Bleeding Disorders LEC 10 2021 – 2022

HEMATOLOGY 2
TRANS 10
2nd Semester
Instructor: Antonio C. Pascua Jr., RMT, MSMT. HEMA312 LEC
Date: May 31, 2022

Outline MUCOCUTANEOUS VERSUS ANATOMIC HEMORRHAGE BY

At the end of the session, the student must be able to learn: RODAKS
 Mucocutaneous hemorrhage is most likely to be associated
I. Bleeding Disorders with thrombocytopenia (platelet count less than 150,000/mL;
A. Hemorrhage Chapter 38), qualitative platelet disorders (Chapter 37), von
B. Bleeding Disorders Willebrand disease (VWD), or vascular disorders such as
C. Acquired Coagulopathies scurvy or telangiectasia (Chapter 37).
D. Trauma-Induced Coagulophaty (TIC)  A thorough patient history and physical examination may
E. Liver Disease distinguish between mucocutaneous and anatomic bleeding;
F. Chronic Renal Failure this distinction helps direct investigative laboratory testing and
G. Vitamin K Deficiency subsequent treatment.
H. Autoanti-Factor VIII Inhibitor and Acquired  Anatomic (soft tissue) hemorrhage is seen in acquired or
Hemophilia congenital defects in secondary hemostasis such as plasma
I. Acquired von Willebrand Disease coagulation factor deficiencies (coagulopathies).
J. Congenital Coagulopathies  Examples of anatomic bleeding include recurrent or excessive
K. Von Willebrand Disease bleeding after minor trauma, dental extraction, or a surgical
L. Clotitng Factor Defects procedure.
M. Hemophilia A  In such cases, hemorrhage may immediately follow a primary
N. Factor VIII Inhibitors event, but it is often delayed or recurs minutes or hours after
O. Hemophilia the event. Anatomic bleeding episodes may even be
spontaneous.
I. BLEEDING DISORDERS  Most anatomic bleeds are internal, such as bleeds into joints,
body cavities, muscles, or the central nervous system, and
A. Hemorrhage may have few initially discernible signs.
 Hemorrhage is an excessive bleeding that requires medical or  Joint bleeds (hemarthroses) cause swelling and acute pain.
physical attention. (heal on its own or should be medically They may not be immediately perceived as hemorrhages,
treated) although experienced hemophilia patients usually recognize
 In general, bleeding can be from primary, secondary or the symptoms at their onset.
fibrinolytic problems. If you have bleeding problems or  Recurrent hemarthroses cause inflammation that may
hemorrhagic disorders so it could be a problem with hemostatic culminate in permanent cartilage damage that immobilizes the
mechanism affecting your platelets, clotting factor or fibrinolytic joint. Bleeds into soft tissues such as muscle or fat may cause
mechanism. nerve compression and subsequent temporary or permanent
 It is important to do laboratory test to identify what causes the loss of function.
bleeding because clinical manifestations itself may look the same.  When bleeding involves body cavities, it causes symptoms
By doing so we can give proper treatment or proper related to the organ that is affected. Bleeding into the central
management to the patient. nervous system, for instance, may cause headaches,
confusion, seizures, and coma and is managed as a medical
LOCALIZED VERSUS GENERALIZED HEMORRHAGE BY emergency.
RODAKS  Bleeds into the kidney may present as hematuria and may be
 Bleeding from a single location usually indicates injury, associated with acute renal failure.
infection, tumor, or an isolated blood vessel defect and is
called localized bleeding or localized hemorrhage. MUCOCUTANEOUS ANATOMIC
 An example of local bleeding is an inadequately cauterized or  Petechiae Acquired or Congenital

ineffectively sutured surgical site or an arteriovenous  Red pinpoint spots defects in secondary
malformation (AVM).  Purpura hemostasis
 Except for AVMs, localized bleeding seldom implies a blood  Purple skin lesion (<3mm)  Minor trauma
vessel defect.  Primary hemostasis  Dental extraction
 In contrast, a qualitative platelet defect, a reduced platelet  Surgical procedure
count (thrombocytopenia), or a coagulation factor deficiency  Internal bleeding
cause systemic and not localized bleeding.  Mucocutaneous is present on skin or certain body orifice and
 Bleeding from multiple sites, spontaneous and recurring usually affects the primary hemostasis particularly the platelet.
bleeds, or a hemorrhage that requires physical intervention is  If primary hemostasis is involved there will be bleeding
generalized bleeding. manifestation like gingival bleeding, hematuria (blood in the urine)
 Generalized bleeding is potential evidence for a disorder of menorrhagia (heavy menstrual bleeding), nose bleeding and
primary hemostasis such as a blood vessel or platelet defect associated with thrombocytopenia or qualitative defects of
(Chapters 10 and 37) or thrombocytopenia (Chapter 38); or platelets.
secondary hemostasis characterized by single or multiple
coagulation factor deficiencies or uncontrolled fibrinolysis. Purpura (larger than petechiae: Petechiae (pinpoint hemorhages :
3 millimiter in diameter) 1 millimiter in diameter)
LOCALIZED GENERALIZED
 Single Location  Multiple sites
 Injury. Tumor, Isolated  Spontaneous and Recurring
Vessel Defect  Requires physical
intervention
 If platelet count is low, and clotting factors are deficient it will fall
to generalized category. It becomes systemic (systemic form).
 If it is generalized it could be mucocutaneous or anatomic
bleeding

