Viper Venom Blood Testing

I’ve had a few people ask me about this test today after I posted about it in my list of blood tests that I’ve had in the last year, so I figured I’d share some more information about it.

For starters,  the test is officially known as the Dilute Russell’s Viper Venom Time (DRVVT). While it’s not a rare test per say, it’s not generally  ordered as a part of routine blood work . Typically, a doctor will order this if they are looking for specific markers relating to certain blood clotting disorders, such as those in Antiphospholipid Syndrome (APS). Still, when I called for my test results the nurse who read my result had never even heard of this test and had no idea what the result meant – other than it was flagged as being abnormal (more about that later). Nevertheless, the test itself is really interesting (and slightly confusing as well).

Although my test was done in the laboratory, this video will give you a good demonstration of how and why viper venom is used to test the coagulation times of human blood.

*Trigger Warning*

If you have a phobia of snakes – DO NOT watch the following video

Pretty amazing, huh?

Also kind of scary to think about what happens to the body when an individual is bitten by such a venomous snake. Luckily, though, that wasn’t the case here.

About the Test:

According to the Practical Haemostasis Website, the “Russell’s viper venom [RVV] isolated from the snake Daboia russelii [orrussellii – contains a potent activator of factor X which in the presence of phospholipid [PL], prothrombin and calcium ions clots fibrinogen to fibrin. In individuals with a lupus anticoagulant [LA] the antibody binds to the phospholipid inhibiting the action of the RVV and prolonging the clotting time.
As the RVV directly activates factor X, the test is unaffected by deficiencies of factors XII, XI, IX or VIII. The DRVVT is frequently combined with a platelet neutralisation procedure to demonstrate the phospholipid specificity of the antibody” (para. 1).

One thing to note here is that the Lupus anticoagulant does NOT test for lupus  – although the test may be positive for some individuals if they have both Lupus AND APS. It’s merely an immunoglobulin that is associated with an increased clotting time.

How It’s Used:

From The American Association for Clinical Chemistry

Lupus anticoagulant testing is a series of tests used to detect lupus anticoagulant (LA) in the blood. LA is an autoantibodyassociated with excess blood clot formation. LA testing may be used to help determine the cause of:

  • An unexplained blood clot (thrombosis) in a vein or artery
  • Recurrent miscarriages
  • An unexplained prolonged PTT test (PTT measures the time it takes in seconds for a person’s blood sample to clot in a test tube after reagents are added.) LA testing helps determine whether a prolonged PTT is due to a specific inhibitor, such as an antibody against a specific coagulation factor, or to a nonspecific inhibitor like the lupus anticoagulant.

LA testing may also be used:

  • Along with tests for cardiolipin antibody and anti-beta2-glycoprotein I to diagnose antiphospholipid syndrome (APS)
  • Along with tests such as factor V Leiden or proteins C and S to help diagnose an excessive clotting disorder (thrombophilia)
  • To determine whether the lupus anticoagulant is temporary (transient) or persistent

LA cannot be measured directly and there is no single test or standardized procedure to detect the presence of LA in the blood. A series of tests is used to confirm or rule out the autoantibody:

  • It is recommended that two tests be used to detect lupus anticoagulant. The most sensitive tests are dilute Russell viper venom test (DRVVT) and a LA-sensitive PTT (PTT-LA), one that uses low levels of phospholipid reagents. Follow-up testing is performed to confirm or exclude the presence of lupus anticoagulant. These may include:

  • Mixing study: an equal volume of patient plasma is mixed with “normal” pooled plasma and a PTT or DRVVT is performed on this mixture.

  • Correction/neutralization: an excess of phospholipids is added to the patient sample and a PTT-LA or DRVVT is performed. (When PTT-LA is measured, the assay is called a hexagonal phase phospholipid neutralization assay).

The Laboratory Method:

From Practical Haemostasis

Pooled normal plasma is mixed with diluted PL at 37°C. Diluted RVV and then calcium chloride are added and the clotting time is measured. The test is then repeated using patient plasma and the ratio of test:normal plasma is calculated.

