Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP 409 cules that are secreted concurrently with the ULVWF multimers from Weibel – Palade bodies [58] . Included among the agents that stimulate endothelial cells to secrete ULVWF multimers are the proinfl ammatory cytokines, tumor necrosis factor (TNF) - α , interleukin (IL) - 8 and IL - 6 (in complex with the IL - 6 receptor), [59] and the Shiga toxins (discussed in the section below on HUS). One of the repeated CUB domains at the carboxyl - termi- nal end of each ADAMTS - 13 enzyme, as well as one or more of the thrombospondin - 1 - like domains along the length of the mol- ecule, may modulate the binding of ADAMTS - 13 to ULVWF multimers as they are secreted by endothelial cells [60 – 62] . Specifi cally, ADAMTS - 13 enzymes may attach under fl owing conditions to accessible A3 domains in the monomeric subunits of ULVWF multimers, [56] and then cleave Tyr842 – 843Met peptide bonds in adjacent A2 domains (Figure 32.4 ). Partial unfolding of emerging ULVWF multimers by fl uid shear stress may increase the effi ciency of ADAMTS - 13 attachment to ULVWF multimers, as well as ULVWF cleavage [45,57] . Platelet GPIba binding to the VWF A1 domain pulls the adjacent VWF A2 domain into a position that is susceptible to proteolysis by ADAMTS - 13 [63] . This may explain why ADAMTS - 13, secreted by endothelial cells along with ULVWF multimeric strings, does not cleave the ULVWF strings until platelet – ULVWF adhering begins. Failure to degrade ULVWF multimers has been suspected since the 1980s to cause familial and acquired idiopathic types of TTP, or to predispose an individual to these disorders (Figures 32.3 & 32.4 ) [9,64] . Critical experiments verifying this concept were reported in 1997 – 8. In 1997, four patients were described with chronic relapsing TTP who had a defi ciency of VWF - cleaving protease activity (ADAMTS - 13) in plasma [8] . No inhibitor of the enzyme was detected, and so the defi ciency was ascribed to This VWF “ processing activity, ” initially described in 1982 [9] , is now known to be a specifi c VWF - cleaving metalloprotease in normal plasma that prevents the persistence in the circulation of ULVWF multimers [8,41,42] . The enzyme degrades ULVWF multimers by cleaving 842Tyr – 843Met peptide bonds in suscep- tible A2 domains of VWF monomeric subunits [43 – 45] . The VWF - cleaving metalloprotease is number 13 in a family of 18 distinct ADAMTS - type enzymes identifi ed to date that share structural similarities [46,47] . “ ADAMTS - 13 ” is a d isintegrin a nd m etalloprotease with eight t hrombo s pondin - 1 - like domains. More precisely, plasma ADAMTS - 13 is composed of an amino - terminal reprolysin - type metalloprotease domain followed by: a disintegrin domain; a thrombospondin - 1 - like domain; a cyste- ine - rich domain containing an arginine - glycine - aspartate (RGD) sequence; a spacer domain; seven additional thrombospondin - 1 - like domains; and two non - identical CUB - type domains at the carboxyl - terminal end of the molecule (Figure 32.2 ). CUB domains contain peptide sequences similar to: c omplement sub- components C1r/C1s; embryonic sea u rchin protein egf; and b one morphogenic protein - 1 [48] . ADAMTS - 13 is a Zn 2+ - and Ca 2+ - requiring 190 000 - Da glyco- sylated protein that is encoded on chromosome 9q34. It is pro- duced (predominantly) by endothelial cells [49,50] , and by hepatic stellate cells [51 – 53] . Plasma ADAMTS - 13 activity is inhibited by the strong divalent cation - chelating agent, EDTA. Functional assays of the enzyme in vitro are usually performed in plasma anticoagulated using citrate, a weak divalent cation chela- tor [8,41 – 47,54,55] . ULVWF multimers are cleaved by ADAMTS - 13 as they are secreted as long “ strings ” from stimulated endothelial cells (Figure 32.3 ) [56,57] . The ULVWF multimeric strings may be anchored in the endothelial cell membrane to P - selectin mole- CUB Cysteine- rich / Spacer P MP Disintegrin TSP TSP TSP TSP TSP TSP TSPTSP CUB 20% 56% 100% 28% 64% Autoantibodies (% in 25 patients) Acquired Idiopathic TTP Familial TTP Mutations Amino-terminal Carboxy-terminal ADAMTS-13 ** * * ** ****** * ** Figure 32.2 Domain structure of ADAMTS - 13 (the plasma VWF - cleaving metalloprotease). P, propeptide; MP, metalloprotease (proteolytic) domain; TSP, thrombospondin - 1 - like domain (eight are present); CUB, two non - identical domains containing peptide segments similar to c omplement components, C1r/C1s, a sea u rchin protein, and a b one morphogenic protein. * Indicates the location of mutations in familial TTP patients that affect secretion or function of ADAMTS - 13 (above enzyme structure). The percentages of polyclonal autoantibodies directed against specifi c domains of ADAMTS - 13 in 25 patients with acquired idiopathic TTP are indicated below the enzyme structure [79] . 410 ULVWF multimeric “string” Weibel-Palade Body Platelet adherence Flow Endothelial Cell Platelet adherence aggregation Endothelial Cell Flow ULVWF multimeric “string” Weibel-Palade Body TTP : ADAMTS-13 deficient type (familial or autoantibody-induced) Uncleaved ULVWF multimers Platelets CUB ADAMTS-13 Endothelial Cell MP Weibel-Palade Body • IL-6 (+ soluble IL-6 receptor) • IL-8 • TNF- • Estrogen • Shiga-like toxins-1 or -2 Endothelial Cells Increased ULVWF Secretion Normal cleavage of ULVWF multimers ADAMTS-13 ADAMTS-13 Flow Endothelial Cell = VWF-cleaving metalloprotease Weibel-Palade Body ULVWF multimeric “string” Stimulated endothelial cell Endothelial Cell Flow ULVWF = “Unusually Large” Von Willebrand Factor Weibel-Palade Body AB C D E F Figure 32.3 Proposed mechanism for the cleavage of unusually large von Willebrand factor (ULVWF) multimeric strings by ADAMTS - 13. (a) Stimulation of endothelial cells causes secretion of long ULVWF multimeric strings. (b) Platelets from fl owing blood adhere to the long ULVWF multimeric strings immediately after string secretion. (c) Additional blood platelets then cohere (aggregeate) onto those initially adherent to the ULVWF multimeric strings. (d) Adequate quantities of ADAMTS - 13 enzymes are present in the plasma of normal individuals to cleave quickly the ULVWF – platelet strings. (e) Absent or severely reduced activity of ADAMTS - 13 in the plasma of patients with TTP prevents the timely cleavage of ULVWF multimeric strings as they are secreted from endothelial cells. Uncleaved ULVWF multimers induce the adhesion and subsequent aggregation of platelets in fl owing blood. TTP can be caused by familial defi ciencies of ADAMTS - 13 secretion or activity caused by ADAMTA - 13 gene mutations, or by acquired autoantibody - induced defects of ADAMTS - 13 activity (or survival). (f) Stimulation of ULVWF multimeric secretion by cytokines or toxins may precipitate TTP episodes in individuals who have marginal levels of plasma ADAMTS - 13 activity. Stx, Shiga toxin (Stx - 1 and - 2 are from enterohemorrhagic E. coli ); TNF, tumor necrosis factor; IL, interleukin. Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP 411 ery. The plasma assays used in the 1997 – 8 studies were “ non - physiologic; ” they were, however, innovative and informative. IgG autoantibodies against components of the enzyme probably accounted for the lack of protease activity in most of the acquired idiopathic TTP patients reported in 1998 [41,42,65] . The expla- nation for the transient immune dysregulation, as well as for the an abnormality in the production, survival or function of the protease. The following year, the pathogenesis of the more common acquired idiopathic type of TTP was elucidated [41,42,65] . Acquired idiopathic TTP patients have little or no plasma VWF - cleaving protease activity during acute episodes; however, the activity often returns towards normal upon recov- A3 domain Endothelial Cell 842-3 Von Willebrand Factor (VWF) A1 domain n (A2 domain) monomer n monomers = multimer EC multimers = “unusually large” (UL)VWF Weible- Palade Body P-selectin A3 domain ADAMTS-13 Endothelial Cell P-selectin 842-3 ULVWF monomeric subunit A1 domain n CUB (A2 domain) MP Normal Weible- Palade Body A1 domain A3 domain ADAMTS-13 Endothelial Cell P-selectin 842-3 n ULVWF monomeric subunit GPIb (A2 domain) CUB MP Normal Platelet Weible- Palade Body A3 domain ADAMTS-13 Endothelial Cell P-selectin 842-3 ULVWF monomeric subunit A1 domain n CUB (A2 domain) MP TTP Weible- Palade Body AB CD Figure 32.4 Proposed mechanism of ULVWF multimeric string cleavage by ADAMTS - 13. (A) One of the many monomeric subunits that comprise an ULVWF multimeric string secreted by stimulated endothelial cells. The ULVWF multimeric strings may be anchored in the endothelial cell membrane to P - selectin molecules that are secreted concurrently with the ULVWF multimers from Weibel - Palade bodies. The A1, A2 (with the tyr842 - 843met ADAMTS - 13 proteolytic cleavage site), and A3 domains are shown. (B) Adequate quantities of ADAMTS - 13 enzymes are present in the plasma of normal individuals. The carboxy - terminal CUB domain is indicated, and the metalloprotease domain (MP) is drawn as a pincer - like structure on the amino - terminal portion of the enzyme. (C) Platelets from fl owing blood adhere to the long ULVWF multimeric strings immediately after string secretion. Platelet adherence (via platelet GPIb α ) to the A1 domain of ULVWF monomeric subunits increases the exposure of neighboring A2 tyr842 - 843met peptide bonds in ULVWF multimeric strings. ADAMTS - 13 molecules may attach via one of their CUB domains (and possibly the spacer domain) to the A3 domain of ULVWF monomeric subunits, and cleave the adjacent (and now - exposed) tyr842 - 843met bond. ADAMTS - 13 cleavage by this mechanism occurs in various monomers along the length of ULVWF multimeric strings. The smaller VWF forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood fl ow. (D) Absent or severely reduced activity of ADAMTS - 13 in the plasma of patients with TTP prevents the timely cleavage of ULVWF - multimeric strings. Chapter 32 412 [7,25,66,70,71] . In severe familial defi ciencies of ADAMTS - 13 activity, episodes of TTP usually commence in infancy or child- hood. In some of these patients, however, overt TTP episodes may not develop for years (e.g. during a fi rst pregnancy) [25,72] . This latter observation suggests that in vivo ADAMTS - 13 activity on ULVWF multimers emerging from stimulated endothelial cells may exceed the plasma enzyme activity measured by in vitro (non - physiologic) assays. Additionally, or alternatively, accentu- ated secretion of ULVWF multimers by endothelial cells induced by estrogen or proinfl ammatory cytokines [59] may be required to provoke TTP episodes in some patients with severe plasma ADAMTS - 13 defi ciency (Figure 32.3 ). In some infants with less than 5 – 10% ADAMTS - 13 and neo- natal onset of familial chronic relapsing TTP, transient or pro- gressive renal failure is a prominent component of the disorder [73] . These patients clinically resemble two children described in 1960 by Schulman et al. [9,74] and in 1978 by Upshaw [9,75] and so this pediatric subgroup is sometimes said to have “ Upshaw – Schulman syndrome. ” Many patients with acquired idiopathic TTP have absent or severely reduced plasma ADAMTS - 13 activity during an initial episode, as well as during any later recurrence [41,42,65] (Table 32.2 ). ADAMTS - 13 activity usually increases in these patients following recovery from either a single, or recurrent, episode. IgG antibodies (presumably autoantibodies) that inhibit plasma ADAMTS - 13 activity can be detected in 44 – 94% of patients using the non - physiologic techniques currently available [25,41,42,65,76,77] . These results suggest a transient, or intermit- tently recurrent, defect of immune regulation in many patients who have acquired idiopathic TTP associated with transient, or recurrent, ADAMTS - 13 defi ciency. Antibodies that inhibit plasma ADAMTS - 13 have also been demonstrated in a few patients with ticlopidine - or clopidogrel - associated TTP [13,78] . It is not yet known if there is a transient, severe defect of ADAMTS - 13 production or survival in patients with acquired TTP who do not have detectable autoantibodies against the enzyme. Alternatively, failure to detect autoantibodies in some patients may refl ect the limited sensitivity of the test systems in current use. In one recent study [79] of polyclonal autoantibodies against ADAMTS - 13 in 25 acquired TTP patients, the epitope targets of autoantibodies always included the cysteine - rich/spacer domain sequence. The CUB domains were additional antigenic targets of other autoantibodies in about two - thirds of the patients in this study (Figure 32.2 ). Autoantibodies either inhibit the activity of ADAMTS - 13 or decrease its survival. Relapses occur in 23 – 44% of patients with acquired idiopathic TTP, [25,76,80,81] , often in the fi rst year after the initial episode [25] . These relapsing patients usually have acquired idiopathic TTP with severe plasma ADAMTS - 13 defi ciency that is often due to the presence of detectable auto- antibodies against ADAMTS - 13 [25] . In a few instances, pregnancy - related TTP episodes have been demonstrated to be caused by autoantibodies against ADAMTS - selective antigenic targeting of the VWF - cleaving protease, is not yet known. Most patients with familial TTP have less than about 5 – 10% of normal ADAMTS - 13 activity