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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
Bruise or ecchymosis (1 cm or larger)
 Even if it is purpura, petechiae or ecchymosis it means that
there has been damaged on your blood vessel resulting to
extravasation of cells.
 Anatomic bleeding goes with soft tissues. It can be
caused by trauma, dental extraction, and internal bleeding
(severe complications if left untreated)
 Below are hematologic test that should be requested by a
physician or performed by medical technologist.
 CBC is performed so you can have hemoglobin, hematocrit,
cell counts to know the extent (gano kalala) of the bleeding.
 To pinpoint what causes the bleeding, certain coagulation
test can be performed like PT, APTT, TT , specific clotting
factors assay, mixing studies or immunologic testing to
further identify if bleeding is associated with antibody
conditions or autoantibody.
B. Bleeding Disorders
 Diseases that could lead to bleeding may be associated with
various problems or underlying conditions. It could root from
infection, autoimmune disorder, organ dysfunction particularly
LIVER. These bleeding disorders are not automatically acquired
or congenital.
 When you say bleeding, you can have such condition if it is
acquired or congenital.
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ACQUIRED VERSUS CONGENITAL BLEEDING DISORDERS BY
RODAKS
 Liver disease, kidney failure, chronic infections, autoimmune
disorders, obstetric complications, anemia, dietary deficiencies
such as vitamin C or vitamin K deficiency, blunt or penetrating
trauma, and inflammatory disorders may all be associated with
bleeding. If a patient’s bleeding episodes begin after
childhood, are associated with some disease or physical
trauma, and are not duplicated in relatives, they are probably
acquired, not congenital. When an adult patient seeks
treatment of generalized hemorrhage, the physician first looks
for an underlying condition, disease, drug effect, or event and
records a personal and family history. The important elements
of patient history are age; sex; current or past pregnancy; a
systemic disorder such as diabetes or cancer; trauma; and
exposure to drugs, including prescription drugs, over-the-
counter nutritional supplements, alcohol abuse, and drugs of
abuse. The physician determines the trigger, location, and
volume of bleeding and then orders initial hemostasis
laboratory assays (Table 36.1). These tests take on clinical
significance when the history and physical examination have
already established the existence of abnormal bleeding.
Because of their propensity to generate false positive results in
the absence of indications, hemostatic laboratory tests are
ineffective when employed indiscriminately as population
screens for healthy individuals (Chapter 2).8 Congenital
hemorrhagic disorders are uncommon, occurring in fewer than
1 per 100 people, and are usually diagnosed in infancy or
during the first years of life.9 There may be firstdegree
relatives with similar symptoms. Congenital bleeding disorders
lead to recurrent hemorrhages that may be spontaneous or
may occur after minor injury or in unexpected locations, such
as joints, body cavities, retinal veins and arteries, or the central
nervous system. Patients with mild congenital hemorrhagic
disorders may have no symptoms until they reach adulthood or
experience some physical challenge, such as trauma, dental
extraction, or a surgical procedure. The most common
congenital deficiencies are VWD, factor VIII (FVIII, hemophilia
A) and factor IX deficiencies (FIX, hemophilia B), and platelet
function disorders (Chapters 37 and 38). Inherited deficiencies
of fibrinogen, prothrombin, and factors V, VII, X, XI, and XIII
are rare
ACQUIRED CONGENITAL
 After childhood (8 years up)  Uncommon
 Disease  Diagnose during infancy or
 Trauma first year of life
 Not duplicated in relatives  Relatives with similar
symptoms
 Recurrent bleeding
 Ex. vWDs, Hemophilia A,
Hemophilia B
C. Acquired Coagulopathies
 Occur after childhood
 Coagulopathies refer to clotting factors or platelet problems that
results to bleeding
 Trauma-induced
 Liver Disease
 Chronic Renal Failure
 Vitamin K Deficiency
 Autoanti-FActor VIII Inhibitor and Acquired Hemophilia
 Acquired von Willebrand Disease
 DIC
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
ACQUIRED COAGULOPATHIES BY RODAKS
 We begin with the acquired coagulopathies because more
patients experience acquired bleeding disorders secondary to
trauma, drug exposure, or disease than possess inherited
coagulopathies. Chronic disorders commonly associated with
bleeding are liver disease, vitamin K deficiency, and renal
failure. In all cases, laboratory test results are necessary to
confirm the diagnosis and guide the management of acquired
hemorrhagic events.10 Trauma-I
D. Trauma-Induced Coagulophaty (TIC)
 Trauma means there has been an injury in your body that leads
to bleeding. That injury can be due to different factors such as:
 Injury related acute inflammation (physical trauma)
 Hypothermia – changes in body temperature that leads to
damage in tissues or vessels
 Acidosis – changes in body’s pH
 Hypoperfusion – poor distribution of blood in tissues because
of low blood pressure.
 If it is TIC, there is an element of systemic shock. Systemic
shock may lead to Thrombotic thrombocytopenic purpura (TTP)
TIC may also need surgical procedures to stop and control the
bleeding.
TRAUMA-INDUCED COAGULOPATHY BY RODAKS
 In North America, unintentional injury is the leading cause of
death among those aged 1 to 45 years.
 The total rises when statisticians include self-inflicted,
felonious, and combat injuries. In the United States alone,
trauma caused 214,000 deaths in 2015, or 63 per 100,000
residents.
 Severe neurologic displacement accounts for 50% of trauma
deaths, with most deaths occurring before the patient arrives
at the hospital; however, of initial survivors, 20,000 die of
hemorrhage within 48 hours.
 Trauma-induced coagulopathy (TIC) accounts for most
instances of fatal hemorrhage, and 3000 to 4000
hemorrhagerelated deaths can be prevented through
coagulopathy management.
 Coagulopathy is defined as any single or multiple coagulation
factor or platelet deficiency, and TIC is triggered by the
combination of injury-related acute inflammation, hypothermia,
acidosis, and hypoperfusion (poor distribution of blood to
tissues associated with low blood pressure), all of which are
elements of systemic shock.
 Systemic shock leads to acute reduction of ADAMTS13 (a
disintegrin and metalloprotease with a thrombospondin type 1
motif, member 13; also called VWF cleaving protease) with a
related rise in ultra-large VWF multimers and VWF-triggered
platelet activation.
 Shock also leads to tissue factor release, coagulation factor
activation, loss of coagulation control proteins, and
hyperfibrinolysis.
 This series of events resembles the pathophysiology of
thrombotic thrombocytopenic purpura (TTP, Chapter 38), as
well as conditions generated by major surgery, ruptured aortic
aneurysm, gastrointestinal bleeding, esophageal varices, and
postpartum hemorrhage where massive transfusion may be
required
TIC Management
 Massive Transfusion - not all patients should receive blood
components. Should meet the requirements below.
 <90 mmHg, >120 beats min, <7.25 pH, <32%hct,
10g/dLHGB, >1.5 INR (very high)
 “Emergency case” - assess by doctor and decide whether the
patient is a candidate for blood transfusion or not.
 Plasma
 FP (freeze plasma) – can freeze within 24hours, stored 1-
6 degree Celsius for 5 days
 Usual term: FFP: fresh frozen plasma
 Plasma is given until clotting factors has been stabilized
 If fibrinogen level is <100mg/dl can receive cryoprecipitate
 Platelet Concentrate
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 If <50,000/uL, ineffective in Immune Thrombocytopenic
purpura (ITP), Thrombotic Thrombocytopenic purpura
(TTP),Heparine-induced Thrombocytopenia (HIT)
 In these conditions, platelets are rapidly consumed so
platelet transfusion is non sense
 Concentrates (specific clotting factor concentrates)
 Cryoprecipitate in microvascular bleeding and fibrinogen of
<100mg/dL
 If specific clotting factor is missing after identifying through
laboratory testing, like mixing studies or immunologic or
chromogenic assays we can give specific CF concentrates
so that we can reduce adverse effect of blood transfusion -
TACO//TRALI (transfusion associated circulatory
overload/transfusion related acute lung injury)
 Monitoring
 TEG (thromboelastography), PC, PT, PTT Aggregation
studies
 To monitor entire hemostatic mechanism
TIC MANAGEMENT BY RODAKS
MASSIVE TRANSFUSION
 Massive hemorrhage is defined as blood loss exceeding total
blood volume within 24 hours, loss of 50% of blood volume
within a 3-hour period, blood loss exceeding 150 mL/min, or
blood loss that necessitates plasma and platelet transfusion.
 An MTP is triggered when the emergency medical team
encounters an otherwise healthy trauma victim whose systolic
blood pressure is less than 90 mm Hg, pulse is more rapid
than 120 beats/min, pH is less than 7.25, hematocrit is less
than 32%, hemoglobin is less than 10 g/dL, urine output is
diminished, and PT is prolonged to more than 1.5 times the
mean of the reference interval or generates an international
normalized ratio (INR) of 1.5 or greater.
 These limits vary by institution, and many or all are employed
in formal MTP-prediction scoring systems.
 For example, the assessment of blood consumption (ABC)
score assesses 1 point each for up to four nonlaboratory
parameters: penetrating mechanism, positive focused
assessment sonography for trauma (FAST), arrival systolic
blood pressure of 90 mm Hg or less, and arrival heart rate of
120 beats/min.
 Any two of the four parameters activates the MTP. Trauma
center MTPs specify that unmatched thawed group AB or
group A plasma be warmed and administered to the victim en
route or immediately on hospital arrival.
 Clinicians continue by administering equal amounts (1:1:1) of
warmed red blood cells (RBCs), plasma, and single (random)
donor platelet concentrate, approximating the makeup of
whole blood.
 Though RBCs are essential for their oxygencarrying capacity,
their administration need not exceed the volumes of the other
components.
 In most instances, clinicians administer pheresis platelet
concentrate preparations that provide the equivalent of four to
six random platelet concentrate preparations; consequently the
practical component ratio is actually 6:6:1, with 1 representing
pheresis platelet concentrate.
PLASMA
 Plasma is a key TIC management component. Donor services
separate and freeze plasma within 24 hours of collection,
officially naming the product FP-24.
 From time-honored habit, laboratory practitioners, nurses, and
physicians are inclined to call the product fresh frozen plasma
(FFP), though the term no longer fits the product.22 FP-24
may be subsequently thawed and stored at 1° C to 6° C for up
to 5 days, a product officially named thawed plasma.
 Trauma centers and mobile emergency services maintain an
inventory of group A or AB thawed plasma ready for
emergency administration.
 VWF and coagulation factor V and VIII activities decline to
approximately 60% after 5 days of refrigerator storage, so
thawed plasma may require supplementation with factor
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.

concentrates, especially in patients with VWD or hemophilia concentrate therapy.

PLATELET CONCENTRATE
 Most trauma center MTPs now specify that platelet
concentrate be administered as a standard component in
equal proportion with red cells and plasma, though some
stipulate platelet concentrates only be administered when the
platelet count is less than, for example, 50,000/µL.
 Platelet concentrate inventories are limited and costly to
manage, but concentrate contributes to positive outcomes
because platelets halt microvascular bleeding.
 Platelet concentrate therapy is generally ineffective when the
patient has immune thrombocytopenia, thrombotic
thrombocytopenic purpura, or heparin-induced
thrombocytopenia (Chapter 38).
 In these conditions, therapeutic platelets are rapidly
consumed, and their administration may therefore be
contraindicated, although they may provide temporary rescue
in emergent situations
 Once TIC has been stabilized, additional hemostasis-related
therapy is seldom required.
E. Liver Disease
 Why having liver disease affects the coagulation mechanism?
 In coagulation we need clotting factors, liver synthesize
clotting factors. Aside from CF, it synthesizes special
proteins essential for hemostasis.
 If you don’t have enough vitamin K there will be a problem
with the participation of vitamin K dependent protein
(X,IXVII,II) in coagulation mechanism. Because having liver
disease alter vitamin K dependent proteins.
 If factor V level is declining, it is more specific marker in
identifying liver diseases. Factor V is not a vitamin K
dependent protein so it is not affected by diet.
 It is more specific because if the liver is healthy and yet have
vitamin K deficiency, it still end-up with bleeding.

