approach to autoimmune hemolytic anemia

1. Autoimmune Hemolytic Anemia
Dr. Ajay Kumar yadav
PGY2,Internal medicine
IOM-TUTH, Kathmandu
2074/9/25

2.  Layout
• Case discussion
• Introduction
• Clinical feature
• Diagnosis
• Management
• Take home mesage

3. • 74 yrs male , ex-smoker and alcohol consumer , non-diabetc , non-
hypertensive but with background h/o COPD for 4 yrs under R/H presented
with 1. fever w/o C/R for 3 days ,10 days back 2. increase in SOB for 10 days
3. yellowish discoloration of eyes with high colored urine for 7 days
• O/E : pallor and icterus present
• Vitals : stable other than Sao2 maintained on O2
• Lab investigations
o Hb : 5.1—2 pint BT ---7.4 g/dl ( TC and platelet : WNL )
o PBS : N/N anemia , polychromasia ,few schistiocytes , no atypical cells
o TB/DB : 44/15 mmol/l : increased unconjugated bilirubin
o LDH : 803 U/L
o Reticulocyte : 8 %

4. o USG Abdomen : Mild splenomegaly
o Serology and VDRL : NR
o ANA / dsDNA : negative
o DCT : couldn’t be done due to autoagglutination of blood immediately after
withdrawing blood
• Bone marrow examination : Hypercellular marrow with erythroid hyperplasia
• CECT chest and abdomen : s/o COPD ( to r/o solid organ mallignancy )
• Sr. protein electrophoresis : awaited ( to r/o MGUS , MM )
• Dx : AIHA : CAD

5. Introduction
• AIHA is a decompensated acquired haemolysis caused by the host’s
immune system acting against its own red cell antigens.
• Incidence : approx. 1 per lakh population/year.
• Age : any age but incidence rises with increasing age.
• Serologically
o Warm type (65%)
o Cold type (CHAD : 29% , PCH : 1% )
o Mixed AIHA (5%).
• 50 % primary + 50 % secondary

6. Clinical feature

7. Cl/f
• Symptoms of anaemia (weakness 88%, dizziness 50%, dyspnoea
9%)
• Haemolysis (jaundice 21%, dark urine 3%) or
• Symptoms of an underlying disorder (Pirofsky, 1975).
• O/E
o Unremarkable
o Mild pallor or splenomegaly.
o Less often, severe haemolysis : hepatosplenomegaly,
haemoglobinuria and signs of heart failure (Packman, 2008).

8. Cl/f cont.
• CHAD can present as a primary chronic clonal disorder, usually occurring in middle
age or in the elderly.
• Cold-induced acrocyanosis or Raynaud phenomenon : 40–90% of patients
(Berentsen et al, 2006; Swiecicki et al, 2013).
• Secondary CHAD : can be self-limiting,eg following childhood infection
• Paroxysmal cold haemoglobinuria (PCH)
o Typically transient, presenting 1–2 weeks after an URTI or other childhood illness
o Acute fever, abdominal, back or leg pain and haemoglobinuria (Gehrs & Friedberg,
2002).
o Haemolysis can be severe and intravascular but usually settles over several weeks.

9. Acrocyanosis
Livedo reticularis

10. Diagnostic approach to suspected AIHA

11.  Is there haemolysis ?
 Is the haemolysis autoimmune ?
 What is the type of AIHA ?

12. Is there haemolysis?
• Bilirubin (unconjugated) – increased
• Reticulocyte count – increased
• LDH – may be normal or increased
• Haptoglobin – reduced
• PBS – spherocytes, agglutination or polychromasia
• Urinalysis/dipstick test positive for blood but urine microscopy negative for red
cells - if haemolysis is intravascular, leading to haemoglobinuria
• Urinary haemosiderin - can be detected approx. 1 week after onset of intravascular
haemolysis

13. Is the haemolysis immune?
• A positive direct antiglobulin test (DAT) indicates the presence of IgG or
complement (usually C3d) bound to the RBC membrane
• A positive DAT is not specific and is also a/w wide range of non-haemolytic
disease states, possibly through passive deposition of Igs or immune
complexes
o liver disease
o Chronic infection
o Malignancy
o SLE
o Renal disorders
o Drugs such as IVIg or ATG

