Cryoglobulinemia: The Triple Whammy

Triple whammy

Cryoglobulinemia: The Triple-Whammy!

Cryo has a way of hitting you from three different directions. Usually when we are flaring we only experience one or two of them. But in a big, bad flare it can really hit you hard with all three.

1) Hyperviscosity syndrome: Accumulating cryoglobulins can make your blood a lot thicker if the concentration is high. It can lead to some pretty nasty effects due to circulation being obstructed in the skin, muscles, and various organs, as circulation can rapidly become impaired in the smaller blood vessels. This can cause numerous problems. Hyperviscosity is a particularly onerous problem with type I cryo, but can also happen in types 2, 3, as well as mixed/combined types.

One problem that often occurs with hyperviscosity is damage to the eyes. In particular, the retina and optic nerve. We had a couple of people in this group experience a bad flare with effects on vision likely due to hyperviscosity syndrome last winter. You need to be alert to sudden changes in vision such as blurry vision, flashes of light in your side vision or a sudden increase in “floaters” in your eyes. This is a serious problem that could damage your vision permanently in hours if not treated right away, so be alert.

2) Autoimmune Vasculitis: Cryoglobulinemia is a vasculitis affecting small and medium blood vessels. Cryoglobulins are unusual molecules. They are large, heavy, and in the immune system they act as both antibodies and antigen. Once cryo starts, there is a tendency for it to not stop. The immune system processes the cryoglobulins and in the process a lot of inflammatory agents and autoimmune components are released which cause inflammation in small and medium blood vessels, and vasculitis results. Rashes, skin lesions, skin ulcers, and symptoms similar to rheumatoid arthritis are not uncommon. The process continues, usually until the cryoglobulins are gone or, more commonly, until the immune system is forced into remission and the inflammatory process is halted with medication.

3) Cryoprecipitation: Once the cryoglobulins have been processed by the immune system, the already large molecules tend to link up vis-a-vis a bond facilitated by immune system compliment molecules. Once this happens the cryoglobulins may rapidly begin to precipitate if the skin temperature drops below the core body temperature. This causes even more problems with outright plugging , and vasculitis in medium and small blood vessels. This will continue as long as cryoglobulins are available if the temperature is allowed to remain below the core body temperature. If cryoglobulins are present and you are not actively flaring, it is still possible to have cryoprecipitation.

Quantitative vs. Qualitative Cryoglobulinemia Testing and a Second Positive Cryo Test

Qualitative vs Quantitative testing for Cryoglobulins

The qualitative test for cryoglobulins is a test for the presence of cryoglobulins only. It gives no indication of the level or type of cryoglobulins found. The quantitative test for cryoglobulins returns the type and level of cryoglobulins present.

A single qualitative positive test for cryoglobulins qualifies as a diagnosis for cryoglobulinemia. Some doctors like to use the quantitative cryocrit test to measure the level of cryoglobulins as a diagnositic indicator.

The level of cryoglobulins in the blood are NOT good indicators for the severity or diagnosis of cryoglobulinemia.

It is well known that the cryoglobulin levels are highly variable from one patient to the next, and in any individual patient can fluctuate greatly, and may actually be absent altogether at times. Furthermore, while many labs make claims of accuracy, the accuracy of cryocrit measurements has never been well established, and a “standard” level for cryoglobulins as a diagnostic does not exist.

The bottom line is , one patient might have 3% cryoglobulins in their blood and be extremely ill with cryoglobulinemia, and yet another patient might have 11% cryoglobulins, and be completely asymptomatic. We don’t know why. . Every now and then one encounters a doctor who insists that cryoglobulin levels must be greater than 11% for a diagnosis of cryoglbulinemia. This is completely wrong, and arbitrary, and is simply not supported by the facts. Cryoglobulinemia is defined as the presence of cryoglobulins in the blood. Because of this clear and simple definition, the mere presence of cryoglobulins is taken as the diagnostic indicator for cryoglobulinemia. If you have cryoglobulins, regardless of the level, you have cryoglobulinemia, by definition.