Reagent Explanation
Platelet poor Plasma A source of coagulation factors, particularly thrombin and fibrinogen.
Dilute Russell’s Viper venom Typically this is diluted to give a clotting time in normal plasma of between 30-35s as this optimises sensitivity to antiphospholipid antibodies.
Phospholipid To provide a surface for thrombin generation. This should be diluted to a sufficient degree that it becomes the rate limiting step and any inhibition by a LA prolongs coagulation.
Calcium To initiate coagulation

My Test Results:

DVRTT

Although my test results were out of the normal limits, it is not considered a positive test because my result would need to be higher than normal range (slower clotting time) and mine was below the average (faster than the normal clotting time).  Make sense? No idea if a low score has any clinical significance – haven’t found anything that even mentions it.

Below are some explanations about the meaning of the results and how to determine a positive test.


Result Interpretation:

From The American Association for Clinical Chemistry

The results of the series of LA tests either lead toward or away from the likelihood of having LA. The laboratory report may be somewhat complicated, but it usually provides an interpretation of the results and states whether LA is present or absent. LA testing results, like those of other tests for clotting disorders, are difficult to interpret and are best evaluated by physicians with experience with excessive clotting disorders.

Although the initial tests performed for LA may vary, they usually begin with a PTT that is prolonged. A PTT that is normal (not prolonged) may mean that there is no LA present. However, the test may not be sensitive enough to detect LA and the LA-sensitive PTT (PTT-LA) may need to be done.

Additional details on LA testing results

Lupus anticoagulant testing is often done in conjunction with tests for cardiolipin antibody and anti-beta2-glycoprotein I antibodies to help diagnose antiphospholipid syndrome. The results are interpreted together, along with clinical criteria, in order to make a diagnosis.

Results of other tests that may be performed to help rule out other causes of a prolonged PTT include:

  • If a thrombin time test is normal, then heparin contamination is excluded as a cause of prolonged PTT.
  • If a fibrinogen test is normal, then it is likely that there is sufficient fibrinogen for clot formation.

Other tests that may be done to help confirm the diagnosis of a lupus anticoagulant include:

  • Coagulation factor assays – these may be ordered to rule out factor deficiencies that may cause a prolonged PTT and bleeding episodes; a panel of factor assays may also help in detecting lupus anticoagulant.
  • Complete blood count (CBC) – the CBC test includes a platelet count; mild to moderate thrombocytopenia (low platelet count) is often seen along with the lupus anticoagulant; moderate to severe thrombocytopenia may develop in patients receiving anticoagulant (heparin) therapy for lupus anticoagulant-associated thrombosis.
  • Tissue thromboplastin inhibition test (rarely performed nowadays)

Clinical Explanation:

From Practical Haemostasis

If the DRVVT is not prolonged then the correction test (sometimes referred to as the neutralisation test) is not indicated.

DRVVT Interpretation
DRVVT
Ratio [Test DRVVT/control DRVVT]
Reference Range: 29-42s
Reference Ratio: 0.9-1.05
Ratio [Test DRVVT/control DRVVT] >1.05 Possible LA
Exclude deficiencies of factors II, V, X, fibrinogen or another non-LA inhibitor
Prolonged DRVVT which corrects with normal plasma Clotting factor deficiency
[A weak LA can sometimes be masked in a 1:1 mix with normal plasma and some labs recommend a 1:4 mix [Normal plasma:Test plasma] to try and minimise this]
Prolonged DRVVT which corrects with PL Lupus anticoagulant

Calculating the percentage correction:

1. The percentage correction is calculated using the formula below where ‘+ PL’ is the DRVVT with additional phospholipid i.e. the neutralisation step.

2. The percentage correction of the ratio is calculated using the formula below where again ‘+ PL’ is the DRVVT with additional phospholipid. The final result is multiplied by 100 to convert it into a percentage:

This latter calculation is that currently recommended by the British Committee for Standardisation in Haematology [BCSH.]

In the following example:

Sample dRVVT Clotting Time [s] Ratios
Patient Plasma 69.2 s [Patient Plasma]/[Reference Plasma] = 1.82
Reference Control [Normal] Plasma 37.9 s
Patient Plasma + Phospholipid 39.5 s [Patient Plasma + Phospholipid]/Reference Control [Normal] Plasma +  Phospholipid] = 1.21
Reference Control [Normal] Plasma +  Phospholipid 32.5 s

From the data above: [1.82 – 1.21/1.82] x 100 = 33.5% correction. So in a patient in whom the dRVVT is prolonged as in this case [69.2s] the 33.5% correction is consistent with the presence of a lupus anticoagulant.