14. • Outside of AIHA, a positive DAT may also be seen with
• Alloantibodies in a recipient of RBC or plasma transfusion
• Antibodies from maternal circulation that cross the placenta and coat the fetal
RBCs
• Antibodies directed against certain drugs that bind to the RBC membrane (e.g.,
penicillin)
• Nonspecifically adsorbed proteins including immunoglobulins and Wharton's jelly
• RBC-bound complement
• Antibodies produced by passenger lymphocytes in transplanted organs or
hematopoietic components. Further

16. The DAT: Recommendation
 At a minimum, the DAT should include monospecific anti-IgG and anti-C3d (1C)
 DAT positive, evidence of haemolysis. Before diagnosing AIHA, ask the following 5 questions:
• Is there a history of blood transfusion in the last 3 months?
o Consider a delayed haemolytic transfusion reaction (HTR)
• Has the patient received a solid organ or allogeneic haematopoietic stem cell transplant (HSCT)?
o Consider alloimmune haemolysis caused by major ABO mismatch (HSCT) or passenger lymphocyte
syndrome (PLS) (solid organ or HSCT).
• In infants, could this be haemolytic disease of the newborn (HDN)?
• Has the patient received any relevant drugs?
o Consider drug-induced immune haemolytic anaemia(DIIHA).
• Is there another known cause of haemolysis?

17. Drug induced AIHA (DIIHA)
• 1970s and 1980s : α-methyldopa and high-dose penicillin
• Second and third generation cephalosporins, especially cefotetan
and ceftriaxone : ˜80% of cases.
• Purine nucleoside analogs : fludarabine, cladribine, and pentostatin

18. DIIHA cont.
 three major mechanisms:
• The drug adsorption mechanism, in which the antibody reacts with a drug
tightly bound to the RBC membrane
• The neoantigen or immune complex mechanism, in which the drug combines
loosely with the RBC membrane and the antibody reacts with new antigenic
site(s) created by the combination of drug and membrane
• The autoimmune mechanism, which is indistinguishable from true AIHA
without drug exposure

19. DIIHA cont.

20. DIIHA cont.

21. DIIHA cont.

22. Investigation of DAT-negative haemolysis
 Recommendation
• In patients with unexplained haemolysis and a negative screening DAT,
retest with a column agglutination DAT method that includes
monospecific anti-IgG, anti-IgA and anti-C3d (1B).
• If also negative, consider red cell elution technique (2C).
 Patients with DAT-negative AIHA generally have a milder anaemia and are
steroid responsive.
 The Donath-Landsteiner test may be considered in children with
haematuria

23. DAT-negative haemolysis cont.
 Cause
• low affinity antibody
• low levels of red cell bound antibody or
• Ig not tested for (e.g. IgA-only AIHA).

24. What type of AIHA is present?
Warm AIHA Mixed AIHA CAs CHAD PCH
Typical DAT IgG or IgG + C3 IgG + C3 Negative C3 C3
Antibody
specificity
Usually a high
incidence Ag .
~3% have
specificity (e.g.
anti-e, anti-E or
anti-c)
Warm IgG usually
lacks specificity.
The cold antibody
may be anti-I, anti-i
or lack specificity
Usually anti-I Usually anti-I
(~90%),
sometimes
anti-i, rarely
anti-Pr
Usually
anti-P
Antibody
titre (at 4°C)
Not applicable Cold antibody may
have a low titre
(<1:64)
Usually <1:64 Usually
>1:500 but
can be less
Usually
<1:64
Thermal
amplitude
Bind optimally at
37°C
Usually ≥30°C Usually
<25°C
Usually
≥30°C
Usually
<20°C

25. Wintrobe’s clinical hematology 13th edition

26. Identifying the type of AIHA
 Recommendations by BSH
• Patients with AIHA and a DAT positive for C3 ± IgG should be screened for a cold antibody
using a direct agglutination test (DAggT) at room temperature (1C)
• Patients with a positive cold autoantibody screen should be further investigated with an
antibody titre in a laboratory performing these tests on a regular basis (2C).
• Received EDTA-anticoagulated samples should be warmed to 37°C in a water bath for 1 h
prior to removal of the plasma for testing (1C).
• In patients with suspected CHAD, the clotted sample for protein electrophoresis and
immunofixation should be kept at 37°C until the serum has been separated (1C).
• All cases of suspected primary CHAD should be reviewed by an appropriately constituted
haemato-oncology multidisciplinary team (1C)