in their plasma, regardless of whether the sample is obtained during or after acute episodes (provided that they have not recently received plasma infusions). Most patients with acquired idiopathic types of TTP have less than 5 – 10% of normal activity of ADAMTS - 13 in their plasma, but this is only during (or for a variable period following) acute TTP episodes [7,41,42,65,66] . Severe defi ciency of ADAMTS - 13 activity in TTP patient plasma correlates with a failure to cleave ULVWF multimeric strings as they emerge from the surface of endothelial cells (Figures 32.3 & 32.4 ) [57] . As a consequence, ULVWF multimers secreted by endothelial cells remain anchored to the cells in long strings [57] . The anchoring may be via P - selectin molecules, which have transmembrane domains and are secreted along with ULVWF multimers from the Weibel – Palade bodies of endothelial cells [58] . (P - selectin molecules are predominantly retained in the cell membrane as the Weibel – Palade contents are secreted.) Passing platelets adhere via their GPIba receptors to these long uncleaved ULVWF multimeric strings [57] . (Platelets do not adhere to the smaller VWF forms that circulate after cleavage of ULVWF multimers [36] .) Many additional platelets subsequently aggregate under fl owing condi- tions, probably via their activated membrane integrin aIIbb3 (GP IIb – IIIa) complexes, onto the ULVWF multimeric strings to form large, potentially occlusive, platelet thrombi [57,67] (Figure 32.3 ). Plasma ADAMTS - 13 activity is almost always absent or severely reduced in familial TTP patients, [8,68,69] as a consequence of homozygous (or doubly heterozygous) mutations in each of the two ADAMTS - 13 9q34 genes (Table 32.2 ) [7,25,66,70,71] . Mutations in familial TTP have been detected all along the gene structure, in regions encoding different domains (Figure 32.2 ) Table 32.2 TTP : inadequate cleavage of ULVWF multimers secreted by endothelial cells. VWF - cleaving metalloprotease (ADAMTS - 13) plasma activity “ absent (or < 5 – 10 %) ” Familial (congenital) TTP (often “ chronic relapsing ” ): Severe defect of ADAMTS - 13 production, function or survival Doubly heterozygous or homozygous mutations Acquired idiopathic TTP ( “ out of the blue ” ): Severe defect of ADAMTS - 13 function or survival Autoantibodies (often IgG) detectable in 44 – 94% of patients who are ADAMTS - 13 defi cient Types Transient single episode Recurrent (irregular intervals) Ticlopidine/clopidogrel HIV/AIDS Pregnancy ULVWF, unusually large von Willebrand factor. Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP 413 Table 32.3 TTP : ADAMTS - 13 - defi cient types. Familial TTP (ADAMTS - 13 mutations ; often chronic relapsing): Plasma (or cryosupernatant) infusion alone ( ∼ every 2 – 4 weeks) Acquired idiopathic TTP (ADAMTS - 13 autoantibodies ): Plasma (or cryosupernatant) exchange (plasma infusion with plasmapheresis) (daily) Other therapy for acquired idiopathic TTP: Glucocorticoids Transfusion: RBC (as needed) Platelets only for emergency bleeding, surgery or invasive procedures No aspirin Rituximab (anti - CD20 on B - lymphocytes) Splenectomy Cytoxan; vincristine; cyclosporine? Future: recombinant ADAMTS - 13? The reason why the infusion of normal ADAMTS - 13 only about every 3 weeks prevents TTP episodes in some of these patients is not known. The plasma t 1/2 of the infused ADAMTS - 13 activity is relatively long (about 2 days) [69] . The functional t 1/2 of the enzyme may be even longer, as a result of ADAMTS - 13 docking and cleaving on one ULVWF multimeric string after another as each string is secreted from endothelial cells [56,62] . Adults and some older children with acquired idiopathic TTP episodes associated with ADAMTS - 13 defi ciency require daily plasma exchange (Table 32.3 ). Plasma exchange combines plas- mapheresis (which may remove circulating ULVWF – platelet strings; cytokines, hormones or agents that stimulate endothelial cells to secrete ULVWF multimers; and autoantibodies against ADAMTS - 13) and the infusion of FFP or cryosupernatant (con- taining uninhibited ADAMTS - 13). Skipping even 1 day before complete remission may lead to rapid relapse. More than one exchange (or multiple plasma volumes) per day has not been demonstrated to be benefi cial. Infusion of normal FFP at the rate of about 30 mL/kg/day can be used initially until plasma exchanges are arranged. This should be as quickly as practical, but often requires from a few to many hours. Plasma infusion alone is less effective in acquired idio- pathic TTP than plasma exchange [95] and may result in volume overload. TTP patients with coma, cardiac failure, or severe renal dysfunction should receive plasma exchange commencing as soon as possible. Plasma exchange with FFP or cryosupernatant allows about 80% ± 10% of acquired, “ out - of - the - blue ” idio- pathic TTP patients who have severe ADAMTS - 13 defi ciency to survive an episode [25,95,96] . Lower titers of plasma ADAMTS - 13 autoantibodies may be associated with better responses to plasma exchange procedures than higher levels of ADAMTS - 13 autoantibodies produced for longer periods [81,97,98] . Autoantibodies are, however, diffi cult to quantify precisely using currently available assay procedures. In association with plasma exchange, production of ADAMTS - 13 13 [25] . The risk of recurrent TTP during any subsequent preg- nancies is controversial, with estimates of possible recurrence (per woman) ranging from 26 to 73% [25] . Plasma ADAMTS - 13 activity in healthy adults ranges from approximately 50 to 178% using currently available static, non - physiologic assays. Activity is often reduced below normal in liver disease, disseminated malignancies, [82] chronic metabolic and infl ammatory conditions and pregnancy, and in newborns [83] . With the exception of those peripartum women who develop overt TTP, [25,76] the ADAMTS - 13 activity in these conditions is not reduced to the extremely low values ( < 5 – 10% of normal) found in most patients with familial or acquired idiopathic TTP. Other o bservations About twice as many women as men develop acquired idiopathic TTP. Most patients are 20 – 60 years old, no racial or seasonal predisposition is obvious, and case clustering is rare. The major- ity of patients who develop acute idiopathic TTP have no identifi - able associated risk factor. TTP during pregnancy or the postpartum period accounts for a small percentage of total TTP cases [24 – 26] . Neame [84] suggested that abnormal immune modulation might contribute to the etiology in these circum- stances. Indeed, a specifi c defect in immune regulation is likely to be the basis for the “ escape ” of autoantibody production against ADAMTS - 13 in most acute idiopathic TTP patients. The possibility that immunologic events are involved in acute idiopathic TTP is supported by studies that suggest macrophage/ lymphocyte activation in some patients [85,86] . Elevated levels of IL - 1, IL - 6, the soluble IL - 2 receptor, TNF - α , and transforming growth factor - β (TGF - β ) have all been reported in the disorder. There is also one report that patients lacking the class II HLA antigen, DR53, may be more susceptible to thrombotic microan- giopathy [87] . Acquired idiopathic TTP has been associated occasionally with diseases characterized by autoimmune or other types of abnormal immune responses, including systemic lupus erythromatosus (SLE) [88] , autoimmune “ idiopathic ” thrombocytopenic purpura (ITP), [89] and the acquired immunodefi ciency syndrome (AIDS) [90 – 92] . Treatment The demonstration by Byrnes and Khurana in 1977 [93] that TTP relapses could be prevented or reversed by the infusion of fresh frozen plasma or cryosupernatant (plasma depleted of VWF - rich cryoprecipitate, fi brinogen, fi bronectin and IgM) was followed in 1985 by the observation that the processing of ULVWF multimers was restored in patients with familial, chronic relapsing TTP by transfusing fresh frozen plasma, cryosupernatant [40,94] or (in 1994) solvent/detergent - treated plasma [10] . These plasma prod- ucts contain functionally active ADAMTS - 13, and are effective alone (in quantities varying from one to several units), without the need for concurrent plasmapheresis [41,42] , in patients with familial TTP who produce inadequate quantities or functionally defective forms of ADAMTS - 13 (Table 32.3 ) [7,8,41,42,69] . Chapter 32 414 in order to detect incipient relapse. If TTP does recur, the same treatment program (i.e. glucocorticoids and plasma exchanges) that has previously induced remission should be repeated. In some adult patients with acquired idiopathic TTP who turn out to have recurrent episodes, many will have their fi rst recur- rence during the year following their initial episode [25] . In others, episodes do not recur for months to years after an initial episode. A small study of a few patients suggests that frequent relapses may be controlled by splenectomy [105] . In patients who achieve only a partial response, or worsen during therapy, plasma exchanges should be continued for a period of a few to many additional days in an effort to achieve a complete remission. In these patients, concomitant heparin - asso- ciated thrombocytopenia (HIT) or bacterial infection (e.g. from the plasma exchange catheter) should be suspected. HIT is espe- cially likely if platelets begin to decrease without a concomitant increase in the LDH values that have been decreasing progres- sively toward normal during therapy. In the latter situation, all exposure of the patient to heparin should be eliminated (includ- ing via keep - open intravenous lines or indwelling catheters, during dialysis, or on the tips of Swan – Ganz catheters). It is not known if any additional treatment for HIT, other than heparin removal, is required (e.g. hirudin or argatroban) in patients who are also undergoing plasma exchange for TTP. In the absence of evidence to the contrary, the addition or hirudin or argatroban during therapy for TTP is probably too dangerous. First - line treatment does not work in some patients with acquired idiopathic TTP episodes. Other forms of therapy can be added if plasma exchanges with FFP or cryosupernatant, gluco- corticoids, and rituximab are unsuccessful or incompletely suc- cessful. (Table 32.3 ). These other options include: addition of vincristine [111] , which depolymerizes platelet microtubules and may alter the availability of GPIb - IX - V or GPIIb/IIIa receptors for VWF on platelet surfaces; splenectomy [107] ; and addition of other immunosuppressive agents in an attempt to suppress production of ADAMTS - 13 autoantibodies (e.g. azathioprine [Imuran] [40] , cyclophasphamide [Cytoxan] [103] , or even cyclosporine [104] . Aspirin may exacerbate hemorrhagic compli- cations in these severely thrombocytopenic patients [112] . If the differential diagnosis in an adult patient includes TTP as a serious possibility, then plasma infusion/exchange should com- mence immediately and be continued until the precise diagnosis is clarifi ed. Possible f uture t reatment The sequence of the 190 000 - Da ADAMTS - 13 has been deter- mined, and the enzyme has been partially purifi ed from normal human plasma fractions [43,46,47] . Recombinant, active ADAMTS - 13 has also been prepared [113] , and may soon be produced in therapeutic quantities using insect, mammalian or bacterial cells. As a consequence, purifi ed or recombinant ADAMTS - 13 may soon be developed for therapeutic use in TTP. It may also be possible to produce active, truncated forms of recombinant ADAMTS - 13 that have less binding affi nity for autoantibodies may be suppressed by high - dose glucocorticoids [96] , 4 – 8 weekly doses of rituximab (monoclonal antibody against CD20 on B - lymphocytes) [99 – 102] rituximab combined with cyclophosphamide [25,103] , (possibly) cyclosporine [31,104] , or (most radically) splenectomy to remove a major organ comprised of immunologic cells (Table 32.3 ) [105 – 107] . Recovery from TTP is not usually associated with persistent, overt organ damage [95,96] ; however, some compromise of cog- nitive function may be detectable subsequently by careful testing [25] . Almost all TTP recurrences can be recognized quickly by blood counts/smears and LDH measurements. If a patient with a TTP episode is taking either ticlopidine or clopidogrel, or any other suspicious drug (e.g. mitomycin, cyclosporin, quinine), then this medicine should be stopped immediately. Although adult patients have recovered from TTP episodes without receiving glucocorticoids, in one large series a subset of TTP patients recovered in association with glucocorticoid therapy alone [96] . On the basis of this study by Bell and colleagues [96] , it is probably prudent to institute glucocorticoid therapy – in association with plasma exchange – in all adult patients with initial or recurrent TTP episodes, unless there is a strong contra- indication. The usefulness of glucocorticoids may refl ect the pro- posed autoimmune pathogenesis in many adult patients (e.g. glucocorticoids may suppress the production of autoantibodies against ADAMTS - 13). Bell and coworkers [96] administered prednisolone intravenously immediately following diagnosis in a dosage of about 200 mg/day, and continued it until the patient recovered. Depending on the hemoglobin level and intensity of hemolysis, red blood cell transfusions may be required. Transfusion of