3. What constitutes a positive correction ratio? Most laboratories regard a correction of >10% with PL as being a positive test.

In individuals in whom a LA is identified, the test should be repeated in 12 weeks. It should also be remembered that not all tests including the DRVVT will identify all LAs and therefore, if the index of suspicion that a specific patient has a LA then other tests should be undertaken e.g. Silica Clotting Time [SCT]. Finally – the causes of a LA should be screened for e.g. ANA, drugs, viruses etc.


References: 

American Association for Clinical Chemistry (2014). Lupus Anticoagulant Testing. Retrieved from https://labtestsonline.org/understanding/analytes/lupus-anticoagulant/tab/test/

Practical Haemostasis  (2016). Dilute Russell’s Viper Venom Time [DRVVT]. Retrieved on June 6, 2016, from http://www.practical-haemostasis.com/Thrombophilia%20Tests/APS/drvvt.html

Sports One Media (2012, July 12). Viper Venonom Turns Blood Into Jelly [Video File]. Retrieved from https://www.youtube.com/watch?v=PwT8vDzjCSQ&list=PLXGuqM-FQFlipPDC8hcLvG7CQ2F8divMo&oref=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3DPwT8vDzjCSQ%26list%3DPLXGuqM-FQFlipPDC8hcLvG7CQ2F8divMo&has_verified=1

Oh doctor, doctor, I must have gotten this sick somehow. I’m going to ask you a series of questions, and I want them answered on the spot, right now.

Patience has never been a virtue of mine, as many of my friends and family can attest to.

But I feel that I have been extremely patient with my doctors, maybe more than I should be.

I wasn’t planning to do an update until I received the final confirmation from my doctors,

but it seems like that won’t be happening anytime soon,

so I figured that no time is better than the present.

It’s been just about a month since my abnormal tests came back. I have left multiple messages for both doctors, one every week, hoping for a callback or at least an idea as to whether or not I need to come in for an appointment to discuss the test results in person.However, all I got was silence. I literally felt my blood boiling each day that went by that I didn’t receive a call. 

I’d whine about how:

“They’re delaying my care.”

“Sure, just because I’ve been sick forever, no reason to rush or anything.”

“I don’t know how doctors can get away with not calling when tests are abnormal.”

And, of course, the classic:

“I’m going to die before they ever figure out what this is.”

I was feeling sorry for myself, to say the least. I felt alone, abandoned, and lost as to what to do next. It was really starting to mess with my head. I hated being this way but I hated how these doctors were making me feel even more.

I felt like they were completely disregarding everything I have gone through

in my search for a diagnosis.

The years of life I have lost due to being sick.

The hours spent driving to appointments.

The amount of time in hospitals and doctor’s offices.

The high levels of radiation and all the discomfort in medical testing.

The countless pills prescribed, which often caused more side-effects than actual relief.

The procedures and surgeries, which also didn’t fix my disease.

The friends and family I lost, because they didn’t understand.

My career goals and aspirations that have been placed on hold.

Everything I once was and what I could be.

My whole life is on hold!

And here, right in front of you, are these abnormal tests

that provide answers to my chronic, undiagnosed illness

that I’ve fought so hard, for so long, to find

and you can’t pick up the phone to call me? 

Maybe I am being impractical,

but a month spent waiting seems way too long.

That’s a month to complete more testing or get second opinions.

Four weeks of treatment or management.

30 days of my life lost, left waiting.

FINALLY, a nurse from my GI, Rheumatologist/Immunologist, and Cardiologist’s office called, but she only caused  more confusion and frustration than before. She tells me my fecal cultures came back normal, which I already knew. She then says my cortisol levels were low (again, I’ve had my test results for weeks) and the doctor would like me to rerun it to be sure. She’s going to mail the paperwork so I can at least have my blood drawn in town, instead of driving over an hour. Great, thank you. She also tells me to stop taking my lupus medications… wait, what? The GI doctor and the Rheumatologist/Immunologist agree that I should stop taking them, because I’m not autoimmune. Um… ok. How come she originally, as did all the other doctors, think it was seronegative autoimmune disease? Specifically, Lupus?  I’m not in the mood to argue, I’ve been feeling terrible. I ask if I stop them forever, she says yes and the conversation is over.

