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Hemorrhage and Coagulopathy Tests Used to Establish Presence of Coagulopathies Interpreting PT and PTT Results in Combination PTT Mixing Study Treating Multiple Factor Deficiencies with Fresh Frozen Plasma (FFP) Treating Fibrinogen and Factor XIII Deficiency with Cryoprecipitate (CRYO) Diagnosing Scurvy and Treating with Vitamin C Disseminated Intravascular Coagulation (DIC) Profile Von Willebrand Disease Primary vWD Laboratory Profile VWD Follow-up Testing VWD Treatment Options Congenital Single Factor Deficiencies (Hemophilias) Factor VIII Concentrates Factor IX Concentrates Activated Prothrombin Complex Products: FEIBA FHÒ, Autoplex TÒ Activated Recombinant Factor VII (NovoSevenÒ) Other Congenital Single Factor Deficiencies Prothrombin Complex Concentrates (PCCs) Steps in Dispensing Factor Concentrates (Summary)

   Hemorrhage and Coagulopathy
Most bleeding episodes stem from local tissue injuries, not coagulopathies. A coagulopathy may be suspected when bleeds issue from multiple sites, are spontaneous, inappropriately excessive, or recurrent.

Systemic (mucocutaneous) bleeding

Petechiae, easy bruising, epistaxis, hematemesis, or menorrhagia characterize systemic mucocutaneous bleeds. Systemic bleeds usually imply a defect in primary hemostasis: thrombocytopenia, a platelet qualitative abnormality, von Willebrand disease, or a vascular disease such as scurvy.

Anatomic (soft tissue) bleeding

Anatomic bleeds occur into joints, muscles, the peritoneum, or the central nervous system. Anatomic bleeds usually imply the impairment of secondary hemostasis: coagulation factor deficiencies.

Many patients have more than one defect or are taking medications that interfere with hemostasis. Most coagulopathies of primary or secondary hemostasis are acquired due to an underlying systemic disorder.

Acquired Vs. congenital bleeding

Most coagulopathies are acquired, a few are congenital. Acquired bleeds are seen most often in adults, follow identifiable events or an underlying disorder, and show no familial pattern. Congenital bleeds, with the classic example of hemophilia, usually occur in children, may be spontaneous, recurrent, or have a positive family history.

When a coagulation disorder is suspected, treatment may include fresh frozen plasma, cryoprecipitate, platelet transfusion, or specific coagulation factor concentrates.

 

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Tests Used to Establish Presence of Coagulopathies
Perform these tests in the absence of anticoagulant therapy but when bleeding suggests a coagulopathy.

Prothrombin time (PT)

If the PT is over 1.5   the mean of the reference interval, suspect single or multiple deficiencies of the "extrinsic" and "common" factors prothrombin, fibrinogen, V, VII, or X. The factor with the greatest impact on the PT is VII.

Partial thromboplastin time (PTT)

If the PTT is over 1.5  the mean of the reference interval, suspect single or multiple deficiencies of the "intrinsic" and "common" factors prothrombin, fibrinogen, V, VIII, IX, X, or XI. Deficiencies of the "contact" factors XII, Fletcher (prekallikrein), or Fitzgerald (high molecular weight kininogen, HMWK) also prolong the PTT but are not associated with bleeding. Very prolonged PTT results (> 200 s) are due to heparin until proven otherwise.

 

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Interpreting PT and PTT Results in Combination 
Useful when anticoagulant therapy has been ruled out and when bleeding suggests a coagulopathy. Unreported heparin may be ruled out in the laboratory using the thrombin time, which is prolonged to > 21 seconds when heparin is present.

 



PT

PTT

Acquired Disorder

Congenital Disorder

Long

Normal

Liver disease or vitamin K deficiency

Factor VII deficiency

Normal

Long

Acquired factor VIII inhibitor

Factor VIII, IX, or XI deficiency

Long

Long

DIC, liver disease, Lupus anticoagulant (LA)

Fibrinogen, prothrombin, factor V or X deficiency

Normal

Normal

Thrombocytopenia, qualitative platelet disorder

Mild factor deficiency, mild von Willebrand disease, factor XIII deficiency

 

  1. To distinguish liver disease from vitamin K deficiency, assay factors V and VII. If only VII is deficient, suspect vitamin K deficiency; however if both are deficient, suspect liver disease.