plate- lets is likely to be necessary if the platelet count is very low and (i) bleeding (e.g. GI hemorrhage) is a primary problem; (ii) serious bleeding is anticipated in association with an operative or invasive diagnostic procedure); or (iii) intracranial bleeding is demonstrated by computed tomography or magnetic resonance imaging. Otherwise, it may be better to withhold platelet transfu- sions because they have been temporally associated too frequently with exacerbation of the microcirculatory thrombotic process in the central nervous system [35,108] . The study by Bell, et al. also suggests that plasma exchange should be continued for more than 3 days [96] after patients attain complete remission (i.e. a normal neurologic status, a platelet count of 150 000 – 200 000/mL, a rising hemoglobin value, and a normal serum LDH level) in order to prevent incomplete response with rapid relapse. This is more aggressive than recommenda- tions by blood bank organizations [109] . Plasma exchange should then be stopped, and the glucocorticoid dosage tapered and dis- continued over a period of several weeks. Schistocytes in declin- ing numbers often persist for many days on peripheral blood fi lms, and so cannot be used as a reliable marker for remission [110] . Either tapered or intermittent plasma exchanges over days or weeks has not been demonstrated to provide additional benefi t in most patients. Platelet counts should be monitored regularly Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP 415 Exogenous estrogen should especially be avoided in a woman who has already had an episode of TTP during the estrogen “ fl ood ” (and ADAMTS - 13 decline) of pregnancy. Option 1 is safer, and defi nitely preferable, if the woman had a complicated therapeutic course during a previous TTP episode (e.g. a pro- longed number of plasma exchange procedures required for remission; hypotensive allergic reaction to plasma components [114,115] ; venous access infection; HITT; or any other life - threatening condition associated with therapy). O p t i o n 2 If the patient who has a previous episode of TTP becomes preg- nant (especially if the previous episode was provoked by preg- nancy), then blood counts/smear and serum LDH level should be determined at baseline, about every other week through the second trimester, and every week thereafter. It would also be helpful to obtain plasma ADAMTS - 13 values at baseline, about monthly through the second trimester, and weekly thereafter. Rapid and reliable laboratory testing and turnaround are, however, currently unavailable generally. (This may change soon.) Access to the services of a major medical center also is prudent. If platelets progressively fall, schistocytes appear, LDH increases, or ADAMTS - 13 values drop toward 10% of normal, plasma infusion or exchange (especially in the presence a detect- able ADAMTS - 13 inhibitor) should commence. The baby should be delivered as soon as possible using induction via the vaginal route or by Caesarean section, depending on fetal age and mater- nal condition. Other t hrombotic m icroangiopathies Some patients develop the characteristic clinical manifestations of thrombotic microangiopathy without either overt associated conditions or plasma ADAMTS - 13 defi ciency (at least as mea- sured by techniques currently available) [76,80,81,116,117] . The etiology of the disorder in this subgroup of patients, who have a higher mortality rate than patients with severe ADAMTS - 13 defi ciency, is unknown. In some of these patients, any possible relationship with ADAMTS - 13 defi ciency is clouded by the transfusion of normal blood products containing ADAMTS - 13 before the testing of patient plasma for enzyme activity [25] . Neither bone marrow/stem cell transplantation - associated thrombotic microangiopathy nor diarrhea - associated HUS (caused by Shiga toxin - producing enterohemorrhagic E. coli) is usually associated with an absence or severely reduced level of plasma ADAMTS - 13 activity [12,41,80,118,119] . The explana- tion for VWF abnormalities in the plasma of some chemother- apy/transplant - associated thrombotic microangiopathy patients [15] is not known. Differential d iagnosis The initial diagnostic algorithm should include a review of the blood counts and peripheral blood smear, and ordering of additional laboratory studies (LDH, creatinine, prothrombin time and activated partial thromboplastin time, D - dimer and ADAMTS - 13 autoantibodies. This type of ADAMTS - 13 might be useful in the treatment of acquired idiopathic TTP [53] . Specifi c o bstetric i ssues The plasma levels of VWF increase throughout normal preg- nancy, probably in response to estrogen. Concurrently, plasma ADAMTS - 13 levels steadily decline, possibly because of compen- satory attachment of plasma ADAMTS - 13 to the increased secre- tion ULVWF strings by estrogen - stimulated endothelial cells. It is anticipated, therefore, that pregnancy is likely to provoke epi- sodes of TTP in women who have congenital defects in ADAMTS - 13 production, function or survival. Occasionally, the initial TTP episode may occur during a fi rst pregnancy in these susceptible women with familial defects of ADAMTS - 13. Recurrences of TTP are likely during subsequent pregnancies in familial TTP. Regular infusions of FFP (containing ADAMTS - 13) are probably neces- sary to prevent relapses. More commonly, TTP episodes during pregnancy (usually, but not inevitably, around the time of delivery) may be caused by maternal production of autoantibodies against ADAMTS - 13. This escape from immune regulatory control of a specifi c auto- antibody against ADAMTS - 13 may be an uncommon and anom- alous consequence of the immune alterations associated with pregnancy. Only a small number of patients with apparently acquired TTP episodes during pregnancy have had plasma ADAMTS - 13 activity/inhibitor titers determined. In several, ADAMTS - 13 was severely reduced or absent and, in a few, inhibi- tors (presumably autoantibodies) were detectable using the imperfect testing systems currently in use. Fortunately, infants delivered successfully from mothers with pregnancy - related, presumably ADAMTS - 13 autoantibody - mediated, TTP usually do not have the disorder. This indicates that maternal ADAMTS - 13 autoantibodies do not cross the pla- centa into the fetal circulation in suffi cient quantities to cause neonatal TTP. The risk of a recurrent TTP episode during a subsequent preg- nancy after an episode of acquired idiopathic (ADAMTS - 13 auto- antibody) TTP, either “ out of the blue ” or during a previous pregnancy, varies widely in the modest number of individuals reported in several studies [24 – 26] . It is not possible on