Lupus anticoagulant

Lupus Anticoagulant and thrombosis, monitoring of anticoagulation

Thrombotic complications are limb threatening and life threatening.  There are multiple risk factors for thrombosis in the arteries and veins. Lupus anticoagulant is one of the risk factors for the development of thrombosis. Dr. Lockard Conley, haematologist discovered the Lupus Anticoagulant in 1947. The two words in this term are misnomers. This acts as an anticoagulant in the invitro and as procoagulant in vivo. It was first discovered in Systemic Lupus Erythematosus patient, but not seen in all patients with Lupus. Lupus anticoagulant (LA) is see in 2-4% of the general population. Presence of LA increases the risk of thrombosis 3.6 folds.  LA is positive in 10-30% of the SLE patients. Lupus Anticoagulants are autoantibodies targeting phospholipids and proteins associated with phospholipids on the outer cell membranes. Patients with some infections or those taking certain medications can develop Lupus anticoagulants. Nearly, 20% of the deep vein thrombosis patients with or without pulmonary embolism are associated with antiphospholipid antibodies. The tests are done in 2 stages. At first PTT-LA, DRVVT are done. Then Anticardiolipin antibodies, Beta-2 glycoprotein1 antibody, anti-prothrombin antibodies are tested to confirm the antiphospholipid syndrome (APS) in patients.

It is important to give special attention to the monitoring of warfarin therapy in APS patients. We are concerned about the reliability of INR determinations in this group of patients with DVT/ PE. It was observed that in 6.5% to 10% of patients with Lupus Anticoagulant, antiphospholipid antibodies (aPLs) may prolong the prothrombin time assay leading to an unreliable INR.^1,2,3  It is helpful to validate the INR in individual patients using a coagulation assay that is not affected by aPLs, suc as Factor II activity assay.⁴ After an APS patient is on warfarin with a stable INR of 2.0 to 3.0, an INR and factor II activity assay should be checked simultaneously. If the INR is in range and the factor II level is therapeutic (approximately 15% to 25%), the level of anticoagulation in adequate and the INR is reliable. If the INR is in range but the factor II level is >30%, the level of anticoagulation is inadequate. For such a patient, an individualized INR target range corresponding to a therapeutic factor II level should be established, or the factor II level itself could be followed.⁴

1.      Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997; 127: 177–185.

2.      Sanfelippo MJ, Sennet J, McMahon EJ. Falsely elevated INRs in warfarin-treated patients with the lupus anticoagulant. WMJ. 2000; 99: 62–64.

3.      Rosborough TK, Shepherd MF. Unreliability of international normalized ratio for monitoring warfarin therapy in patients with lupus anticoagulant. Pharmacotherapy. 2004; 24: 838–842.

4.      Kasthuri RS, Roubey RA. Warfarin and the antiphospholipid syndrome: does one size fit all? Arthritis Rheum. 2007; 57: 1346–1347.

Impact of COVID-19 on vascular surgery practice

       Fig. Impact of COVID -19 on Vascular Surgery

The pandemic is still growing, but our knowledge of it also continues to improve. The outlook is optimistic considering that some patients have already been cured of it and a vast amount of knowledge has been gathered so far. Also, young doctors are incorporating this priceless experience into their personal and professional growth.

Vascular surgery: Elective surgery and outpatients 

Most arterial surgery is either urgent or emergency in nature and should continue at present where possible.  

Outpatients: Where possible, only urgent outpatients should be seen, and virtual clinics should be considered.

On discharge, many vascular patients will either need no outpatient follow (but be given a telephone number to ring if in trouble) or can be reviewed in remote outpatient clinics. 

Elective surgery: Elective arterial surgery and venous surgery should be deferred. Asymptomatic carotid surgery and surgery for claudication should be deferred. The size threshold for AAA surgery needs to weigh up risk of rupture in the next few months with risk of intervention and resource limitation. >7cm or imminent rupture AAA currently is recommended. 

Urgent/emergency vascular surgery

On call arrangements:  A second on-call consultant is advisable to help with both the emergency workload (and also if self-isolation becomes common). A vascular consultant surgeon should be on call and available to see all referrals. Trusts should consider having another vascular surgeon on call for delivering the surgery. 

Investigations 

Emergencies are likely to need a CT angiogram and proceed to surgery as appropriate. 

AAA: Ruptured aneurysms should ideally be treated by EVAR whenever possible to reduce dependence on the High Dependency Unit and reduce length of stay. Open surgery should only be considered when EVAR is inappropriate or unavailable and in cases where there is a good chance of success. ITU capacity will need to be considered prior to intervention. 