  2. Congenital factor VII deficiency is rare and causes bleeding in childhood. Further, there is no direct correlation between factor level and bleeding.

  3. Acquired factor VIII inhibitor is rare, causes "acquired hemophilia" with severe bleeding. The inhibitor is first identified using the PTT mixing study and the factor VIII assay and measured using the Bethesda titer.

  4. Factor VIII and IX deficiencies are X-linked and are diagnosed in childhood. They are called hemophilia A and hemophilia B, respectively. Factor XI deficiency (hemophilia C) is autosomal recessive, is more common is Jewish patients, and the factor level is not directly associated with bleeding.

  5. LA is seldom associated with bleeding, unless it binds to prothrombin and causes deficiency of this factor.

  6. Fibrinogen deficiency prolongs both PT and PTT only when < 100 mg/dL.

  7. Factor XIII deficiency is established using the urea solubility test

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PTT Mixing Study 
When the PTT is prolonged at least 5 seconds beyond the upper limit of the refer-ence interval, the patient's plasma is mixed 1:1 with normal plasma and the PTT is repeated:

  • If the PTT corrects to within 10% of the normal plasma PTT and the patient is bleeding, suspect a coagulation factor deficiency. Proceed with factor levels, assaying the most likely one first.

  • If the PTT fails to correct, and the patient is not bleeding, suspect a lupus anticoagulant. Proceed with lupus anticoagulant confirmation as detailed under "Thrombophilia."

  • Some specific LAs and factor inhibitors (such as factor VIII) are time- and temperature-dependent. If the PTT corrects to within 10% of the normal plasma PTT, repeat the mixing study by incubating the mixture for one to two hours at 37ºC. If the incubated PTT fails to correct, the presence of an inhibitor is determined.

Heparin interferes with mixing studies. Unreported heparin may be ruled out using the thrombin time, which is prolonged > 20a when heparin is present.

 

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Donor Blood Components 
Treating multiple factor deficiencies with fresh frozen plasma (FFP)

FFP is the plasma from a unit of whole blood separated by centrifugation and frozen within 8 hours of collection. It is stored at -18ºC or colder for up to 12 months, thawed at 30-37ºC and kept at 1-6ºC for no longer than 24 hours after thawing. FFP contains an average of 1 IU/mL of each coagulation factor, including the labile factors V and VIII.

FFP is primarily used to treat bleeding due to acquired multiple factor deficiencies that occur in liver disease, vitamin K deficiency, disseminated intravascular coagulation (DIC), and massive transfusion. Less frequently, it may be used to treat the rare congenital single factor deficiencies of II, V, VII, X, or XI, or deficiencies of proteins C or S.

FFP may be used for immediate short-term reversal of over-anticoagulation with Coumadin . However, because of its short half-life of 3-5 hours, factor VII is difficult to replace with FFP without volume overload. Thus, vitamin K and FFP are indicated in patients who have a high INR and are bleeding.

FFP is the replacement fluid of choice in therapeutic plasma exchange for thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

A dose of 10-20 mL of FFP/kg of body weight will increases any factor level by 20-30%. Frequency of transfusion depends on the half-life of the deficient factor(s). FFP is not indicated unless the PT or PTT is >1.5 x  the mean of the normal range.  FFP should not be used as a volume expander, or to "correct" a mildly prolonged PT or PTT. A patient may have a mildly prolonged PT or PTT and yet have hemostatically stable levels of coagulation factors.

 

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Treating Fibrinogen and Factor XIII deficiency with Cryoprecipitate (CRYO)

CRYO is the protein precipitate left after FFP is thawed at 4oC and the supernatant liquid plasma is removed. CRYO is refrozen and stored at -18oC or lower for up to 12 months. After thawing at 30-37oC, it is kept at 20-24oC for no longer than 6 hours, or if pooled, no longer than 4 hours. A unit contains at least 80 IU of factor VIII, 150-250 mg of fibrinogen, 50-75 IU of factor XIII, and vWF.