Some doctors like to have a second positive for cryogobulins to confirm the diagnosis. This approach is likely not workable most of the time unless you can find a facility that does the test themselves, does it correctly, does it reliably, and you don’t mind repeating the test *A LOT*. This is because the test for cryoglobulins is not done correctly by most labs, and a false negative is returned about 70-75% of the time, At the same time false positives are uncommon.

In very real terms, one positive in the face of symptoms for cryo is compelling, and this is where most doctors will make the call, and call it cryoglobulinemia. The hard part is finding what is causing the cryo…

NOTE:  putting heparin in the test tube is another way to get a false positive if the tech does not know how to tell fibrin deposits from cryoglobulins.

A second positive cryo test is something to try for, but is sometimes not possible or practical to obtain. I’ve had ONE positive qualitative test, and have been tested for quantitative cryoglobulins about 6 times. The trouble is that the only time I was tested for cryoglobulins when I was flaring, and I clearly observed that the specimen was collected and handled correctly, was the single qualitative positive. On one other occasion blood was drawn correctly and the sample was then placed in a thermos for mailing to an outside lab for a quantitative test… but at that time I was in remission and we were trying to make sure I was in remission before changing the meds…. of course it came back negative. Other attempts at getting a cryoglobulin test were clearly done incorrectly from the beginning with the blood simply being drawn, the test-tube placed in a rack and the sample shipped to an outside lab. The lab doing the test in most cases was LabCorp. My first positive was taken at Washington Adventist hospital, and it was drawn and handled carefully by a head nurse,, not just a phlebotomist. My most recent test was done at the University of Maryland Medical Center, and I had requested a test for cryogobulins while there. At no time was a blood specimen drawn and handled with regard to temperature. The hospital records reported a negative test result, but I’m not even sure the test was actually performed.

Animals, Cryo and So Much Unknown.

Scary Worst Case Body Stuff

Picture by Dale Sears
Internal organ involvement is insidious. You might not feel any pain or discomfort until the affected organ is severely damaged. Fortunately, this does not happen most of the time.
The thing one has to remember is that cryo is a systemic vasculitis and can affect any organ and any system in the body. Some things are more likely than others, but pretty much anything can happen. This is why it is important to try to keep your core body temperature up , because if the cryoglobulins start precipitating deep inside your body, you are then setup for internal organ damage.
But sometimes you simply can’t tell that something bad is about to happen until it does happen. A sudden clotting cascade can be life threatening, and a necrotic lesion on the heart or in the brain can be so rapidly fatal that they are frequently found post mortem. A lesion in the brain or heart are simply catastrophic. In some cases people develop various problems from them, but is frequently instantly fatal. One simply falls over dead. Fortunately these are NOT very common. Several people in our support group have had clots in the heart, head, arteries and strokes associated with cryo, and survived (Eileen Propp has survived 2 blood clots – one in the transverse sinus and one in the internal jugular vein.)
  • Kidney involvement can be spotted with a simple urinalysis.
  • Lung involvement is easily checked with a CT scan once in a while.
  • A full metabolic panel is good for checking liver functionality.
Another thing that has not been discussed is the association of antiphospholipid syndrome with cryo. A small percentage of people who have cryo have a tendency to clot excessively. You can wind up with a pulmonary embolism and expire pretty fast. A really bad situation is when someone goes into a clotting cascade, and doctors might not have sufficient time to treat it. Usually it is treated successfully, but death can be rapid, otherwise. you will basically know you have a stroke when (and if) you have one.

Cryoglobulinemia: Labeled a disease in 1930’s.

Remission in Essential Cryo: A simplified explanation.

This is a  *vastly* simplified breakdown of how remission probably works in essential cryo.

The cryoglobulin is both an antigen AND an antibody. Cryoglobulins are produced on the surface of B cells that apparently have matured past the usual age at which they are programmed to die. In essence, the immune system wakes up due to an inflammatory process, and promptly attacks itself. This process never ends because the T cells remember to tell the immune system to make the cryoglobulins as a response to the activity. Using immunosuppressants tend to kill off fast growing cells such as B cells and T cells. The B cells are the cryo factory, and the T cells are the memory of what to attack. The thinking is, that if you suppress the immune system deeply, for a long enough period to eliminate the cryoglobulins, the T cells sometimes eventually “forget” about cryoglobulins altogether, and you have a “true” remission that can often be maintained for long periods after the immunosuppressant is withdrawn (typically withdrawn slowly, over the period of a year or more). In a very, very few cases, the cryo never comes back.

