adamts 13 yacht

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Adams 13 is a 43 ′ 1 ″ / 13.1 m monohull sailboat designed by Joe Adams and built by Adams Yachts and NSW Australia between 1978 and 2000.

Rig and Sails

Auxilary power, accomodations, calculations.

The theoretical maximum speed that a displacement hull can move efficiently through the water is determined by it's waterline length and displacement. It may be unable to reach this speed if the boat is underpowered or heavily loaded, though it may exceed this speed given enough power. Read more.

Classic hull speed formula:

Hull Speed = 1.34 x √LWL

Max Speed/Length ratio = 8.26 ÷ Displacement/Length ratio .311 Hull Speed = Max Speed/Length ratio x √LWL

Sail Area / Displacement Ratio

A measure of the power of the sails relative to the weight of the boat. The higher the number, the higher the performance, but the harder the boat will be to handle. This ratio is a "non-dimensional" value that facilitates comparisons between boats of different types and sizes. Read more.

SA/D = SA ÷ (D ÷ 64) 2/3

• SA : Sail area in square feet, derived by adding the mainsail area to 100% of the foretriangle area (the lateral area above the deck between the mast and the forestay).
• D : Displacement in pounds.

Ballast / Displacement Ratio

A measure of the stability of a boat's hull that suggests how well a monohull will stand up to its sails. The ballast displacement ratio indicates how much of the weight of a boat is placed for maximum stability against capsizing and is an indicator of stiffness and resistance to capsize.

Ballast / Displacement * 100

Displacement / Length Ratio

A measure of the weight of the boat relative to it's length at the waterline. The higher a boat’s D/L ratio, the more easily it will carry a load and the more comfortable its motion will be. The lower a boat's ratio is, the less power it takes to drive the boat to its nominal hull speed or beyond. Read more.

D/L = (D ÷ 2240) ÷ (0.01 x LWL)³

• D: Displacement of the boat in pounds.
• LWL: Waterline length in feet

Comfort Ratio

This ratio assess how quickly and abruptly a boat’s hull reacts to waves in a significant seaway, these being the elements of a boat’s motion most likely to cause seasickness. Read more.

Comfort ratio = D ÷ (.65 x (.7 LWL + .3 LOA) x Beam 1.33 )

• D: Displacement of the boat in pounds
• LOA: Length overall in feet
• Beam: Width of boat at the widest point in feet

Capsize Screening Formula

This formula attempts to indicate whether a given boat might be too wide and light to readily right itself after being overturned in extreme conditions. Read more.

CSV = Beam ÷ ³√(D / 64)

From BlueWaterBoats.org :

One of designer Joe Adams’ most popular, the Adams 13 is well known in Australia. It was introduced in 1978, which is surprising as the boat seems modern even by todays standards. Adams took quite an innovative approach with the Metre series of boats, with the Adams 13 it’s essentially a 36 foot yacht stretched to 43 feet to produce a narrow hull that’s roomier below deck and more slippery through the water. Best of all, the Adams 13 retains much of the affordability of a 36 footer.

The boat is versatile; she’s nimble enough for racing around the buoys, has had a long successful career as an offshore racer, and has also proven to be a competent, seakindly blue water cruising vessel. Most have centerboards, which when pulled up aids down wind performance and usefully draws barely over one metre for cruising into those shallow bays. Not surprisingly owners report the boat is easily handled and fun to sail.

The Adams 13 was penned around 1977-78 shortly after the introduction of her smaller sibling, the Adams 10 Metre. Designer Graham Radford, who was a partner in Adams Yacht Design for a decade during those years, tells us the Adams 10 was the first boat produced in the “Adams Metre” range. These were light displacement, narrow beamed performance cruising yachts.

When we asked about the design goals of the Adams 13 Radford commented:

“It was really just a small but long cruising boat. Not a big volume boat, it’s narrow, it’s long, it’s got the accommodation volume of a 36 footer but in 43 feet of length … The centerboard was to give it very shallow draft for cruising. That style of centerboard we used on quite a few designs from little boats right through to 56 footers. It’s proved very popular and has done a lot of sea miles.”

Interestingly the Adams 13 was a boat Joe Adams initially designed for himself, he invested a lot of time dialing in this particular design. The moulds were funded by a syndicate of five owners including Adams himself. Each put in one fifth of the cost and after the five boats were built the moulds were sold off and since then they have changed hands multiple times.

The very first boat was called Fanny Adams which was built for an owner in Sydney who did some offshore racing with her. Since then an estimated 80 boats have been built by various builders and we hear the last hull to have popped off the moulds was in 2002. The moulds are presently owned by Peter Rigby of Adams Yacht Sales, who are open for new orders.

No history on the Adams 13 would be complete without a mention that although designed as a cruising yacht, the boat has had a successful career as an offshore racer including many entries in the Sydney-Hobart race. She remains competitive to this day.

Configuration & Layout

One look at the Adams 13 and you can tell this is not your average blue water cruiser. Narrow and sleek to an extreme with a nearly straight sheerline, it flies in the face of conventional cruising yacht design circa late-1970s. Her displacement and beam measurements reads that of a regular 36 foot cruising yacht, yet her length is 43 feet overall with a long waterline of nearly 41 feet.

The boat was expressly designed for a couple to sail and see the world, the way Adams went about this goal was to stretch the boat to provide extra room below deck, while retaining the lighter displacement and associated rigging thereby keeping costs closer to that of the smaller boat. The payoff is obvious; speed.

Along the performance theme, the boat employs a fractional cutter rig boasting a healthy 1075 square feet of sail area. The rudder is transom-hung with tiller steering for simplicity and reliability. Below the waterline is a keel/centerboard arrangement which when pulled up enhances downwind performance by reducing wetted area and draws a shallow 1.04m of depth allowing close-in anchoring.

Of note is the mainsheet/traveller system which is located right in the middle of the cockpit and can get in the way of cruising activities; on some boats owners have relocated the sheeting control further forward to open up the cockpit area.

There is an Adams 13E variation of the boat better suited to the needs of offshore racing, the “E” representing “extended cockpit” with an open transom. The centerboard is gone in favour of a fixed keel and the rudder relocated under the hull behind a sturdy skeg with wheel steering.

Interiors vary a lot between boats, this is the case with most Adams boats. Many boats were bought as hull and decks and finished professionally by various boatbuilders or fitted out by their owners. The standard accommodation layout provides for four to six people with 5′ 11″ of headroom. The saloon is forward of the centerboard case and provides a cosy area removed from the working part of the accommodation. There are two large quarter berths aft which may be singles or doubles. The saloon can accommodate two extra in single berths if required and in the V-berth are two single berths or a double. A large toilet/shower compartment is enclosed alongside the centerboard case.

Construction

The hull is of fiberglass sandwich construction using an Airex foam core. The decks are in fiberglass using end-grain balsa coring, though some decks used Airex foam. The stub keel is made from solid GRP skins with moulded lead ballast, the structure is encapsulated in fiberglass and the structural floors are then fitted.

The Adams 13 is easily handled, rather nimble and owners report it as being fun to sail. The boat’s motion is comfortable and seakindly, and it is said crossing oceans in her can often be less effort than a 36 foot yacht. Not surprisingly with such a narrow hull and light displacement, the boat is easily driven. You’ll often find these boats fitted with incredibly small engines, some having 2 cylinder 20hp diesels or even smaller.

They are particularly fast off the breeze with their centerboard up, a useful strength given a decent amount of miles covered when offshore cruising is done off the wind. The tradeoff is the high center of gravity of the ballast in the stub keel, which makes the boat relatively tender which detracts from windward performance. The boat needs to be reefed early despite the large amount of sail area the boat can carry.

Though setup as a cutter rig, the favourite for long distance passage-making, when sailing inshore she is commonly sailed as a sloop with headsails of modest size. Her best point of sail is in a broad reach when most of the sail area can be used in to good effect without reefing.

Buyers Notes

As of 2010, the asking price of the Adams 13M in the used market is in the range of: $110k-$140k AUD.

New hull and deck kits are available from Adams Yacht Sales for $58k AUD.

Links, References and Further Reading

» A History of Graham Radford’s time at Adams Yacht Design on Radford’s official site.

Thanks goes out to Graham Radford of  Radford Yacht Design and Michele Pippen for their assistance in the research of this article.

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The Adams 13 is a 43.11ft cutter designed by Joe Adams and built in fiberglass between 1978 and 2000.

80 units have been built..

The Adams 13 is an ultralight sailboat which is a very high performer. It is very stable / stiff and has an excellent righting capability if capsized. It is best suited as a fast cruiser. The fuel capacity is originally small. There is a short water supply range.

Adams 13 for sale elsewhere on the web:

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Introduction

Biology of adamts13, assays of adamts13 activity, conclusions and future directions, the role of adamts13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis.

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Camila Masias , Spero R. Cataland; The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis. Blood 2018; 132 (9): 903–910. doi: https://doi.org/10.1182/blood-2018-02-791533

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ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP.

The term microangiopathic hemolytic anemia (MAHA) is used to describe the mechanical destruction of red blood cells that may occur in the setting of hemodynamic turbulence or in thrombotic microangiopathies (TMAs), as the red blood cells are sheared by microthrombi in the arterioles. It is the hallmark of diseases such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), but it can also be seen in many other acute illnesses, such as sepsis, malignant hypertension, and preeclampsia. These diseases may have similar clinical presentations yet very different treatments and prognoses. Whereas a majority of patients with immune-mediated TTP (iTTP) will respond to plasma exchange (PEX) and steroids, only 30% of patients with complement-mediated HUS (cm-HUS) will respond to PEX, and most will require complement-inhibition therapy with eculizumab. The treatment of other diseases presenting with TMA findings is directed toward treating the underlying illness. 1  

TTP can be distinguished from other causes of MAHA by the finding of severely deficient ADAMTS13, typically <10% of normal. 2   ADAMTS13 is a plasma protease responsible for the cleavage of von Willebrand factor (VWF), preventing the accumulation of ultra-large VWF (ULVWF) multimers that can spontaneously interact with platelets, leading to microvascular thrombosis.

The role of ADAMTS13 goes beyond TTP. Endothelial activation resulting from inflammation can induce the release of VWF into the circulation with subsequent ADAMTS13 consumption, leading to moderately decreased ADAMTS13 activity. This can be seen in other forms of TMA and thrombotic disorders, such as myocardial infarction and ischemic stroke. The ADAMTS13 protease has also been the focus of recent research toward the development of novel agents, 3-8   with exciting new potential therapeutic options for patients with TTP. In the same way, a better characterization of the function of ADAMTS13 in maintaining normal vascular homeostasis has opened the door for potential new treatments in patients with inflammatory and thrombotic disorders but only moderately decreased ADAMTS13.

This article will discuss the structure and function of ADAMTS13, its role in the pathophysiology of TMAs, and potential future directions and clinical utilities of ADAMTS13 activity testing in the diagnosis and treatment of TMAs and other thrombotic conditions ( Figure 1 ).

ADAMTS13 deficiency. ADAMTS13 deficiency is the cause of TTP but also has a significant role in the pathophysiology, diagnosis, and prognosis of other TMAs and thrombotic disorders, such as stroke and myocardial infarction.