Critical leg ischemia / diabetic foot: Those legs immediately threatened require urgent intervention. Others may be diverted to a hot foot clinic for further assessment. Interventional radiological approaches may allow more appropriate utilisation of scarce high dependency beds. There may be situations where primary amputation may be more appropriate than complex revascularisations, multiple debridements and potential prolonged hospital stay.

Carotids: Crescendo TIAs would normally need urgent surgery. If there are severe resource limitations, aggressive best medical therapy more appropriate for recently symptomatic carotids.  

Spoke hospitals

Spoke hospitals allow patients to be cared for outside the hub. Currently, vascular surgical input is in the form of ward referrals, venous work, outpatient clinics, and angioplasties. These activities will need to be reviewed. There will need to be local flexibility, the but inpatient ward reviews, possibly in a virtual fashion may be appropriate. 

 Trainees

Surgeons in training will have keys roles to play in this crisis but the underlying principles of appropriate supervision, working practices, rest and pastoral care remain. 

Vitamin K and vascular calcification

In 1929 a Danish Biochemist work on the cholesterol metabolism in chicken fed on a low-fat diet, free from sterols lead to the discovery of Vitamin K. He noticed subcutaneous and intramuscular hematomas in the chicken fed on a low-fat diet for 6 weeks or more. When he re-fed them fatty food the hemorrhagic effect was not reversed. Instead, he fed them Hempseed and the hemorrhagic effect got reversed. So, he called this antihemorrhagic factor. In German, it is known as Koagulation–vitamin. It has got its name Vitamin K from Koagulation. Vitamin K1 (phylloquinone) is from plant-based foods and Vitamin K2 (MK7 menaquinone) is from other sources. Henrik Dam and Edward Doisy received Nobel prize 1943 for their discovery of Vitamin K.

Vitamin K2 is linked with vascular calcification. Vascular smooth muscle cells produce Matrix Gla Protein (MGP). Vitamin K acts as a cofactor for gamma-carboxylation of MGP after which it inhibits the vascular calcification. When the MGP gene was deleted from the rats there was complete arterial calcification and they died in 6 weeks. Similarly, when rats were treated with Warfarin, they developed vascular calcification. Treating them with high doses of Vitamin K, it resulted in reversal of the calcification.

It was observed that high doses of Vitamin K will reduce the arterial stiffness and increase vascular elasticity. This mechanical effect will improve cardiovascular functions. In a recent paper published, M K Shea et al 2020 (nearly 4000 patients) observed a relation between the all-cause mortality and serum levels of Vitamin K. When serum levels were lower than 0.5 nmol/ L, the all-cause mortality was 19% higher than the patients with higher levels (> 1.0 nmol/ L) of serum vitamin K in 13 years follow up. But surprisingly there was no such association noted between cardiovascular disease and serum levels of vitamin K.

We need more studies to understand the reversal effect on vascular calcification and improvement of haemodynamic effects in the calcified vessels. Currently we are treating diabetic patients with tibial arterial disease with guidewires, balloons and stents in addition to the statins, antiplatelets, CE/ARBs and antidiabetics. Vitamin K2 (menaquinone) induced correction of vascular calcification is an additional benefit to the patients, but this needs to be proved in more number of robust trials.  

M Kyla Shea, Kathryn Barger, Sarah L Booth, Gregory Matuszek, Mary Cushman, Emelia J Benjamin, Stephen B Kritchevsky, Daniel E Weiner. Vitamin K status, cardiovascular disease, and all-cause mortality: a participant-level meta-analysis of 3 US cohorts. The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1170–1177,

Cerebral small blood vessel disease

Cerebral small blood vessel disease (in standard preoperative imaging reports) is independently associated with increased risk of CV death following carotid endarterectomy. This statement is produced by an article published in the European Journal of vascular and endovascular surgery2020.

1). What is cerebral small blood vessel disease?

Cerebral small vessel disease (CSVD) is composed of several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. Neuroimaging features of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence.

2). What are cerebral small blood vessels?

Cerebral small vessels comprise two components. First, the leptomeninges vasoganglion, which is derived from subarachnoid space covering, and the convex surface of the brain. Second, perforating arteries are derived from anterior, middle, posterior cerebral arteries that supply the subcortical parenchyma. The cerebral small vessels are crucial to the maintenance of adequate blood flow to the sub-surface brain structure. They include small arteries, arterioles, venules, and capillaries which are commonly sized at 50–400 µm.