Short term remission is a bit different. The cryo is gone because the immunosuppression has killed off the B cells. As soon as the body generates a new batch of B cells , a flare is likely. This can be anywhere from a few days to a few weeks after withdrawing the immunosuppresant.

Essential Cryo: Flare Remission Cycle

Essential Cryoglobulinemia: Flare/Remission Cycle:

One researcher stated that “Cryoglobulinemia is a disorder characterized by periods of remission followed by periods of flaring….“.

  • One of the interesting things about truly essential cryo is that it can sometimes be driven into full remission using medication, and if the meds are slowly withdrawn over a long period of time, the remission can remain , so you end up with a medication free remission.
  • Typically a medication free remission can last from weeks to months, and sometimes people remain in remission for a year or more. In a few cases the cryo never returns and after 10 years of medication free remission with no symptoms, the patient is deemed “cured”.
  • If one looks at the success rate of this approach, about 50% of patients with a medication free remission will flare within the first year.
    • Of the remaining patients still in remission about 10% will have a long term remission lasting longer than a year.
    • Also, the longer you are in remission, the better the chances seem to be for continued remission (I have no numbers for that but this is based on 8 years of anecdotal experience).
    • So lets assume that something like 3% of cryo patients have truly essential cryo (meaning there is no co-occuring cancerous, autoimmune or viral disease causing the cryo).
      • the odds of being “cured” in this manner come out to be about 1/10 of one percent if one is looking at all patients with cryo.
      • the odds of being “cured” and about two percent for patients with truly essential cryo.

My personal experience with flares and remission.

  • In general, if I am not in full remission, I flare anywhere from days to weeks of withdrawing medication. If I have been in full remission for a long time, I can go for weeks, to months. I have had one period of about a year of medication free remission. Genrally if I am going to flare big, it is in the fall months. But I have had flares in the summer too. It does not seem to be predictable, but it also seems as though things that stimulate my immune system make a flare more likely. On one occasion I caught a cold in the summer, anfter a couple of days of that I started to flare, the cold went away on a few days, but th flare persisted for a couple of weeks. It is like that old song “The weight”. a line in it says “I gotta go, but my friend can stick around…”
  • I’m lucky in that I seem to respond well to treatment. Even at that, I get surprised regularly and there are unforeseen medical events, and sudden flares.

NOTE: Cryo *always* requires vigilance. Being alert to your condition is the best way to reduce the risks of bad things happening.

Managing My Cryo: Imuran, Steroids and Balance

Starting on Imuran: 

  • I’ll be starting on Imuran this weekend. I was on a combination of cyclophosphamide, antibiotics, and prednisone for 3 months, to force remission and withdrew the cyclophosphamide two weeks ago to “wash out” a bit before starting the transition to Imuran.
  • Right now I am on 30 mg prednisone per day only and still seem to be in full remission. My tolerance of cold is basically “normal” right now….. if my life can be described as normal at all…..
  • Imuran is a very slow acting immunosuppressant.
    • It takes weeks for it to have any effect at all, and is typically a month or two before it is at full effect. (In the near term I expect to remain on antibiotics.)
  • Right now the plan is to start Imuran at 50 mg, twice a day, and in two weeks I’ll taper down the prednsone to 20mg/day and hold there until I get blood work done again in another month.
  • Once the Imuran is in full effect, and if I am not flaring, I’ll start tapering off of the prednisone completely and remain on imuran for remission maintennence….
    • This is the teter toter of transitioning off one medicine to another.. If down too fast on steroids I may flare. It is a balance that is difficult to maintain and is unpredictable.
  • Using steroids in conjunction with Imuran (or other immune suppressants) is a fairly standard protocol for establishing remission in essential cryoglobulinemia.

*NOTE:  It is really not what one would do in the case of cryo that is secondary to some other cause. In those cases the primary cause is usually treated first.