27. Investigations

28. Investigation
 Primary evaluation
• Haemolytic screen
o FBC, blood film, LDH, haptoglobin, bilirubin, DAT, reticulocyte
• Urine : Dipstick test , microscopy , hemosiderin
• Detection of underlying disorders
o Serum Igs and electrophoresis with immunofixation
o HIV, HBV, HCV
o Anti-dsDNA, ANA
o CT chest, abdomen and pelvis

29. Inv. Cont.
 Additional investigation in selected patients with AIHA
• Bone marrow examination: CHAD, age ≥60, features in history, examination,
FBC or film suggesting possible marrow infiltration
• RFT , LFT, clotting, BP, urine dipstick: If pregnant or thrombocytopenic : To
exclude DIC or pregnancy-associated TMA
• Infection screening
• r/o Evans syndrome
• Parvovirus, haematinics : If reticulocytopenia

30. Inv. Cont.
 Additional serological investigation in selected patients with AIHA
• Direct agglutination test (DAggT) : If DAT positive for C3 ± IgG
• Cold antibody titre : If DAggT positive
• Monospecific DAT for IgM, G, A, C3 : If DAT-negative AIHA suspected
• Red cell eluate : If (monospecific) DAT- negative AIHA suspected
• Donath-Landsteiner : If DAT is positive for C3 ± IgG and
o DAggT negative or insignificant CAs and
o Age <18 years or haemoglobinuria or cold associated
o Symptoms or atypical serology
• Cold autoagglutinin thermal amplitude If clinical significance of cold autoagglutinin unclear

31. British Journal of Haematology, 2017

33. Management

34. Rescue (emergency) therapy
• General Strategies for all AIHA
o Investigations may reveal a treatable underlying cause, such as infection.
o If drug-induced AIHA is suspected, relevant medication should be
stopped.

35. Rescue therapy cont.
• Transfusion: Recommendations
o If anaemia is life threatening in the time required for full compatibility
testing, transfuse with ABO, Rh and K matched red cells (1C)
o Consider the use of a blood warmer for transfusion in patients with cold
AIHA (CHAD, mixed AIHA and PCH) (2C)

36. Rescue therapy cont.
 Rescue therapy - warm AIHA: Recommendation
• Consider IVIg or plasma exchange for severe or life threatening anaemia
(2C)

37. Rescue therapy cont.
• IVIg
o 40% of patients respond to IVIg 0.4–0.5 g/kg/day for 5 days
o Most responders maintained their Hb for ≥3 weeks (Flores et al, 1993).
o Short term treatment when the Hb is <60 g/l (but higher in patients with
co-morbidities) or as a temporising measure prior to splenectomy
(Wimperis et al,2011).

38. Rescue therapy cont.
• Emergency splenectomy and splenic embolisation
o Patients with severe transfusion-dependent haemolysis who have not
responded to immunosuppression
o If the patient is not vaccinated 2 weeks prior to splenectomy, this should
be deferred until 14 days post-splenectomy as functional antibody
responses are improved (Davies et al, 2011).

39. Rescue therapy cont.
 Rescue therapy – Primary CHAD: Recommendation
• Consider plasma exchange or steroids for severe or lifethreatening
anaemia (2C)
o Steroids : Overall response 14–69% : trial of prednisolone 1 mg/kg/day
o Plasma exchange : Responses are often transient : in conjunction with
alternative : Daily or alternative day exchange of 1–1.5 times plasma
volume

40. Non-emergency management
 General strategies
• Thromboprophylaxis : Recommendation
o Thromboprophylaxis with LMWH is recommended for in-patients with an
acute exacerbationof haemolysis (1C) and should be considered in
ambulatory patients during severe exacerbations (Hb <85 g/l) (2C)
• Folic acid: Recommendation
o Patients with AIHA should receive folic acid supplementation (1B)

41. Non-emergency management cont.
• Gastric protection : Recommendation
o Patients receiving corticosteroids who are at increased risk for PUD e.g. concomitant
thrombocytopenia, prior history of PUD, concurrent use of NSAIDs , anticoagulant or
anti-platelet agent and age ≥60 years, should receive a PPI (2C)
• Osteoporosis prevention: Recommendations
o All patients should receive oral calcium and vitamin D supplements while taking
corticosteroids (1A)
o Postmenopausal women and men age ≥50 years commencing corticosteroids should
receive a bisphosphonate when treatment is anticipated to be ≥3 months at a dose of
prednisolone ≥7.5 mg/day (1A)