3). What are the outcomes of cerebral small vessel disease (CSVD) of the brain?

Small vessel disease accounts for up to 25% of all ischemic strokes but also put patients at twice the risk for these conditions. In addition, CSVD is a leading cause of functional loss, disability and cognitive decline in the elderly.

4). What are the neuroimaging findings of CSVD?

Neuroimaging of CSVD primarily involves visualizing recent small subcortical infarcts, lacunar infarct, WMH, microbleeds, enlarged perivascular spaces, and brain atrophy.

5). What are lacunar infarcts?

Gattringer and colleagues recommended the new term ‘recent small subcortical infarct’ instead of the lacunar infarct.

Gattringer T, Eppinger S, Pinter D, Pirpamer L, Berghold A, Wunsch G, Ropele S, Wardlaw JM, Enzinger C, Fazekas F. Morphological MRI characteristics of recent small subcortical infarcts. Int J Stroke. 2015;10(7):1037–1043.

Lacunar stroke accounts for up to a quarter of all acute ischemic strokes. it is a small fluid-filled cavity that was thought to mark the healed stage of a small deep brain infarct. In neuroimaging, a lacuna is a round or ovoid, subcortical, fluid-filled cavity with a similar signal to cerebrospinal fluid (CSF). It measures between 3–15 mm in diameter, which is consistent with a previous acute small deep brain infarct or hemorrhage in the territory of one perforating arteriole. Lacunar infarcts are typically located in the basal ganglia, internal capsule, thalamus, corona radiata, centrum semiovale (CSO), and brainstem. Poirier and colleagues divided the lacunas into three subtypes based on the formation: Subtype I lacunas are secondary to old lacunar infarction; subtype II lacunas secondary to old hemorrhagic lesions; subtype Ⅲ lacunas are secondary to enlarged perivascular spaces. Herve and colleagues classified the lacunar lesions by three-dimensional MRI reconstruction, according to their shapes into four types: Slab, stick, multiple components, or ovoid/spheroid, then proposing that most of the lacunar infarcts (83%) were ovoid or spheroid. Infarct lesions manifest isolated, adjacent to or fused into white matter hyperintensity.

Moreau and colleagues found that lacunas almost always present at 90 days after acute lacunar infarction and appear as a central CSF-like hypointensity with or without a surrounding border of hyperintensity on FLAIR sequence but only CSF-like hypointensity and hyperintensity on T1-weighted and T2-weighted, respectively. Moreover, the sensitivity of FLAIR for cavitation was greatly lower than for T1-weighted sequences.

6). What is the effect of CSVD on people undergoing carotid endarterectomy?

The presence of SVD in pre-operative brain imaging reports can serve as a predictor for the three-year risk of cardiovascular death in symptomatic patients undergoing CEA but does not predict peri-operative or long term risk of stroke. Published: April 21, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.02.004

Nephrogenic Systemic Fibrosis (NSF)

Vascular surgery patients with arterial problems generally require angiograms to evaluate the patency of the vascular lumen. There is always a concern about doing an angiogram ( CT angio or conventional angio) in those patients with decreased eGFR. Some times MRangiogram with gadolinium is recommended in. those patients. But that can result in nephrogenic systemic fibrosis (NSF).

Nephrogenic systemic fibrosis (NSF) incidence was found to be found to be 4.3 cases per thousand patient-years. When gadolinium is used in a patient there is 2.4% risk of nephrogenic systemic fibrosis. NSF is also known as nephrogenic fibrosing dermopathy. This was first described in 2006 in the Journal of American Society of nephrology by Marckmann P et al describing a case series of 13 patients. New contrast agents are introduced with the hope that they have a lesser risk of NSF. Gadobenate dimeglumine is one such newer agent. Clinically NSF looks like scleroderma and eosinophilic fasciitis but histologically it looks like scleromyxedema. Biopsy shows proliferation of dermal fibroblasts, dendritic cells, thickened collagen bundles,   increases elastic fibers and mucin deposition. Toll-Like Receptors (TLR) four and seven seems to play an important role in the development of NSF. 

Although NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations (Joseph Lunyera 2020).

Capricious Corona and new normalcy without contact in the coming future?

