Transfusion Medicine and

Bleeding Disorders
Ashley Inman
November 6, 2014
 Bleeding Disorders Result From:
Increased fragility of vessels
Platelet deficiency or dysfunction
Derangement of coagulation
 Vascular wall ( Endothelium)
Antithrombotic properties
Antiplatelet effects
Anticoagulant properties
Fibrinolytic properties
Prothrombotic properties
Von Willebrand factor
Tissue factor
Fibrinolysis inhibitors
Bleeding Disorders Due to Vessel Wall
Abnormalities
Infections
Drug Reactions
Scurvy
Ehlers-Danlos Syndrome
Henoch-Schonlein Purpura
Hereditary Hemorrhagic Telangiectasia
(Weber-Osler-Rendu Syndrome)
75-y.o. female with pinpoint superficial
hemorrhage. PT, PTT, PFA-100 and Platelet
count normal. Hct. 36%. WBC 6,000/mm3.
D-Dimer not increased. Diagnosis?

A. Cirrhosis
B. Chronic renal failure
C. Meningococcemia
D. Scurvy
E. Metastatic melanoma
 Answer D (scurvy)
Vitamin C deficiency with vascular fragility
Gingival hemorrhages
Hemorrhagic perifollicular hyperkeratotic
papules (corkscrew hairs)
Meningococcemia would give high WBC
 Bleeding Disorders Result From:
Increased fragility of vessels
Platelet deficiency or dysfunction
Derangement of coagulation
 Platelets

Adhesion= to the extracellular matrix after vascular injury with

vWF (*** vWF - glycoprotein Ib association) and undergo
shape change
Secretion or release reaction= of granule contents soon after
adhesion.
Release of calcium and ADP.
Calcium is for coagulation cascade
ADP mediates platelet aggregation
Aggregation= with platelets via glycoprotein IIb/ IIIa forms
the primary hemostatic plug. With platelet contraction, a
secondary, irreversible plug is formed. Fibrin cements the plug
 Primary Hemostasis Tests
Platelet counts
Tests of platelet function:
Platelet aggregation test
Von Willebrand factor
Bleeding time
 Bleeding Disorders Due to
Thrombocytopenia
4 major categories:
1. Decreased platelet production
2. Decreased platelet survival
3. Sequestration
Hypersplenism
4. Dilution
Transfusion
 Decreased Platelet Production
Drug-induced
Infections
Nutritional deficiencies (B12; folate)
Bone marrow failure or ineffective
hematopoiesis (aplastic anemia; MDS)
Bone marrow replacement (leukemia;
metastatic carcinoma)
 Decreased Platelet Survival
Immunologic destruction
Primary autoimmune:
Immune thrombocytopenic purpura (ITP)
Secondary autoimmune:
Systemic lupus erythematosus
Posttransfusion
Nonimmunologic destruction
Disseminated intravascular coagulation
Thrombotic microangiopathies
25-y.o female with hx of bleeding gums.
Sister and uncle also bleed. PT normal,
PTT elevated, ristocetin (+). Factor 8 is 30%
and mixing studies correct the PTT. DX?

A. Needs allogeneic BMT

B. Joints will be deformed
C. Needs warfarin (coumadin)
D. Might have severe bleed after oral surgery
E. Splenectomy required
 Answer D (vWD)
vWD
Factor VIII low but not at clinically significant
level
No severe bleed unless significant injury- eg,
oral surgery in this case
40-y.o. female has pinpoint hemorrhages on
legs. Hct. 43%. Platelets 19,000/mm3. PFA-100
normal. Corticosteroids fail to increase platelets,
but splenectomy results in an increase to
150,000 platelets/mm3. Diagnosis?

A. Decreased platelet production

B. Suppressed pluripotent stem cells
C. ITP
D. Excessive menstrual bleeding
E. Defective platelet-endothelial interaction
 Answer C (ITP)
Patient has antibodies directed against her
own platelets. The Ab-coated platelets are
removed by the spleen (which also
contributes to the Ab production).
Corticosteroids fails and splenectomy is an
option
 Immune Thrombocytopenic Purpura (ITP)

Cause
Antiplatelet antibodies
Antigen - platelet membrane glycoprotein complexes IIb-
IIIa and Ib-IX
Morphology
Peripheral Blood
thrombocytopenia, abnormally large platelets
(megathrombocytes or Giant platelets),
Marrow
Normal or Increased magakaryocyte #
Diagnosis - by exclusion
Bleeding time - prolonged, but PT & PTT - normal
Fatigued 35-y.o. female. Hct. 34%; Plts.
150K; Spherocytes and nucleated RBCs
present. Coombs test (+) at 37C but (-) at
4C. Diagnosis?