Disease Modifying Anti-Rheumatic Drugs (DMARD’s) and Monoclonal Antibody Therapy (MAB)

Disease Modifying Anti-Rheumatic Drugs (DMARD’s)

  •  If you are being treated for cryo, chances are that you are on one of the drugs that I have listed here or are considering them as options with your doctor.
  • DMARDs are a class of drugs commonly used to treat a variety of autoimmune disorders.
  • Some were developed primarily for the treatment of cancer, malaria, or for preventing organ rejection in transplant patients.
  • DMARDs are sometimes referred to as “steroid sparing” drugs because they often allow greater overall effectiveness at maintaining remission of autoimmune disorders when used in combination with low dose prednisone. In some cases more than one DMARD may be used in combination.
  • Each DMARD is a bit different from the others, effectiveness varies from one condition to the next and the side effect profiles are also highly variable.
  • Some DMARDs have a greater risk of potentially dangerous conditions and the patient must be monitored continuously for their safety.

Below , I have listed some common DMARDs in order of their basic action on the body, this list is not complete and you will want to search the internet and find further information on your favorite DMARD with regard to risks, safety, drug interactions, and side effects.

  1. The following drugs include the antimalarial agents, are frequently slow to take effect and some have significant long-term side effects.
    1. gold (rarely used) Sometimes effective for rheumatoid arthritis). This treatment has been around since the Victorian era! It is not well understood and tends to cause increasingly severe side effects over time.
    2. hydrochloroquine (Plaquenil) An anti-malaral agent. Often used in combination with steroids, commonly used to treat Lupus.
    3. methotrexate commonly used for a variety of autoimmune disorders and may be used in cmbination with other DMARDs
    4. sulfasalazine Often used to treat Chron’s disease, may be used with other DMARDs.
    5. cyclosporine Developed to prevent organ rejection in transplant patients. This drug may have serious long term safety issues. It is sometimes used in cases where nothing else works.
  2. The following drugs are the immunosuppressants. They can be slow to take effect and carry a risk from infection due to suppression of the immune system. Side effects vary, some are not so bad, but others have *significant* risks and side effects and the patient must be closely monitored.
    1. cyclophosphamide (cytoxan) Commonly used in oral and IV form, frequently used in combination with prednisone to force remission. Has a relatively big risk and side effect profile. This is generally viewed as a serious “big gun” that suppresses the immune system deeply.
    2. Imuran (Azathioprine) Commonly used to maintain remission after remission is established. Commonly used with low dose prednisone.
      1. Less risk and fewer side effects than cytoxan. Slower to take effect than cytoxan. Does not suppress the immune system as deeply as cytoxan.
      2. Imuran carries a small, but real risk of causing the immune system to die off rather quickly, so your blood counts must be monitored carefully.  Low white blood cells and low producing neutophils are a risk.
    3. leflunomide Sometimes used alone, but may be used with another DMARD, or a biological agent.
    4. mycophenolate-mofetil (cellcept) Originally developed to prevent organ rejection in transplant patients. Often used in combination with other DMARD’s, and more recently used in combination with biological DMARDs.
  3. Biological Agents (so-called bDMARDs)
    1. Tumor Necrotic Factor (TNF) Inhibitors
    2. including etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab,
  4. Specific Biological Agents with specific targets (also called Monoclonal Antibody Therapy = MAB)
    1. These drugs are basically designer antibodies that have very specific targets.
    2. For example: rituximab (rituxin) targets B cells specifically.
    3. including anakinra, abatacept , rituximab, tocilizumab, and tofacitinib. These medications are often combined with methotrexate or other DMARDs to improve efficacy.

*Author NOTES:

  • Plaquenil is not a heavy hitter like the above immunosupressants are, but it is a lot safer and has fewer side effects, so if it works for you , it works…. and that is a good thing.
  • If you need to take the medication , you take it.
  • It is all about risk management. For a more serious situation a bigger risk may be warranted in order to gain more effectiveness. The doctor has to make this kind if decision… and so do you the patient. For example, using cyclophophamide with prednisone to force remission in a case of cryo is not unusual. Once remission is established, one can tansition to something like Imuran, methotrexate, or cellcept. Often a patient might not tolerate one of the medications very well, forcing a change to another.
  • Some get along with imuran very well, so it is a good choice, and has less risk than staying on cyclophosphamde.
  • Also, Imuran is a reasonably safe drug to stay on if you have to take it long-term. So it really boils down to risk management vs effecrtiveness and having a list of possible options.