CRYO is most commonly transfused to replace fibrinogen due to acquired deficien-cies either due to DIC or thrombolytic therapy, or for congenital hypofibrinogenemia or dysfibrinogenemia. CRYO is the only source of concentrated fibrinogen available. A fibrinogen level of 50-100mg/dL is considered hemostatically effective, and can be achieved using a general guideline of infusing one unit CRYO/7 kg of body weight. Fibrinogen has a half-life of 100-150 hours. CRYO is also used to treat the rare congenital or acquired deficiency of factor XIII. Factor XIII has a long half-life, 7-12 days, so the recommended treatment for factor XIII deficiency is one unit of CRYO/10 kg every 7 days.

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DiagnosingScurvy and Treating with Vitamin C

The diagnosis of scurvy requires a high index of suspicion. In western countries, the incidence appears to be on the rise. Populations at least include the elderly, chronic alcoholics, diet faddists, the mentally ill, and patients with cancer, malabsorption, or who are on renal dialysis.

The symptoms of scurvy are weakness, lassitude, depression, arthralgias, petechiae, perifollicular hemorrhage (corkscrew hairs), follicular hyperkeratosis, purpura, ecchymoses, gingival swelling, hemorrhage, halitosis, poor wound healing, and loss of teeth. Typical plaque-like ecchymoses of the lower extremities may also be present.

Adults should receive 100 mg of vitamin C 3-5  x a day up to 4 grams followed by 100 mg/day. Infants and children should receive 10-25 mg 3 x a day. Symptoms disappear within 3-5 days.



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Disseminated Intravascular Coagulation (DIC) Profile 
DIC is generalized activation of coagulation secondary to systemic conditions such as septicemia, carcinoma, and severe inflammation or pregnancy complications. The presence of high concentrations of D-dimer, often > 20,000 ng/ml, is the sine qua non criterion of DIC, as it reflects increased fibrin production and breakdown. In acute DIC, activation of the tissue factor (intrinsic) pathway results in a decrease in factors II, VII, IX and X, prolonging the PT and PTT. However, an increase in factor VIII production coupled with von Willebrand factor released from the endothelium may make the PTT less useful than the PT in laboratory diagnosis of DIC. The PT is also expected to be abnormal before the PTT because it is highly dependent on factor VII level, which has a very short half-life of 3-5 hours.

 



Assay

Expected Results in DIC

PT

Usually prolonged (even before PTT becomes prolonged)

PTT

Usually prolonged above upper limit of reference interval

Fibrinogen

Low; but may be normal or high due to acute phase reaction; sequential measurements are helpful

Quantitative D-dimer

Significantly above the limit of reference interval

·        Single most important assay to establish DIC

·        In compensated DIC, D-dimer may be the only abnormal test

Complete blood count with platelet count

Anemia with schistocytes

Low platelet count reflects significant consumption but count may be near normal due to marrow response

 

DIC treatment issues

 

The most important aspect of treating DIC is to remove the underlying cause of the syndrome. Secondly, it is key to maintain the blood pressure and to correct electrolyte imbalances to improve tissue oxygenation. Transfuse FFP, CRYO and platelets if there are signs of ineffective hemostasis, such as profuse oozing or frank bleeding. The PT, PTT, fibrinogen and or platelet count suggest the cause of the abnormal coagulation. High D-dimer levels suppress platelet function.

 

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Von Willebrand Disease 
Von Willebrand disease (vWD) is a deficiency or abnormality of plasma von Wille-brand factor (vWF), a 5-20 million Dalton multimeric protein essential to platelet adhesion. VWF is also the plasma carrier of coagulation factor VIII. VWD affects 1 to 2 % of the general population. Clinicians must differentiate the various types and subtypes of vWD before establishing treatment.

VWD type 1

Type 1 vWD is a mild to moderate quantitative vWF deficiency in 80% of vWD patients. It varies in severity among patients and over time in individual patients, and may cause systemic mucocutaneous (platelet-type) bleeding.

VWD type 3

Type 3 vWD is caused by the homozygous absence of vWF. Type 3 is rare but causes severe systemic and anatomic bleeding because factor VIII is also low.

VWD type 2

Type 2 vWD is a moderate to severe qualitative vWF deficiency in 15 to 20% of vWD patients. There are four subtypes.