ADAMTS13 has a structure similar to that of other members of the ADAMTS family, composed of 14 different domains: a metalloprotease, a disintegrin, a first thrombospondin type 1 repeat (TSP1), cys-rich, and spacer domains. The distal part of the protease contains 7 additional TSP1 repeats and 2 CUB domains. 9 , 10   Each domain has a different role in the function of ADAMTS13 activity, with the CUB and spacer domains being particularly important in TTP. Even though ADAMTS13 is released as an active enzyme, 11 , 12   it circulates in a closed conformation through the interaction between CUB and spacer domains. 13 , 14   When VWF binds to ADAMTS13, the protease changes its configuration and becomes activated. Roose et al 15   used antibodies that recognized cryptic epitopes in the spacer domain to further elucidate the conformational changes in the protease. Although ADAMTS13 was found to circulate in a folded conformation in all healthy donors and in 78% of patients in TTP remission, it was found to have an open conformation (defined as a conformation index of >0.5) in 92% of patients with acute TTP. Additional studies are needed to determine the role of these conformational changes of ADAMTS13 in the diagnosis and prognosis of TTP.

ADAMTS13 is synthesized primarily in the interstitial area of hepatic stellate cells, 10 , 16 , 17   but it is also produced in trace amounts in the endothelial cells, 11 , 18   megakaryocytes, platelets, 19 , 20   renal podocytes, and tubular epithelial cells. 21 , 22   Studies in rats and humans have shown that ADAMTS13 activity can drop 30% to 40% after a partial hepatectomy, suggesting that ADAMTS13 produced in other tissues has a small but important contribution to normal plasma protease levels. Endothelial-derived ADAMTS13 may cleave newly formed ULVWF multimers, contributing to the maintenance of a cell surface that is free of hyperadhesive VWF. 12 , 23   Although the amount of ADAMTS13 produced outside the liver is small, it may still be biologically important because of its role in thrombus formation, although more studies are needed to better understand this relationship.

ADAMTS13 has a plasma half-life of 2 to 3 days, 24   with 3% to 5% of ADAMTS13 circulating bound to VWF. 25   There are no data regarding the clearance of the protease, nor any known inhibitor of its function. Therefore, the regulation of ADAMTS13 is likely to be at the substrate level (VWF), with 3 factors known to regulate its activity: (1) fluid shear stress, found in the microcirculation, which allows VWF to unfold and expose its A2 domain for ADAMTS13 binding; (2) factor VIII, which enhances the ADAMTS13 proteolytic activity by affecting the A1A2A3 domain-domain interaction when ADAMTS13 binds VWF under shear forces 26 , 27   ; and (3) platelet glycoprotein 1bα (GP1bα), which increases ADAMTS13 function under static or shear conditions by exposing the VWF A2 domain when it binds to the A1 domain. 28   The main function of the ADAMTS13 protease is the binding and cleavage of cell-bound ULVWF strings at the Tyr1605-Met1606 bond. 29 , 30   Under shear stress, as seen in the microcirculation or after thrombus formation, VWF undergoes conformational changes that unfold its A2 domain, making the ADAMTS13 cleavage site accessible. 31-34  

There are several ADAMTS13 biomarker assays that are either available for routine clinical use or under study for their potential clinical applications. The most common types of these ADAMTS13 assays measure in vitro functional ADAMTS13 activity.

ADAMTS13 activity assays

Measuring ADAMTS13 activity has become increasingly important in the evaluation and treatment of patients with TTP. One of the primary limitations of ADAMTS13 activity assays remains the need for nonphysiologic assay conditions (guanidine hydrochloride to expose the VWF cleavage site, low potential of hydrogen and sodium chloride concentrations) to simulate the high shear forces important for in vivo ADAMTS13 function. This limitation has been overcome using a VWF substrate with the VWF cleavage site instead of the full-length VWF molecule.

There have been multiple assays developed in the past 20 years, with the FRETS-WWF73–based assay 35   being the most commonly used in clinical settings given the relative ease to perform it, although it is still primarily done in reference laboratories.

ADAMTS13 antigen assay

The levels of the ADAMTS13 antigen can be measured by an enzyme-linked immunosorbent assay (ELISA). Although this test is not yet part of routine testing for patients with TTP, Awan et al 36   recently showed that patients with the ADAMTS13 antigen at presentation in the lowest quartile (<1.5%) had a higher TTP-related mortality rate, compared with those with higher levels of the antigen, suggesting a prognostic value of the test.

ADAMTS13 autoantibody and inhibitor assays

Patients with iTTP will have an autoantibody that targets the spacer domain of the protease. 37   The detection of an acquired inhibitor is essential to differentiate iTTP from congenital TTP (cTTP). Most of the autoantibodies against ADAMTS13 are of the immunoglobulin G (IgG) isotype (with IgG4 being the most common, followed by IgG1), although IgM and IgA have also been reported. 38 , 39   However, quantifying the amount of anti-ADAMTS13 antibodies through an ELISA does not confirm the functional activity of the antibody. Although most of the autoantibodies will have an inhibitory function (which can be measured by a Bethesda-like assay), ∼10% to 25% of patients with iTTP have autoantibodies that do not neutralize the protease, but rather are thought to be involved in its in vivo clearance. 40 , 41   In the evaluation of patients with TTP, the use of the Bethesda-like assay to demonstrate inhibitory function is important to confirm the diagnosis of iTTP and exclude cTTP.

ADAMTS13-specific CICs

Anti-ADAMTS13 autoantibodies can circulate freely in plasma or bind to ADAMTS13, forming a complex 42-44   that can be detected by an ELISA. Circulating immune complexes (CICs) are found in patients with TTP, during acute episodes and in remission. Although the role of CICs in the pathophysiology of TTP is not entirely clear, Mancini et al 45   noted a higher risk of recurrence in those patients who had CICs detected during acute episodes of TTP.

Assays of ADAMTS13 in TTP

When a patient presents with thrombocytopenia and MAHA without an alternative clinical explanation, ADAMTS13 activity of <10% confirms the diagnosis of TTP. Additional studies to detect the presence of an inhibitor of the protease with a Bethesda-like assay, as described in “ADAMTS13 autoantibody and inhibitor assays,” will help to differentiate between iTTP or cTTP. If no inhibitor is detected, and the clinical picture is consistent with cTTP (first manifestation in childhood, more rapid initial recovery, persistently deficient ADAMTS13 activity over time with a full recovery of activity with plasma infusion), then an ADAMTS13 mutational analysis should be ordered to confirm the diagnosis of cTTP.

Once a patient with iTTP has achieved clinical response (platelet count >150 × 10 9 /L and normal lactate dehydrogenase, with stabilization or improvement of symptoms), 3 scenarios can occur 2   : (1) clinical remission (continuous clinical response after cessation of PEX, maintained for >30 days); (2) exacerbation, defined as a recurrent thrombocytopenia and the need to restart PEX within 30 days of the last PEX procedure, which can occur in 40% to 50% of cases 46   ; and (3) relapse, defined as a recurrence of TTP >30 days after the last PEX procedure (incidence of ∼30%-50%). 46-48   Interestingly, neither the normalization of ADAMTS13 activity nor the variability during remission has been incorporated into the clinical definitions of TTP.

Although there is no question regarding the diagnostic role of ADAMTS13 testing at the time of clinical presentation, 47 , 49-52   there are uncertainties regarding the role of these assays at different points of the disease ( Table 1 ).

Prediction of relapse using different ADAMTS13-related biomarkers at different points of disease activity

Ab, antibody; Ag, antigen.

ADAMTS13 activity during the acute episode

Wu et al 53   reported the prognostic value of ADAMTS13 activity when measured daily during PEX in 19 patients with iTTP who were severely deficient (<10%) at presentation. The first PEX did not significantly change the ADAMTS13 activity levels. Even after 3 PEX procedures, 14 of the 19 patients still had ADAMTS13 activity <10% (measured immediately before the next PEX procedure). After a week of PEX procedures, 12 of the 19 patients had not achieved ADAMTS13 activity >10%.

Compared with those who recovered their activity before day 7, these patients took a longer time to achieve a clinical response ( P = .001). There was also a trend toward more exacerbations in the group with more delayed recovery of ADAMTS13 activity in the first week, but the difference was not statistically significant. These data confirm that even in situations in which ADAMTS13 activity is not measured before initiating PEX, there is still a diagnostic role for the test, with a sensitivity of 89%, 83%, and 78% after days 1, 2, and 3 of PEX, respectively.

ADAMTS13 at clinical response of TTP

A retrospective study at out institution evaluated the role of ADAMTS13 activity measured at clinical response to predict exacerbations in 44 acute episodes from 26 patients with iTTP. 54   In this study, African American race and lower pretreatment ADAMTS13 activity were both associated with an increased risk for exacerbation.

ADAMTS13 activity measured in the first week after stopping PEX was significantly lower in those patients who experienced an exacerbation (1.2% vs 22.5%) compared with those who did not, but the difference was no longer significant after accounting for race as a covariable.

Two recent studies evaluating caplacizumab, a nanobody that binds to the A1 of VWF, preventing the interaction between platelets and VWF, also provide important information regarding the prognostic value of ADAMTS13 to predict exacerbation. In the TITAN study, 55   75 patients with a clinical diagnosis of iTTP were randomly assigned to receive caplacizumab or placebo daily with PEX and to continue 30 days after the last PEX. In this study, 11 patients (28%) experienced an exacerbation in the placebo arm, compared with 3 (8%) in the caplacizumab group, supporting the hypothesis that caplacizumab prevents exacerbations of iTTP. Importantly, ADAMTS13 activity was <10% at the time of clinical response in 13 of the 14 patients who experienced an exacerbation. In the follow-up phase 3 Hercules study, a similar decrease in exacerbations was seen in the caplacizumab arm compared with placebo (3% vs 28%), with the presumption that persistently severely deficient ADAMTS13 activity was a significant factor in the development of exacerbations. 56   In this study, physicians were encouraged (but not required) to continue caplacizumab until there was clear improvement and correction of the severe ADAMTS13 deficiency to avoid recurrences of TTP after stopping caplacizumab.

These data provide the rationale for the use of ADAMTS13 at the time of PEX discontinuation to identify those patients who may be more prone to exacerbations and would benefit from additional immune suppressive therapy.

The French Clinical and Biological Network on Adult TMA published its experience regarding the prognostic value of ADAMTS13 activity and anti-ADAMTS13 antibody characteristics (Ig isotype, titer, and inhibitory effect) in a cohort of 35 patients. 38   Samples were obtained within 7 days of achieving clinical response. Thirteen patients (41%) had undetectable activity at the time of clinical response. These patients had a higher relapse rate (38.5%) when compared with those who recovered their activity at clinical response (5%). A high IgG autoantibody level at clinical presentation was also associated with persistently deficient ADAMTS13 activity at clinical response.

Although presently the treatment of acute TTP is directed only at the correction of the thrombocytopenia and any end-organ injury present, these results suggest that weekly monitoring of ADAMTS13 activity after PEX is discontinued may be an equally important biomarker of treatment response, with the goal of correcting the severely deficient ADAMTS13 activity with immune suppressive therapy to prevent exacerbations and relapse of iTTP.