the basis of the observations available to make decisions with a high level of confi dence on the danger of TTP recurrence during a subse- quent pregnancy in women who have previously had episodes of acquired idiopathic TTP. The following are management sugges- tions to consider until the matter is resolved with additional clinical and laboratory observations. O p t i o n 1 Most women have a progressive decline in plasma ADAMTS - 13 level as pregnancy proceeds; consequently, a subsequent preg- nancy after a previous TTP episode (especially an episode pro- voked by pregnancy) is too dangerous and should be discouraged. Estrogen - containing birth control pills should also be avoided because these promote ULVWF secretion by endothelial cells. Chapter 32 416 This relatively common disorder is characterized by obstruction of the glomerular microvasculature by platelet – fi brin thrombi, acute renal failure, thrombocytopenia, intravascular hemolytic anemia, elevated plasma VWF antigen, and plasma levels of ADAMTS - 13 activity that are within a broad normal range. This latter fi nding may partially explain the poor response of these patients to plasma infusion or exchange [7,12,41] . It was recently demonstrated [126] that Stx - 1 and Stx - 2 stimu- late the rapid and profuse secretion of unusually large ULVWF multimeric strings from human endothelial cells, including glo- merular microvascular endothelial cells. Perfused normal human platelets immediately adhere to the secreted ULVWF multimeric strings, and the rate of ULVWF – platelet string cleavage by ADAMTS - 13 is delayed in the presence of Stx - 1 or Stx - 2. These studies suggest that Stx - induced formation of ULVWF strings, along with impairment of ULVWF – platelet string cleavage by ADAMTS - 13, explain the initial platelet adhesion atop Stx - stimulated glomerular endothelial cells in diarrhea - associated HUS. The fi ndings may explain glomerular microvascular occlusion and acute renal failure, associated with consumptive thrombocytopenia, in diarrhea - associated HUS [126] . Recurrent episodes are common in familial TTP. Truly recur- rent TTP episodes (i.e. not a single protracted episode with brief intervening periods of incomplete remission) [96] occur in about one - third of acquired idiopathic TTP patients. In contrast, diar- rhea - associated HUS usually occurs as a single episode. Some patients, however, have a familial and recurrent type of the disease. In these latter patients (often children), the level of the plasma complement control protein, factor H, may be abnor- mally low. The result is excessive activation of complement com- ponent 3 (C3) whenever the alternative complement pathway is stimulated [127,128] . A similar clinical syndrome results from defi ciency in another alternative complement pathway C3 control substance, membrane cofactor protein (MCP) [127,128] , or from defi ciency of C3b - cleaving protease (C3 inactivator, or factor I) [129] . In adults, a thrombotic microangiopathy that clinically more often resembles HUS than TTP may follow (sometimes after weeks to months) the administration of mitomycin, cyclosporin, bone marrow or solid organ transplantation, total - body irra- diation, gemcitabine or multiple chemotherapeutic agents [20,130,131] . More recent exposure to quinine also induces a similar syndrome. Plasma ADAMTS - 13 levels are within a broad normal range, and the pathophysiology of these entities is cur- rently unknown [7,119] . If excessive microvascular platelet adhesion/aggregation is sys- temic and extensive, and especially if the central nervous system is involved, the disorder is usually called “ TTP. ” If platelet adhe- sion/aggregation (and secondary fi brin formation) predomi- nantly involves the kidneys, the patient is considered to have “ HUS ” . Severe renal involvement in a “ TTP ” patient, or extrare- nal manifestations in a patient with “ HUS, ” can cloud clinical boundaries between the two syndromes. This situation will persist until there are rapid, trustworthy and accessible clinical labora- fi brinogen levels, and direct Coombs ’ test). The constellation of thrombocytopenia, hemolysis with schistocytosis, and LDH ele- vation also occurs (to an extent that is usually less extreme than in TTP) in HUS, disseminated intravascular coagulation (DIC), pre - eclampsia/eclampsia, the HELLP syndrome (pre - eclampsia - associated hemolytic anemia with elevated liver enzymes and low platelets), malignant hypertension, severe vasculitis, scleroderma with associated hypertension and renal failure, Evans ’ syndrome (concurrent autoantibody - mediated thrombocytopenia and hemolysis with positive direct Coombs ’ test), malfunctioning prosthetic cardiac valve, and, occasionally, after cocaine use [7,120] . Heparin - induced thrombocytopenia/thrombosis (HITT), which causes progressive thrombocytopenia and throm- bosis, is not usually accompanied by schistocytes. Among all of the above entities, only familial and acquired idiopathic types of TTP are associated with absent or severely reduced plasma ADAMTS - 13 levels. Hemolytic – u remic s yndrome ( HUS ) Platelet adhesion/aggregations on uncleaved ULVWF multimeric strings in the microcirculation in TTP produce fl uctuating isch- emia or infarction in various organs, including the brain in 50 – 71% of episodes [95,96] . In the closely related hemolytic – uremic syndrome (HUS), initially reported by Gasser and colleagues in 1955 [121] , the ischemia is predominantly renal as a consequence of platelet adhesion/aggregation and fi brin polymer formation atop glomerular endothelial cells. Thrombocytopenia, erythro- cyte fragmentation, and increased serum levels of LDH are often less extreme in HUS. However, the variability of organ dysfunc- tion in TTP (including minor to modest renal abnormalities in 50 – 75% of episodes) [95] and the extrarenal manifestations that may complicate HUS can make the two syndromes diffi cult to distinguish [7,57,95,96,122] . Furthermore, clinical presentations resembling either TTP or HUS are sometimes associated with similar underlying conditions (e.g. transplantation, chemother- apy/total - body irradiation). Clinical f eatures, l aboratory fi ndings, c auses and p athophysiology HUS is a triad of thrombocytopenia, acute renal failure, and intravascular hemolytic anemia with schistocytosis and elevated serum LDH. Renal dysfunction is severe in HUS, in contrast to most cases of TTP, and often requires dialysis. Oliguria, anuria, chronic renal failure, and hypertension may complicate HUS, whereas this is uncommon in patients who recover from episodes of TTP. Although the microvascular thrombi in HUS are usually predominantly renal, other organs are sometimes involved [7,122,123] . Especially in children, HUS is frequently preceded by hemorrhagic enterocolitis caused by cytotoxin - producing serotypes of Escherichia coli (e.g. O157:H7) or Shigella species [7,122,124,125] . Shiga toxin (Stx) - 1 and Stx - 2 produced by enterohemorrhagic E. coli usually cause diarrhea - associated HUS. Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP 417 Whether or not either the factor V Leiden or the prothrombin 20210 gene mutations is a risk factor for HELLP is controversial [145 – 147] . Most (90%) HELLP patients have malaise and right upper quadrant or epigastric pain; 45 – 86% have nausea or vomiting; 55 – 67% have edema; 31 – 50% have headache; and a few report visual changes. Fever is atypical. Hypertension is found in 85% [140] . Laboratory f eatures Schistocytes, consistent with microangiopathic hemolytic anemia, are seen on the peripheral blood fi lms of 54 – 86% of patients [140] . Reticulocytosis can be present. Absent haptoglobin levels indicate intravascular hemolysis [148,149] . Haptoglobin often returns to normal within 24 – 48 hours postpartum [149] . The serum LDH level is increased considerably above normal. The ratio of LDH 5 (LDH isoenzyme found specifi cally in the liver) to total LDH has been reported to be elevated in proportion to the severity of pre - eclampsia [150] . The elevated LDH value is, therefore, more likely due to liver damage than intravascular hemolysis [149] . Serum levels of aspartic acid transaminase (AST) and alanine transaminase (ALT) can be increased by 100 - fold; in contrast, elevations of alkaline phosphatase and total bili- rubin are usually less extreme. In most patients, liver enzymes return to baseline values within 3 – 5 days postpartum [140] The severity of thrombocytopenia has been utilized to predict maternal morbidity and mortality, rapidity of postpartum recov- ery, risk of disease recurrence, perinatal outcome, and the need for plasmapheresis. In this “ Mississippi triple class system, ” patients with platelet counts below 50 000/ µ L are “ class 1 ” (13% incidence of bleeding); those with platelets of 50 000 – 100 000/ µ L are “ class 2 ” (8% incidence of bleeding); and those with platelets over 100 000/ µ L are “ class 3 ” (no increased bleeding) [142,143] . Patients with “ class 1 ” HELLP syndrome have the highest inci- dence of perinatal morbidity and mortality, and the most pro- tracted recovery postpartum [143] . Thiagarajah et al. [151] also found a direct correlation between the severity of thrombocyto- penia and liver enzyme abnormalities; however, this association was not observed when the underlying hepatic histopathologic abnormalities were reviewed [152] . Abundant megakaryocytes are found bone by bone marrow aspiration/biopsy, consistent with a consumptive thrombocyto- penia (platelet life span reduced from ∼ 10 to 3 – 5 days [143] ). The platelet count nadir usually occurs 23 – 29 hours postpartum, with subsequent normalization within 6 – 11 days [142,143] . The prothrombin time (PT) is usually within normal limits, and the activated partial thromboplastin time (APTT) can be either normal or prolonged. Although low fi brinogen levels are inconsistently found, other indicators of increased coagulation and secondary fi brinolysis may be positive. These include decreased protein C and antithrombin III (AT III) levels, and increased D - dimer and thrombin - ATIII values [153] . In some patients, hepatic ultrasonography reveals large, irregu- lar, well - demarcated areas of increased echogenicity [154] . Biopsy tory tests available for plasma ADAMTS - 13 activity. Furlan and colleagues initially reported in 1998 that patients diagnosed with TTP usually have little or no plasma ADAMTS - 13 activity, in contrast to the normal (or nearly normal) levels in patients con- sidered to have acquired idiopathic HUS [12,65,66] . This may eventually provide the laboratory basis for more rapid and precise differentiation of the two entities. Treatment Neither plasma infusion nor exchange is consistently useful in Shiga toxin - induced HUS [7] . Discontinuation of any putative disease - inducing drug should occur immediately. Patients in the “ pathogenesis - unknown ” category of thrombotic microangiopa- thies often also respond poorly to plasma exchange [7,20] . It has been demonstrated recently, however, that some of these latter patients may improve in association with exchange [76] . It is, therefore, appropriate to commence daily plasma exchange pro- cedures and continue for a suffi cient period to determine effectiveness. Several patients with HUS - like thrombotic microangiopathy following solid organ transplantation have been reported to respond to plasma exchange plus intravenous IgG [132,133] . Plasma adsorption over staphylococcal protein A columns was reported in one 1986 study to be useful in thrombotic microan- giopathy associated with mitomycin C exposure [134] . HELLP s yndrome The constellation of severe eclampsia, hemolysis and thrombocy- topenia was initially described by Stahnke in 1922 [135] . Pritchard et al. [136] subsequently described three other cases and sug- gested that an immunologic process might account for both the pre - eclampsia/eclampsia and the hematologic abnormalities. Although initially known as edema – proteinuria – hypertension gestosis type B [137] , the more enduring “ HELLP syndrome ” ( h emolysis, e levated l iver enzymes in serum, and l ow p latelets) was applied to this life - threatening pre - eclampsia/eclampsia complication by Weinstein in 1982 [138] . Clinical f eatures HELLP syndrome occurs in approximately 5 per 1000 pregnan- cies [139] , in 4 – 12% of pregnancies complicated by pre - eclamp- sia, and in 30 – 50% of pregnancies complicated by eclampsia. About 15% of women ultimately diagnosed with HELLP syn- drome do not have either hypertension or proteinuria [140] . Two - thirds of HELLP diagnoses are made antepartum, frequently between 27 and 37 weeks, and more often in white, multiparous women over 34 years of age. HELLP is diagnosed in the remaining third within hours to 6 days following delivery (the majority within 48 hours [141 – 143] ). Although the homozygous cytidine to thymidine polymorphism at position 677 of the methylenetet- rahydrofolate reductase gene may be a modest risk factor for pre - eclampsia, this is not true for HELLP syndrome [144] . Chapter 32 418 of fl uids and electrolytes, transfusion of red cells and/or platelets, as needed, possible stimulation of fetal lung maturation with betamethasone if less than 34 weeks and delivery is to be delayed, and consideration of rapid delivery [143] . Indications for imme- diate delivery include maternal or fetal distress, worsening