Cryo and Mortality

Cryoglobulinemia and Mortality

This is a topic which I have been avoiding to keep from alarming those who have been newly diagnosed without good reason to do so.

After researching this , and thinking about it for some time, I decided that I should talk about this in a post on the forum.

Based on work done by Claudio Ferri (2004) it appears that the mortality rate for persons with cryoglobulinemia are about 42 percent, possibly as high as 50 percent in the first 6 years after diagnosis. Rossa et-al (2008) included the work of Ferri and others to arrive at similar results.

Rieu et-al (2002) examined outcomes for various comorbid conditions with cryoglobulinemia and determined that a more positive outcome was likely in patients who did not have liver, kidney or lung involvement with cryoglobulinemia.

Later work by Bryce et-al (2006) revisited mortality and observed that for all patients in their study, overall the mean 50 percent survival time was about seven years, and that for patients over the age of 57.6 years, the 50 percent survival time was a little better than 5 years.

In all three of these studies, researchers point out that the outcome is likely to be significantly better if there is no involvement of the kidneys, liver, or lungs. Surprisingly, in spite of the seriousness of potential involvement of these organs, the leading single cause of death in cryoglobulemia appears to be vasculitis.

With a cure for hepatitis C now available and with patients getting treated successfully, I would expect to see the 5 year survivor rates improve over the next few years as the number of people having liver involvement with cryoglobulinemia ought to decline markedly. Unless a breakthrough in treatment is achieved, I would expect to see vasculitis continue to be the leading cause of death in persons with cryoglobulinemia.

ADDENDUM: One thing that should be mentioned is that treatment of cryo has improved a lot in the last 2-3 decades. The expected survival of a person with severe cryoglobulinemia would be a matter of a few months, at most, without treatment.

I just added a citation for Rossa (2008). I had used his information but had not cited it.

If I Could Design Cryo Research

Cold Weather and the Cryo Patient’s Attempt to Control Temperature

I find it remarkable when doctors think that colder weather/climate is not a problem for people with cryoglobulinemia. Particularly when so .  . . so many people with cryo have a rather immediate response to cold. It is also known that individual responses to cold appear to be highly variable among people with cryoglobulinemia. There are also accounts of people moving to colder climates from warmer climates who suddenly display symptoms of cryoglobulinemia.

The debate over controls of precipitation temperature for cyoglobulins in the blood has neen a longstanding issue. In fact there is a lot more to it than just concentration and temperature, but the basic property of solubility is controlled by concentration and temperature as the saturation point will change with temperature. This is a fundamental physical property. The question does remain that the behavior of cryoglobulins in a petri dish is not guaranteed to be the same as in a living person, and the blood contains a lot more than just water and cryoglobulins, and the chemistry of it is rather dynamic… so technically it may well be correct to state that one can not clearly show that concentration and temperature are the big controls the precipitation of cryoglobulins.

At the same time common sense clearly suggests that given no other metric, one should seriously consider it from the standpoint of safety, especially since cryoglobulins DO precipitate/gel at temperatures below normal body temperature, and persons with cryogloblinemia DO experience adverse physical reactions to cold. Maybe some really bright grad student needs to get some funding and go after this rather fundamental question ?

Eating well and getting exercise is important and improving physical strength is helpful, always. It is particularly important when recovering from a long battle with a flare. It can take awhile to regain strength and wellness, so taking care of oneself is important.

As a normal emotional response  I do realize that it is easy to become fearful of cold when one has cryoglobulinemia, but realistically after a couple of bad experiences with cryo we have ample reasons to feel that way. It should not be surprising that some of us might be a little “over the top” with our cautions regarding cold. The reasons for that are quite sound. We don’t know for sure what the “safe” operational limits are.