42. Non-emergency management cont
 Specific management strategies
 Primary warm AIHA - first line treatment: Recommendations
• First line therapy is prednisolone 1 mg/kg/day (1B)
o Approx. 80% of pts. respond to corticosteroids at a dose equivalent to prednisolone 60–100
mg/day and approximately two-thirds achieve complete remission (CR).
o The initial response may take several weeks but absence of response by 21 days should be
considered a steroid failure.
o In responding patients : once Hb >100 g/l or after a maximum of 3 weeks, reducing to 20–30
mg over 4–6 weeks, and then by 5 mg every month.
o Relapse was more common if steroids were tapered to ≤10 mg in less than 2 months and if
stopped in less than 6 months (Dussadee et al, 2010).
o Approximately 20% of patients remain in remission after steroids are discontinued .

43. Non-emergency management cont
 Primary warm AIHA - second line treatment: Recommendation
• Second line therapy should be considered if (2C):
o No response to 1 mg/kg/day after 3 weeks
o Relapse during or after steroid reduction
• Rituximab and splenectomy (1B)
• Approx. 70% of cases respond to splenectomy but even higher response
rates are reported with rituximab.

44. Non-emergency management cont
• With Rituximab
o 79% responded with CR in 42% (Reynaud et al, 2015).
o Median time to response is approximately 3–6 weeks (range 2–16 weeks).
o Relapse occurs in 14–25% after a median of 15–21 months and in 50% by 30
months .
o Reactivation of hepatitis B virus (HBV) is a potentially fatal complication
o Screening with serology for HBV surface antigen and HBV core antibody is
recommended
o The standard regimen is 375 mg/m2 weekly for four consecutive weeks

45. Non-emergency management cont.
 Primary warm AIHA - third line treatment: Recommendations
• Azathioprine, ciclosporin, danazol, mycophenolate mofetil, splenectomy
(2C)
 T/t options for patients failing third line therapies.
• Alemtuzumab
• Cyclophosphamide
• HSCT

46. Non-emergency management cont
 Patients with AIHA undergoing splenectomy : Recommendations
• Radioisotope studies to determine the main site of red cell destruction are not currently recommended
when considering splenectomy (1C)
• Patients should be counselled on infection risk and be vaccinated at least 2 weeks before splenectomy
(1C).
• There should be a low threshold for investigating patients with post-operative fever, abdominal pain or
ileus with Doppler ultrasound to exclude portal or splenic vein thrombosis (1B)
• Patients without a contra-indication should receive thromboprophylaxis with LMWH following
splenectomy (1C). Extended prophylaxis following discharge may be considered in patients considered
high risk (2C).
• After splenectomy, patients should be discharged on prophylactic antibiotics, provided with a course of
antibiotics for emergency use and given advice on risk factors for infection. Long-term follow-up should be
organised for revaccination in primary or secondary care (1C).

47. Non-emergency management cont
 Mixed AIHA: Recommendations
• First line therapy for mixed AIHA is prednisolone 1 mg/kg/day (1C)
• If AIHA is secondary, optimize treatment of the underlying disorder (1C).
• If AIHA is primary, consider immuno-suppression as second line therapy
similar to primary warm AIHA (2C).

48. Non-emergency management cont.
 Treatment of primary CHAD: Recommendations
• Patients should be advised to avoid cold exposure where possible (1C)
• Indications for treatment: symptomatic anaemia, severe circulatory
symptoms or transfusion dependence (1C)
• First line treatment: rituximab, or if clonality has been demonstrated, the
addition of fludarabine may be considered (1B)

49. Non-emergency management cont.
 CHAD, Cold agglutinins and surgery: Recommendations
• In patients with CHAD, take measures to ensure the patient is
normothermic during and immediately after surgery (1C)
• All cardiothoracic units should have a policy for CA screening prior to cold
cardioplegia and for management of unexpected agglutination detected
during cold cardioplegia (2C)

50. Childhood AIHA
• Can occur at any age during childhood from infancy through to
adolescence but with a peak incidence <5 years.
• Usually self-limiting illness
• Warm AIHA predominates followed by PCH, typically triggered by a viral
infection.
• CHAD is less common in children compared to adults, and often follows a
mycoplasma infection.
• Immunological disease (most commonly Evans syndrome or CVID) is
associated with approximately 50% of cases.

