Bleeding Guidelines

Hemorrhage and Coagulopathy
Tests Used to Establish Coagulopathies
Interpreting PT and PTT Results in Combination
PTT Mixing Studies
Disseminated Intravascular Coagulation (DIC) Profile
Von Willebrand Disease
Primary vWD Laboratory Profile
VWD Follow-up Testing
VWD Treatment Options
Treating Congenital Single Coagulation Factor Deficiencies
Factor VIII Concentrates
Factor IX Concentrates
Factor IX Complex Products
Dosing of FEIBA
Dosing of NovoSeven
Blood-derived Components

Hemorrhage and Coagulopathy

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

Systemic Bleeding Episodes
Petechiae, easy bruising, epistaxis, hematemesis, or menorrhagia characterize systemic bleeds. Systemic bleeds usually imply thrombocytopenia, a platelet qualitative abnormality, anemia, or a vascular disease such as scurvy.

Anatomic Bleeding Episodes
Anatomic bleeds are bleeds into joints, muscles, and cavities such as the peritoneum or central nervous system. Anatomic bleeds usually imply coagulation factor deficiencies.

Acquired Vs. Congenital Bleeding
Most coagulopathies are acquired. Acquired bleeds are seen in adults, follow identifiable events or an underlying disorder, and show no familial pattern. Acquired bleeds often follow the use of aspirin, other NSAIDs, or other drugs.
Congenital bleeds are uncommon, usually occur in children, may be spontaneous, recurrent, and have a familial distribution.
In an acute hemorrhage in which no coagulopathy is suspected, plasma expanders and red cells are used to replace blood volume. When a coagulation disorder is suspected, treatment may include fresh frozen plasma (FFP), cryoprecipitate (CRYO), platelet concentrate, and specific coagulation factors.
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Tests Used to Establish Coagulopathies

Perform these tests in the absence of anticoagulant therapy but when bleeding suggests a coagulopathy.

Prothrombin time (PT)
If the PT is over 1.5xmean of the reference interval, suspect single or multiple deficiencies of the "extrinsic" and "common" factors prothrombin, fibrinogen, V, VII, or X.

Partial thromboplastin time (PTT)
If the PTT is over 1.5xmean 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, or Fitzgerald factors also prolong the PTT but are not associated with bleeding.

Platelet count
* When the count is greater than 50 x 109/L (50,000/µL): systemic bleeding signifies von Willebrand disease or a qualitative platelet disorder.
* When the count is between 10-50 x109/L: systemic bleeding follows a triggering event.
* When the count is less than 10 x 109/L: spontaneous systemic bleeding occurs.
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Interpreting PT and PTT Results in Combination

Interpret these tests 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 beyond 60 seconds when heparin is present.

1. To distinguish liver disease from vitamin K deficiency, perform factor V and VII assays. If only VII is deficient, suspect vitamin K deficiency, if both, suspect liver disease.
2. Congenital factor VII deficiency is rare and would cause bleeding in childhood.
3. Lupus anticoagulant is not usually associated with bleeding, but is a thrombosis risk factor.
4. Acquired factor VIII inhibitor is rare, causes "acquired hemophilia" with severe, often fatal, bleeding. The inhibitor is identified using mixing studies.
5. Factor VIII and IX deficiencies would cause bleeding in boys in childhood. Factor XI deficiency may affect both sexes, has variable effects, and 50% of cases are seen in people of Jewish parentage.
6. Fibrinogen deficiency prolongs both PT and PTT only when severe, less that 100 mg/dL.
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Prolonged PTT Mixing Studies

When the PTT is prolonged at least 5 seconds beyond the upper limit of the reference interval, the initial specimen 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 deficiency identification.
    * If the PTT fails to correct, and the patient is not bleeding, suspect a lupus anticoagulant. Proceed with lupus anticoagulant confirmation as detailed in "thrombophilia."
    * Some factor inhibitors are time- and temperature-dependent. If the PTT corrects to within 10% of the normal plasma PTT but there is clinical suspicion for an inhibitor, repeat the mixing study by incubating the mixture for two hours at 37°C. If the PTT fails to correct, suspect a factor inhibitor such as anti-factor VIII.
Heparin interferes with mixing studies. Unreported heparin may be ruled out in the laboratory using the thrombin time, which is prolonged to more than 60 seconds when heparin is present.
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Disseminated Intravascular Coagulation (DIC) Profile

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Von Willebrand Disease

Von Willebrand disease (vWD) is a deficiency or abnormality of plasma von Willebrand factor (vWF), a 5-20 million Dalton multimeric protein essential to platelet adhesion. VWF is also the plasma carrier of coagulation factor VIII. VWD may be diagnosed in 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 present in 80% of patients. It varies in severity among patients and over time in individual patients, and causes systemic bleeding.