ADAMTS13 monitoring during remission

There are uncertainties surrounding the measurement of ADAMTS13 activity during remission, including how often should it be monitored, the level of ADAMTS13 activity that would prompt the use of preemptive rituximab or another immune suppressive agent, and the correlation of the known variability of ADAMTS13 activity during remission with relapse risk. Jin et al 57   found an association between lower ADAMTS13 activity measured in remission and an increased risk of relapse in 24 patients with iTTP followed with serial ADAMTS13 monitoring during remission for an average of 23 months. There was no association found between the risk of relapse and the ADAMTS13 IgG levels. Another study involving 109 patients with iTTP with samples obtained during remission (most commonly 1 sample per patient, at variable times after achieving clinical response; range, 1-96 months) found that ADAMTS13 activity was severely deficient in 32% of patients at remission. Of these 109 patients, 46 had a recurrence. The prevalence of severe ADAMTS13 deficiency was higher in patients with recurrent TTP (46% vs 22%; P = .01). The likelihood of recurrence associated with severe ADAMTS13 deficiency when adjusted in the multivariate analysis was statistically significant (odds ratio, 2.9; 95% confidence interval [CI], 1.3-6.8). Despite lower ADAMTS13 antigen levels in the relapse group (median, 36% vs 58%; P = .003), the odds ratio did not predict relapse. Finally, regarding the anti-ADAMTS13 antibody analysis, autoantibodies were present in 64% of patients in the relapse group, compared with 36% in the nonrelapse group. 58  

These studies and others ( Table 1 ) form the basis to consider prophylactic rituximab to prevent relapses in patients who are found to have severely deficient ADAMTS13 activity during remission. 59-61   However, there are also data from patients with iTTP and persistently deficient ADAMTS13 activity in remission who do not uniformly experience relapse, with some patients having an isolated ADAMTS13 activity <10% that improves spontaneously. 62   We recently calculated the sensitivity and specificity of ADAMTS13 activity measured during remission to predict relapses in the following 30 and 90 days. 63   The assays were obtained every 3 months in 39 patients (total of 557 samples). There was a significant variability in ADAMTS13 activity, with 145 (26%) of the samples showing severely deficient activity of <10%; however, only 11 of these were followed by a relapse in the subsequent 90 days. We estimated that the sensitivity and specificity of ADAMTS13 activity <10% to predict a relapse in the next 30 and 90 days were 40.74% and 74.72%, respectively (likelihood ratio, 1.61; CI, 1-2.6). When we used 20% as a threshold, the sensitivity and specificity were both 66% (likelihood ratio, 1.97; CI, 1.47-2.64).

In summary, although severely deficient ADAMTS13 activity in remission may be a risk factor for relapse, it does not mean a relapse will absolutely occur. For decisions regarding prophylactic treatment with rituximab, ADAMTS13 activity <20% may be a more useful threshold than ADAMTS13 <10%. Better models for a more accurate prediction of relapse, incorporating additional biomarkers, are needed. The most appropriate use of these ADAMTS13 activity data would be to have an informed discussion with patients to balance the risk of relapse with the risks of prophylactic rituximab therapy. Our approach to the use of ADAMTS13 testing and prophylactic rituximab therapy is shown in Figure 2 . We follow patients after their first acute TTP episode indefinitely, not only to try to prevent relapses, but also to monitor the long-term complications described in these patients. 64-66  

Approach to patient follow-up after initial diagnosis of iTTP. CBC, complete blood count; LDH, lactate dehydrogenase.

ADAMTS13 activity in other TMAs

Although severely deficient ADAMTS13 activity (<10%) is unique to TTP, there is ample evidence showing that ADAMTS13 is moderately decreased in other TMAs. Martin et al 67   reported moderately decreased ADAMTS13 activity in 30 patients with severe sepsis (43.2%; interquartile range, 32.7-67.0) when compared with 29 patients with organ failure resulting from other causes (67.8%; interquartile range, 57.4-87.9; P < .05) and 30 healthy participants (105.6%; interquartile range, 87.2-125.6; P < .001). A study in 53 patients with TMAs associated with different systemic illnesses, including sepsis, solid organ transplantation, malignancy, and autoimmune diseases, showed decreased ADAMTS13 activity (median activity, 33.5%; range, 16%-47%) when compared with control patients and healthy participants. 68   Similar findings have been reported in patients with malignant hypertension, in which the median ADAMTS13 activity was 64%. 69   Increased release of VWF in the setting of endothelial stimulation seen in these disorders is thought to be the cause of the lower ADAMTS13. 70   These studies and many others highlight the delicate balance between the ADAMTS13 protease and VWF to permit physiologic hemostasis while at the same time preventing pathological thrombosis. Although low ADAMTS13 activity is not the cause of TMAs other than TTP, it seems to have an important prognostic role.

ADAMTS13 in thrombotic disorders

Via its cleavage of VWF, ADAMTS13 is thought to have antithrombotic properties. It is no surprise then that the protease may also have a role in the pathophysiology of cardiovascular disease (CVD). In animal models, ADAMTS13 − / − mice showed significantly larger infarctions after middle cerebral artery occlusion compared with wild-type (WT) mice. 71   Fujioka et al 72   found similar results, noting progressively decreased regional cerebral blood flow in ADAMTS13 − / − mice compared with WT mice after reperfusion after an induced middle cerebral artery occlusion. VWF is released from Weibel-Palade bodies in endothelial cells during episodes of ischemia, making the function of ADAMTS13 even more important, not only before the event but also after reperfusion. Another animal model showed a significant reduction in microvascular length and area, as well as decreased perfusion, in ADAMTS13 − / − mice 14 days after stroke. ADAMTS13 − / − mice had significantly reduced endothelial proliferation 2 weeks after stroke, with decreasing neovascularization. They also had an 82% increase in blood-brain barrier permeability compared with WT mice. The mechanism involved in this process may be related to downregulation of angiopoietin-1 and galectin-3, as well as a decrease in phosphorylation of VEGFR-2 in ADAMTS13-deficient mice. 73   These studies noted abnormal findings in ADAMTS13 − / − mice, but mice that were also deficient in VWF behaved similarly to WT mice, implying that the role of ADAMTS13 in stroke is dependent on its action on VWF.

Although severely deficient ADAMTS13 activity in TTP may lead to microthrombi that can be clinically evident as seizures, focal neurologic deficits, and coma, a moderate reduction in ADAMTS13 activity has been found to be a risk factor for ischemic stroke and coronary occlusion. The most complete information in humans comes from the Rotterdam study, a population-based cohort study in which almost 6000 individuals had their ADAMTS13 activity measured at enrollment to evaluate the association between ADAMTS13 activity, VWF/Ag level, and stroke. Over a median follow-up of 10.7 years, 461 participants had a stroke, 306 of which were ischemic, and 315 individuals had a transient ischemic attack. Patients were divided into 4 quartiles based on their ADAMTS13 activity. Comparing the group in the lowest quartile (ADAMTS13 activity <80%) with those with the highest activity (>102.27%), the former had higher risk of ischemic stroke (absolute risk, 7.3% vs 5.3%), transient ischemic attack (absolute risk, 6.8% vs 4%), and all cerebrovascular events (absolute risk, 17.8% vs 9.3%). Moreover, adding ADAMTS13 to the traditional risk factors used to predict a stroke improved the performance of the model. The investigators also observed a 5.68% decrease in ADAMTS13 activity per 10-year increase in age and an 8.6% higher activity in women compared with men. Diabetes and smoking were also associated with decreased ADAMTS13 activity. These findings were all statistically significant in the population studied. 74   A case-control study measuring ADAMTS13 antigen and plasma VWF levels in 85 healthy volunteers, 104 patients with an acute ischemic stroke, and 112 patients with chronic cerebrovascular disease found that patients with an acute ischemic stroke had significantly lower levels of ADAMTS13 antigen than healthy volunteers (82.6% ± 21.0% vs 110.6% ± 26.9%; P < .0001). Patients with chronic cerebrovascular disease also had lower ADAMTS13 activity than healthy volunteers (99.6% ± 24.5%; P < .03), but not as low as those with an acute stroke ( P < .0001). Furthermore, a higher VWF/ADAMTS13 ratio was associated with stroke severity. 75  

Moderately decreased ADAMTS13 is seen not only in patients with neurovascular disorders but also in those with CVD. A study of 27 patients undergoing emergency cardiac catheterization for ST-elevation myocardial infarction showed moderately decreased ADAMTS13 activity (median, 75%). The study also showed significantly reduced ADAMTS13 activity in coronary blood compared with peripheral blood. 76   Another subset of the Rotterdam study evaluated the risk for coronary artery disease (CAD) based on ADAMTS13 activity. Of almost 6000 individuals followed for a median of 9.7 years, 456 had CAD; 156 of these cases occurred in the group with ADAMTS13 activity in the lowest quartile (mean, 70.5%), compared with only 85 cases in the group in the highest quartile of ADAMTS13 activity (mean,114.3%), 77 , 78   suggesting a 42% higher risk of developing CAD with moderately deficient ADAMTS13 activity. A follow-up study also reported an association with low ADAMTS13 activity and higher cardiovascular mortality (hazard ratio, 1.46; 95% CI, 1.09-1.96). 77   Taken together, these findings should be the basis for clinical trials that may lead to new prognostic tools and treatment options for patients with CAD and CVD.

In the evaluation of a patient with suspected TTP, severely deficient ADAMTS13 <10% will confirm the diagnosis of TTP and differentiate it from other forms of TMA. A better understanding of the role of ADAMTS13 TTP has led to insights regarding its role in CVD, as a regulator of thrombi formation and neovascularization through its action on VWF.

Recombinant ADAMTS13 has shown promising results in a phase 1 study of patients with cTTP in whom the drug was well tolerated, without ADAMTS13 antibody detection, and a good clinical response was seen. 3   Moreover, the drug has shown preclinical activity in iTTP via the neutralization of autoantibodies in vitro 8   and ADAMTS13 immune complex formation in animal models, 6 , 79   with reconstitution of ADAMTS13 activity. In thrombotic disorders, infusion of rADAMTS13 in animal models of ischemic stroke has been shown to reduce stroke volume, 71   increase endothelial cell proliferation and perfusion, and decrease the permeability of the blood-brain barrier. 73   A model using occlusive VWF-rich thrombi in the middle cerebral arteries of mice showed dissolution of the thrombi with rhADAMTS13 but not with tissue plasminogen activator. 80   These results suggest a role for rADAMTS13 beyond cTTP and comprise the rationale for future studies.

Contribution: C.M. and S.R.C. both wrote, edited, and reviewed the manuscript.

Conflict-of-interest disclosure: S.R.C. serves as a consultant to Ablynx and Shire Pharmaceuticals. The remaining author declares no competing financial interests.

Correspondence: Spero R. Cataland, Department of Hematology, Ohio State University, A361 Starling Loving Hall, 320 W. 10th Ave Columbus, OH 43210; e-mail: [email protected] .

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Bluewater Sailboat – Adams 13 Metre

The Bluewater Sailboat Adams 13 is one of Joe Adams’ most well-known designs, and it is highly known in Australia. Its 1978 debut is astonishing given how advanced the boat seems even by today’s standards.

With the Metre series of boats, Adams adopted a really novel technique; the Adams 13 is essentially a 36-foot yacht stretched to 43 feet in order to provide a narrow hull that is more spacious below deck and more nimble through the water. The Adams 13 is still largely affordable, which is the best part.

The sailboat is adaptable; she has a long and successful career as an offshore racer, is quick enough for racing around buoys, and has also shown to be a capable, sea-friendly blue water cruising yacht. The majority of them have centerboards, which, when raised, improve downwind performance and advantageously draw just a little bit more than one metre for navigating those narrow harbours. Owners claim that the boat is simple to manage and enjoyable to sail, which is no surprise.