Three Core Cryo Symptoms: Meltzer’s Triad

Meltzer’s Triad

In 1956 Meltzer and Franklin described arthralgia, purpura and weakness as the three core symptoms of essential cryoglobulinemia. These are generally seen in people who have type II and type III cryoglobulinemia. It is seen in 25-30% of patients with cryo. I just thought I’d share this.

Cryo Symptoms: Points to Consider

Symptoms of Cryo: Points to Consider

Sometimes cryoglobulinemia will present with very few symptoms externally, before you have a full-blown flare. I have listed of a few of the more subtle things, and some of the weird things that have happened to me as symptoms some sort of serve as a warning that I am in the early stages of a flare, others only happen when the flare is a big one.

You also need to be aware that cryoglobulinemia can affect any organ, and any system in the body. Cryo can affect so many parts of the body, but below are what I believe to be the most common aspects of cryoglobulinemia. Keep these 14 points in mind when tracking your own symptoms.

  • Malaise.
    • I sometimes get a general feeling of “not well”, but “not sick” days or weeks before a flare.  Malaise is a general felling of “not well”.
    • Plus after a week or so of a full-on flare it is very hard to remember what normal is, and everything becomes a struggle.
    • It is hard to be happy when you are as sick as a dog, with no end in sight, and not really knowing what bizarre life-threatening medical event might or might not strike you at any time. You sort of go into survival mode.
  • Muscle weakness.
    • Don’t confuse this with feeling tired. You might not be tired at all but your muscles are actually weak.
    • This is because people with cryo often experience muscle degeneration, or myopathy in the early stages of a flare and this means weak, sometimes sore muscles.
    • This takes months to heal after cryo is driven into remission. A good combination of rest and exercise helps a bit.
    • Don’t try to push weak injured muscles hard during a flare or you will just pull a muscle and have more pain. Take it easy.
  • Aches and Pains.
    • General aches and pains, mostly sore muscles…. just kind of achy and nondescript pain for a while before a flare.
  • Fatigue.
    • You simply feel tired. Your body is burning a lot of energy on an runaway immune system You can expect to feel tired.
  • Rapid Weight Loss.
    • Rapid weight loss. You will lose a lot of weight as the flare progresses. Some of it is due to muscle loss, some is just weight loss in general.
  • Splinter lesions.
    • Splinter Lesions under the fingernails are tiny blood-filled lesions under the nail that appear suddenly. They are tiny, long, and thin.
    • They form instantly and it takes months for the nail to grow out enough for them to go away.
    • Splinter.Lesionsplinter.lesions.2
  • Fever
    • Fever of unknown origin: You wind up running a fever with no apparent cause.
  • Janeway Lesions
    • I have had janeway lesions that form right at the corner where the end of the nail meets the skin. These seem to start as a tiny spot that forms suddenly. I generally feel a small, but sharp pain the moment they form due the blood vessels rupturing. Look at the picture above (the white arrow). In my case they usually grow and turn into necrotic lesions as the flare progresses. This results in dry gangrene which takes anywhere from 3-6 months to heal. I have lost the tips of two fingers to these. They start out really tiny… smaller than the head of a pin.
  • Arthralgia
    • Arthralgia is arthritis like symptoms. In some cases people with cryo have rheumatoid arthritis as the primary condition, others have symptoms that seem to mimic rheumatoid arthritis, but without the rapid damage to tissues in the joints. Some never experience this.
  • Raynaud’s Phenomena
    • Raynaud’s phenomena, the patriotic symptom: Sudden changes in blood circulation in the hands and/or feet.  Sometimes the circulation in my fingers is compromised by the cryo.  My fingers may turn white, or blue, and eventually will turn red when the circulation returns. Sometimes the palms of my hands will be a very bright red.
  • Achy Joints
    • Stiff/Achy joints: The RA-like swelling in the joints can cause stiffness and pain.
  • Swelling
    • The RA-like symptoms will cause swelling in the joints. Most notably in the ankles, knees , wrist and hands/fingers.
    • Usually the swelling, stiffness, and pain from RA is symmetrical…. that is if the knees are affected, it is typically both knees, not just one, etc. Another interesting thing is that when the joints in the fingers swell , the very last joint toward the end of the finger is always unaffected… no swelling there.
    • Beyond the swelling caused by RA, you have edema, mostly in the lower legs, feet and ankles. This is caused by poor circulation. It can be to the extent that your shoes no longer fit. It does not feel good, and for me, my feet feel rather awful, I am aware of every bone in my feet at this point, and walking is uncomfortable.
    • Massaging the lower legs helps a little, elevating the feet helps a bit. I like to use a heating pad under my feet to keep them warm in an attempt to force cryoglobulins back into solution. it all helps a bit, but the real cure is to get the cryo back into remission.
    • You also need to know that many medications can cause edema in the feet and ankles. Steroids are known for this and it tends to compound the problem.
  • Skin: skin rash, lesions, necrosis, and other things