She calls again yesterday, just to tell me to stop taking the Lupus medications… again. Yes, you told me the day before. Both doctors think it may be causing my painful and urgent diarrhea.Um, I have had on and off urgent diarrhea for… like… ever. But ok. So it’s not because it can’t possibly be autoimmune? I’m confused. She asks if the medication has helped. I said I’m over the initial side effects. I’ve had constipation for the past few days, so don’t think it’s causing diarrhea, and I haven’t had any extreme photosensitivity as in the past weeks, but still having outbreaks of rashes. I don’t know what is causing what anymore. My symptoms are too random and sporadic. She says to call next week or the week after, let them know if being off the medication makes me feel better or not, and then we will restart it if it’s not the problem. Wait… so let me get this straight? Now you’re taking me off it, to see if it’s having side effects I have had forever, only to restart it and have to adjust to it once again? Are you kidding me? Well, it may be affecting your cortisol levels, so they want to see if I stop it if it’ll change my blood test.  I am beyond confused and frustrated at this point. I went and redid my cortisol blood test this morning, so I guess we’ll just wait and see what that tells us.

Still haven’t gotten a call from the vascular surgeon. My CT Angiography was the one I was MOST worried about and  I fretted every night about him not calling me to discuss the findings. . Finally fed up, having left four messages now, I called and scheduled an appointment to discuss. I don’t know whether or not I trust him to treat at this point, given the lack of respect of promised phone calls with no answers, but he may just not know what to do or say about the finding. This is the doctor who didn’t believe in Nutcracker Syndrome at all for his own, valid reasoning, but admitted my original CT Scan showed the most convincing case of Nutcracker Syndrome that he has seen in over 30 years. He ran the CTA to “prove him wrong”. On the order form for the test, he even wrote “to exclude Nutcracker Syndrome”, instead of “evaluate for Nutcracker Syndrome”. He was really convinced I couldn’t have it, it’s too rare, and most vascular surgeons don’t think it’s a real thing.

Well, guess what? I proved him wrong. Not only that, they found two more (even rarer)  vascular compressions. The radiologist noted both May-Thurner Syndrome and Superior Mesenteric Artery Syndrome, although the Nutcracker Syndrome is the most extensive. So perhaps, maybe he is lost as to what to do or say at this point, I don’t know. But I’d rather him tell me that if that is, in fact, the case, rather than be silent about it. But I have an appointment now, so he can’t ignore me. So we’ll see how that goes.

I also had my consultation with cardiology last week. It had gone way better than expected and I really liked the doctor. He not only listened to me, he caught things other cardiologists had  missed in the past, and had my notes completed (and accurate) by the end of the day. I was fearful for this appointment, as I have not had the best luck with cardiologists in the past. They always say they hear a “murmur” or “valve issue”, order tests, and then call me crazy. This has happened on multiple occasions, both in my teens and early twenties. So you can see how I’d be nervous about going straight into an appointment saying “I think I have POTS syndrome and so does my neurologist and the immunologist (although she seems to have forgotten EVERYTHING she told me in my last appointment, so maybe she doesn’t think I do anymore, who knows)”. I show him the letter from the neurologist and my ‘poor man’s tilt table test’ results. He says that it looks like I have POTS, but he wanted to have some “orthostatic fun” in the office just to see. He measured my heart rate and blood pressure while laying down, sitting up, and standing.  Sure enough, my blood pressure dropped really low and my heart rate increased up to 150. Yep, he’s pretty convinced that it is POTS, but because of the missed information in previous cardio tests, he wants to rerun them again just to make sure it’s not something “easier” or misdiagnosed.