A. Infectious mononucleosis
B. Mycoplasma pneumoniae
C. ITP
D. E. coli sepsis
E. SLE
 Answer E (SLE with autoimmune
hemolytic anemia)
Warm autoantibody. Anti-RBC-Abs are
destroyed in the spleen. Nucleated RBCs
indicate a hemolytic anemia
4C agglutination is c/w Mycoplasma infection
60-y.o. female with blurred vision,
confusion; 40 C; petechiae; platelets
28,000/mm3; PT, PTT normal; CBC shows
fragmented RBCs; BUN 40 mg/dL. Dx?

A. ITP
B. TTP
C. HUS
D. Hemophilia A
E. DIC
 Answer B (TTP)
Pentad of TTP
Thrombocytopenia
Fever
Renal disease
CNS disease
MAHA- microangiopathic hemolytic anemia
Peripheral blood smear shows helmet cells
and schistocytes
Thrombus in small
Blood vessel
 Thrombotic Microangiopathies
**BOTH *Fever, Thrombocytopenia, MAHA*

HUS Feature TTP

Absent Neurological Prominent

symptoms
Prominent Acute Renal Failure Less prominent
Children Age Adults
Infection Cause Genetic
( E.coli O157 : H7) (vWF metalloprotease-
ADAMTS 13)
deficiency
Supportive Rx. Plasma Exchange

Good in children Prognosis Better with plasma

Bad in adults exchange
 Bleeding Disorders Result From:
Increased fragility of vessels
Platelet deficiency or dysfunction
Derangement of coagulation
 Coagulation pathway

Two pathways for fibrin clot formation:

Intrinsic
Initiated by negatively charged surface
Extrinsic
Initiated on tissue injury
Both pathways converge on a final common
pathway
Prothrombin Thrombin (Most critical step )
Fibrinogen Fibrin Clot
The pathways are complex and involve many
different proteins (called blood clotting factors)
 Coagulation Cascade - continued

Control of coagulation
Antithrombins (e.g., antithrombin III)
Proteins C and S
Fibrinolytic cascade
Plasminogen plasmin fibrin break down products
(*FDP or FSP) d-dimer is most important of the
FDPs

*FDP / FSP Fibrin degradation products / Fibrin split products

 Secondary Hemostasis Tests
Prothrombin time (PT):
Tests extrinsic and common coagulation pathways
Partial thromboplastin time (PTT):
Tests intrinsic and common coagulation pathways
50-y.o female with Hep C and ALT and AST
of 310 and 300 U/L, respectively. Serum
ammonia is elevated. What coagulation
test is most likely to be abnormal?
A. Von Willebrand Factor assay
B. Platelet count
C. PT
D. D-Dimer
E. Platelet aggregation
 Answer C (PT)
Evidence of liver failure is present- loss of
hepatocytes (and elevated ammonia) and thus
decreased clotting factors. vWF is made by
endothelial cells.
65-y.o. male with metastatic pancreatic
carcinoma shows elevated PT and PTT,
platelets 15,000/mm3 and elevated D-
Dimer. On a PBS you would see?

A. Howell-Jolly bodies
B. Plasmodium vivax
C. Macro-ovalocytes
D. Schistocytes
E. Target cells
 Answer D (schistocytes)
Fragmented RBCs
Also called helmet cells or schistocytes
Pt has DIC with fibrin strands in small BVs that
slice up the RBCs
Schistocytes also present in TTP and HUS; also
present in artificial heart valves; also seen in
APML (acute promyelocytic leukemia)
 Common clinical conditions
associated with DIC
Sepsis Vascular disorders

Trauma Reaction to toxin (e.g. snake

venom, drugs)
Head injury
Fat embolism Immunologic disorders
Severe allergic reaction
Malignancy Transplant rejection

Obstetrical complications
Amniotic fluid embolism
Abruptio placentae
 Disseminated Intravascular Coagulation
continued

Lab = PT And PTT Are typically prolonged.