• LOA: 13.14 m. (43′ 1.5″) – 13.5 m. (44′ 6″)
• LWL: 12.38 m. (40′ 7.5″)
• Beam: 3.1 m. (10′ 2″)
• Draft, centerboard up: 1.04 m. (3′ 4.25″)
• Draft, centerboard down: 2.67 m. (8′ 9″)
• Displacement: 6,560 kg. (14,460 lbs.)
• Ballast: 3,630 kg. (8000 lbs.)
• Sail Area: 99.82 sq. m. (1075 sq. ft.)
• Headroom: 1.80 m. (5′ 11″)
• Water: 300 l.**
• Fuel: 160 l.**
• Engine: Various from 13hp upwards
• Year Introduced: 1978
• Year Ended: 2000
• Designer: Joe Adams
• Builder: Adams Yachts, NSW Australia

Soon after the debut of her smaller sibling, the Adams 10 Metre, in 1977–1978, the Adams 13 was written. The Adams 10 was the first boat made in the “Adams Metre” range, according to designer Graham Radford, who spent ten years as a partner in Adams Yacht Design. These were performance cruising ships with light displacement and narrow beams.

The Adams 13’s design objectives are said to be a little, long cruise boat. Not a big volume boat, it is long, slender, and has the same amount of space as a 36-footer but is just 43 feet long. For cruising, the centerboard was supposed to give it an extremely shallow draught. From little boats to 56-footers, that sort of centerboard is used on many different designs. It has racked up a lot of sea miles and proven to be highly popular.

It’s interesting to note that Joe Adams spent a lot of time perfecting the design of the Adams 13, a boat he first built for himself. A syndicate of five proprietors, including Adams, paid for the molds. Each contributed one-fifth of the total cost, and after the five boats were constructed, the molds were sold off. Since that time, their ownership has changed several times.

The first vessel, Fanny Adams, was built for a Sydney-based owner who participated in some offshore racing with her. Since then, multiple builders have reportedly constructed 80 boats, with the latest hull to pop off the molds occurring in 2002. Adams Yacht Sales’ Peter Rigby currently owns the molds and is accepting new orders.

The fact that the Bluewater Sailboat Adams 13 has had a successful career as an offshore racer, including numerous entries in the Sydney-Hobart race while being built as a cruising yacht, must be mentioned in order for the history of the boat to be considered comprehensive. She is still competitive now.

The hull is made of sandwiched fiberglass with an Airex foam core. Some of the fiberglass decks used Airex foam, but most used end-grain balsa coring. The structure is encased in fiberglass, the structural floors are installed, and the stub keel is constructed from solid GRP skins with molded lead ballast.

Performance

The Adams 13 is simple to handle, and quite nimble, and its owners say it’s enjoyable to sail. It is stated that because of the sailboat’s smooth motion and sea-friendliness, crossing oceans in her frequently requires less work than in a 36-foot yacht. The boat is simple to drive, which makes sense given its tiny displacement and thin hull. These boats frequently have relatively tiny engines, some of which have just two cylinders and 20 horsepower (hp).

With their centerboard up, they are especially quick off the breeze, which is a strength considering the significant number of miles covered when offshore cruising off the wind. The boat is relatively fragile due to the high center of gravity of the ballast in the stub keel, which reduces windward performance. Despite the boat’s ability to carry a lot of sail area, the reef needs to be put in early.

Although designed as a cutter rig, preferred for long-distance passage-making, she is typically sailed as a sloop with moderate size headsails when sailing inshore. Her optimum point of sail is on a broad reach when she can effectively utilize the majority of the sail area without reefing.

Looking for a used sailboat for sale? Check out the Bluewater sailboat data and specs to make an informed decision. Ocean Wave Sail has data for over 10000+ boats that can help you select one to meet your sailing needs.

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STAT: < 24 hours (7 days a week)

Draw Tube: Blue Top

Sample Type: Citrated Plasma

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Adams 13 Boats For Sale in Australia

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Adams 13 Centre Board

Modified Adams 13m sail boat. Transom hung rudder. Sugar scoop added to stern. Deck ...

• 43' / 13.10m

New Adams 13.5 Hull And Deck (Assembled)

Adams 45ft yacht fibreglass hull and deck. Suit world cruising, live-aboard or racing. DIY ...

• 44' 7" / 13.60m
• AU $29,900 Huge price reduction - New & In Stock

Adams 13 Mast Head Cutter Rig

Adams 13 metre Dagger board with transom hung lifting rudder & tiller steering. ...

• AU $145,000 Now reduced

Immaculately presented Adams 13 Designed by Joe Adams as a cruiser racer originally from ...

• 44' / 13.40m
• 1985 approx
• AU $145,000 Or nearest offer

Adams 40 Off Grid Adventure Sailor

This Adams 40 has been set up for true off grid adventure sailing. With a steel hull and swing ...

• 40' / 12.19m
• 1976 approx
• AU $89,500 Or nearest offer

Adams 10 Cruising

Perfect for a first time yacht owner or for someone stepping up to a larger, faster yacht. ...

• 33' 0" / 10.06m
• 1983 approx
• AU $24,000 Negotiable

Adams 10 Modified

Adams 10's need very little introduction. They are a great allround weekend racing yacht. ...

• 32' 10" / 10.00m

Adams 12 This iconic yacht, one of Joe Adams best and built by Trewartha Brothers in ...

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Joe Adams 36 built in 1986 and designed by Joe Adams is now exclusively for sale through DBY ...

• 36' / 10.97m

Adams 40 Centre Cockpit

Vendor very motivated to sell. Inspections highly reccomended and offers encouraged. There ...

• 40' 0" / 12.20m

Adams 45 Cutter Sloop Centre Cockpit - A Capable, Safe & Strong Ocean Voyager

Gondwana is a Joe Adams designed 45ft centre cockpit cutter sloop. This solid cruising yacht ...

• 45' 0" / 13.72m
• AU $190,000

Very well maintained and upgraded, turn key, Racer/cruiser Performs in the Hamilton island ...

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Test Catalog

Test id : adams, adamts13 activity assay, plasma.

• Clinical & Interpretive
• Performance
• Fees & Codes
• Setup & Updates

Useful For Suggests clinical disorders or settings where the test may be helpful

Assisting with the diagnosis and monitoring of congenital, immune, or acquired thrombotic thrombocytopenic purpura

Method Name A short description of the method used to perform the test

Fluorescence Resonance Energy Transfer (FRET)

NY State Available Indicates the status of NY State approval and if the test is orderable for NY State clients.

Reporting name lists a shorter or abbreviated version of the published name for a test, aliases lists additional common names for a test, as an aid in searching.

Metalloprotease

Microangiopathy

Protease Activity Inhibitor for TTP

Thrombotic Microangiopathy

von Willebrand Factor Cleaving Protease

VWF protease activity and inhibitor

microangiopathic hemolytic anemia

Specimen Type Describes the specimen type validated for testing

Plasma Na Cit

Ordering Guidance

Consider ordering in patients with known diagnosis of congenital, immune, or acquired thrombotic thrombocytopenic purpura.

Specimen Required Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Patient Preparation: Fasting preferred

Collection Container/Tube : Light-blue top (3.2% sodium citrate)

Submission Container/Tube : Plastic vials

Specimen Volume : 2 mL in 2 plastic vials each containing 1 mL

Collection Instructions :

1. Specimen must be collected prior to replacement therapy.

2. For complete instructions, see Coagulation Guidelines for Specimen Handling and Processing .

3. Centrifuge, transfer all plasma into a plastic vial, and centrifuge plasma again.

4. Aliquot plasma (1 mL per aliquot) into 2 separate plastic vials, leaving 0.25 mL in the bottom of centrifuged vial.

5. Freeze plasma immediately (no longer than 4 hours after collection) at -20 degrees C or, ideally, below -40 degrees C.

Additional Information :

1. Double-centrifuged specimen is critical for accurate results as platelet contamination may cause spurious results.

2. Each coagulation assay requested should have its own vial.

Specimen Stability Information: Frozen 2 years

Special Instructions Library of PDFs including pertinent information and forms related to the test

• Coagulation Guidelines for Specimen Handling and Processing

If not ordering electronically, complete, print, and send a Renal Diagnostics Test Request (T830) with the specimen.

Specimen Minimum Volume Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

Reject due to identifies specimen types and conditions that may cause the specimen to be rejected.

Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Thrombotic thrombocytopenic purpura (TTP), a rare (estimated incidence of 3.7 cases per million) and potentially fatal thrombotic microangiopathy syndrome, is characterized by a pentad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia (intravascular hemolysis and presence of peripheral blood schistocytes), neurological symptoms, fever, and kidney dysfunction. A large majority of patients initially present with thrombocytopenia and peripheral blood evidence of microangiopathy and, in the absence of any other potential explanation for such findings, satisfy criteria for early initiation of plasma exchange, which is critical for patient survival. TTP may rarely be congenital (Upshaw-Shulman syndrome) but, far more commonly, is acquired. Acquired TTP may be considered primary or idiopathic (the most frequent type) or associated with distinctive clinical conditions (secondary TTP) such as medications, hematopoietic stem cell or solid organ transplantation, sepsis, and malignancy.

The isolation and characterization of an IgG autoantibody frequently found in patients with idiopathic TTP clarified the basis of this entity and led to the isolation and characterization of a metalloprotease called ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13 repeats), which is the target for the IgG autoantibody, leading to a functional deficiency of ADAMTS-13. ADAMTS-13 cleaves the ultra-high-molecular-weight multimers of von Willebrand factor (VWF) at the peptide bond Tyr1605-Met1606 to disrupt VWF-induced platelet aggregation. The IgG antibody prevents this cleavage and leads to TTP. Although the diagnosis of TTP may be confirmed with ADAMTS-13 activity and inhibition studies, the decision to initiate plasma exchange should not be delayed pending results of this assay.

ADAMTS13 activity results can have an impact on overall survival, ultimate clinical outcome, responsiveness to plasma exchange, and relapse are still controversial in recent literature. Therefore, clinical correlation is essential.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

> or =70%

Although not verified, the pediatric (<1 years old) reference range could be similar to or lower than that of adults.

Interpretation Provides information to assist in interpretation of the test results

Less than 10% ADAMTS-13 activity is highly indicative of thrombotic thrombocytopenic purpura (TTP) in an appropriate clinical setting.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This ADAMTS-13 activity assay is an in vitro assay using a synthetic substrate peptide in a static liquid environment. The measured ADAMTS-13 activity may not reflect the true in vivo biological ADAMTS-13 activity.

Not all patients with a clinical diagnosis of idiopathic thrombotic thrombocytopenic purpura (TTP) have a severe ADAMTS-13 deficiency. Conversely, patients with other non-TTP conditions may have a severe ADAMTS-13 deficiency (< or =10%). These conditions include hemolytic uremic syndrome, hematopoietic stem cell and solid organ transplantation, liver disease, disseminated intravascular coagulation, sepsis, pregnancy, and certain medication. Therefore, TTP remains a clinical diagnosis.

Interferences of the ADAMTS-13 activity assay include high levels of endogenous von Willebrand factor, hyperlipidemia, hyperbilirubinemia (bilirubin concentration >30 mg/dL), and cleavage by other proteases.

Samples collected in EDTA instead of 3.2% sodium citrate will result in artificially reduced ADAMTS-13 activity.

Recent plasma exchange or plasma transfusion may falsely normalize ADAMTS-13 levels, thus potentially masking the diagnosis of TTP.