51. Childhood AIHA
• Childhood AIHA: Recommendations
• Transfusion can usually be avoided unless there are signs of cardiac
decompensation (2C)
• Test for additional immunological diseases before starting treatment (1A).
• Investigations should also include liver function tests (2C).
• First line therapy is corticosteroids, typically given as prednisolone at a starting
dose of 2 mg/kg/day with responses in 81–100% of children with primary or
secondary AIHA
• The best-studied second line agent is rituximab, with response rates of 75–100%

52. Paroxysmal cold haemoglobinuria ( PCH )
• Triad : intermittent attacks of pain, fever, and hemoglobinuria following
exposure to cold.
• D-L antibody occurs in three clinical syndromes:
o chronic PCH associated with late-stage or congenital syphilis
o acute transient PCH occurring after an infectious illness
o chronic idiopathic PCH.
• The most common form of PCH is acute and transient, following an
infectious illness in childhood.

53. • Account for up to 40% of AIHA in younger children.
• Precipitating factors
o Usually URTI : include varicella, adenovirus, EBV , CMV , H. influenzae, E. coli,
M. pneumoniae, measles, mumps and measles vaccination.
• Typically, PCH antibodies are polyclonal IgG against P Ag.
• 5 Ps
o Pain ( abdomen , limb , back )
o Pyrexia
o Paroxysmal hemoglobinuria
o P Ag
o Polyclonal IgG ( hemolysin )

54. PCH cont.
 Recommendations (PCH)
• Encourage cold avoidance and avoid active cooling for fever (2C).
• Steroids should only be considered in severe or persistent disease (2C)

55. AIHA in pregnancy
 Recommendations
• A positive DAT should prompt taking a history, examination and laboratory testing to exclude AIHA
(1C)
• Patients should have serial USGfrom 20 weeks to assess fetal growth and Doppler ultrasound of
the fetal middle cerebral artery to screen for fetal anaemia (2C)
• Antenatal care should involve joint haematology and obstetric care with access to a specialist in
fetal medicine (1C)
• The neonatologist should be informed of the delivery date and the increased risk of neonatal
anaemia and hyperbilirubinaemia (1C) AIHA is a risk factor for thrombosis. Consider antenatal and 6
weeks postnatal prophylaxis in context of other risk factors (2C)
• First line treatment (warm AIHA): prednisolone (individualise starting dose based on disease
severity and taper to minimum effective dose) (2C)

56. AIHA in pregnancy
• Second line treatment (warm AIHA): factors influencing treatment include the
ability to maintain Hb with transfusional support, stage of pregnancy,
primary/secondary AIHA and presence of fetal anaemia : Consider IVIg and
azathioprine (2C)
• Following delivery, test cord blood for DAT. If neonatal jaundice or positive DAT,
take a capillary blood sample from the neonate for a full blood count, reticulocyte
count, bilirubin, DAT and cross-match (in case exchange transfusion is required)
(1C)
• Monitor the neonate for anaemia and hyperbilirubinaemia. Management should
be similar to that of HDN (1C)
• Follow-up the infant for 6 weeks in case late onset anaemia occurs (2C)

57. Take home message
• How to diagnose AIHA ?
• How to diff. Warm AIHA vs Mixed AIHA vs CAD vs PCH ?
• How to manage AIHA ? Rescue Vs Non-emergency management ?

58. Synopsis of treatment

60. • Cold-active antibodies typically have little, if any, activity at body
temperature but have greater affinity for RBCs as the temperature
decreases toward 0°C.
• Conversely, warm-active antibodies have their greatest affinity at
37°C.
• Generally speaking, cold-active antibodies are typically IgM, fix
complement, and lead to immediate intravascular RBC destruction
or hepatic-mediated clearance.
• In contrast, warm-active antibodies are typically IgG, may or may
not fix complement, and primarily lead to RBC loss by splenic
mediated clearance of sensitized cells.

61. Etiology of immune response in AIHA
• Immunologic tolerance is a state in which the individual is incapable of
developing an immune response to a specific antigen.
• Self-tolerance refers to lack of responsiveness to an individual's own
(self) antigens, which is the normal state.
• Autoimmunity results from a loss of self-tolerance
• Central tolerance refers to the normal deletion of self-reactive T-and B-
lymphocyte clones during their maturation in the central lymphoid
organs (thymus for T-cells; bone marrow for B-cells)

62. • The mechanisms by which self-reactive T-cells that escape intrathymic
negative selection and are deleted in the peripheral tissues constitute
peripheral tolerance, including anergy, suppression by regulatory T-cells,
and clonal deletion by activation-induced cell death
• Anergy refers to prolonged or irreversible functional inactivation of
lymphocytes.