Thrombocytopenia
low Fibrinogen
Elevated plasma Fibrin split products (D-DIMER)
Prognosis = Highly variable
Depends upon:
Underlying disorder
Degree of intravascular clotting
Activity of mononuclear phagocytic system
Amount of Fibrinolysis
Treatment of the underlying disorder is most important!!
13-y.o. boy hx of bruising and deep muscle
bleeds; joints abnormal; similar hx for
other male family members; Platelets
normal; PT normal; PTT elevated. **NOT
corrected by mixing study. Dx?
A. Factor V mutation
B. DIC
C. Hemophilia B
D. Hemophilia A due to factor 8 inhibitor
E. Von Willebrand disease and anti-platelet Abs
 Answer D (inhibitor)
Hemophilia A due to inhibitor
PTT prolonged
Bleeding time, platelet count, and PT all
normal
Mixing with normal serum does not correct
PTT
 Hemophilia A and B
Hemophilia A Hemophilia B
(Classic hemophilia) (Christmas disease)
Factor VIII deficiency Factor IX deficiency
X-linked recessive X-linked recessive
1/10,000 males 1/50,000 males

*Indistinguishable by clinical presentation or inheritance pattern

 Hemophilia continued
Severity is related to factor level:
o <1% - Severe - spontaneous bleeding
o 1-5% - Moderate - bleeding with mild injury
o 5-25% - Mild - bleeding with surgery or trauma
Bleeding into muscles, subcutaneous tissues,
and joints
Pregnant female with fetal death in utero.
BP 80/40 mm Hg, blood in stool, elevated
D-Dimer, increased PT and PTT, low
platelets and fibrinogen. Cause?

A. Vascular fragility
B. Endothelial damage
C. Reduced platelet production
D. Consumptive coagulopathy
E. Platelet aggregation defect
 Answer D (consumptive coagulopathy)

DIC
Factors and platelets consumed
Thromboplastins from dead fetus (not
ecclampsia as BP is low)
25 year old male with celiac disease
presents with hem occult positive
stools. What vitamin deficiency should
you consider?

A. Vitamin C deficiency
B. Vitamin A deficiency
C. Vitamin K deficiency
 Answer C (Vitamin K Deficiency)
Usually caused by fat malabsorption from
pancreatic or small-bowel disease in adults
Celiac disease
Prolonged antibiotic use
Also seen in neonates breast milk is deficient
in vitamin K and the intestine not completely
colonized by bacteria that synthesize vitamin K
Decreased activity of clotting factors II, VII, IX and
X prolonged PT and PTT
Disorder Plt Bleed T PT PTT
count PFA-100
TTP low high N N
Or ITP
vW Dis N high N N/high

Hem A N N N high

DIC low high high high

Warf/VK N N high N
Liver N N high high
Transfusion Medicine
 The blood product that is most likely to be
contaminated with bacteria is:

A. Packed RBCs
B. Washed RBCs
C. Irradiated RBCs
D. Fresh Frozen Plasma
E. Platelets
 Answer E (platelets)
Platelets are stored at room temperature
Platelets are tested for bacterial
contamination before administration
 IgA deficient female has hx of anaphylaxis
after blood transfusions. You should order?

A. Washed RBCs
B. Leukocyte-poor RBCs
C. Irradiated RBCs
D. Whole Blood
E. Packed RBCs
 Answer A (washed RBCs)
Washed RBCs have 99% of plasma proteins
removed
 Saline Washed Red Blood Cells
Indications:

1. History of allergic or febrile reactions secondary to plasma

proteins not prevented by pre-transfusion administration of
antihistamines and leukocyte reduction
2. IgA deficiency with documented IgA antibodies
3. History of anaphylactic reaction to blood components
Transmission of CMV by blood transfusion
can be greatly reduced by using?

A. Washed RBCs
B. Leukocyte-poor RBCs
C. Irradiated RBCs
D. Whole Blood
E. Packed RBCs
 Answer B (leuko-poor)
Leuko-poor RBCs
CMV infected WBCs are largely removed
Leukocyte-Reduced Red Blood Cells
Indications:

1. Prevention of HLA/WBC alloimmunization

2. Prevention of recurrent non-hemolytic febrile reactions
3. Prevention of CMV transmission in select groups of patients
 Irradiated Blood Products
Indications: preventing graft versus host disease

1. Immunocompromised patients
2. Directed donations from blood relatives
3. Premature infants 1200 gms
4. Fetuses receiving intrauterine transfusions
5. Neonatal exchange transfusions
You have decided to order some
cryoprecipitate for a patient because it has
high concentrations of?

A. Factors 2,7,9 and 10

B. Fibrinogen and factor 8
C. Platelets
D. Platelet concentrate
E. Neutrophils
 Answer B (VIII and fibrinogen)
Cryo has lots of fibrinogen and also factor 8
Primarily used to replace fibrinogen
 Cryoprecipitate
Indications:

1. Hypofibrinogenemia ( 100 mg/dl)

2. Dysfibrinogenemia
3. Factor XIII deficiency - rare
 Frozen Plasma
Indications:

1. Treatment of coagulopathy due to clotting factor deficiencies

2. Patient is bleeding actively with PT and/or PTT greater than 1.5
normal (INR > 1.8) and platelet count above 50,000
3. Coumadin overdose with major bleeding or impending surgery
4. Treatment of TTP
5. Massive Transfusion Protocol (MTP)
A patient with Hemoglobin of 8.0 g/dL is
transfused 2 units of packed RBCs. What
will the HCT be after transfusion?
A. 10g/dL
B. 11 g/dL
C. 30%
D. 36%
E. 45%
 Answer C (30%)
10 g/dL hemoglobin
HCT 30 %
1 g increase for every unit of packed cells or
3% increase in HCT
A 45-year-old male patient dies after an
aortic valve replacement that required
transfusion of 4 units of packed cells.
Transfusion-related deaths are most often
caused by which of the following?
A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. TRALI
E. Anaphylaxis
 Answer D (TRALI)
TRALI is not well understood but appears to be the
leading cause of death
Factors in transfused blood product trigger activation
of neutrophils in the lung microvasculature
Clinically similar to overload, but do not respond to
diuretics
Incidence low (<1 per 10,000 transfusions), but higher
in patients with preexisting lung disease
Higher incidence with fresh frozen plasma and platelets
(products that contain higher levels of donor
antibodies)
If a patient is blood group AB+. That means
they have what antibodies in their serum?

A. Anti-A and Anti-B

B. Neither Anti-A nor Anti-B
C. Anti-A
D. Anti-B
E. Anti-D
 Answer B (neither)
AB types have neither anti-A nor anti-B so
they make excellent plasma donors; they are
called the universal recipient (of red cells)
AB type RBCs have both A and B antigens
Type O is the universal donor (of red cells) but
they have anti-A and anti-B in plasma
 ABO Antigens and Antibodies
Blood Group Antigen on Red Antibodies in serum
Blood Cell

Group O H (neither A nor B) Anti-A, Anti-B

Group A A Anti-B
Group B B Anti-A
Group AB A and B Neither anti-A nor
anti-B
Mom is type O and baby is type A. HDN is
extremely rare because anti-A and anti-B
are:

A. IgA
B. IgG
C. IgM
D. IgD
E. IgE
 Answer C (IgM)
ABO antibodies are IgM are very rarely cross
the placental barrier
Rh(D) antibodies are IgG and readily cross

Anti D is given to prevent immunization of

Rh(-) moms who give birth to Rh(+) babies.
HDN usually occurs in 2nd or 3rd pregnancies
after immunization by a prior pregnancy
Hemolytic Disease of the Newborn
Maternal IgG antibodies cross the placenta
and cause hemolytic anemia in the fetus
Can result in kernicterus and encephalopathy
in the newborn or intrauterine fetal demise
Can be related to ABO or Rh incompatibility
Rh HDN prevented by giving mother anti-D
globulin at 28 weeks gestation
A type O, 50-y.o. male is transfused with 2 units
of type AB blood causing an acute hemolytic
transfusion reaction. Why did this most likely
occur?
A. Delayed hemolytic transfusion reaction due to low
titer Abs missed by the crossmatch
B. Use of expired RBCs
C. Cross-match error in the blood bank missed high
titer Abs
D. Clerical error occurred in the lab or on the floor
E. Use of washed RBCs
 Answer D (clerical errors)
Most surveys show the leading cause to be
clerical errors
Mislabeled specimens on floor or in the lab
Blood given to wrong patient due to typing
the wrong blood sample; hanging a unit of
blood and giving to the wrong patient
55-y.o female gets 2 units of whole blood and
becomes hypoxic. CXR shows total whiteout of
both lungs. Diuretics are given, then fever
develops and BP collapses. BNP is normal. WBC
not elevated. She dies. Autopsy shows no
evidence of infection. You suspect?

A. Acute hemolytic transfusion reaction

B. TACO
C. TRALI
D. DIC
 Answer C (TRALI again)
TRALI
Hypoxia and lung whiteout but normal BNP
Diuretics worsen the problem
Overall, the most common complication of
RBC transfusion is?

A. HIV infection
B. Hepatitis C infection
C. Hepatitis B infection
D. TRALI
E. Hives
 Answer E (HIVES)
Allergic reaction but not life-threatening
Type I IgE-mediated hypersensitivity reaction
against proteins in the donor blood
May pretreat with benadryl etc.
A 29-y.o. female is pregnant with child # 2 and in
active labor. She has had no prenatal care for
this baby and the other child was born in
another State. Mom is Rh(-) and baby is Rh(+).
Baby #2 is born jaundiced and dies with massive
kernicterus. This could be prevented by.

A. anti-D IgG
B. anti-D IgM
 Answer A (IgG)
RhoGAM is IgG anti-D prepared from males
primed with Rh(+) blood