The impact of ADAMTS-13 levels and presence of inhibitors on overall survival, ultimate clinical outcome, responsiveness to plasma exchange, and relapse are still controversial. Therefore, clinical correlation is recommended.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112(1):11-18. doi.org/10.1182/blood-2008-02-078170

2. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116(20):4060-4069. doi:10.1182/blood-2010-07-271445

3. Upshaw JD: Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med. 1978;298(24):1350-1352. doi:10.1056/NEJM197806152982407

4. Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ Program. 2018;2018(1):530-538. doi:10.1182/asheducation-2018.1.530

5. Mackie I, Mancini I, Muia J, et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of ADAMTS13. Int J Lab Hematol. 2020;42(6):685-696. doi:10.1111/ijlh.13295

Method Description Describes how the test is performed and provides a method-specific reference

The ADAMTS-13 activity is measured by a fluorescence resonance energy transfer-based assay using a synthetic fragment of von Willebrand factor as substrate. Cleavage of this small fragment by the ADAMTS-13 protease generates fluorescence that is directly proportionate to the quantification of ADAMTS-13 activity. (Package insert: ATS-13 ADAMTS13 Activity Assay 2.0. Immucor; 08/2023)

PDF Report Indicates whether the report includes an additional document with charts, images or other enriched information

Day(s) performed outlines the days the test is performed. this field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. some tests are listed as continuously performed, which means that assays are performed multiple times during the day..

Monday through Friday, Sunday

Report Available The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

Specimen retention time outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded, performing laboratory location indicates the location of the laboratory that performs the test, fees several factors determine the fee charged to perform a test. contact your u.s. or international regional manager for information about establishing a fee schedule or to learn more about resources to optimize test selection..

• Authorized users can sign in to Test Prices for detailed fee information.
• Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
• Prospective clients should contact their account representative. For assistance, contact Customer Service .

Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing. CPT codes are provided by the performing laboratory.

Loinc® information provides guidance in determining the logical observation identifiers names and codes (loinc) values for the order and results codes of this test. loinc values are provided by the performing laboratory..

Test Setup Resources

Setup files test setup information contains test file definition details to support order and result interfacing between mayo clinic laboratories and your laboratory information system..

Excel | PHP Pdf | CMS Pdf

Sample Reports Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports

• Research article
• Open access
• Published: 20 June 2024

Imbalance of the von Willebrand Factor — ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

• Max Braune 1   na1 ,
• Moritz Metelmann 2   na1 ,
• Jonathan de Fallois 3 ,
• Christian Pfrepper 4 ,
• Alonso Barrantes-Freer 1 ,
• Grit Gesine Ruth Hiller 5 ,
• Susette Unger 6 ,
• Evelyn Seelow 7 ,
• Jan Halbritter 3 , 7 &
• Johann Otto Pelz   ORCID: orcid.org/0000-0003-4391-2280 2  

Neurological Research and Practice volume  6 , Article number:  32 ( 2024 ) Cite this article

Metrics details

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1 . Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S.

vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls.

While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs ( p  < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 ( p  = 0.00056).

Conclusions

These findings point to an imbalance of the vWF – ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.

Introduction

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S, MIM 192,315) is an ultra-rare, autosomal-dominant small vessel disease [ 1 , 2 ]. Systemic features may start early from the age of 20 onwards with vascular retinopathy, and may further comprise Raynaud`s phenomenon, chronic kidney disease (CKD), liver disease, anemia, and gut disease [ 3 ]. Typically, cerebral involvement becomes clinically apparent in the fifth decade with cognitive deficits and is characterized in the magnetic resonance imaging (MRI) by progressive white matter lesions, long-term contrast enhancement, and long-term diffusion restrictions [ 3 , 4 ]. Although the genetic cause of RVCL-S, heterozygous loss-of-function mutations in the TREX1 gene (encoding the 3-prime repair exonuclease 1; MIM 606,609), was identified more than 15 years ago [ 5 ]. The underlying mechanisms for the putative endothelial dysfunction and prominent involvement of small vessels in RVCL-S are still unknown [ 3 ]. So far, there is no specific treatment; corticosteroids were most often used and temporarily reduced the cerebral vasogenic oedema but, overall, had no effect on the underlying lesions nor on clinical parameters [ 1 ].

Based on the in-depth characterization of two patients, this study aimed to further elucidate the etiology of the endotheliopathy that underlies RVCL-S. For this purpose, we integrated clinical and laboratory data, as well as extensive immunohistochemical examinations of the distribution of the von Willebrand Factor antigen (vWF-Ag) in the brain, as well as in other affected organs (case 1). Furthermore, the initial kidney biopsies of both patients were re-examined with focus on the distribution of the vWF-Ag.

The legal guardian of case 1 and case 2 himself gave informed consent to participate in the study and for publication of the study data in a medical journal.

Clinical characteristic and molecular genetics

At the age of 40, the male patient was diagnosed with a retinopathy that was attributed to arterial hypertension. Five years later, he underwent a kidney biopsy to further clarify a history of progressive CKD, liver disease, and positive anti-double-stranded DNA antibodies. The renal biopsy showed signs of a glomerular thrombotic microangiopathy (TMA) with microthrombi but no signs of a lupus nephritis. A complement gene panel diagnostics was unremarkable at the time. Within the next three years, the patient repeatedly presented in another stroke unit with ischemic strokes attributed to small vessel disease. Furthermore, because of anemia he underwent a colonoscopy that showed signs of chronic intestinal bleeding. In light of a family history of CKD, the patients father had died in his forties because of a kidney disease, and the microvascular involvement in several organ systems (brain, retina, kidney), a genetic disease was suspected. As a consequence, clinical exome sequencing revealed a heterozygous C-terminal frameshift mutation in TREX1 (NM_033629.6: c.703dup, p.(Val235Glyfs*6)). This variant is absent from population databases (gnomAD) and was previously reported in two independent patients with RVCL-S [ 1 , 5 ], deeming the variant definitely pathogenic according to the standardized criteria of the American College of Medical Genetics and Genomics (ACMG [ 6 ])

Eight years later, the 48-years old patient presented in our tertiary hospital with the suspicion of another ischemic stroke with encephalopathy and a facial paresis on the left side. Cerebral MRI showed a tumefactive lesion with a slightly space-occupying edema and, compared to previous cerebral MRI, long-term diffusion restrictions. Examination of the cerebrospinal fluid showed a slight protein elevation but no pleocytosis. Treatment with high-dose cortisone had no effect on the space-occupying edema. Because of thrombocytopenia at admission in combination with an encephalopathy and fever, ADAMTS-13 activity, concentration and antigen was measured. Table  1 presents an overview about vWF-Ag, ADAMTS-13, and C-reactive protein (CRP) over the course of the disease. Elevated levels of CRP would serve as an indicator for an acute phase reaction, which could influence the levels of vWF-Ag and ADAMTS-13. The patient’s clinical condition continuously deteriorated with repeated lower gastrointestinal bleedings that required transfusions of erythrocytes, severe thrombocytopenia, acute on chronic kidney failure that required dialysis, and repeated septicemia. The regular administration of fresh frozen plasma (FFP) during the last seven days did not result in an increase of thrombocyte count nor another clinical improvement. The patient finally deceased due to a septic shock.

The 23-years old male acutely presented with a hypertensive crisis, and a hitherto unknown proteinuric kidney disease. The kidney biopsy showed a glomerular TMA with microthrombi. Serum vWF-Ag presented slightly elevated, while ADAMTS-13 activity was in the lower normal range (Table  2 ). Moreover, he reported symptoms indicative for a Raynaud phenomenon, and two years earlier, an ischemic retinopathy had been diagnosed. Remarkably, another four family members were reported to suffer from CKD and retinopathy, three of which had died in their forties, prompting us to investigate genetic causes of familial CKD (Fig.  1 ). Again, clinical exome sequencing yielded a heterozygous in-frame deletion in TREX1 (NM_033629.6: c.868_930del, p.(Pro290_Ala310del)), which was found absent from population databases (gnomAD) and was previously reported in a patient with the recessive form of TREX1 -mediated disease, the so called Aicardi-Goutières syndrome (MIM 225,750; [ 7 ]). For these reasons, the variant was classified as likely pathogenic according to ACMG criteria [ 6 ].

Pedigree of case 2 with the most relevant symptoms of affected relatives. ESKD end-stage kidney disease

Immunohistochemistry

Autopsy was performed in Case 1 two days postmortem and samples of kidney, liver, and lung were taken following standard protocols. The brain was fixated in Formalin (4%) for two weeks and subsequently brain section was performed. Macroscopically, multiple subcortical lesions were identified in the frontal and temporal lobe. Samples underwent further histological processing. Histochemical and immunohistochemical stainings were performed according to standard protocols. Detailed information about the applied antibodies can be found in the supplement (Table  3 ). Distribution and intensity of immunohistochemical vWF-Ag staining was compared to brain tissue of four patients without a former ischemic stroke (C1 to C4) and to four patients with a subacute ischemic stroke (I1 to I4). Demographics, causes of death, and comorbidities of controls are shown in Table  4 in the supplement. Observers were blinded to the status of patients and to clinical data when evaluating staining intensity.

Methylome analysis

For methylome analysis in case 1, two subcortical brain regions from the temporal and frontal lobe with only slight lesions were chosen. Additionally, eight corresponding brain regions from controls without cerebral infarctions were analyzed. Detailed epidemiological information regarding age, sex, comorbidities, and cause of death are given in Table  5 in the supplement. Shortly, DNA was extracted and subsequently bisulfite conversion was performed. Samples were analyzed using Infinium™ Methylation EPIC v1.0. (850k) arrays according to the manufacturer’s instructions. Array data analysis was performed with the R programming environment (v.4.2.1), using the Chip Analysis Methylation Pipeline (ChAMP) r package [ 8 ]. Loading of the raw data and pre-processing was done with the minfi package [ 9 ]. Subsequently, probes with single nucleotide polymorphisms in the probe sequence were filtered out based on Zhou and colleagues [ 10 ]. Probes with a detection p-value above 0.01 and probes located on X and Y chromosome were removed from the analysis. Normalization and type-2 probe correction was performed based on beta mixture quantile dilation [ 11 ]. Calculating differentially methylated positions (DMP) is based on the limma package [ 12 , 13 ]. The Benjamini-Horchberg-procedure was used to correct for multiple testing and to control the false discovery rate.

In the macroscopic postmortem brain section multiple lesions were identified in the subcortical white matter (frontal left, basal ganglia right, frontotemporal, temporal), characterized by a softened texture of the brain parenchyma. Hemorrhagic lesions were not found. Histologically, these lesions showed multiple infarctions in the subcortical white matter, which were characterized by pseudocystic changes and invasion of macrophages, corresponding to subacute and chronic infarctions. The infarcted areas ranged from microinfarcts (diameter less than 0,5 cm) to large confluent necrotic areas (Fig.  2 A–C). Within the lesions and the perilesional regions multiple small vessels with thickened endothelium and perivascular lymphocytic infiltrations were identified (Fig.  2 B, D). Immunohistochemical analysis, using primary antibodies against the amyloid precursor protein (APP), revealed numerous axonal spheroids within infarcted areas (Fig.  2 C). Further, the inflammatory infiltrates consisted mostly of T-cells, which were positive for CD4 and CD8 (Fig.  2 E, F), while markers for other immune cells (CD20, CD15) were negative. Histological examination of the kidney and lung showed multiple thrombi (Fig.  2 G, I), while the liver showed micronodular liver cirrhosis (Fig.  2 H).