 Procoagulant Deficiency
 Hepatitis, cirrhosis, obstructive jaundice, cancer, poisoning,
CONCENTRATES and congenital disorder of bilirubin metabolism
 ADAMTS13 concentrate and PCCs, either activated or  Alters Vitamin K dependent factors
nonactivated, may be used in conjunction with the  Declining Factor V
antifibrinolytic lysine analog tranexamic acid (TXA;  Dysfibrinogenemia Factor 1 level = <100mg/dL
Cyklokapron, Pharmacia).  Unaffected vWF, VIII, XIII (found in tissues)
 First US FDA cleared in 1986 to prevent bleeding in  Platelet Abnormalities
hemophilic patients about to undergo invasive procedures,  If liver is abnormal, spleen will be enlarged, more platelets
TXA is effective and commonly employed for TIC, though this are sequestered that results to platelets shortened survival.
too is an off-label application. Administration of cryoprecipitate  Moderate thrombocytopenia
is indicated when there is microvascular bleeding and the  It may also affect quality of platelets leading to a problem in
fibrinogen concentration is less than 100 mg/dL. platelet aggregation or secretion of its different
components.
 In postpartum hemorrhage, plunging fibrinogen levels are of
particular concern because they signal the risk of major blood
 DIC
loss.
 More of complication of liver disease. Usually, DIC leads to
 A 15 to 20 mL cryoprecipitate unit provides 150 to 250 mg of
decrease in thrombin regulators: Protein C and Protein S
fibrinogen, and the risk of TACO is lower than the risk
 A failing liver cannot clear activated clotting factors. So CF
associated with plasma. A target fibrinogen level of 100 mg/dL
are not inhibited due to decrease regulatory proteins.
should be maintained, though some recommend 200 mg/dL in
 All coagulation test in DIC will be prolonged or abnormal
postpartum hemorrhage.
and positive with D-dimer.
 Postpartum hemorrhage may also be managed with TXA.  Remove or treat first the underlying cause.
 Von Willebrand factor and FVIII concentrates are also  Treatment
indicated when the patient has a preexisting deficiency.  Vitamin K therapy, Blood Transfusion
 Recombinant activated coagulation factor VII (rFVIIa,  If there is DIC and bleeding, patient need to receive certain
NovoSeven) was US FDA cleared in 1999 for treating blood components (more on plasma contents)
hemophilia A or B when anti-FVIII or factor IX (FIX) inhibitors
are present, respectively; its application in the treatment of TIC
is off-label. A NovoSeven dosage of 30 mg/kg is rapidly
effective in halting microvascular hemorrhage in
nonhemophilic trauma victims, and NovoSeven does not
cause DIC.
 However, studies found a possible link between off-label
NovoSeven use and arterial and venous thrombosis in patients
with existing thrombotic risk factors.
MONITORING THERAPY
 A skilled operator employing TEG or TEM technology may
monitor the effects of plasma, platelet concentrate, PCC,
activated PCC, four-factor PCC, TXA, and rFVIIa.
 Cryoprecipitate efficacy may be measured using the fibrinogen
assay.
 Also, laboratory directors characteristically advise surgeons
and emergency department physicians to monitor the
effectiveness of all TIC therapy indirectly by checking for the
correction of platelet count, PT, and PTT to within their
respective reference intervals.
 Platelet aggregometry may be used to measure post-therapy
platelet function, and coagulation factor assays are valuable as
follow-ups to PT and PTT to determine whether the target
activity of 30 units/dL has been met for each.
 Although PT, PTT, platelet count, and platelet function assays
are accepted approaches, TEG and TEM provide immediate
feedback and may be more sensitive to small physiologic
improvements.
 ADAMTS13 assays are necessary in monitoring ADAMTS13
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
LIVER DISEASE COAGULOPATHY BY RODAKS
 The bleeding associated with liver disease may be localized or
generalized, mucocutaneous or anatomic.
 Enlarged and collateral esophageal vessels called esophageal
varices are a complication of chronic alcoholic cirrhosis;
hemorrhaging from varices is localized bleeding, not a
coagulopathy, though often fatal.
 Mucocutaneous bleeding occurs in liver disease–associated
thrombocytopenia, often accompanied by decreased platelet
function.
 Anatomic bleeding is the consequence of procoagulant
dysfunction and deficiency.
PROCOAGULANT DEFICIENCY
 The liver produces nearly all of the plasma coagulation factors
and regulatory proteins.
 Hepatitis, cirrhosis, obstructive jaundice, cancer, poisoning,
and congenital disorders of bilirubin metabolism may suppress
the biosynthetic function of hepatocytes, reducing either the
concentrations or activities of the plasma coagulation factors to
less than hemostatic levels (,40 units/dL).
 Liver disease alters the production of the vitamin K-dependent
factors II (prothrombin), VII, IX, and X and control proteins C,
S, and Z. In liver disease these seven factors are produced in
their des-g-carboxyl forms, which cannot participate in
coagulation (Chapter 35).
 At the onset of liver disease, factor VII, which has the shortest
plasma half-life at 6 hours, is the first coagulation factor to
exhibit decreased activity.
 Because the PT is particularly sensitive to factor VII activity, it
is characteristically prolonged in mild liver disease, serving as
a sensitive early marker.
 Vitamin K may become deficient when the diet is limited.
Vitamin K deficiency independent of liver disease produces a
similar effect on the PT.
PLATELET ABNORMALITIES
 Moderate thrombocytopenia occurs in one-third of patients
with liver disease.
 Platelet counts of less than 150,000/mL may result from
sequestration and shortened platelet survival associated with
portal hypertension and resultant hepatosplenomegaly.
 In alcoholism-related hepatic cirrhosis, acute alcohol toxicity
also suppresses platelet production.
 Platelet aggregation and secretion properties are often
suppressed; this is reflected in reduced platelet aggregometry
and lumiaggregometry results (Chapter 41).
 Occasionally, platelets are hyper-reactive. Although
controversial, aggregometry may be used to predict bleeding
and thrombosis risk.
DISSEMINATED INTRAVASCULAR COAGULATION
 Chronic or compensated DIC (Chapter 39) is a significant
complication of liver disease that is caused by decreased liver
production of regulatory antithrombin, protein C, or protein S
and by the release of activated procoagulants from
degenerating liver cells. The failing liver cannot clear activated
coagulation factors.
 In primary or metastatic liver cancer, hepatocytes may also
produce nonspecific procoagulant substances that trigger
chronic DIC, leading to ischemic complications.
 In acute, uncompensated DIC, the PT, PTT, and TT are
prolonged, the fibrinogen level is reduced to less than 100
mg/dL, and D-dimers are significantly increased.58 If the DIC
is chronic and compensated, the only elevated test result may
be the Ddimer assay value, a hallmark of unregulated
coagulation and fibrinolysis.
 Although DIC can be resolved only by removing its underlying
cause, its hemostatic deficiencies may be corrected
temporarily by administering RBCs, plasma, activated or
nonactivated PCC, TXA, platelet concentrates, or antithrombin
concentrates, which include synthetic ATryn (rEVO Biologics)
and plasma-derived Thrombate III (Grifols).
HEMOSTATIC TREATMENT TO RESOLVE LIVER DISEASE–
RELATED HEMORRHAGE
Page 5 of 14
 Oral or intravenous vitamin K therapy may correct the bleeding
associated with nonfunctional des-g-carboxyl factors II
(prothrombin), VII, IX, and X; however, the therapeutic effect of
vitamin K is short lived compared with its effect in dietary
vitamin K deficiency because of the liver’s impaired
biosynthetic ability.
 In severe liver disease, plasma transfusion provides all of the
coagulation factors in hemostatic concentrations, although
VWF and factors V and VIII may be reduced.
 Because of its small concentration and the short half-life of
factor VII, plasma is unlikely to return the PT to within the
reference interval.
 A unit of plasma provides a volume of 200 to 280 mL. The
typical adult plasma dose for liver disease is 2 units, but the
dose varies widely, depending on the indication and the ability
of the patient’s cardiac and renal system to rapidly excrete
excess fluid.
 TACO is likely to occur when 30 mL/kg has been administered,
but it may occur with even smaller volumes in patients with
compromised cardiac or kidney function.
 If the fibrinogen level is less than 50 mg/dL, spontaneous
bleeding is imminent and cryoprecipitate or fibrinogen
concentrate (RiaSTAP, CSL Behring) may be selected for
therapy.
 Plasma and cryoprecipitate present a theoretical risk of virus
transmission, as do other untreated single-donor biologic blood
products, and allergic transfusion reactions are more common
with plasma-containing products.
 Other therapeutic options for patients with liver disease-related
bleeding are platelet concentrates, PCC, antithrombin
concentrate, rFVIIa, and TXA.
F. Chronic Renal Failure
 Leads to Platelet dysfunction
 Platelet dysfunction goes with adhesion and aggregation
problems.
 Having kidney disease lead to poor platelet adhesion and
aggregation primarily because of “GSA” (guanidinosuccinic
acid) or because of phenolic compounds that coats
platelets.
 Manifested by: Mucocutaneous bleeding
 Hemostasis activation syndromes
 Associated with:
 DIC
 HUS (hemolytic uremic syndrome)
 TTP (thrombotic thrombocytopenic purpura)
 Tx: renal dialysis, DDAVP (desmopressin)
 In chronic renal failure, since it affects more on platelets, PT and
APTT are normal.
 Nephrotic Syndrome: increased glomerular permeability
(proteins can easily pass-through urine)
 II, VII, IX, X, XII, anti-thrombin, protein C in urine
 NOTE: in treating patients with renal failure, do not give
platelet inhibitors like aspirin, clopidogrel since the problem
is the platelet itself.
CHRONIC RENAL FAILURE AND HEMORRHAGE BY RODAKS
 Chronic renal failure of any cause is often associated with
platelet dysfunction and mild to moderate mucocutaneous
bleeding.
 Platelet adhesion to blood vessels and platelet aggregation are
suppressed, perhaps because guanidinosuccinic acid or
phenolic compounds coat the platelets.
 Decreased RBC mass (anemia) and thrombocytopenia
contribute to the bleeding. Dialysis, RBC transfusions, or
erythropoietin therapy (epoetin alfa, Procrit, Janssen
Pharmaceutica) may correct these disorders.
 Hemostasis activation syndromes that deposit fibrin in the
renal microvasculature reduce glomerular function. Examples
are DIC, hemolytic uremic syndrome, and thrombotic
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
thrombocytopenic purpura.
 Although these are by definition thrombotic disorders, they
invariably cause thrombocytopenia, which may lead to
mucocutaneous bleeding.
 Fibrin also may be deposited in renal transplant rejection and
in the glomerulonephritis syndrome of systemic lupus
erythematosus.
G. Vitamin K Deficiency
 Source from food: green leafy vegetables
 Essential in gamma carboxylation of clotting factors (prothrombin
group: II,VII,IX X). In short, it is essential for CF metabolism and
activity.
 Having deficiencies means failure of prothrombin group to
interact with others thus resulting to failure to form a clot.
 Even you have II, VII, IX, and X but without vitamin K, clot is not
easily formed.
Vitamin K deficiency because of the ff:
 Biliary duct obstruction, fat malabsorption, chronic diarrhea
 Hemorrhagic Disease of the Newborn (gastrointestinal tract is not
well established)
 Low II, VII, IX, X
 Breast milk does not contain enough amount of vitamin K, in
some cases breast feeding prolong vitamin k deficiency because
it delays the establishment/development of your gastrointestinal
tract. Microbial flora is needed in GIT, but because of antibodies
received from breast milk, it delays GIT development and Vit K is
deficient.
 Vitamin K Antagonist (coumadin)
 Interrupts g-carboxylation of coagulation factors
 Protein induced by Vitamin K antagonists (PIVKA)
 Prolonged PT, Prolonged Normal PTT
 Oral or Intravenous Vitamin K, PCC(prothrombin complex
concentrate) it contains II,VII,IX,X
 If taking drugs that acts against vitamin k = vit k deficiency
 II, VII, IX, X - not gamma carboxylated it will not participate in
coagulation mechanism.
 If taking Caumadin or Vitamin K antagonist and produce protein
II, VII, IX, X, Protein C, S, and Z it is called (PIVKA). The protein
is made even not gamma carboxylated (dysfunctional protein).
 In treating you will give Vitamin K intravenously or orally, or
prothrombin complex concentrate and it can control the bleeding.
VITAMIN K DEFICIENCY AND HEMORRHAGE BY RODAKS
 Vitamin K, required for normal function of the vitamin K
dependent prothrombin group of coagulation factors is
ubiquitous in foods, especially green leafy vegetables, and the
daily requirement is small, so pure dietary deficiency is rare.
 Body stores are limited, however, and become exhausted
when the usual diet is interrupted, as when patients are fed
only with parenteral (intravenous) nutrition for an extended
period or when people embark upon fad diets.
 Also, because vitamin K is fat soluble and requires bile salts
for absorption, biliary duct obstruction (atresia), fat
malabsorption, and chronic diarrhea may cause vitamin K
deficiency.
 Broad-spectrum antibiotics that disrupt normal gut flora may
cause a slight reduction because they destroy bacteria that
produce vitamin K
HEMORRHAGIC DISEASE OF THE NEWBORN CAUSED BY
VITAMIN K DEFICIENCY
 The g-carboxylation cycle of coagulation factors is interrupted
