Group

C2
Physiology Laboratory
Small Group Discussion
Output

January 20, 2016

[ACQUIRED PROTHROMBIN COMPLEX DEFICIENCY]

By: ASUBARIO, Olufunmilola Omonike; BALADAD, Alvin Byron; DE JESUS, Chrislou; GURUNG, Man
Bahadur; KALANYEG, Kristie; MAHALEE, Naphitcharak; MONTHATHONG, Thanapol; PANLASIGUI,
Rikkimae Maria; SAMSON, Chino Paolo; SOLONIO, Natalie Keith; VALDEZ, Gregorio
 ACQUIRED PROTHROMBIN COMPLEX DEFICIENCY

Acquired Prothrombin complex deficiency is a disorder characterized by

hemorrhage due to the lack of the Prothrombin complex coagulation factors in the blood
(Factors 2, 7, 9, 10 and less involved are factors C, S and Z).

Multiple etiologies may cause this type of coagulation disorder, but the most
common causes are: 1) Vitamin K deficiency due to several causations and 2)
Administration of coumarin-type drugs, such as warfarin, which interfere with vitamin K
function. Due to the Vitamin K dependency of these factors, they are severely affected
by loss of vitamin K function.

Role of Vitamin K in coagulation

Vitamin K is a quinone found in green leafy vegetables, fish, and liver, and is
produced by the intestinal bacteria B. fragilis and E. coli in the gut. It catalyzes an
essential posttranslational modification of the prothrombin group proteins. Glutamic acid
is modified into gamma-carboxyglutamic acid when a 2nd carboxyl group is added to
the gamma-carbon. With two ionized carboxyl groups, the gamma-carboxyglutamic
acids gain a net negative charge, which attracts and make them bind to calcium (ionic).
The bound calcium permits the vitamin K dependent proteins to bind negatively charged
PL such as phosphatidylserine. (Fig 1)

In vitamin K deficiency, the vitamin K-dependent procoagulants are released

from the liver without the second carboxyl group added to the gamma-carbon. These
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are called des-gamma-carboxyl proteins or Proteins in vitamin K antagonism (PIVKAs).
Because they lack the second carboxyl group, they cannot bind to calcium and PL and
therefore cannot participate in coagulation.

Vitamin k 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 nutrition for an extended period or when
patients embark upon fad diets. Also, vitamin k is fat soluble and requires bile salts for
absorption, biliary duct obstruction, fat malabsorption, and chronic diarrhea may causes
deficiency.

Forms of Acquired Prothrombin Complex Deficiency

Hemorrhagic disease of the newborn due to vitamin K deficiency

Due to sterile intestines and minimal concentration of vitamin K in milk, newborns

are constitutionally vitamin K deficient. This disease was common in the US before the
legislation of routine administration of vitamin k to infants in the 1960s, and it still occurs
in developing countries. The activity levels of the prothrombin complex are lower in
infants than in adults, and their concentration is even lower in premature newborns.
Breastfeeding prolongs the deficiency, because passive antibodies delay establishment
of gut flora.

Usage of Vitamin K antagonists

The gamma carboxylation cycle of coagulation factors is interrupted by coumarin-

type oral anticoagulants such as warfarin that disrupt vitamin K epoxide reductase and
vitamin K quinone reductase reactions. PIVKAs are formed. 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 factors. 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. Warfarin overdose is the single most common
reason for hemorrhage associated emergency department visits.

Diagnosis

Clinical suspicion of vitamin K deficiency is supported by a prolonged PT with or

without prolonged PTT. In PT and PTT mixing studies, PPP corrects the results due to
Prothrombin complex deficiency. Specific single-factor assays always detect low factor
7 because of its short half-life, followed by decreases in factor 9, 10 and 2. The
standard therapy is oral (intravenous if emergency) vitamin K. because synthesis of
functional factors requires at least 3 hrs, in the case of severe bleeding, FFP may be
administered. INR must be restored to about 2.0 to 3.0.

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Deficiency
Medical Care
Initial treatment of hypoprothrombinemia is aimed at controlling hemorrhage. Numerous
products that provide prothrombin are available. Frozen plasma contains about 1 U/mL
of prothrombin. It is readily available and contains other factors that may be useful if the
hypoprothrombinemia is associated with multiple factor deficiencies. Concentrates of
prothrombin complex (eg, Proplex T, Konyne 80, Bebulin VH) are concentrated sources
of prothrombin. However, these products also contain other vitamin K–dependent
factors in high concentration, and use of these products at high doses has been
associated with thromboembolic complications. Prothrombin-complex concentrates may
contain activated clotting factors, and their use has been associated with
thromboembolic complications. No pure concentrate of prothrombin factor is available.
When lupus anticoagulant-hypoprothrombinemia syndrome is associated with systemic
lupus erythematosus, treatment with steroids, intravenous immunoglobulin, fresh-frozen
plasma, or azathioprine has been successful in reducing lupus anticoagulant levels, in
increasing prothrombin levels, and in controlling bleeding. However, prothrombin levels
have decreased in some patients with the drugs were tapered.
In vitamin K deficiency and warfarin overdose, vitamin K is the treatment of choice
unless clinically significant bleeding is present and quick correction of the coagulopathy
is desired. In these cases, use either frozen plasma or a prothrombin-complex
concentrate.
The question of prophylactic treatment in patients with hypoprothrombinemia is
controversial. No replacement protocols are standard. Prophylaxis has been reserved
for patients who have had severe, recurrent episodes of bleeding. Case reports of
patients with severe hypoprothrombinemia who were treated weekly with prothrombin-
complex concentrates described a reduction in hemorrhagic episodes and improved
quality of life.