Isolated microinfarcts (asterisks, A ) and confluent necrotic infarctions with vessels with broadened basement membranes (arrows, B ) were identified in subcortical lesioned areas. Accumulation of APP (asterisks) confirms axonal damage by infarction ( C ). The pathological vessels are surrounded by small lymphocytic infiltrates ( D ) of CD4 ( E ) and CD8 positive ( F ) T-cells. Multiple thrombi (arrows) in the kidney ( G ) and lung ( H ) are shown. The liver shows small nodular liver cirrhosis ( I )

Analyzing the staining pattern for vWF-Ag, an increased accumulation of endothelial and intravascular vWF-Ag was observed in the autoptic sections of the brain and the kidney in the patient with RVCL-S (case 1, Figs.  3 A and B and 4 A and B). Controls with brain infarctions only demonstrated a slight increase in the staining for the vWF-Ag (Fig.  3 C–F). In autoptic controls without a brain or kidney pathology there were only faint stainings for vWF-Ag in cerebral and renal specimen (Figs.  3 G–J and 4 C–E).

Multiple small vessels with endothelial accumulation of vWF-Ag in the brain of patient 1 (P1) were identified ( A ,  B ). In infarcted areas of controls (exemplary shown I1-4, C - F ) and in brain slices of patients without histological evidence of infarction (exemplary shown C1-4, G - J ) staining for vWF-Ag was reduced compared to P1 ( B ,  C )

In the autopsy , the kidney of P1 shows multiple very small ( A ) and some larger ( B ) vessels with increased endothelial and intravascular staining for vWF-Ag compared to controls (C1-3) without known TREX1 mutation ( C - E )

In the former kidney biopsy from case 1, obtained four years before his death, no clearly increased vWF-Ag staining was observed (Fig.  5 A, C). In the kidney biopsy from case 2 only a slight staining occurred in some renal vessels, that still appeared to be in the normal range (Fig.  5 B, D).

Kidney biopsy tissue of P1 shows no vWF-Ag accumulation ( A ,  C ) while biopsy of patient 2 (P2) shows only slight increase of vWF-Ag staining ( B ,  D )

Comparing the RVCL-S patient with the eight controls without brain pathology, calculation of differentially methylated positions (DMPs) yielded 115 differentially methylated CpGs with a significance level of p  < 0.05 (Fig.  6 ). In most cases, these DMPs were hypomethylated. The top 70 genes enriched by significant CpGs are shown in Fig.  6 A. One of the DMPs was located on the CpG shore (cg04243082, 2 kb flanking the island) for the gene that codes for ADAMTS-13 ( p  = 0.00056). Other DMPs were located on genes involved in vascular growth (ANPT1, ANGPT4, STAB1), T-cell mediated immune response (NFATC1, IL2RA, HLA-DMB), extracellular matrix related (Ablim1, FMN1) and TGF-beta pathway related genes (ANGPT1, ANGPT4, CSF2RB, DLX1, IL2RA, TGFB1), while others seemed to be non-specific (for example LCN6, IFT43) (Fig.  6 A). Noteworthy, the variance for the methylome analysis was low for RVCL-S and controls (Fig.  6 c).

Top 70 genes with significantly enriched CpGs are shown ( A ). Hypomethylation status is shown (blue) with only some hypermethylated (green) DMPs ( A ). The heatmap of the 115 differentially methylated CpGs is shown with p level of < 0.05 ( B ). Boxplot of beta values of controls and patient 1 with TREX1-mutation is shown, showing significant hypomethylation ( p  = 0.00056) of cg04243082 corresponding to a CpG shore of ADAMTS13 ( C )

In this study, we further investigated the mechanisms of endothelial dysfunction in patients with RVCL-S and found evidence for an ongoing imbalance of the vWF – ADAMTS-13 axis. This imbalance of the vWF – ADAMTS-13 axis was progressive over the course of the disease in our first case and finally resulted in a severe affection and failure of multiple organs, not only the brain.

These results confirm and expand the findings of Pelzer and colleagues who reported elevated levels of circulating endothelial markers (vWF-Ag, vWF-Ag propeptide, and angiopoietin-2) in RVCL-S [ 14 ]. While this former study had a cross-sectional design, we provide longitudinal individual data over a course of up to five years. Like in case 1, massively elevated levels of circulating endothelial markers, including vWF-Ag, were noted around the 40th year of life [ 14 ]. The beginning of the fifth decade seems to be a threshold when most of the systemic features of RVCL-S become clinical apparent. However, first clinical symptoms of RVCL-S may already occur during the 3rd decade, involving Raynaud’s phenomenon, and – like in our both cases – prominent vascular retinopathy and kidney disease [ 3 ]. Although vWF-Ag was strongly increased in case 1, the activity of ADAMTS-13 was still sufficient to prevent a relevant accumulation of vWF-Ag in the small vessels since there was no relevant staining for vWF-Ag in the renal biopsy about 5 years before his death. The decrease of ADAMTS-13, which was further aggravated by a systemic inflammation, finally resulted in an insufficient cleavage of vWF-Ag as demonstrated by a strong staining for vWF-Ag in the autopsy of different organs including the kidneys.

vWF-Ag is synthesized in endothelial cells but also in megakaryocytes, the precursor cells of platelets [ 15 ]. The massive staining of vWF-Ag in the capillaries of the brain and to some degree also in the kidney, i.e. in those organs that were clinically most severely affected, points to the endothelium as the main source of the elevated vWF-Ag in RVCL-S. The combination of a strong expression of vWF-Ag, thrombosis of small vessels, and perivascular lymphocytic infiltrates [ 16 , 17 ] suggests a specific mechanism of vascular reaction that was recently termed thromboinflammation or immunothrombosis [ 18 ].

Since vWF-Ag is an acute phase protein, its level can considerably increase during infections. Notably, Yagi and colleagues reported that in vitro highly elevated plasma levels of vWF-Ag accelerated the formation of platelet thrombus under high shear stress in plasma with deficient ADAMTS-13 activity [ 19 ]. Their study was driven by the observation, that gravida with late-onset-type congenital thrombotic thrombocytopenic purpura (TTP) often developed their first episode of TTP during the second or third trimester when vWF-Ag is physiologically increased to 200–500% [ 20 ]. Thus, constantly increased levels of vWF-Ag like in RVCL-S may even further increase during infections, thus, facilitating thrombus formation. On the other hand, the expression of ADAMTS-13 can be downregulated in some cells by inflammatory cytokines [ 21 ]. Both effects might further aggravate the imbalance of the vWF – ADAMTS-13 axis, in particular during chronic low-grade inflammation [ 22 ]. Gulati and colleagues reported a patient with RVCL-S whose chronic kidney disease became apparent during a co-infection with Ehrlichiosis and Lyme disease [ 23 ]. Interestingly, the strong aggravation of RVCL-S in case 1 co-incided with an urosepsis followed by a neutropenic septicemia. Minor infections also often precede acute TMA. Fuchs and colleagues suggested that extracellular DNA and histones, which were released during the inflammatory response, could provide the second hit and precipitated acute TMA in patients with pre-existing risk factors [ 24 ]. Noteworthy, TREX1 degrades intracellular single-stranded DNA but also to a lesser degree double-stranded DNA [ 25 , 26 ]. Unlike in Aicardi–Goutières syndrome, where mutations in the catalytic domain of TREX1 lead to a loss of enzymatic activity, TREX1 mutations in RVCL-S are found in the C-terminal domain that links TREX1 to the endoplasmatic reticulum [ 5 , 20 ]. This alteration of the C-terminal domain finally results in a reduction of the perinuclear localization of catalytic active TREX1 during DNA replication in the S-phase or in response to genotoxic stress [ 25 ]. However, it is still unclear why this impaired intracellular redistribution of TREX1 from the endoplasmatic reticulum towards the nucleus may lead to a severe and chronic affection of the small vessels and how TREX1 might interfere with ADAMTS-13. In healthy humans, ADAMTS-13 is synthetized only in a few organs like in the liver (hepatic stellate cells), in the vasculature (endothelial cells), and in the brain (astrocytes and microglial cells) [ 27 ]. Future research might address whether there are differences in the expression, the intracellular redistribution of TREX1, or its response to stimuli like genotoxic stress between these organs.

The hypothesis of an imbalance of the vWF – ADAMTS-13 axis in RVCL-S is also supported by our finding of a hypomethylation of the CpG shore of the ADAMTS-13 gene locus in the cerebral methylome analysis. Methylome analysis is an established array based method in neurooncology [ 28 ], but is increasingly used in non-oncological diseases to identify differentially methylated genes in order to gain insight into gene regulation and pathogenic mechanisms [ 29 , 30 ]. Hypomethylation of CpG shores has been shown to be associated with increased gene expression [ 31 , 32 ]. Thus, the hypomethylation of the CpG shore of the ADAMTS-13 gene in autoptic brain specimen might point to a compensatory cerebral upregulation of ADAMTS-13. Noteworthy, hypomethylated CpG shores were also located on genes that are associated with vascular growth, extracellular matrix, T-cell mediated immune response, and in particular with the TGF-beta pathway. Since we used specimen from several brain regions in all cases and found a low variance within the methylome analysis, we consider the hypomethylation of the CpG shore of the gene for ADAMTS-13 in case 1 as robust. However, due to an overall small sample size the results of the methylome analysis should not be over-interpreted.

The observed imbalance of vWF-Ag / ADAMTS-13 may primarily serve as a biomarker for microvascular stress and clinical exacerbation and needs confirmation in a larger study. If confirmed, in a next step, therapeutic interventions, such as FFP, recombinant ADAMTS-13 [ 33 ], or caplacizumab might deserve preclinical testing. For the time being, clinical application of such measures should be reserved for compassionate use programs (life-threatening situations without any other treatment options available). Based on these considerations, we treated our first case with FFP. However, the administration of FFP over seven days had no effect on the severely decreased thrombocyte count nor on other relevant clinical symptoms.

The main limitation of this study is its sample size and, thus, its generalizability. RVCL-S is an ultra-rare disease with approximately 46 unrelated families worldwide ( https://rvcl-research.wustl.edu/research/ ). Since our second case originally came from India and the lineage of case 1 ended with his death, we are currently aware of only one other family in Germany that was included in a former study [ 1 ]. Thus, we cannot exclude a selection bias. Moreover, our second case is relatively young with now 26 years, while most patients become clinical apparent in their 4th and 5th decade. However, the finding of increased serum levels of vWF-Ag fits well to previous findings in a large Dutch cohort [ 14 ]. While a longitudinal study would be especially laborious in such an ultra-rare disease, our hypothesis might be proved with reasonable effort in a cross-sectional study including patients of different age. So far, only C-terminal frameshift variants with consecutive truncation (like case 1) were assumed to be associated with RVCL-S. Correspondingly, the increase of endothelial markers was found in patients with the p.(Val235fs) and the p.(Leu287fs) mutation [ 14 ]. However, we also demonstrated that an in-frame deletion within the TREX1-C-terminus is sufficient to cause disease (case 2). Finally, the immunohistochemical staining for vWF-Ag could not discriminate between the platelet-hyperadhesive ultralarge vWF-Ag multimers and the cleaved short multimers.