by coumarin-type oral anticoagulants such as warfarin
(Coumadin) that disrupt the vitamin K epoxide reductase and
vitamin K quinone reductase reactions
 In this situation the liver releases dysfunctional des-g-carboxyl
factors II (prothrombin), VII, IX, and X and proteins C, S, and
Z; these inactive forms are called proteins induced by vitamin
K antagonists (PIVKA) factors.
 Therapeutic overdose or the accidental or felonious
administration of warfarin-containing rat poisons may result in
moderate to severe hemorrhage because of the lack of
functional K-dependent factors.
Page 6 of 14
 The effect of brodifacoum or “superwarfarin,” often used as a
rodenticide, lasts for weeks to months, and treatment of
poisoning with this substance requires repeated administration
of vitamin K with follow-up PT monitoring.
 Inadvertent Coumadin overdose is the single most common
reason for hemorrhage-associated emergency department
visits.
DETECTION OF VITAMIN K DEFICIENCY OR PIVKA FACTORS
 A prolonged PT with or without a prolonged PTT supports the
clinical suspicion of vitamin K deficiency. In PT and PTT
mixing studies, if commercial platelet-free normal plasma (NP;
CRYOcheck Pooled Normal Plasma, Precision BioLogic) is
combined with patient plasma, the mixture yields “corrected”
PT and PTT results, which indicate that factor deficiencies
caused the initially prolonged PT and (perhaps) PTT.
Singlefactor assays will detect low factor VII (a common
finding because of the short half-life of factor VII), followed in
sequence by decreases in factors IX, X, and II (prothrombin),
depending on the progression of the patient’s abnormality. The
standard therapy for vitamin K deficiency is oral—or, in an
emergency, intravenous—vitamin K. Because synthesis of
functional vitamin K-dependent coagulation factors requires at
least 3 hours, in the case of severe bleeding, plasma or four-
factor PCC may be administered.76 The primary assays for
plasma or four-factor PCC efficacy are TEG or TEM, but the
patie
H. Autoanti-Factor VIII Inhibitor and Acquired Hemophilia
 Refrs to Acquired antibodies against clotting factor II, V, VIII, IX,
XIII, vWF
 Autoantibody against VIII is most common autoantibodies for
Acquired Hemophilia
 Acquired Hemophilia
 The autoantibodies develop against clotting factor VIII
when you have Rheumatoid arthritis, inflammatory bowel
disease, systemic lupus erythematosus or
lymphoproliferative disease
 After delivery Pregnancy
 For treatment VII concentrates DDAVP (Desmopressin)
 Tx: Immunosuppressive therapy
 Acquired Hemophilia is different from Hemophilia
 Hemophilia don’t produce factor VIII.
 Acquired Hemophilia destroying the factor VIII it was acquired
because of underlying factor that stimulated the body to produce
an antibodies against Factor VIII
 Example if you have SLE, RA it will destroy factor VIII
 It testing it will go with clot based test, PT, PTT, Thrombin Time,
mixing studies or Factor VIII assay, chromogenic or immunologic
testing.
 Bethesda Inhibitor assay it can quantify factor VIII
AUTOANTI-FACTOR VIII INHIBITOR AND ACQUIRED
HEMOPHILIA BY RODAKS
 Acquired autoantibodies that specifically inhibit factors II
(prothrombin), V, VIII, IX, and XIII and VWF have been
described in nonhemophilic patients.
 Autoanti-factor VIII is the most common. Patients who develop
an autoantibody to factor VIII, which is diagnostic of acquired
hemophilia, are often older than 60 and have no apparent
underlying disease.
 Acquired hemophilia is occasionally associated with
rheumatoid arthritis, inflammatory bowel disease, systemic
lupus erythematosus, or lymphoproliferative disease.
 Pregnancy appears to trigger acquired hemophilia 2 to 5
months after delivery.
 Patients with inhibitor autoantibodies are prescribed
immunosuppressive therapy, although autoantibodies that
develop after pregnancy typically disappear spontaneously.
 Altogether, acquired hemophilia has an incidence of 1 per
million people per year.
 Patients experience sudden and severe bleeding in soft
tissues or bleeding in the gastrointestinal or genitourinary tract.
 Acquired hemophilia, even when treated, remains fatal in at
least 20% of cases.
WONDER PETS & DOGFUR – TRANSCRIBERS
 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
 Autoantibodies to other procoagulants are less common but
create similar symptoms.
I. Acquired von Willebrand Disease
 Acquired because of underlying factor that leads to the
deficiency of vWF.
 von Willebrand is an inherited disease, if it is inherited you don’t
have vWF
 If it’s acquired similar to hemophilia there is underlying problem
leads to destruction of vWF
 Decreased VWF production, adsorption of VWF to abnormal cell
surface, it develop specific VWF autoantibody against vWF
 Hypothyroidism
 Benign monoclonal gammopathies
 Wilms tumor
 Intestinal angioplasia
 Congenital heart disease
 Pesticide exposure
 Uremia
 Lupus erythematosus
 Autoimmune
 Diminished VWF activity and VWF antigen by immunoassay
 In testing APTT is Prolonged, PT is normal
 vWF carries factor VIII having vWF diseases will affect APTT
prolong.
For treatment DDAVP(stimulate endothelial cell and releases vWF_or
vWF concentrate
ACQUIRED VON WILLEBRAND DISEASE BY RODAKS
 Acquired VWF deficiency, with symptoms similar to those of
congenital VWD, has been described in hypothyroidism,
benign monoclonal gammopathies, Wilms tumor, intestinal
angiodysplasia, congenital heart disease, pesticide exposure,
uremia, lupus erythematosus, and autoimmune,
lymphoproliferative, and myeloproliferative disorders.
 The pathogenesis of acquired VWD may involve decreased
VWF production; adsorption of VWF to abnormal cell surfaces,
as seen in association with lymphoproliferative disorders and
Wilms tumor; or, in less than 2% of cases, a specific VWF
autoantibody.
 Acquired VWD manifests with moderate to severe
mucocutaneous bleeding and may be suspected in any patient
with recent onset of bleeding who has no hemorrhage-related
medical history.
 Although the PT is not affected, the PTT may be moderately
prolonged if the VWF reduction is severe enough to reduce
factor VIII to less than 40 units/dL, because VWF serves as
the factor VIII carrier molecule.
 As in congenital VWD, the diagnosis is based on a finding of
diminished VWF activity and diminished VWF antigen by
immunoassay. It may be difficult to differentiate between mild,
previously asymptomatic congenital VWD and acquired VWD.
 If the patient requires treatment for bleeding, DDAVP or a
plasma-derived factor VIII/VWF concentrate such as HumateP
(Behring), Wilate (Octapharma), or Alphanate (Grifols) is
effective at controlling the symptoms.
 Cryoprecipitate is no longer recommended for treatment of
VWD because it does not undergo viral inactivation
J. Congenital Coagulopathies
 An acquired coagulapathies their is underlying disease that leads
to deficiency of a particular protein essential for coagulation
 If it’s inherited it can go with congenital coagulopathies that leads
to bleeding.
 Von Willebrand Disease
 Hemophilia A
 Hemophilia B
 Hemophilia C
Page 7 of 14
K. Von Willebrand Disease
 Quantitative deficiency or qualitative abnormalities of vWF
 vWf is essential with platelet adhesion on damage vessel, vWF
carries factor VIII. Since factor VIII is labile on plasma
 vWF disease -platelets will fail to adhere on damage vessel will
end up of bleeding because of unavailability of Factor VIII
 vWF- consider largest molecules in plasma synthesize by
endothelial cells, it can recover to megakaryocytes and present
in alpha granules of platelets. It could be stored in Weibel
palade bodies
 500,000 to 20,000,000 Daltons
 Synthesized by endothelial cells
 Function:
 Reduced platelet adhesion it is affected even quantitative or
qualitative leads to mucucotaneous bleeding
 Epistaxis
 Ecchymosis
 Menorrhagia
 Hematemesis
 Gastrointestinal, and surgical bleeding
 Results Factor VII deficiency because no more binding site and it
will deteriorated
VON WILLEBRAND DISEASE BY RODAKS
 VWD, first described by Finnish professor Erik von Willebrand
in 1926, is the most prevalent inherited mucocutaneous
bleeding disorder. Any one of dozens of germline mutations
may cause VWD as these mutations produce quantitative
(type 1) or qualitative (functional, type 2) VWF abnormalities.
 Both quantitative and functional abnormalities lead to
decreased platelet adhesion to injured vessel walls, impairing
primary hemostasis.
 When solely defined by laboratory assays as VWF deficiency,
VWD is reputed to afflict approximately 1% of the global
population.
 However, when defined by the number of patients who
experience bleeds serious enough to seek medical assistance,
prevalence is 1 in 20,000 (0.05%).
 The prevalence of VWD in women who report menorrhagia is
24%.
 VWD inheritance is autosomal dominant and affects both
sexes.
Pathophysiology of von Willebrand Disease
 Structural (qualitative) or quantitative VWF abnormalities
reduce platelet adhesion, which leads to mucocutaneous
hemorrhage of varying severity: epistaxis, ecchymosis,
menorrhagia, hematemesis, gastrointestinal, and surgical
bleeding. Symptoms vary over time and within kindreds
because VWF production and release are susceptible to a
variety of physiologic influences.
 In addition, severe quantitative VWF deficiency creates factor
VIII deficiency as a result of the inability to protect unbound
factor VIII from proteolysis. Many “low VWF” people have VWF
levels in the intermediate range of 30% to 50% of normal and
maintain a factor VIII level sufficient for competent coagulation.
 When factor VIII levels decrease to less than 30 units/dL,
anatomic bleeding into joints and body cavities accompanies
the typical mucocutaneous bleeding pattern of VWD.
WONDER PETS & DOGFUR – TRANSCRIBERS
 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
vWDse Types
Type 1 vWF deficiency (40-70% of cases)
Type 2 vWF levels may be normal or moderately
decreased Reduced Function
Subtype 2A Normal slight reduced vWF antigen
Loss of HMW and IMW multimers
Reduced platelet adhesion
Subtype 2B (Platelets) Mutation with A1 domain (gain of function)
binds more with increase vWF too much adhesion in
platelets platelets even it is not needed,
Lack of HMW multimer
RIPA Ristocetin induced
aggregation
Platelet -type vWDse/pseudo vWdse
Pseudo because the problem is not in vWF,
it affects the adhesion but the problem is
within the platelets.
Their is a platelet mutation which bind more
to vWF glycoproetein 1b in platelets
Subtype 2M (Platelets) Qualitative VWF variant poor platelets
receptor binding it is qualitative more of the
function
Page 8 of 14
Subtype 2N (Factor Impaired factor VIII binding site factor VIII
VIII) can’t bind to vWF
Autosomal hemophilia
Type 3 Null Allele rare and no vWF one of the
deadliest results to bleeding
 Normal you will have a lot of vWF, type 1 and 2 deficiency of low
or high molecular wight multimers, type 3 no vWF
VON WILLEBRAND DISEASE TYPES AND SUBTYPES BY
RODAKS
TYPE 1 VON WILLEBRAND DISEASE.
 Type 1 VWD is a quantitative VWF deficiency caused by one
of several autosomal dominant frameshifts, nonsense
mutations, or deletions that may occur anywhere in the VWF
gene.
 Type 1 comprises 40% to 70% of VWD cases.
 The plasma concentrations of all VWF multimers and factor
VIII are variably, albeit proportionally, reduced (Figure 36.4).
 There is mild to moderate systemic bleeding, usually after a
hemostatic challenge such as dental extraction or surgery.
 In women, menorrhagia, which predicts postpartum
hemorrhage, is a common complaint that leads to the
diagnosis of VWD.
 However, because mucocutaneous (systemic) bleeding
symptoms occur in normal people to varying degrees,
diagnosis requires scrupulous laboratory testing
TYPE 2 VON WILLEBRAND DISEASE
 Type 2 VWD encompasses four qualitative VWF
abnormalities. VWF levels may be normal or moderately
decreased, but VWF function is consistently reduced.
 Laboratory testing is essential to identifying and confirming
type 2 subtypes because the diagnosis affects treatment
choices.
SUBTYPE 2A VON WILLEBRAND DISEASE
 Approximately 10% to 20% of all VWD patients suffer from
subtype 2A, which arises from well-characterized autosomal
dominant point mutations in the A2 and D1 structural domains
of the VWF molecule.
 These mutations render VWF susceptible to increased
proteolysis by ADAMTS13, which leads to a predominance of
smallmolecular-weight plasma multimers (Figure 36.4).
 The smaller multimers support less platelet adhesion activity
than the normal high- or intermediate-molecular weight
multimers.
 Patients with subtype 2A VWD have normal or slightly reduced
VWF antigen levels as measured by immunoassay, with
moderate to markedly reduced VWF activity as a result of the
loss of the high-molecular-weight and intermediate-molecular-
weight multimers essential for platelet adhesion.
SUBTYPE 2B VON WILLEBRAND DISEASE
 In subtype 2B VWD, identified in less than 5% of all VWD
platelet patients, mutations within the A1 domain raise the affinity of
VWF for platelet GPIb/IX/V, its customary binding site; these
are hence “gain-of-function” mutations.
 HMW-VWF multimers spontaneously bind resting platelets.
 The abnormal HMW-VWF multimers are consequently
unavailable for normal platelet adhesion as they are cleared
with the bound platelets. The electrophoretic multimer pattern
is characterized by lack of HMW-VWF multimers, but
intermediate-molecular-weight multimers may still be present
(Figure 36.4).
 Subtype 2B VWD may be confirmed using a specially
WONDER PETS & DOGFUR – TRANSCRIBERS
 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.