Surgical Care
Surgery could result in clinically significant bleeding in patients with
hypoprothrombinemia. Avoid surgery whenever possible. Use concentrates of
prothrombin complex in patients with factor II deficiency who require surgery. If an
inhibitor is present, attempt to decrease the inhibitor titer before the surgical procedure,
if possible.

Activity
Patients with hypoprothrombinemia must avoid activities and situations that could result
in clinically significant trauma, especially head trauma.
Several variables determine a child's risk of bleeding. Among them are the nature and
severity of the trauma, the severity of the bleeding disorder, and the speed at which
treatment can be administered.

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Risk of bleeding during athletic activity increases as the level of competition increases
and as the likelihood of collision at top running speed increases.

Medication Summary

Hemostatic agents
Class Summary
Vitamin K can be administered intravenously or orally. Slowly administer
intravenous infusions over 10-20 minutes. In addition, premedicating the patient with
diphenhydramine (Benadryl) may be helpful. The only current oral formulation of vitamin
K available in the United States is in tablet form; however, a liquid formulation has been
developed and is currently being used in Europe and Japan.
Acquired hypoprothrombinemia due to vitamin K deficiency is treated with vitamin
K1 (phytonadione). In the presence of severe or life-threatening bleeding, frozen plasma
or prothrombin-complex concentrates are administered to immediately increase the
levels of vitamin K–dependent coagulation factors. Other clotting factors (eg,
concentrate of clotting factors II, VII, IX, and X [Proplex T]) may also be required.
Solvent-detergent–treated frozen plasma is now available.
Epsilon aminocaproic acid (Amicar) can be used to minimize the severity of
mucosal bleeding and enhances hemostasis when fibrinolysis contributes to bleeding.
Amicar is especially useful in acquired hypoprothrombinemia secondary to anti–factor II
circulating antibodies because of the immediate neutralization of prothrombin upon
infusing plasma or prothrombin-complex concentrates.
For inherited hypoprothrombinemia, concentrates of prothrombin complex (eg,
Autoplex T) are used. No recombinant factor II product is available.

Aminocaproic acid (Amicar)

A 6-aminohexanoic acid that inhibits fibrinolysis by inhibiting plasminogen
activator substances and, to some degree, antiplasmin activity.

Anti-inhibitor coagulant complex (Feiba VH Immuno)

Prothrombin-complex concentrates contain vitamin K–dependent clotting factors.
Prepared from pooled normal human plasma. Some products contain more activated
factors than others. Presence of activated factors increases risk of thromboembolic
complications.

Phytonadione (aquamephyton, Mephyton)

Promotes liver synthesis of clotting factors. Aqueous colloidal solution of vitamin
K1 for parenteral injection. This form has same activity as naturally occurring vitamin K.
Vitamin K is essential cofactor for microsomal enzyme that catalyzes posttranslational
carboxylation of several specific peptide-bound glutamic acid residues in inactive

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hepatic precursors of vitamin K–dependent factors. Results in gamma-carboxyglutamic
acid residues necessary for calcium-dependent phospholipid membrane binding.

Fresh frozen plasma

Plasma is fluid compartment of blood that contains soluble clotting factors. For use
in patients with deficiencies of blood products. Indications include bleeding in patients
with congenital coagulation defects and deficiencies of multiple coagulation factors
(severe liver disease).

Further Outpatient Care

Patients with inherited prothrombin deficiency should receive follow up with a
hematologist at a comprehensive center that cares for patients with bleeding disorders.
Follow-up should occur on a yearly basis as a minimum.
A hematologist should initially evaluate patients with acquired hypoprothrombinemia.
Follow-up care depends on the underlying cause.

Prognosis
Patients with lupus anticoagulant-hypoprothrombinemia syndrome after a viral
infection can be expected to spontaneously recover.
Few patients with systemic lupus erythematosus–associated lupus anticoagulant-
hypoprothrombinemia syndrome (most cases) have spontaneously recovered.
Immunosuppressive therapy successfully controls bleeding and increases prothrombin
levels in most patients, though some have had a recurrence of symptoms when drug
therapy was tapered.
The prognosis for patients with inherited prothrombin deficiency varies. The
degree of deficiency does not always predict the clinical course, as patients with severe
deficiency with only mild bleeding tendencies have been reported. Impairment of the
procoagulant and anticoagulant activities of prothrombin are speculated to result in a
delicate coagulation balance in patients who have mild or no symptoms.
References
1.Meeks SL, Abshire TC. Abnormalities of prothrombin: a review of the
pathophysiology, diagnosis, and treatment. Haemophilia. 2008 Nov. 14(6):1159-
63.
2.Xue J, Wu Q, Westfield LA, et al. Incomplete embryonic lethality and fatal
neonatal hemorrhage caused by prothrombin deficiency in
mice. ProcNatlAcadSci U S A. 1998 Jun 23. 95(13):7603-7. [
3.Acharya SS, Coughlin A, Dimichele DM, et al. Rare Bleeding Disorder Registry:
deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J
ThrombHaemost. 2004 Feb. 2(2):248-56.

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Deficiency
 4.Pasmant E, Dumont B, Lacapere JJ, Dautzenberg MD, Bezeaud A. A severe
neonatal presentation of factor II deficiency. Eur J Haematol. 2011 Nov.
87(5):464-6.
5.Kim JS, Kim MJ, Bae EY, Jeong DC. Pulmonary hemorrhage in pediatric lupus
anticoagulant hypoprothrombinemia syndrome. Korean J Pediatr. 2014 Apr.
57(4):202-5.

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