Return to normalcy, a return to the way of life before World War I, was United States presidential candidate Warren G. Harding's campaign slogan for the election of 1920. Although detractors of the time tried to belittle the word "normalcy" as a neologism as well as a malapropism, saying that it was poorly coined by Harding (as opposed to the more accepted term normality), there was contemporaneous discussion and evidence that normalcy had been listed in dictionaries as far back as 1857. Harding's promise was to return the United States' pre-war mentality, without the thought of war tainting the minds of the American people. To sum up his points, he stated:

America's present need is not heroics, but healing; not nostrums, but normalcy; not revolution, but restoration; not agitation, but adjustment; not surgery, but serenity; not the dramatic, but the dispassionate; not experiment, but equipoise; not submergence in internationality, but sustainment in triumphant nationality.

Harding's position attracted support and was important during the 1920 United States presidential election, which he won with 60.3% of the popular vote.^[3]

During the campaign, Harding addressed the issue of the word's origin, claiming that "normalcy" but not "normality" appeared in his dictionary.

Now our war with Covid19 is coming to a stance(end), what will be our new normalcy in all the spheres of life and medical practice?

Signs of dramatic changes are everywhere even in GP surgeries. The New York Times published an interesting report on how the work of GPs in London is being transformed by the virus. “We’re basically witnessing 10 years of change in one week,” one GP told the paper. “It used to be that 95% of patient contact was face-to-face: you go to see your doctor, as it has been for decades, centuries. But that has changed completely.” Before the virus, video appointments made up only 1% of annual appointments with British GPs and other practice staff. But the NHS has urged thousands of clinics across the country to start switching to remote consultations and has fast-tracked approval of digital providers to ramp up their offerings.

We are seeing a sudden increase in the webinars and online consultations. Many companies are providing these services to the doctors. We are surprised to see the sudden change that has taken place in view of Covid-19 based on the physical distancing slogan. This is the new Normalcy after lifting the lockdowns of covid-19.   

Risk factors for the development of venous ulcers

Venous ulcers are the most common type of chronic lower extremity ulcers, affecting 1% to 3% of the U.S. population. Venous hypertension as a result of venous reflux (incompetence) or obstruction is thought to be the primary underlying mechanism for venous ulcer formation .

Risk factors for the development of venous ulcers include

1.Age 55 years or older,

2.Family history of Chronic venous insufficiency,

3. Higher body mass index,

4.History of pulmonary embolism or superficial/deep venous thrombosis,

5. Lower extremity skeletal or joint disease,

6.Higher number of pregnancies,

7.Parental history of ankle ulcers,

8.Physical inactivity,

9.History of ulcers,

10.Severe lipodermatosclerosis, and

11. Venous reflux in deep veins.

Bonkemeyer Millan S, Gan R, Townsend PE. Venous Ulcers: Diagnosis and Treatment.

Am Fam Physician. 2019 Sep 1;100(5):298-305

Effects of smoking on blood vessels – can we reverse them?

The effects of nicotine replacement therapy (NRT)-aided smoking cessation on vascular function are not fully clarified. We investigated 100 healthy smokers who were motivated to quit and received NRT for a 3-month period. Vascular endothelial function (measured by reactive hyperemia-peripheral arterial tonometry [RH-PAT]), arterial stiffness (measured by augmentation index [AI] and brachial-ankle pulse wave velocity [baPWV]), and systemic inflammation markers (including serum soluble intercellular adhesion molecule-1 [sICAM-1] and interleukin-1β [IL-1β]) were assessed at baseline and 3 and 12 months of follow-up. After 3 months of intervention, endothelial function, arterial stiffness, and inflammatory markers significantly improved (RH-PAT increased, AI and baPWV decreased, sICAM-1 and IL-1β decreased, all P < .05) for the participants who abstained from smoking completely, but for those who did not abstained completely, RH-PAT, AI, baPWV, and IL-1β remained unchanged. At 12 months follow-up, endothelial function (RH-PAT), arterial stiffness (AI and baPWV), and inflammatory markers (sICAM-1 and IL-1β) were further improved in participants who abstained from smoking (P < .001), while the above parameters deteriorated in continued smokers (P < .05). In conclusion, vascular dysfunction can be reversible after NRT-aided smoking cessation in healthy smokers and vascular function could be further damaged if they continue smoking[1].

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[1]. Xue C1, Chen QZ1, Bian L1, Yin ZF1, Xu ZJ1, Zhang AL1, Xie YS1, Zhang HL1, Du R2, Wang CQ1. Effects of Smoking Cessation with Nicotine Replacement Therapy on Vascular Endothelial Function, Arterial Stiffness, and Inflammation Response in Healthy Smokers. Angiology. 2019 Sep;70(8):719-725