designed reduced-concentration, ristocetin-induced (RIPA)

platelet agglutination assay. Pitfalls in von Willebrand Disease Diagnosis
 There may also exist moderate thrombocytopenia caused by  Factors affecting diagnosis:
chronic platelet activation because multimer-coated platelets  Genetics
indiscriminately bind the endothelium and become cleared.  ABO blood group can have problem with vWF specially o
and A
 some have low vWF to classify it, it should be 50%=low
SUBTYPE 2M VON WILLEBRAND DISEASE vWF, vWFDse= 30% activity
 Subtype 2M VWD describes a qualitative VWF variant that  Inflammation
possesses poor platelet receptor binding despite generating a  Age
normal multimeric distribution pattern in electrophoresis.  Phystical stress
 The distinguishing feature of subtype 2M that separates it from  Oral contraceptive
type 1 is a discrepancy between the concentration of VWF:Ag  Hormone Replacement
and its activity as measured using the VWF ristocetin cofactor  Ristocetin cofactor poor reproducibility of the result because of
assay described later, despite a normal multimeric pattern. changes
 Subtype 2M is often incorrectly identified as type 1 or subtype  Variability of VWF: RCo assa- new collagen
2A. It may be that the 10% to 20% prevalence data for subtype  Specimen mishandling
2A and the 40% to 70% date for type 1 are artificially elevated  Poor collection’
by misdiagnosed subtype 2M cases.  Tourniquet
SUBTYPE 2N VON WILLEBRAND DISEASE (NORMANDY  Refrigerated plasma
VARIANT; AUTOSOMAL HEMOPHILIA)  False positive or negative result
 An autosomal VWF gene missense mutation in the D9 domain
impairs the protein’s factor VIII binding site function.
 This condition, present in less than 5% of VWD patients,
results in factor VIII deficiency despite a normal VWF antigen
concentration assay result, normal VWF activity, and a normal
multimeric pattern.
 The disorder is also known as autosomal hemophilia because
its clinical symptoms are indistinguishable from the symptoms
of hemophilia except that it affects both men and women.
Subtype 2N is suspected when a girl or woman is diagnosed
with hemophilia subsequent to anatomic bleeding symptoms.
 In boys or men, subtype 2N is suspected when a male patient
misdiagnosed as a hemophilia A sufferer fails to respond to
factor VIII concentrate therapy.
 The poor therapeutic response occurs because free factor VIII
has a plasma half-life of mere minutes.
 The diagnosis of VWD subtype 2N is confirmed using a
molecular assay that detects the specific mutation responsible
for the abnormal FVIII binding function
TYPE 3 VON WILLEBRAND DISEASE.
 “Null allele” VWF gene translation or deletion mutations that
may occur anywhere on the gene produce severe
mucocutaneous and anatomic hemorrhage in compound
heterozygotes or, in consanguinity, homozygotes. This is the
most rare form of VWD, where the VWF concentration
measured by immunoassay or by activity assay is less than
10% (Figure 36.4).
 Factor VIII is proportionally diminished or absent, and primary
and secondary hemostasis is impaired.