VWD Type 3
Type 3 vWD is caused by the absence of vWF, a gene deletion. Type 3 is rare but causes severe systemic and anatomic bleeding.

VWD Type 2
Type 2 vWD is a moderate to severe qualitative vWF deficiency present in 15 to 20% of patients. There are four subtypes.
* Type 2A vWD: Absence of large vWF multimers caused by dysfunctional production.
* Type 2B vWD: Absence of large vWF multimers caused by increased platelet membrane binding. This is a "gain of function" mutation. There is also a "pseudo-vWD" also called "platelet-type" in which a mutation of the platelet membrane receptor causes excess vWF binding. In both the platelet count may be reduced.
* Type 2N vWD: "Normandy type " or "autosomal hemophilia" A vWF mutation that reduces its capability for carrying factor VIII.
* Type 2M vWD: All vWF multimers are present but a point mutation reduces their ability to bind platelets. Often mistaken for type 1.

Acquired vWD
Acquired vWD is usually caused by the presence of an anti-vWF autoantibody, seen in monoclonal gammopathy of unknown significance (MGUS), Non-Hodgkin's lymphoma (NHL), multiple myeloma, solid tumors, hypothyroidism, and treatment with 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

VWD Primary Profile Limitations
* VWF is an acute reactant that rises during pregnancy, hemorrhage acute infection, and strenuous exercise. All results should be confirmed with subsequent testing.
* In particular, in patients with high clinical suspicion, results within the reference range should be repeated.
* Some experts test women between the 5th and the 7th day of the menstrual cycle.
* The VWF level varies significantly by blood group:

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VWD Follow-up Testing

* Low-dose ristocetin induced platelet aggregation (RIPA) also called ristocetin response curve. 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 type 1 and 2, also subtypes 2A and 2B.
* There is no effective clinical laboratory method to distinguish vWD type 2M from type 1.
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VWD Treatment Options

Desmopressin (DDAVP)
* Optimal dose of DDAVP is 0.3 mg/kg-up to 28 mg total dose-in 15 to 30 mL 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 minutesHalf life of vWF is 12 hoursFibrinolysis inhibitors
* EACA (Amicar): load with 100 mg/kg IV or PO, maintain at 500-1000 mg/h
* Tranexamic acid: load with 10 mg/kg IV, maintain at 10 mg/kg q 6-8 h or 25 mg/kg PO q 6-8 h

Conjugated estrogens
0.6 mg/kg IV every 4-5 d or 50 mg PO for 7 d

Plasma-derived factor concentrates
· Humate-P®; Alphanate®

Calculating vWF concentrate (Humate P®or Alphanate) dose for vWD
The reference interval for vWF is 50-150% (or 0.5 to 1.5 IU). The target value for vWD therapy is 50%, or 0.5 IU, vWF.
The formula for computing the first, or loading dosage is:

Where…
· IU is international units, defined as amount per mL of plasma. 1 IU/mL = 100%
· Desired activity is the therapeutic level to be achieved; 50% for vWF
· Current activity is measured using the vWF activity assay, not vWF antigen
· PV is plasma volume in mL computed as follows:

Where…
· HCT is hematocrit or packed cell volume (PCV)
· BV is blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)

The maintenance dosage is 50% of the loading or initial dosage and is administered 12 hours after the first dosage, as the half-life of vWF is 12 hours. Subsequent dosages are administered at 12-hour intervals and are monitored by repeat vWF activity assays collected just prior to the next administration.