  • Type 2A vWD: Absence of intermediate and large vWF multimers caused by increased proteolysis which cause decreased hemostatic efficiency.

  • Type 2B vWD: Absence of large vWF multimers in plasma caused by in-creased platelet binding. This is a "gain of function" mutation affecting vWF affinity for platelet receptors. "Pseudo-vWD" or "platelet-type vWD" is a plate-let membrane receptor mutation that causes excessive vWF binding. In both instances, the platelet count may be reduced.

  • Type 2N vWD: "Normandy type" or "autosomal hemophilia" is due to a vWF mutation which reduces its capability for carrying factor VIII.

  • Type 2M vWD: Normal appearing vWF multimers but with a mutation that reduces their ability to bind platelets. Often mistaken for type 1. 

Acquired vWD

Acquired vWD is multifactorial and may arise as a consequence of an anti-vWF autoantibody, reduced vWF production, or increased turnover. It is associated with monoclonal gammopathy of unknown significance (MGUS), non-Hodgkin lymphoma, multiple myeloma, solid tumors, hypothyroidism, and sodium valproate and ciprofloxacin.

 

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Primary VWD Laboratory Profile 
  • VWF functional assay (also called ristocetin cofactor)
  • VWF antigen assay
  • Factor VIII activity
VWD primary profile interpretation (expected)

 



VWD Type

Functional

Antigen

Factor VIII

1

Mildly decreased

Mildly decreased

Mildly decreased

3

Severely decreased (< 10%)

Severely decreased (< 10%)

Severely decreased (< 10%)

2A

Lower than antigen

Mildly decreased

or normal

Mildly decreased

or normal

2B

Lower than antigen

Mildly decreased

or normal

Mildly decreased

or normal

2N

Normal

Normal

Decreased

2M

Lower than antigen

Mildly decreased

Normal



VWD primary profile limitations

  • VWF is an acute phase reactant that rises during stress, pregnancy, hemorrhage, acute infection, estrogen therapy and exercise. Negative must be repeated if there is strong clinical suspicion based on personal or family history of bleeding.

  • Some experts test women between the 5th and the 7th day of the menstrual cycle, the "vWF nadir"

  • The vWF level varies by blood group :





Blood Group

Mean vWF

Reference Interval

O

75%

36-157%

A

105%

48-234%

B

117%

57-241%

AB

123%

64-238%

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VWD Follow-up Testing 


  • Ristocetin induced platelet aggregation (RIPA), also called the ristocetin response curve, is used when vWD type 2B is suspected (disproportional decrease in vWF activity). Platelets in type 2B vWD aggregate in response to low concentrations of ristocetin.

  • VWF multimeric analysis is a specialized assay requiring SDS-polyacrilamide gel electrophoresis. Multimeric patterns distinguish among qualitative defects such as subtypes 2A and 2B. Multimeric analysis is unnecessary when type 1 or type 3 vWD are apparent from the primary profile.

  • There is no effective laboratory method to distinguish type 2M from type 1.

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VWD Treatment Options 
Desmopressin (DDAVP)

  • Useful in types 1, 2A and 2M, since it releases intracellular stores of vWF from platelets and endothelial cells, increasing its plasma concentration

  • Optimal dose of DDAVP is 0.3  micrograms/kg-up to 28 micrograms total dose-in 15 to 30 mL of saline

  • Given by slow IV push or drip over 15 to 30 minutes

  • Peak vWF release effect of DDAVP is achieved in 30 to 60 minutes

  • Half life of released vWF is 12 hours

Fibrinolysis inhibitors

  • EACA (Amicar) and Tranexamic acid

  • Useful in dental and urinary tract procedures as topical therapy

Plasma-derived factor concentrates

  • Humate-P  (most commonly used); Alphanate

  • These are labeled with the number of units of factor VIII and vWF

Calculating factor concentrate dose

The normal level of vWF is roughly 50-150%, or 0.5 to 1.5 IU (see effect of blood type above). A level of 50% is regarded as effectively hemostatic under normal conditions, although for major surgery one may aim for a higher level. The formula for computing the first, or loading dose, is:



 