Diagnosis PITFALLS IN VON WILLEBRAND DISEASE DIAGNOSIS BY

 History Family, Clinical History
 Clinical manifestation
 Lab test to asses bleeding
 CBC to rule out thrombocytopenia
 PT to check problem possibly for clotting factor
 PTT
 FVIII:C activity
 vWF:RCo
 vWF: Ag
 Aggregation test
 Glass bead retention test to check platelet adhesion test
 vWF disease mistaken to be hemophilia A( don’t produce
factor VIII), if their no vWF their will be no factor VIII
because it decreases when you have vWF diseases, APTT
test will not be helpful. Hemophilia A APTT is prolonged,
vWF APTT increases prolonged.
 If patients has bleeding mnemonic called
 PRICE- Protect, Rest, Ice,Compression, Elevate (lower
extremities mostly)
 Treatment DDAVP, Factor VIII concentrate, Epsilon
Aminocaproic acid , Tranexamic acid - it manages bleeding
anti-fibrinolysis
RODAKS
 Varying genetic penetrance, ABO blood group, inflammation,
hormones, age, and physical stress influence VWF activity.
 Raised estrogen levels during the second and third trimesters
of pregnancy nearly normalize plasma VWF activity even in
women with moderate VWF deficiency.
 However, VWF concentration and function decrease rapidly
after delivery, which may lead to acute postpartum
hemorrhage in VWD, for which the obstetrician is watchful.
 Oral contraceptives and hormone replacement therapy also
raise VWF activity, and activity waxes and wanes with the
menstrual cycle.
 VWF activity rises substantially in acute inflammation such as
occurs postoperatively, subsequent to trauma, or during an
infection. Physical stress such as cold, exertion, or a child’s
crying or struggling during venipuncture causes VWF activity
to rise. VWF activity rises when the phlebotomist allows the
tourniquet to remain tied for more than 1 minute before
venipuncture and descends if the specimen is stored in the
refrigerator before testing.
 VWD patients experience fluctuation in disease severity over
time, and the clinical manifestations of the disease vary from

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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.

person to person within kindred, despite the assumption that

everyone in the family possesses the same mutation.
 When the clinical presentation indicates VWD, the VWD
laboratory assay panel should be repeated at least once, or
until the results are conclusive.
 Adding to VWD diagnostic confusion is concern over the
variability in the results of the VWF:RCo assay, which is based
on platelet aggregometry but is performed using a variety of
instruments and methods as detailed before.
 Ristocetin avidity varies from lot to lot. In the United States
proficiency surveys consistently reveal VWF:RCo assays to
have an unimpressive interlaboratory coefficient of variation of
30% and a least detectable activity range of 6% to 12%.
 The key tendency is overdiagnosis of VWD; nevertheless,
restrictive laboratory assay panels and inappropriate testing
such as the bleeding time test or PFA-100 may miss  Laboratory tests, because if we go to clinical manifestation as
documentable VWD. Rheumatoid factor and heterophile discussed above, they may just be the same which they all
antibodies interfere to cause false positives. exhibit bleeding
 Occasionally, physicians may diagnose hemophilia A in  Important: go with laboratory tests so you can further identified
patients with VWD type 3, having failed to order a VWF which is which because by doing so, you can give proper
primary profile. Moderate VWD may fail to appear until management and proper treatment for the patient
adulthood, leading to a false diagnosis of acquired VWD.  Pwede kang magbigay specific clotting factors concentrate
 Specimen mishandling such as prolonged tourniquet  Recall: PT is for extrinsic pathway and APTT is for intrinsic
application, plasma refrigeration, filtration, or pathway, Thrombin Time is specific for factor I
ultracentrifugation lead to false positives, false negatives, or  To make it easily you just need to point out which pathway
false phenotypes such as misidentifying a type 1 as a type 2 clotting factors belong
VWD.  If the factor belongs to extrinsic pathway expect that the PT
will then be prolonged
L. Clotting Factor Defects  If the factor belongs to intrinsic pathway expect that the
 Factor I deficiency APTT will then be prolonged
o Afibrinogenemia  If the factor belongs to common pathway expect that both
 depending on the level fibrinogen PT and APTT will then be prolonged
 Normal fibrinogen 200-400 mg/dL  Look Factor II and factor V and Factor X
o Hypofibrinogenemia  The results are same
 Structure is abnormal  How will you know what factor is affected? Mixing studies,
o Dysfibrinogenemia specific clotting factor assays
 Factor II deficiency
 Factor V deficiency AKA Owren’s Disease and
Parahemophilia (resembles factor VIII deficiency)
 If factor V is deficiency goes along with Factor VIII
deficiency (both low) usually it could be attributed to a
problem with chromosome 18
 Factor VII deficiency
 Factor VIII deficiency AKA Hemophilia A
 Factor IX deficiency AKA Hemophilia B
 Factor XI deficiency AKA Hemophilia C
 Factor XII
 Factor XIII deficiency
 Inability to stabilize the clot
 Prekalekrein deficiency AKA Fletcher Trait
 HMWK deficiency
 Problem with Prelalekrein and HMWK may lead to
thrombotic episodes

*kindly refer to the last page for a larger picture*

M. Hemophilia A
 Deficiency in Factor VIII
 Classical Hemophilia
 Second to VWD in prevalence among congenital bleeding
disorders
 X-linked
 Men manifest the disease whereas women serve as carrier
 Anatomic Bleeding (hematoma)
 Complications
 Bleeding on CNS, kidneys, GIT and even joints
(hemarthrosis)
 Because of bleeding you can expect that there could be
certain musculoskeletal lesions on patients and sometimes