symp- toms and signs of HELLP syndrome, and under most circumstances a gestational age of greater than 32 weeks [140] . Cesarean section under general anesthesia is used in 60 – 97% of cases; however, induction of labor and vaginal delivery is a consideration if the maternal and fetal condition are favorable. Whether or not post- partum curettage is helpful in lowering the mean arterial pressure and increasing urinary output and platelet count is not resolved [143,160] . Adjunctive antepartum and postpartum therapy for HELLP with dexamethasone and plasma exchange have been reported [142,161,162] . Dexamethasone (10 mg intravenously every 12 hours) is believed by some to increase urinary output and platelet count, decrease AST and LDH levels and decrease time to deliv- ery, and may reduce neonatal morbidity/mortality [142] , without affecting the rate of infection or maternal recovery postpartum. Those who support steroid use have recommended continued use for at least 2 days following delivery, in order to prevent a recur- rence of liver enzyme elevation (including LDH), thrombocyto- penia and oliguria [143] . Not all studies have been positive, however, and Fonseca et al. [161] reported no benefi t in the reso- lution of HELLP syndrome with dexamethasone in a prospective, double - blind, placebo - controlled, clinical trial in 132 women. The patients in the steroid group received 10 - mg doses of dexa- methasone intravenously every 12 hours until delivery and three additional doses after delivery. Puerperal women received three 10 - mg doses of dexamethasone after delivery. The same schedule was used in the placebo group. Although the main outcome vari- able was the duration of hospitalization, other parameters evalu- ated were time to recovery of laboratory and clinical parameters, as well as frequency of complications. The mean duration of hospitalization was not signifi cantly affected by the dexametha- sone treatment (6.5 vs 8.2 days; p = 0.37) and there were no signifi cant differences between the two groups in terms of the time to recovery of the platelet count (hazard ratio [HR] 1.2; 95% CI 0.8 – 1.8), lactate dehydrogenase (HR 0.9; 95% CI 0.5 – 1.5), aspartate aminotransferase (HR 0.6; 95% CI 0.4 – 1.1), or develop- ment of complications. These results were similar in both pregnant and puerperal women. Matchaba and Moodley [162] published a review on the subject in 2004 in the Cochrane Library. They reviewed fi ve studies (n = 170), of which three were ante- partum and two postpartum. In four of the studies patients were randomised to standard therapy or dexamethasone. One study compared dexamethasone with betamethasone. There were no signifi cant differences in the primary outcomes of maternal mor- tality and morbidity due to placental abruption, pulmonary edema, or liver hematoma and rupture. Analysis of the secondary maternal outcomes demonstrated a tendency to a greater platelet count increase over 48 hours, statistically signifi cantly shorter hospital stay (weighted mean difference (WMD) − 4.50 days; 95% samples may show periportal or focal necrosis, fi brin deposits in the sinusoids, and vascular microthrombi. As the disease pro- gresses, large areas of necrosis can coalesce and dissect into the liver capsule, producing subcapsular hematomas or hepatic rupture [139] . Causes and p athogenesis Trophoblastic invasion into the decidua during normal preg- nancy occurs at 10 – 12 days, and again at 16 – 22 weeks. These specialized placental epithelial cells replace the endothelium of uterine spiral arteries and intercalate within the arterial muscular tunica, thereby increasing vessel diameter (and decreasing resis- tance). As a result, the spiral arteries are remodeled into hybrid vessels composed of fetal and maternal cells with a high fl ow/low resistance design that is protective against the effects of vasocon- strictors circulating in the maternal bloodstream [155] . In a pre - eclamptic pregnancy, the second wave of trophoblastic invasion fails to penetrate the spiral arteries of the uterus completely, pos- sibly because of inadequate placental expression of syncytin - mediated cell fusion processes during placentogenesis [156] . As a consequence, the poorly perfused placenta may release factors that include soluble fms - like tyrosine kinase 1 (sFlt - 1), an anti - angiogenic protein that binds placental growth factor and vascu- lar endothelial growth factor (VEGF) and prevents their interaction with endothelial cell receptors. The result may be endothelial dysfunction [157] with increased vascular tone, alter- ation of prostacyclin/thromboxane ratios, and enhanced platelet adhesion/aggregation. Excessive thrombin generation may occur, and this potentiates further activation of the coagulation cascade, systemic platelet and fi brin polymer deposition in capillaries, additional platelet aggregation and thrombocytopenia, and mul- tiorgan microvascular obstruction. The microvascular obstruc- tion is the likely cause of the microangiopathic hemolytic anemia and the enzyme release from ischemic, injured or necrotic hepatic cells [139] . In one study [158] , all women with HELLP syndrome had modestly lower plasma levels of ADAMTS - 13 activity (median, 31% of normal) than healthy pregnant (71%) or non - pregnant women (101%). These lower plasma ADAMTS - 13 values, which are distinct from the absent or severely reduced plasma levels in many patients with TTP, normalized (to 115%) as the HELLP patients recovered. Inactivating autoantibodies against ADAMTS - 13 were not detected in HELLP plasma, in contrast to patients with acquired idiopathic TTP. The levels of VWF antigen in this HELLP study were higher than the (elevated) levels associated with normal pregnancy, perhaps because of endothelial cell injury or excessive stimulation in HELLP. ULVWF multimers have not been found to be circulating in HELLP plasma [158,159] , in contrast to the plasma of patients with congenital TTP (and sometimes acquired idiopathic TTP). Treatment Therapy for HELLP includes intravenous magnesium sulfate to prevent eclamptic seizures, control of hypertension, management . post- partum curettage is helpful in lowering the mean arterial pressure and increasing urinary output and platelet count is not resolved [ 143, 160] . Adjunctive antepartum and postpartum. reduced from ∼ 10 to 3 – 5 days [ 143] ). The platelet count nadir usually occurs 23 – 29 hours postpartum, with subsequent normalization within 6 – 11 days [142, 143] . The prothrombin time (PT). bleeding) [142, 143] . Patients with “ class 1 ” HELLP syndrome have the highest inci- dence of perinatal morbidity and mortality, and the most pro- tracted recovery postpartum [ 143] . Thiagarajah