Dose in IU = (desired activity – current activity) x PV

Where…

·        IU is international units, defined as amount per mL of plasma. 1 IU= 100%

·        Desired activity is therapeutic level to be achieved

·        Current activity is measured using the vWF activity assay

·        PV is plasma volume in mL computed as follows:

PV = Blood volume x (1-hematocrit)

 

Where

·       Blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)

 

Blood Volume Multiplier

Body Type

70 mL/kg

Slim

60 mL/kg

Obese

50 mL/kg

Morbidly obese



 

The maintenance dosage is 50% of the loading or initial dosage and is administered 12 hours after the first dosage. Subsequent dosages are administered at 12-hour intervals and are monitored by repeat vWF antigen assays collected just prior to the next dose (through level).

 

Example for calculating factor concentrate dosage

 

A woman with type 3 vWD arrives with an acute abdominal bleed. Her initial laboratory results are:

 

vWF activity

<1%

vWF antigen

<1%

Factor VIII activity

<1%

HCT

30%



 

She weighs 132 lbs and is 4’11” tall, moderately obese, blood volume multiplier is 60 mg/kg.

 

1.   Compute blood volume:

132 lb x 0.453 lb/kg = 60 kg

BV = 60 kg x 60 mL/kg = 3600 mL

2.   Compute plasma volume:

PV = 3600 mL x (1-.30) = 2520 mL

3.   Compute dosage:

Dose in IU = (0.5 IU – 0 IU) x 2520 Dose = 1260 IU

4.   She is given an initial dose of 1260 IU of vWF in the form of Humate-PÒ and subsequent maintenance doses of 630 IU every twelve hours. VWF activity should remain between 25% and 50% and dosage adjustments should follow factor levels.

 

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Congenital Single Factor Deficiencies (Hemophilias) 
Calculating factor VIII concentrate dosage

The normal level of factor VIII is 50-186% (or 0.5 to 1.86 IU/ml). Effective therapeutic levels vary from 30% to 100% depending on clinical condition of the patient. The formula for computing the first or loading dose of factor is the same as that for vWF:

Dose in IU = (desired activity – current activity) x PV

Where…

·        IU is international units, defined as amount per mL of plasma. 1 IU= 100%

·        Desired activity is therapeutic level to be achieved

·        Current activity is measured using the vWF activity assay

·        PV is plasma volume in mL computed as follows:

PV = Blood volume x (1-hematocrit)

 

Where

·       Blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)

 

Blood Volume Multiplier

Body Type

70 mL/kg

Slim

60 mL/kg

Obese

50 mL/kg

Morbidly obese




It is advisable to check the peak factor VIII level after the loading dose by collecting a sample approximately 15 minutes after the infusion of the factor. If the desired activity was achieved, 50% of the initial dose should be administered 8-12 hours later. Immediately prior to the second dose another factor level will be helpful to estimate the in vivo half-life of factor VIII and will guide calculation of subsequent doses. A bleeding patient is likely to require larger doses than someone who is clinically stable. Changes in hematocrit will also affect the appropriate dose at any given time.




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Factor VIII Concentrates
Plasma-derived products

  • Indicated for patients who have previously received plasma products or who have HBV, HCV, or HIV infection or positive serology
  • After millions of units used, no evidence of viral transmission - very safe!
  • Choices include: Alphanate, Monarc-M , Hemofil-M , Monoclate-P , Koate-HP.  These should be considered equivalent and are labeled with factor VIII IU per vial.
Products prepared using recombinant technology

  • Indicated for previously untreated patients (PUPs), those who have never been exposed to plasma products or whose previous treatment is unknown 
  • Choices include: Kogenate , Helixate , Recombinate , Bioclate  and should be considered equivalent - labeled with factor VIII IU per vial
Calculating factor IX concentrate dosage

  • Compute as for vWF and factor VIII but double the initial dosage because 50% of factor IX distributes to tissue fluid. 
  • The maintenance dosage is 50% of the loading or initial dosage and is administered 24 hours after the first dose, reflecting the half-life of factor IX. Factor levels should be monitored as described for factor VIII above.
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Factor IX Concentrates 
Plasma-derived products

  • Indicated for patients who have previously received plasma products or who have HBV, HCV, or HIV infection or positive serology