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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
even neurologic deficiencies (lead to intracranial
haemorrhage)
 Treatment:
 Remember: the goal of treating haemophilia A is to
increase the patient Factor VIII activity
 Can give plasma derived concentrates or directly you
can give recombinant Factor VIII concentrate
 DDAVP or Vasopressin
 Anti-fibrinolytic
 epsilon aminocaproic acid
 tranexamic acid
 EACA and TXA
 Human plasma derived concetrates
 Alphanate
 Hemofil-M
 Kogenate FS
 Humate P
 Wilate
 Recombinant Factor VIII concentrate
 To compute how much factor VIII should be given:
��
 ������ ������ = ����ℎ� �� �� � 65 � 1 − ℎ���������
��
 ����� ����������� ���� =
������ ������ � (������ ����� ����� − ������� ����� �����)
1st example:
 The father has Hemophilia A (his X chromosome is affected) +
the mother is not affected and not also a carrier
o Offspring:
 The sons not get his father affected X chromosome
since he inherit his X chromosome from his mother
and his Y chromosome is inherit from his father (not
the X chromosome), Hemophilia A is a X linked
Disease, therefore 100% the sons will never got
Hemophilia A
 The daughters have a probability of 100% sure that
she can get Hemophilia A. remember a girl has a 2 X
chromosomes, one from her father and one from her
mother, the problem here is that the father has only
one X chromosome and it is so happen that his X
chromosome has a disease, automatically their
daughters will have Hemophilia A
2nd example
 The father doesn’t have the disease + mother has the one
affected by Hemophilia A (one X of the mother is affected while
the other one is not)
o Offspring: 50/50 chances
 The first offspring is a boy (Y from the father and X
from the mother), and it so happen that this boy got
lucky, what he inherited from his mother is the
normal or healthy X. this boy don’t have Hemophilia
A 
 Similar to other daughter she inherit is the
normal X chromosome and therefore she
does not carry hemophilia gene
 If a boy got unlucky he inherit the affected X
chromosome of his mother, definitely the boy
manifest Hemophilia A
 Similar to the other girl, 50/50. She will
inherit the X from her father (healthy) but
Page 11 of 14
she inherited the affected X chromosome
from her mother, and therefore this girl will
be a carrier of the Hemophilia A
HEMOPHILIA A (FACTOR VIII DEFICIENCY) BY RODAKS
 The hemophilias are congenital single-factor deficiencies
marked by anatomic soft tissue bleeding. Second to VWD in
prevalence among congenital bleeding disorders, hemophilias
occur in 1 in 8000 individuals, mostly males. Of those affected,
85% are deficient in factor VIII, 14% are deficient in factor IX,
and 1% are deficient in factor XI or one of the other
coagulation factors, such as factors II (prothrombin), V, VII, X,
or XIII. Congenital deficiency of factor VIII is called classic
hemophilia or hemophilia A
HEMOPHILIA A (FACTOR VIII DEFICIENCY) BY STEININGER
 Classic hemophilia is recorded to antiquity. It is sometimes
referred to as the “royal disease” as Queen Victoria of England
was a carrier, and the condition eventually spread through
Europe royal families.
 Hemophilia A is a sex-linked disorder transmitted on a X
chromosome by carrier women to their sons. Carrier women
produce clinically normal daughters who may carry the
chromosomal defect. Sons of affected men are unaffected, but
the daughters are obligatory carriers. One third of new cases
occur spontaneously through mutations or variability in the
expression of the X chromosome causing skip generation
Clinical findings
 A bleeding diathesis arises from decreased or defective factor
VIII:C. the severity of the disorder is tied to the degree of
deficiency. Most severely affected patients possess less than
1% activity of factor VIII:C; moderately affected patient have
2% to5% activity; and mildly affected patient’s generally have
more than 5% activity. Clinical bleeding necessitating medical
intervention occurs most frequently in severely affected
hemophiliacs. Patient who maintain factor activity levels above
6% may remain clinically silent until traumatized or submitted
to surgical procedures without prophylactic preparation. A
patients factor activity level remains fairly constant throughout
life
 Typical bleeding episode result from trauma but may be
spontaneous in the most severe cases. Bleeding into soft
tissues (hematoma) or joints (hemarthroses), epistaxis,
hematuria, GI and intracranial hemorrhages, and postoperative
bleeding constitute the majority of hemorrhagic events in the
hemophiliac. Repeated hemarthroses can cripple and deform
over time. The joints of the knee, hip, elbow, ankle, and
shoulder are most vulnerable. Taking analgesics such as
aspirin during these events is contraindicated, as the drug
inhibits platelet function
Laboratory findings
 The screening test to detect factor VIII:C deficiency is the
APTT. Prolonged APTT results that are corrected by fresh
adsorbed plasma but not by serum and results of factor VIII:C
assays identify the deficiency and characterize the activity
levels. Obligatory carriers have been detected by combined
factor VIII:C and VII C:Ag assays. Carrier detection is nor
without error because of procedure variation and unpredictable
X chromosome inactivation (Lyon Hypothesis). Levels of factor
VIII:C differ in the daughters of carrier females (maternal
carriers) and the daughters of hemophiliacs (paternal carriers)
N. Factor VIII Inhibitors
 IgG4
 Detection:
One stage clot- based FVIII assay (if <30 units/dl, mixing
studies)
 <30 expect that it has inhibitor
 If suspected you must proceed to mixing studies
 In mixing studies, if it is not corrected upon the
addition of normal plasma, that is the time that
you confirm that it is an inhibitor and to quantify
how much inhibitor is present you then go with
Bethesda inhibitor assay
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
 >30 it doesn’t have inhibitor (it’s just that your factor
VIII is low)
 Nijmegen-Bethesda assay
 Bethesda unit- one Bethesda unit is the reciprocal of
the dilution that cannot the neutralization of 50% of
factor VIII in Normal Plasma
 Low responders = ≤ 5 Bethesda unit and titers don’t
increase following FVIII administration
 Remain low, meaning Factor VIII activity did
not increased
 Nagbigay ka ng Factor VIII pero hindi parin
tumataas ang activity kasi madami syang
inhibitor. To treat the patient, you increase
dosage of Factor VIII concentrate
 High responders = > 5 Bethesda units and titer
increases following FVIII administration
 You give Factor VIII and they respond well.
What we would give to the patient is PCC
(Prothrombin complex concentrate) to manage
and control the bleeding
 Can also give steroids or immunomodulation
theraphy so you can lessen the activity of the
inhibitors
HEMOPHILIA A AND FVIII INHIBITORS ALLOANTIBODY
INHIBITORS OF FVIII BY RODAKS
 Alloantibody inhibitors of FVIII arise in response to treatment in
30% of patients with severe hemophilia and 3% of those with
moderate hemophilia. The laboratory practitioner suspects the
presence of an inhibitor when bleeding persists or when the
plasma FVIII activity fails to rise to the target level after
appropriately dosed concentrate administration. Most FVIII
inhibitors are immunoglobulin G4, non-complement-fixing,
warm reacting antibodies. It is impossible to predict which
patients are likely to develop inhibitors based on genetics,
demographics, or the type of concentrate used The first step in
inhibitor detection is a one-stage clot-based FVIII assay. If the
FVIII activity exceeds 30 units/dL, no inhibitor is present. If the
level is less than 30 units/dL, the laboratory practitioner
proceeds to perform mixing studies. Some hemostasis
laboratory directors use 40 units/dL as the limit. When plasma
from the bleeding patient produces a prolonged PTT, it is
mixed 1:1 with NP, incubated 2 hours at 37° C, and the PTT of
the mixture is measured. If no inhibitor is present, the
incubated mixture should produce a PTT result within 10% of
the incubated NP PTT. If an inhibitor is present, however, the
FVIII from the NP is partially neutralized and the mixture’s PTT
remains prolonged or “uncorrected,” presumptive evidence for
the inhibitor. If mixing studies and the therapeutic results
suggest the presence of a FVIII inhibitor, the Nijmegen-
Bethesda assay is used to quantitate the inhibitor. NP
providing 100 units/dL factor activity is mixed at increasing
dilutions (decreasing concentrations) in a series of tubes with
the full-strength patient plasma. FVIII assays are performed on
each mixture. The operator then compares the results of the
various dilutions and expresses the titer as Nijmegen-
Bethesda units (NBUs). One NBU is the reciprocal of the
dilution that caused neutralization of 50% of the NP FVIII. The
same assay is employed to measure FVIII inhibitors in
acquired hemophilia. Although the complex kinetics of
acquired autoantibodies diminishes the accuracy of the results
in acquired hemophilia, this method adequately monitors
therapy. Hemophilia patients with inhibitors are classified as
low or high responders. Low responders generate inhibitor
titers of 5 NBUs or less and their inhibitor titers do not increase
significantly after FVIII administration. High responders
generate inhibitor titers that exceed 5 NBUs and their antibody
titers further rise in response to therapy. Each laboratory
director may choose to maintain a database of hemophilia
patients who have inhibitors because previous titers often
predict future inhibitor behavior.
Page 12 of 14
O. Hemophilia
Hemophilia B
 Factor IX deficiency
 X linked Disease
 The manifestation is technically indistinguishable to Hemophilia A