63. IgM-mediated Red Blood Cell Destruction
• Destruction of erythrocytes sensitized with IgM antibodies is mediated by
the complement system, either directly by cytolysis or indirectly via
interaction of RBC-bound activation and degradation fragments of C3 with
specific receptors on reticuloendothelial cells, principally liver
macrophages (Kupffer cells).
• The pentameric structure of IgM enables efficient complement activation

64. IgG-mediated Red Blood Cell Destruction
• IgG is a relatively ineffective initiator of activation of the classical
complement pathway : notable exception is the D-L antibody of
PCH.
• In the absence of complement activation, clearance of IgG-
sensitized erythrocytes is primarily splenic
• The liver clears IgG-coated RBCs less efficiently than the spleen
• Of the four subclasses of IgG, IgG3 has the highest affinity for the
FcγR and therefore is most efficient at causing extravascular
hemolysis (IgG3> IgG1> IgG4>>> IgG2 )

65. Complete Vs Incomplete Abs
• IgM-coated RBCs may spontaneously agglutinate because the pentameric
antibody can directly cross-link RBCs.
• The capability for IgM antibodies to agglutinate saline suspended RBCs
without additional reagents led to the traditional terminology of
“complete” antibodies.
• In contrast, IgG antibodies typically require antihuman globulin (AHG) as a
co-factor to agglutinate saline-suspended RBCs and are thus termed
“incomplete” antibodies.

66. • Erythrocytes have a strong net negative surface charge (“zeta potential”)
produced by the sialoglycoprotein coat, such that the shortest separation
attainable between two RBCs is approximately 18 nm.
• IgM molecules, with their large pentameric structure, create a 30-nm
distance between adjacent binding sites and can therefore bridge two
RBCs.
• The smaller IgG can accommodate a span of only 12 nm between
antigen-recognition sites and thus usually cannot lead to agglutination
alone

67. • DAT reflects in vivo antibody sensitization of RBCs. Erythrocytes are
washed to remove any unbound antibodies, and anti-IgG AHG reagent
(AHG: antihuman globulin) is then added. IgG antibodies cannot cause
direct RBC agglutination, but IgG-coated RBCs will agglutinate in the
presence of AHG containing anti-IgG.
• The IAT is used to detect the presence of IgG antibodies in serum (in
vitro sensitization). Reagent RBCs are incubated in the presence of
serum that may contain antibodies. If they are present, antibodies bind
to their target antigens on the reagent RBCs. After incubation, the
RBCs are washed to remove unbound antibodies. Anti-IgG AHG
reagent is added and will cause IgG-coated erythrocytes to agglutinate

69. • If the DAT is positive for RBC-bound antibody, that antibody can be eluted
(removed) from the RBC with the aid of acid or xylene, and any binding
specificities can be further investigated with a reagent red cell panel.
• Generally, autoantibodies are panreactive, whereas alloantibodies exhibit
antigen specificity, reacting only with specific antigen positive RBCs.

70. • Cold-active antibodies exhibit greater titer and RBC-binding activity as the
temperature decreases toward 0°C.
• Two different clinical syndromes
o Cold agglutinin disease (CAD) is associated with IgM antibodies usually
directed at the RBC I antigen. CAD typically occurs in adult patients and
may be primary or secondary to another disease process, usually
infectious.
o In contrast, PCH is caused by an IgG hemolysin, the Donath-Landsteiner
(D-L) antibody.

71. • Cold agglutinins attach to the RBC in the cooler peripheral circulation. As the
blood returns to the warmer core circulation, the antibody dissociates from
the RBC.
• Both may cause cyanosis and Raynaud phenomenon in cooler temperatures.
However, cryoglobulins do not fix complement on the RBCs or lead to
hemolysis.
• Mild, chronic hemolytic anemia with exacerbations in the winter is the
general rule for CAD. Rarely does the hemoglobin drop below 7 g/dl
• Acrocyanosis can occur from agglutination of RBCs in the cooler vessels of the
hands, ears, nose, and feet. Limbs may manifest livedo reticularis, a mottled
appearance that is readily reversible upon warming of the affected area. Only
rarely does actual gangrene of digits develop, and nearly all of these cases
have an associated cryoglobulin.