  • Very safe

  • Choices include: Alpha Nine SD ; Mononine , and should be considered equivalent - labeled with factor IX IU per vial

Products prepared using recombinant technology

  • Indicated for previously untreated patients (PUPs), those who have never been exposed to plasma products, or whose previous treatment is unknown BeneFIX  (not stocked at UAB)
Determining the plasma factor level from the PTT

When the factor assay is unavailable, such as during nights and weekends, plasma factor VIII or IX levels may be estimated using the PTT. The PTT is correlated to factor VIII or IX sensitivity curves, and these correlations are specific for each reagent used for the assays; thus it varies among laboratories. PTT estimation of the degree of factor deficiency is valid only when the PT is normal, ruling out the presence of vitamin K deficiency or liver disease. The PTT is seldom prolonged beyond 80 seconds in a single factor deficiency when the PT is normal. On the other hand, if the PTT is normal, the patient has been treated and the bleeding may be related to another cause.   Factor inhibitors (two therapy options described below)

Up to 30% of severe hemophilia A patients develop factor VIII inhibitors after a few doses of factor VIII (alloantibodies), rendering concentrate therapy ineffective. Adults who have never had a detectable inhibitor are unlikely to develop one. An inhibitor is suspected when the response to factor VIII concentrates is much less than predicted by the dose calculation. Among hemophilia B patients, only 2-3% develop anti-IX inhibitors. In rare instances, non-hemophilics may develop autoimmune factor VIII inhibitors, causing acquired hemophilia. To establish the presence of a factor inhibitor, order a PTT mixing study (see "Management of Bleeding"). If there is no correction in the mixing study, a quantitative Bethesda assay will determine the relative concentration of inhibitor.



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Activated Prothombin Complex Products (APCCs): FEIBA FHÒ, Autoplex TÒ


FEIBA dosages in IU/kg (per manufacturer recommendations)

  • Joint bleeding: 50 IU/kg q 12 h

  • Mucous membrane bleeding: 50 IU/kg q 6h

  • Muscle bleeding: 100 IU/kg q 12h

FEIBA may induce DIC, therefore…

  • May not exceed 200 IU/kg/24 hours

  • Infusion or injection rate must not exceed 2 IU/kg/minute

  • There is no test to monitor FEIBA. The patient's clinical response is the only guide; for example, monitor the size of the hematoma

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Activated Recombinant Factor VII (NovoSevenÒ)


  • Effective alternative for inhibitor patients who do not respond to FEIBA

  • Cost is ~ $ 1/ microgram

  • May be useful in patients with major bleeding associated with warfarin overdose or liver failure who require fast hemostasis

  • For patients with factor VIII inhibitor: 80-120 micrograms/kg every 2-3 hours

  • For other indications: 25-35 micrograms/kg once or every 6 hours (empiric dose-not scientifically determined).

[top] Other Congenital Single Factor Deficiencies
Rare patients with deficiencies of prothrombin or factors VII and X may also present with bleeding or require invasive procedures. Plasma level of factor VII do not correlate with risk of bleeding, but those of prothrombin and factor X do. Besides FFP as a source of these factors, two types of concentrates are available for these patients and are the products of choice.

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Prothrombin Complex Concentrates (PCCs)
Amount of each factor per vial is relative to the number of units of factor IX. For example, there are 148 units of prothrombin per 100 units of factor IX in Profilnine HT. The vials are labeled with factor IX units only.



Name

Factor II

Factor VII

Factor IX

Factor X

Profilnine HTÒ

148

11

100

64

BebulinÒ

120

13

100

139

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   Steps in Dispensing Factor Concentrates (Summary)
  
Confirm coagulopathy diagnosis

Confirm current indication for factor replacement

Select product:

·              Plasma-derived factors VIII or IX

·              Recombinant factors VIII or IX

·              Bypass products for patients with factor VIII inhibitors

·              von Willebrand factor

Assess availability of product in inventory

Calculate dosage based on clinical indication

Establish treatment frequency (dosing interval)

Establish expected number of repeat treatments required

Establish laboratory monitoring by plasma factor level

·              Precise time interval

·              Frequency of testing



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