 To know if it is Hemophilia A or Hemophilia B do laboratory
testing
 Christmas disease
 Reduces thrombin production and causes soft tissue anatomic
bleeding
 Factor IX concentrates
HEMOPHILIA B (FACTOR IX DEFICIENCY) BY RODAKS
 Hemophilia B, also called Christmas disease, totals
approximately 14% of hemophilia cases in the United States,
although its incidence in India nearly equals that of hemophilia
A. Hemophilia B is caused by deficiency of factor IX (FIX), one
of the vitamin K-dependent serine proteases. Factor IX is a
substrate for both factors XIa and VIIa because it is cleaved by
either to form dimeric factor IXa (Figure 36.5). Subsequently,
factor IXa complexes with factor VIIIa to cleave and activate its
substrate, factor X (FX). FIX deficiency reduces thrombin
production and causes soft tissue anatomic bleeding that is
indistinguishable from that in hemophilia A. It also is a sex-
linked, markedly heterogeneous disorder involving numerous
separate mutations resulting in a range of mild to severe
bleeding manifestations. Determination of female carrier status
is less successful in hemophilia B than in hemophilia A
because of the large number of factor IX mutations and the
lack of a linked molecule such as VWF that can be used as a
normalization index. DNA analysis occasionally may be used
to establish carrier status when hemophilia B has been
diagnosed and its specific mutation identified in a relative.The
laboratory is essential to the diagnosis of hemophilia B. The
PTT typically is prolonged, whereas the PT, fibrinogen assay,
and TT are normal. If the clinical symptoms suggest
hemophilia B, the factor IX assay should be performed even if
PTT is within the reference range, because the PTT reagent
may be insensitive to factor IX deficiencies at the level of 30
units/dL. Immunine (Shire) and Mononine (Behring) are
plasmaderived, immunopurified FIX concentrates. When
applied to on-demand therapy, dosing is calculated the same
way as for FVIII concentrates in hemophilia A, except that the
calculated initial dose is doubled to compensate for FIX
distribution into the extravascular space. Repeat doses of FIX
are given every 24 hours, reflecting the half-life of the factor.
The second and subsequent doses, if needed, are half the
initial dose, provided that factor assays determine that the
target level of FIX was achieved. It is necessary to monitor
therapy with recurring laboratory assays, because FIX
pharmacokinetics are idiosyncratic
FACTOR IX DEFICIENCY (HEMOPHILIA B; CHRISTMAS
DISEASE BY STEININGER
 In 1947, Pavlovsky demonstrate that in vitro mixing of plasmas
from to “haemophilia” patient’s results in correction of the
recalcification time of both plasma. at that time, all male
patients exhibiting haemophilia symptoms were thought to
have classical haemophilia; in which case, these results would
not have been obtained
 In 1952, other investigators found haemophilia patients who
possessed factor VIII in their plasma but whose serum did not
contains another substance that required vitamin K for
synthesis and could be adsorbed to barium salts. The factor
was named plasma thromboplastin component (PTC) or
Christmas factor for the surname of one index patient
Clinical findings
 Factor IX deficiency is a sex-liked recessive trait and is
expressed in mild, moderate and severe forms. It generally is
considered to be a milder form of haemophilia than factor
VIII:C deficiency because clinically, these patients are not as
prone to haemorrhages in the GI, abdomen, CNS or
genitourinary tract. However, the severely factor IX-deficient
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 [HEMA312] 3.03 Bleeding Disorders | Prof. Antonio C. Pascua Jr., RMT, MSMT.
patient is clinically indistinguishable from the factor VIII:C
deficient patient
Laboratory findings
 Moderate to severe factor IX deficiency is revealed by a
prolonged APTT that is corrected with aged serum but not with
adsorbed plasma. Mild cases can produced an APTT value
within normal limits, yet patient may exhibit severe bleeding
with trauma or surgery
Hemophilia C
 Factor XI deficiency
 First inherited disorder covered under intrinsic pathway
 Mild to moderate bleeding symptoms and as to epidemiology it is
quite common among Ashkenazi Jews but it is not limited to only
Jewish people, it can affect anyone
 Rosenthal syndrome
 Ashkenazi Jews
 Frequent plasma infusion during bleeds and times of hemostatic
challenge
HEMOPHILIA C (ROSENTHAL SYNDROME, FACTOR XI
DEFICIENCY) BY RODAKS
 Factor XI (FXI) deficiency is an autosomal dominant
hemophilia with mild to moderate bleeding symptoms. More
than half of the cases have been described in Ashkenazi Jews,
but individuals of any ethnic group may be affected. The
frequency and severity of bleeding episodes do not correlate
with factor XI levels, and laboratory monitoring of treatment
serves little purpose after the diagnosis is established. The
physician treats hemophilia C with frequent plasma infusions
during bleeds and times of hemostatic challenge. In the
laboratory the PTT is prolonged and the PT is normal
FACTOR XI DEFICIENCY (HEMOPHILIA C) BY STEININGER
 Originally described in 1953, factor XI deficiency represents
the first inherited disorder in the intrinsic cascade to which a
clinical bleeding syndrome is attributed. The defect is thought
to be a result of decreased synthesis of the protein rather than
production of an abnormal molecule and is controlled by an
incompletely recessive autosome found largely in Jewish
populations
Clinical findings
 The disorder produces a mild bleeding syndrome that
responds well to therapy. Most factor XI-deficient patient are
symptomatically “silent” until stressed by trauma or surgery.
The clinical syndrome may include episodes of epistaxis (nose
bleeding), haematuria, and menorrhagia. Surgery or trauma
produces exaggerated bleeding. The same patient may differ
in the degree of bleeding response from one event to another
Laboratory findings
 Deficiencies of factor XI produces prolonged APTT values that
are corrected by both adsorbed plasma and aged serum.
Factor assay reveals the specific factor deficiency and activity
levels. Factor XI increases in concentration on storage. This
fact can interfere with laboratory testing for the factor if the test
sample is not handled properly. One stage prothrombin time
(PT) values and bleeding time results are not affected. A
radioimmunoassay procedure has been developed that
correlates positively with assay levels. A two stage test utilizing
a fluorogenic substrate to detect the presence of factor Xia has
been described
Factor XIII Deficiency
 Which leads to inability to stabilize the clot
 There is a weak clot to be dissolve by 5M Urea
 Factor XIII deficiency can be classified to Type I, II, III depending
which protein or tetramer is affected
 Factor XIII is a tetramer of paired A and B monomers (alpha and
beta protein)
Page 13 of 14
FACTOR VII DEFICIENCY BY RODAKS
 Plasma factor XIII is a tetramer of paired a and b monomers.
The intracellular form is a homodimer (two a chains) and is
stored in platelets, monocytes, placenta, prostate, and uterus.
The a chain contains the active enzyme site, and the b chain is
a binding and stabilizing portion. Factor XIII deficiency occurs
in three forms related to the affected chain, as shown in Table
36.9. Patients with factor XIII deficiency have a normal PT,
PTT, and TT despite anatomic bleeds and poor wound
healing. They form weak (non-cross-linked) clots that dissolve
within 2 hours when suspended in a 5-molar urea solution, a
traditional factor XIII screening assay. To confirm factor XIII
deficiency, factor activity may be measured accurately using a
chromogenic substrate assay such as the Behrichrom FXIII
assay (Behring)
OTHER INFORMATION ABOU THE OTHER CONGENITAL
SINGLE-FACTOR DEFICIENCIES BY RODAKS
 Factor VII deficiency causes moderate to severe anatomic
hemorrhage. The bleeding does not necessarily reflect the
factor VII activity level. The half-life of factor VII is
approximately 6 hours, which affects the frequency of therapy.
NovoSeven at 30 mg/mL and non-activated four-factor PCC
preparations are effective and may provide a target factor VII
level of 10 units/dL to 30 units/dL. Many factor VII deficiencies
are dysproteinemias. The PT, but not the PTT, is prolonged in
factor VII deficiency
 Factor X deficiency causes moderate to severe anatomic
hemorrhage that may be treated with plasma or non-activated
PCC to produce therapeutic levels of 10 units/dL to 40
units/dL. The half-life of factor X is 24 to 40 hours. Acquired
factor X deficiency has been described in amyloidosis, in
paraproteinemia, and in association with antifungal drug
therapy. The hemorrhagic symptoms may be life threatening.
The PT and PTT are both prolonged in factor X deficiency. In
the Russell viper venom time test, which activates the
coagulation mechanism at the level of factor X, clotting time is
prolonged in deficiencies of factors X and V, prothrombin, and
fibrinogen. The venom used is harvested from the Russell
viper, the most dangerous snake in Asia. This test may be
useful in distinguishing a factor VII deficiency, which does not
prolong the Russell viper venom clotting time, from
deficiencies in the common pathway, although specific factor
assays are the standard approach.
References:
 Prof. Antonio C. Pascua Jr., RMT, MSMT. HEMA312 Lecture.
Our Lady of Fatima University, Valenzuela City.
 Rodak’s Hematology: Clinical Principles and Applications. 5th
Edition.
 Turgeon M. (Clinical Hematology: Theory and Procedures), 5th
Edition.
 Steininger, Cheryl et.al. (Clinical Hematology: Principles,
Procedures, and Correlations)
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Page 14 of 14 WONDER PETS & DOGFUR – TRANSCRIBERS