Example for calculating vWF (Humate P) dosage
A woman with type 3 vWD arrives with an acute abdominal bleed. Her initial laboratory results are:

She weighs 132 lbs and is 4'11" tall (moderately obese).

1. Compute blood volume:

2. Compute plasma volume:

3. Compute dosage:

4. She is given an initial dose of ~1260 IU of vWF in the form of Humate-P®and subsequent maintenance doses of ~630 IU. VWF activity assays remain at ~50%.
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Treating Congenital Single Coagulation Factor Deficiencies

The normal level of factor VIII or IX is 50-150% (or 0.5 to 1.5 IU). Effective therapeutic levels are assigned by site of bleed as follows:

For factor IX, double the initial dosage because factor IX distributes to tissue fluid. The formula for computing the first, or loading dosage is:

Where…
· IU is international units, defined as amount per mL of plasma. 1 IU/mL = 100%
· Desired activity is therapeutic level to be achieved as selected from the above list
· Current activity is measured using the factor VIII or IX activity assay
· PV is plasma volume in mL computed as follows:

Where…
· HCT is hematocrit or packed cell volume (PCV)
· BV is blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)

The maintenance dosage is 50% of the loading or initial dosage and is administered 12 hours after the first dosage for factor VIII or 24 hours after the first dosage for factor IX. Subsequent dosages are administered at equivalent intervals and are monitored by repeat factor VIII activity or factor IX assays collected just prior to the next administration.

Determining the plasma factor level when the specific factor assay is not available
At the University of Alabama Hospital, when the factor VIII or factor IX assays are unavailable, such as during nights and weekends, plasma levels may be estimated using the PTT and the table below:

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 factor IX activity assays collected just prior to the next administration.
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Factor VIII Concentrates

Intermediate purity plasma digestion factor VIII products
* Use for vWF administration
* Humate-P®, Alphanate®

High purity plasma factor VIII products prepared using monoclonal antibody affinity columns
* These products are treated to remove viruses and have never been demonstrated to infect a recipient.
* Use for patients who have previously received monoclonal products or who have HBV, HCV, or HIV
* Monarch-M®, Hemofil-M®, Monoclate-P®, Koate-HP®

Highest purity non-plasma factor VIII products prepared using recombinant technology
* Use for previously untreated patients, patients who have only received recombinant products in the past, or patients for whom previous treatment is unknown.
* Kogenate, Helixate, Recombinate, Bioclate

Porcine factor VIII
* Used for patients who have an anti-VIII inhibitor.
* Hyate C®
* Check for availability
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Factor IX Concentrates

High purity plasma factor IX products prepared using monoclonal antibody affinity columns
*These products are treated to remove viruses and have never been demonstrated to infect a recipient.
*Use for patients who have previously received monoclonal products or who have HBV, HCV, or HIV
* Alpha Nine SD®; Mononine®

Highest purity non-plasma factor IX product prepared using recombinant technology
* Use for previously untreated patients, patients who have only received recombinant products, or patients for whom previous treatment is unknown.
* BeneFIX®
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Factor IX complex products

Prothrombin complex concentrates for rare factor deficiencies such as prothrombin, F VII or FX

*Factors measured in units per 100 units of factor IX: vial labeled only with units of factor IX.

Activated complex products
* Used for patients who have an anti-VIII or anti-IX inhibitor.
* FEIBA FH®, Autoplex T®
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Dosing of FEIBA

Dose in IU/kg
* 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 for hematoma

Dosing of NovoSeven

NovoSeven®recombinant FVIIa
* 90-120 µg/kg every 2-3 hours when bleeding
* Only to be used in patients with factor VIII inhibitors who failed FEIBA
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Blood-derived Components

* Fresh frozen plasma (FFP): 1 IU/mL, 100%, for every factor in 250-300 mL of plasma. Use for multiple coagulation factor deficiencies.
* Cryoprecipitate (CRYO): 150-250 mg fibrinogen and 50-75 IU factor XIII per 10-15mL unit. Use for fibrinogen and factor XIII replacement therapy.
* Platelet concentrate: Patient PLT count should increase by 5-10,000/µL for each random donor unit or 30-60,000/µL for a 6-unit random donor pool. Apheresis units provide a larger increment, depending upon platelet count in concentrate.
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