In summary, we provide evidence for an imbalance of the vWF-Ag – ADAMTS-13 axis in patients with RVCL-S. We recommend measuring vWF-Ag and ADAMTS-13 activity at regular intervals for the timely assessment of disease severity prior to clinical exacerbation in patients with RVCL-S.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

We thank both patients and the legal guardian of case 1 for agreement in participation in the study and publication for the scientific medical community. JH, JdF, and ES are members of the European Reference Network for Rare Kidney Diseases (ERKNet).

We thank Sarah Richter, Sophie Hickethier, and Sylvia Kurth for excellent technical assistance.

Open Access funding enabled and organized by Projekt DEAL. JH received funding from Deutsche Forschungsgemeinschaft (DFG, HA 6908/4–1, Heisenberg Program). The other authors received no funding.

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Max Braune and Moritz Metelmann contributed equally.

Authors and Affiliations

Paul-Flechsig-Institute for Neuropathology, University Hospital Leipzig, Leipzig, Germany

Max Braune & Alonso Barrantes-Freer

Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany

Moritz Metelmann & Johann Otto Pelz

Division of Nephrology, University Hospital Leipzig, Leipzig, Germany

Jonathan de Fallois & Jan Halbritter

Division of Haemostaseology, Medical Department I, University Hospital Leipzig, Leipzig, Germany

Christian Pfrepper

Institute for Pathology, University Hospital Leipzig, Leipzig, Germany

Grit Gesine Ruth Hiller

Division of Rheumatology, Hospital St. Georg, Leipzig, Germany

Susette Unger

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany

Evelyn Seelow & Jan Halbritter

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Contributions

Study conception and design: M.M, J.O.P; data collection: M.B, A.B-F, G.G.R.H, S.U, E.S, J.H; analysis and interpretation of results: M.B, M.M, J.F, C.P,E.S, J.H, J.P.; draft manuscript preparation: M.B, M.M, J.P. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Jan Halbritter or Johann Otto Pelz .

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Braune, M., Metelmann, M., de Fallois, J. et al. Imbalance of the von Willebrand Factor — ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S). Neurol. Res. Pract. 6 , 32 (2024). https://doi.org/10.1186/s42466-024-00327-2

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2 teens killed in jet ski vs. boat collision on lake in Antioch: Lake County Sheriff

The crash comes following several drowning and water-related incidents in recent days, including a 16-year-old teenage boy who died after falling off a raft on lake michigan waters in chicago, published june 19, 2024 • updated on june 19, 2024 at 6:41 pm.

Two teenagers were killed after a jet ski and boat crashed into each other on a lake in unincorporated Antioch Tuesday evening, the Lake County Sheriff's Office said.

At approximately 5:15 p.m., the Lake County Sheriff's Marine Unit and Patrol Division responded to a jet ski versus boat crash on Lake Marie, a press release from the Sheriff's office said.

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According to the release, a 16-year-old from Lake Forest, California, was operating a Yamaha jet ski with a 13-year-old from Long Grove in the passenger position. They were traveling in a northerly direction near the Gass Lake Channel and the Elime Road Peninsula, the release said.

At the same time, a Sea Ray Cabin Cruiser, operated by a 55-year-old man from Antioch, was traveling westbound in the same area, the release said.

Witnesses told authorities the jet ski appeared to be traveling at a high rate of speed, directly towards the boat. The man operating the boat was unable to avoid a collision, the release said, and the jet ski and boat crashed into each other.

Both occupants of the jet ski were knocked unconscious and thrown into the water, the release said. According to authorities, both jet ski riders were wearing life vests at the time of the collision.

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The four occupants of the boat pulled the teens from the water and called 911, the release stated. One of the teen girls was transported to the shore by the operator of the Sea Ray, while the other was transported by the operator of another passing boat.

The teens were taken to a nearby hospital where they were both pronounced dead, authorities said.

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No other injuries were reported, and an investigation by the Lake County Sheriff’s Office Marine Unit and Illinois Conservation Police remains ongoing.

According to the Handbook of Illinois Boating Laws and Responsibilities, persons at least 12-years-old but less than 18-years-old may operate a jet ski, which is considered a personal watercraft, under the following conditions:

• If they have completed a boating safety course or posses a Boating Safety Certificate issued by the Department of Natural Resources
• If they are accompanied by and under the direct control of a parent, a guardian, or a person at least 18 years old designated by the parent or guardian

Additionally, parents, guardians or designees born on or after Jan. 1, 1998 must have a valid boating safety certificate to supervise a person 10-to 17-years-old operating a motorized vessel.

The crash comes following several drowning and water-related incidents in recent days , including a 16-year-old teenage boy who died after falling off a raft on Lake Michigan waters in Chicago.

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Attorneys make closing arguments in trial of Oshkosh man accused of causing 2022 Fox River boat crash

OSHKOSH – The seventh day of trial for an Oshkosh man accused of recklessly endangering safety in a 2022 boat crash wrapped up Tuesday with closing arguments from prosecution and defense attorneys.

Jurors will return Wednesday morning to begin deliberations.

Jason Lindemann, 53, is charged with two felony counts of second-degree recklessly endangering safety, as well as 12 misdemeanor counts of failing to render aid in a boating accident and one misdemeanor count of negligent operation of a boat.

Assistant attorneys general Emily Thompson and Tara Jenswold say Lindemann's behavior the night of the crash was criminally reckless, and he knowingly created a risk of death or great bodily harm to other people out on the water by driving his boat after a day of drinking, not turning on the proper lights on his boat and operating the boat at a high rate of speed.

"It's Jason Lindemann – and Jason Lindemann alone – who is responsible for this crash," Jenswold said during the prosecution's closing argument.

Lindemann's defense attorney, Scott Ceman, argues the crash was nothing more than an accident and if anyone was at fault, it was the driver of the paddleboat, not Lindemann.

The paddleboat operator, Ceman argued, had bright exterior lights on the boat that are only supposed to be activated when docking, and caused a visibility issue by hiding the paddleboat's navigational lights and blending it in with the bright lights on the shoreline.

Just before 10 p.m. on July 9, 2022, Lindemann crashed his powerboat, filled with six passengers, into a double-decker paddleboat cruise owned and operated by  On The Loos Cruises , on the Fox River in Oshkosh, between the Oregon Street and Wisconsin Street bridges.

Lindemann had accelerated his boat after passing under the bridge — which, Ceman pointed out at trial, is standard practice for boats after exiting the no wake zone.

The owner and operator of the On The Loos Cruise paddleboat, Jeff Loos, told investigators he saw Lindemann's powerboat speeding toward his boat. He said it appeared the powerboat might pass on the left at one point and on the right at another. When Loos realized his boat was going to be hit, he began turning his boat, which attorneys said has a maximum speed of about five miles per hour. Lindemann's boat crashed into the paddleboat's left side, its hull going up in the air.

Prosecutors say after crashing into the paddleboat, Lindemann drove away without stopping to share his identification information or make sure everyone on the boat were all right. Police didn't find Lindemann until the following day, after he had spent the night in his boat on Lake Winnebago.

The paddleboat had 44 passengers on board. No one was seriously injured, but some passengers experienced minor injuries that they received treatment for in the days and weeks after the crash. The 12 charges of failing to render aid in a boating accident correspond with 12 people who suffered injuries in the crash — including one of the six passengers aboard Lindemann's powerboat.

In her closing argument, Jenswold said Lindemann's failure to stop at the scene after crashing and seemingly hiding in his boat until morning is evidence he was aware of his guilt.

"If it was an accident, why'd you leave?" she said.

Jenswold also pointed out that an officer testified earlier in the trial that messages and calls from the evening of the crash into the next morning appeared to have been deleted from Lindemann's phone when officers conducted a search of it.

In the defense's closing argument, Ceman countered that Lindemann did in fact pull up next to the paddleboat after the crash, but could not safely stop due to some intoxicated passengers from the paddleboat acting "aggressive" toward him.

He also said officers never considered that the case was not a hit-and-run, and thus did not properly investigate. Ceman also claimed the boat crash investigation was not thoroughly carried out because there were no serious injuries.

Despite the prosecution's claims, Ceman argued that Lindemann was not drunk that night. Because officers did not get in touch with Lindemann the night of the crash, the prosecution called witnesses who had seen Lindemann at two bars earlier in the day to testify that they believed he appeared intoxicated.

A few witnesses, however, testified that Lindemann was not drinking. Ceman argued these witnesses, who had been spending time with Lindemann during the day, were more credible than people who observed him from afar. Prosecutors said witnesses who had close personal relationships with Lindemann were likely protecting him.

RELATED: Trial begins for Oshkosh man accused of driving his powerboat into a paddleboat on the Fox River in 2022

RELATED: Oshkosh man pleads not guilty to charges in July Fox River powerboat-paddleboat crash

Attorneys similarly disagreed about the credibility of other witnesses.

In his closing argument, Ceman named multiple witnesses who had testified during the trial and claimed they had lied about various things. Some, he said, lied about the crash's impact on them likely for motivations of benefiting from civil lawsuits filed against Lindemann.

He said one passenger's description of blood and glass on the paddleboat's deck after the crash was "just another lie in a parade of lies put forth here by the state."

In the prosecution's rebuttal argument, Jenswold pointed out that of the 54 witnesses the state called to testify at the trial, Ceman claimed in his closing argument that at least 16 of them lied.

"To get up here and say, as the defense did, 'they're all lying' — that just doesn't make sense," Jenswold said. "These people that he has called liars, many of them had no motive to lie."

Jury instructions and closing arguments took up the entire afternoon, about 3½ hours. Winnebago County Circuit Court Judge Michael Gibbs decided to send the jury home instead of beginning deliberations Tuesday evening, after what he said has been a long trial.

Contact Kelli Arseneau at 920-213-3721 or  [email protected] . Follow her on X, formerly Twitter, at  @ArseneauKelli .

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2 teen girls killed after jet ski crashes into boat in Illinois

Girls, ages 16 and 13, killed after jet ski crashes into boat on lake marie in antioch, illinois.

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Two teen girls, ages 16 and 13, were killed at a lake in Illinois on Tuesday after their jet ski crashed into a boat, authorities said.

The 16-year-old girl was operating a Yamaha jet ski while the 13-year-old rode as a passenger when the crash occurred at around 5:15 p.m. on Lake Marie in Antioch, the Lake County Sheriff’s Office said. 

Witnesses told the sheriff’s office that the teens were traveling at a high rate of speed near the channel to Grass Lake directly toward a Sea Ray Cabin Cruiser, which was also approaching the channel.

The two watercraft, however, were unable to avoid a collision.

ALASKA MAN, POLICE OFFICERS RESCUE BABY MOOSE FROM ‘SURE DEMISE’ AFTER GETTING STUCK IN LAKE

Two teen girls were killed at Lake Marie in Antioch, Illinois, on Tuesday after crashing their jet ski into a boat, authorities said. (FOX32 Chicago WFLD)

"It doesn't appear they avoided or tried to make any sharp maneuvers," Lake County Sheriff’s Office Deputy Chief Chris Covelli told FOX32 Chicago. "It appears they went straight into the cabin cruiser. Just seems to be a tragic, unfortunate accident."

The teens on the jet ski, who were both wearing life vests, were knocked unconscious and thrown into the water, according to authorities. The four occupants on the Sea Ray immediately pulled the girls from the water, called 911 and rendered aid.