In my echocardiograms from 2005 and 2007,  he noticed that there was what he called “abnormal electricity” shown, but the EKG didn’t catch it, so it was dismissed. It happened again in my 3D echo from last year. Also, the 3D echo from 2014 showed I had pericarditis, which is a typical sign of autoimmune (particularly Lupus), but, of course, need to rule out other possible causes as well. And finally, my halter monitor from 2007 showed abnormalities and heart beats exceeding 160 bp, which was also dismissed during that time. So he ordered a 3D echo again, to see if the pericarditis has cleared on its own or if it’s gotten worse. He also wants to evaluate the possibility of a hole in my heart (which many people are born with, although it usually clears up on its own as you get older) since they can’t confirm the cause of my hypoxemia, other than the mild sleep apnea that was confirmed through my sleep study last year (although he doesn’t believe that is what is causing it, because again, it was very mild and happens sporadically during the daytime as well). So I’ll be back in the hospital tomorrow to complete all of these cardio tests. If  all the differential diagnoses are excluded, then he will be referring me to the dysautonomia clinic for further treatment, but was comfortable enough to put down Postural Orthostatic Tachycardia Syndrome as an official diagnosis. Again, something I have been saying since I started looking for answers. Finally! So we’ll see how testing goes tomorrow and I guess go from there.


So what does this all mean?

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It’s more than just ONE cause, obviously.

There are multiple conditions feeding off of one another, 

making my conditions not only rare,

but also complicated to treat and manage.

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Here’s what is on the table (so far):

Dysautonomia:

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More specifically —> Postural Orthostatic Tachycardia Syndrome (POTS):

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Nutcracker Syndrome:

“The nutcracker syndrome is quite a rare condition. It is due to the compression of the distal segment of the left renal vein (LRV) between the superior mesenteric artery (SMA) and the aorta (also called left renal vein entrapment).  This syndrome needs treatment when symptoms are disabling” (Hartung, O., 2009, p. 246).

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Superior Mesenteric Artery Syndrome (SMAS):

“Superior mesenteric artery syndrome (SMAS) is a digestive condition that occurs when the duodenum (the first part of the small intestine) is compressed between two arteries (the aorta and the superior mesenteric artery). This compression causes partial or complete blockage of the duodenum. Signs and symptoms may include abdominal fullness; bloating after meals; nausea and vomiting; and abdominal cramping that may be helped by lying in certain positions.” (NIH Office of Rare Diseases, 2014)

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May-Thurner Syndrome:

“May-Thurner syndrome (MTS) is caused when the left iliac vein is compressed by the right iliac artery, which increases the risk of deep vein thrombosis (DVT) in the left extremity. DVT is a blood clot that may partially or completely block blood flow through the vein. Even though DVT itself is not life-threatening, the blood clot has the potential to break free and travel through the bloodstream, where it can become lodged in the blood vessels of the lung (known as a pulmonary embolism). This can be a life-threatening condition” (ClevelandClinic.org)

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Symptoms and Causes of Low Cortisol Levels:

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A lower than normal level may indicate:

  • Addison disease, in which the adrenal glands do not produce enough cortisol
  • Hypopituitarism, in which the pituitary gland does not signal the adrenal gland to produce enough cortisol
  • Suppression of normal pituitary or adrenal function by glucocorticoid medications including pills, skin creams, eyedrops, inhalers, joint injections, chemotherapy

Other conditions for which the test may be ordered include:


Is this a final diagnosis?

Knowing how thing have gone in the past, it’s  highly doubtful.

Maybe there is more to the story…

Maybe there is less significance…

Only time will tell.

Again, I am left waiting…


Now if only I can get all my doctors organized and working together, maybe I can clear up what this all means and what needs to be done next. Surgery? Medications? Again, who knows… 

While I DO know for sure that NONE of these diagnoses will ever be “cured”, I’m hoping we can at least find a way to manage everything so I could hopefully live a semi-normal life again.

I still have to do a hydrogen/methane breath test next week, as well as upcoming appointments the week after with dermatology (to run biopsies on my skin rashes, hopefully to “catch” the autoimmune disease that’s hiding in my skin) and a follow-up with the vascular surgeon. Plus the results from the cortisol testing I did today and the cardio tests tomorrow. Let’s hope we can get the pieces put all together and figure out what’s next as far as treatment goes.

I guess I’ll just have to wait… something that is unfortunately becoming entirely too common at this point, but at least we’re getting somewhere… slowly. 

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