWF-
cleaving metalloprotease ADAMTS13 (a disintegrin and metallopro- NEONATAL ALLOIMMUNE
tease with a thrombospondin type 1 motif member 13) have also been THROMBOCYTOPENIA
described, as have elevated levels of VWF, including the hyperadhe-
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sive ultralarge forms. 349 The platelet count in the fetus reaches normal adult levels (>150 × 10 /L)
9
after the first trimester, and is maintained throughout gestation. How-
HELLP Syndrome ever, thrombocytopenia is more common in preterm infants, of sev-
This syndrome occurs in the peripartum period and is defined by the eral potential etiologies. Severe thrombocytopenia (<50 × 10 /L) is
9
presence of microangiopathic hemolytic anemia, elevated liver enzymes, an important finding in neonates, and should be carefully managed
and low platelets. In approximately 70 to 80 percent of patients, HELLP because of high bleeding risk (Chap. 6). 354
occurs in the setting of preeclampsia. Microangiopathic hemolysis Fetal–neonatal alloimmune thrombocytopenia (NAIT) is a lead-
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results from shearing of the erythrocytes as they pass through arterioles ing cause of severe thrombocytopenia and life-threatening bleeding in
occluded by platelet–fibrin deposits. Adhesion and aggregation of plate- neonates. NAIT is caused by the transplacental transfer of maternal
lets on damaged and activated endothelium presumably accounts for alloantibodies against fetal platelet antigens inherited from the father.
the low platelet count (Chap. 114). HELLP shares a number of features NAIT resembles neonatal alloimmune hemolytic anemia (Rh hemo-
with TTP, including the presence of microangiopathic hemolysis and lytic disease of the newborn) in many aspects. In both diseases, mater-
thrombocytopenia. Involvement of the central nervous system is a more nal alloantibodies against fetal blood cell antigens cross the placenta
prominent feature of TTP, whereas HELLP more commonly displays and destroy antigen-positive fetal cells, resulting in significant fetal/
351
severe liver function abnormalities (Chaps. 7, 49, and 124). Because neonatal morbidity and mortality. However, unlike neonatal alloim-
the two syndromes can be confused with one other, one study attempted mune hemolytic anemia, which tends to spare the first-born child, the
to distinguish the two by measuring the activity of ADAMTS13, which first child is affected in 40 to 60 percent of NAIT cases. Transplacen-
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348
usually is absent or severely deficient in TTP. The study found that tal transfer of antiplatelet antibodies can also occur in babies born from
essentially all 17 patients in a cohort with the HELLP syndrome had mothers with ITP. Nevertheless, maternal ITP rarely causes serious
mild to moderate reductions in the activity of ADAMTS13 in the thrombocytopenia or bleeding in the fetus, whereas thrombocytope-
plasma, and none was severely deficient. nia tends to be more severe and the rate of intracranial hemorrhage
is higher (10 to 20 percent) in NAIT. In contrast to maternal ITP, in
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Acute Fatty Liver of Pregnancy NAIT the maternal platelet count is normal, a key differential diagnos-
This abnormality is a very severe, but fortunately very rare (1 in 20,000 tic finding.
to 100,000 pregnancies) condition that occurs during the third trimes-
ter of pregnancy or early postpartum period. Acute fatty liver of preg-
nancy (AFLP) is characterized by microvesicular fatty infiltration of PREVALENCE AND PATHOGENESIS
liver resulting in hepatic failure and encephalopathy. The “Swansea Cri- The estimated frequency of NAIT varies from 1 in 500 to 1 in 2000
teria” used for the diagnosis of AFLP include encephalopathy, vomiting, livebirths. 355,356 Maternal alloantibodies against human platelet alloan-
abdominal pain, polydipsia/polyuria, elevated transaminases, elevated tigens (HPAs) are responsible for platelet destruction in NAIT. In pop-
ammonia, elevated uric acid, elevated bilirubin, leukocytosis, coagulop- ulations of European ancestry, the most frequently implicated antigens
athy, renal impairment, hypoglycemia, ascites or bright liver on ultra- are HPA-1a or Pl (78 percent of cases) and HPA-5b or Br (19 per-
a
A1
sound evaluation, and microvesicular steatosis on liver biopsy. Six or cent of cases). These antigens are rare in Asian populations. HPA-4a
357
more of these criteria should be present in a patient who has no obvious (80 percent of cases) and HPA-3a (15 percent of cases) are responsible
reason for hepatic failure. Both maternal and fetal mortality rates are for platelet destruction in the majority of Asian NAIT cases. Besides
high, ranging from 7 to 18 percent and 9 to 23 percent, respectively. 352 targeting the HPA system, anti–HLA-2 antibodies have been reported,
Delivery of the fetus is the most effective treatment for preeclamp- but whether they are responsible for NAIT is not clear. 355,358,359
sia, HELLP syndrome and AFLP. The platelet count nadir and the peak The frequency of NAIT in populations of European ancestry is
of serum lactate dehydrogenase may occur postpartum, during the first lower than would be expected given that the prevalence of HPA-1a
postpartum day in most patients, but as late as 5 to 7 days in some. For negativity is 2.5 percent. Only 10 percent of HPA-1a–negative mothers
patients with severe thrombocytopenia and microangiopathic hemo- exposed to HPA-1a–positive platelets during pregnancy become immu-
lytic anemia, plasma exchange may be indicated if the fetus cannot be nized. HPA alloimmunization is strongly correlated with the presence
delivered or if improvement does not follow delivery. This treatment is of specific class II HLA antigens, with increased risk demonstrated
empirically based on the similarity of the clinical picture to that of TTP. in HPA-1a–negative mothers expressing HLA-B8, HLA-DR3, and
Postpartum day 3 often is considered the limit for supportive therapy HLA-DR52a antigens. 317,360,361 The presence of the HLA-DRB3 0101
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