The Lake County Sheriff's Office is investigating the crash. (Lake County Sheriff's Office)

One of the girls was transported to the shore by the operator of the Sea Ray, while the other girl was taken ashore by the operator of another passing boat.

CHILDREN SWIMMING IN VIRGINIA LAKE HOSPITALIZED AFTER E. COLI, GASTROINTESTINAL ILLNESSES

Both girls were then rushed to Advocate Condell Medical Center in Libertyville, where they were each pronounced dead. No other injuries were reported.

The teens were identified as a 16-year-old girl from Lakewood, California, and a 13-year-old girl from Long Grove, Illinois. Authorities have yet to release their names.

The 16-year-old, who was operating the jet ski, and the 13-year-old passenger were both pronounced dead at a hospital after the crash. (FOX32 Chicago WFLD)

The Lake County Coroner’s Office is expected to perform an autopsy Thursday morning. 

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The crash remains under investigation.

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• death investigation

League City police investigate death of second woman at Wharf Marina

LEAGUE CITY, Texas (KTRK) -- For the second time in a matter of weeks, League City police are investigating the death of a woman at a marina.

On Wednesday afternoon, officers were called to the Wharf Marina in the 700 block of Davis Road, where a woman was found not breathing on one of the boats docked there. It's believed the woman died of a suspected drug overdose, but the medical examiner will need to confirm her cause of death.

The woman's identity has not been released. Authorities were questioning one person.

SEE ALSO: Police suspect foul play after mom of 4 found hanged off League City dock

Just last month, neighbors discovered Giselle Salazar-Tapia's body hanging from a dock at the same location. League City police have said they suspect foul play in that case.

The 30-year-old mother of four was found partially submerged in the water. Detectives do not believe Salazar-Tapia hanged herself. Instead, they believe her body was staged to appear as though she had after she died elsewhere.

Several residents told ABC13 on Wednesday that they are scared. They said squatters at the marina had brought drugs into the area, and now two women have died in just three weeks' time.

Salazar-Tapia's cause of death has not yet been determined, and her case remains under investigation.

Police said they have two persons of interest in her case and describe them only as people who were recently the closest to her.

One of Salazar-Tapia's relatives told ABC13 her family wants to find out what happened to her and find the person or persons responsible for her death.

"My sister didn't deserve this at all. She was so kind," the relative said.

For more on this story, follow Jessica Willey on Facebook , X and Instagram .

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• LEAGUE CITY
• DEATH INVESTIGATION
• INVESTIGATION

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2 teens killed when WaveRunner crashes into boat near Antioch

Two girls, 16 and 13, were riding on a waverunner when it hit a boat about 5:15 p.m. tuesday on lake marie..

Two teenage girls died after crashing a WaveRunner into a boat Tuesday on Lake Marie near Antioch.

Two teenage girls died after crashing a Yahama WaveRunner into a boat Tuesday on Lake Marie near Antioch.

A 16-year-old girl was piloting the personal watercraft with a 13-year-old girl about 5:15 p.m. northbound near a channel to Grass Lake when they crashed into a boat, the Lake County sheriff’s office said.

The 55-year-old man driving the Sea Ray Cabin Cruiser was unable to avoid the collision with the WaveRunner, which was traveling at a high rate of speed, the sheriff’s office said.

Both girls, who were wearing life vests, were thrown into the water and knocked unconscious, officials said.

Occupants of the boat pulled them out of the water and rendered aid before taking the girls to shore with another passing boat, officials said.

The girls were taken to Condell Medical Center in Libertyville, where they were pronounced dead, the sheriff’s office said.

No other injuries were reported.

Autopsies were scheduled for Thursday. The girls’ names haven’t been released.

The crash remains under investigation.

• Boy, 14, shot at Columbus Park in Austin

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Boston Celtics championship parade to be held Friday

By Matt Schooley

Updated on: June 18, 2024 / 7:14 PM EDT / CBS Boston

BOSTON – The duck boats are ready and the City of Boston will celebrate the 18th championship in Celtics history with a rolling rally on Friday.

When is the Celtics parade?

Boston Mayor Michelle Wu announced that a rolling rally will be held Friday in the city.

Boston Duck Tours posted "Cue the ducks" on social media overnight, with the caption "Who's ready for a parade?"

What is the Celtics parade route?

According to Wu's office, the parade will begin at 11 a.m. in front of TD Garden.

After turning onto Causeway Street, the duck boats will pass City Hall Plaza and the Boston Common on Tremont Street.

The parade will end on Boylston Street by Hynes Convention Center.

25 duck boats being prepared

The moment the Celtics won their 18th championship, that set into motion an elaborate plan to throw Boston's favorite kind of party.

"We're excited, we want the Celts to win of course," said Boston Duck Tours CEO Cindy Brown. "But then the panic hits in of, oh my gosh, what are the next few days going to be like?"

It's a pretty awesome problem to have. "After doing 12 parades, we pretty much have the parade part figured out. The tricky part is working with the schedule. We have to cancel all the tours we had for Friday," she said.

Twenty-five vehicles are being prepared to carry the Celtics and their entourage through the heart of the city. The ceilings will be removed so the notoriously tall athletes can look down onto the crowd. 

Boston heat wave impacting parade plans

City officials have an extra challenge planning the latest championship parade in Boston. The Celtics clinched the title as a likely heat wave was set to arrive with potentially record-breaking temperatures in Boston.

The National Oceanic and Atmospheric Administration issued its heat risk outlook, with parts of New England categorized in the "extreme" risk area. WBZ-TV executive weather producer Terry Eliasen called this "highly rare" for the region.

Temperatures are expected to be in the mid to upper 90s on Tuesday, Wednesday and Thursday. The city's heat emergency will end Friday, and the latest forecast calls for a cold front to move through the area Thursday night and Friday morning. If the cold front moves in before the parade, temperatures will likely be 10-20 degrees cooler. 

Still, the city is planning to have misting towers at City Hall Plaza and Boston Common. 

The Celtics' road to NBA title

The Celtics earned the duck boat parade thanks to a dominant performance throughout the postseason that continued in the NBA Finals.

Boston stormed out to a 3-0 series lead. Dallas earned a dominant Game 4 victory to send the series back to Boston. But Monday night at TD Garden, the Celtics ended things and broke a tie with the Los Angeles Lakers for the most team NBA titles in history.

Jaylen Brown was awarded the Bill Russell NBA Finals Most Value Player award after the game.

• Boston Celtics

Matt Schooley is a digital producer at CBS Boston. He has been a member of the WBZ news team for the last decade.

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13 Best Boat Shoes for Summery Style on Land or Sea

Boat shoes get a bad rap. We can fix that.

Here's the thing about boat shoes , though: They are damn stylish. In canvas or leather , the nautical-inspired kicks are an elevated alternative to flip-flops , a more approachable version of loafers , and a cooler, better (most of the time) option than sneakers . It all comes down to which boat shoes you wear, and how you wear them. Lucky for you, we've gathered 13 infallible options below.

best iconic boat shoes

Sperry authentic original 2-eye boat shoes.

best elevated boat shoes

Mango split leather nautical shoes.

best comfortable boat shoes

Allbirds tree skippers.

Take the classic Sperrys , for example. What's not to love? They're comfortable and chic and pair wonderfully with a summer barbecue. Or, if you're actually getting on a boat, go for Dockers—they're water resistant, so you can splish and splash as you please. If you want to emulate the air of wealth that boat shoes seem to inherently have, reach for Loro Piana's suede option—but do not get those wet. There's a style below for everyone. Long live Boat Shoe Summer.

When I think of boat shoes, these are the very first pair that comes to mind. I mean, they're classics. Sperry's iconic two-eye design is an easy, stylish way to encapsulate summer elegance, whether or not you're actually on a boat.

Mango does boat shoes as it does all things—with real European style. These are minimalist yet tasteful, with a leather upper and backstitched details. Pair with denim, white pants, or khakis for a classy look.

These are a boat shoe/sneaker hybrid, but we're counting them, because the comfort and cushion provided by Allbirds is so worth it. If you're planning on doing a lot of walking this summer—say, on vacation while playing tourist—this is the chic, comfy shoe you need to have in your rotation.

Dockers Beacon Boat Shoes

For an affordable boat shoe that's as durable as it is comfortable, go for Dockers. This hard-wearing style emulates the classic, timeless design, and when you have these on your feet, you'll love the water- and stain-repellent coating that allows you to roam freely.

Todd Snyder x Sperry Top-Sider Suede Boat Shoes

What could be chicer for summer than a Todd Snyder and Sperry collab? This boat shoe exudes everything a boat shoe should: refined style, a bit of preppiness, and infallible coolness. With cork insoles for all-day comfort and a suede upper that looks as good as it feels.

OluKai Moku Pae Boat Shoes

With a breathable mesh upper and grippy wet soles, this is a boat shoe you can—and should—actually wear on a boat. And, for that matter, anywhere else you go this summer.

Loro Piana Sea-Sail Walk Suede Boat Shoes

If you want to invest in a truly luxurious boat shoe, well, there's no higher luxury than Loro Piana. This style is crafted with a suede upper and a durable rubber sole, with an apron toe that looks good on or off the docks.

J.Crew x Rancourt & Co. Read Boat Shoes

It doesn't get much cooler than these classic boat shoes. Dress them up, dress them down, wear them on land or at sea—point is, you're going to get a lot of use out of 'em.

Sebago Endeavor Boat Shoes

If you've tried Sebago's shoes before, you know the brand is unparalleled when it comes to comfort and style. These boat shoes are cut from the same cloth—they're endlessly cushiony, timelessly cool, and under 200 bucks.

L.L. Bean Casco Bay Boat Mocs

For only $100, L.L. Bean has a timeless, versatile pair of boat shoes. Pair them with anything from a linen button-down to a cotton polo, and be merrily on your way to wherever the season takes you.

Timberland Classic 2-Eye Boat Shoes

If you love your Timberland boots (who doesn't?), you'll definitely love your Timberland boat shoes. These pack the same durable, comfortable construction that the brand's boots are known for, with some serious style points, too.

Polo Ralph Lauren Merton Leather Boat Shoes

PRL does all things with class, preppiness, and grace, and these boat shoes are no different. With white contrast stitching at the toe and a two-eye design, this is what timelessness is all about.

Mr P. Caspian Suede Boat Shoes

And for something with a modern flair, Mr P. has you covered. On a chunky platform sole, these suede boat shoes are a summer statement piece that adds some flair to your dressed-up looks and some refinement to your streetwear fits.

Why You Can Trust Esquire

We won't say something is great unless it’s actually great. Our fashion and e-commerce teams carefully choose every product in Esquire’s roundups.

Every pick on this list—and all our other lists—has been selected through testing and trying it ourselves. We won't tell you to buy something that we wouldn't spend our own money on. We're telling you to buy things we know you'd love, because of how much we love 'em, too.

No two tastes are the same, because no two men are the same. Your proverbial mileage may vary. But if you’re looking for the right place to start, with advice from folks who care (possibly too much!) about this sort of stuff, this is the place to be.

Other Options We Love

There are plenty of great boat shoes out there—the 13 we listed above just so happen to be the best of the best. But if those still aren't doing it for you, we have a few more selects you might like.

• If you're a details guy, Frescobol Carioca has a tasseled style we can't get enough of.
• Or maybe you prefer a rugged, pre-worn, vintage look. If that's the case, here's a handsome leather boat shoe you'll love.
• If you want something clean, classic, and sophisticated, check out Rodd & Gunn's burnished leather style .

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