    • petechiae
      • A rash caused by tiny blood vessels rupturing and bleeding in the skin causing tiny ( < 2mm) papules to form. These can come and go rather quickly.
    • purpura
      • This is also caused by bleeding in the skin. It is a close cousin to petetchiae , only the papules are larger… from 2 mm up to about 10 mm (dime sized).  See the purpura survival guide in the blog for more info on this. These can be painful and may take weeks to heal.
    • skin necrosis
      • Basically, patches of skin turn black and die. This is “dry gangrene”. It is surprisingly fast, It can be extensive, and can result in very bad things. Small necrotic lesions are sometime misdiagnosed as spider bites.
    • Skin ulcers
      • Open sores that won’t heal. The skin dies and breaks down, leaving an open wound. This often requires the services of a wound clinic. Often on the extremities, usually on the feet, between toes, or on the lower legs, but can appear anywhere. Also lesions in the mouth or in the nasal cavity. They can be quite painful; and take a long time to heal, even with proper treatment.
    • Livedo Reticularis
      • This is a really scary looking event when it happens.  Basically the veins just under the skin will dilate (usually in response to a change in temperature) .  The end result is a sometimes-vivid  spider-webbish pattern of purplish veins in the skin.  It generally appears on arms, hands, feet, and legs but can sometimes completely cover the torso.  It looks really scary, but in terms of cyoglobulinemia, is basically harmless… but is also an indicator that something is going on (namely, cryo). It can come and go in seconds.  Sometimes a nice hot shower will make it go away.
  • Neuropathy.
    • Mostly in the form of paresthesias (unusual sensations) caused by damage to the nerves in the hands, feet , arms, and lower legs.
    • In some cases the only presenting symptom of cryoglobulinemia is neuropathy.
    • In some cases sufficient damage is done to nerves in the lower legs that people experience “foot drop” (loss of motor control) in one, or both feet.
    • I have had a bout of paralysis and numbness in my right foot ‘that has partially healed, but my neurologist observed that I often drop the toe in my right foot, apparently due to a bit of a foot drop. It sometimes makes me stumble when I walk.

B Cell and Cryo

It has been speculated that B cells are living too long due to apoptosis failing, as they age past their pre-programmed expiration date they start producing cryoglobulins. It is very likely more complex than this, but failed apoptosis (programmed cell death) is one cause for B cell proliferation. However it is unclear if the failure is in the message sent to the B cells to die or if they are ignoring it. One clue is that in the case for HEPC patients is that cryoglobulins will frequently contain fragments of HEPC RNA. Cryoglobulins do appear to function as an immune system component, but they basically trap targeted antigens by snaring then in their spider-web-ish structure and ripping them apart under electrostatic tension. It is sort of like the Borg in Star Trek. They tear things apart and incorporate them into their molecular structure. The down side is that cryoglobulins behave a bit like both antigens and antibodies which results in a runaway immune system when the immune system basically attacks itself. I tend to interpret the cryoglobulins as the immune systems last desperate effort to rid itself on a source of long standing inflammation. This is not entirely true but it helps me to visualize it. Also, one thing that I suspect may be true is that in cases of non-HEPC cryo, one may benefit from keeping the immune system suppressed long enough, and deep enough to sometimes be effectively “cured”, or at least permanently in remission. This is also speculative, but the fact that stem cell transplants often “cure” cryo strongly suggests that something along this line is going on.