Understanding Coagulopathy: From Liver Disease to Genetic Disorders Involving Platelets and Clotting Factors

A patient presenting with massive blood loss and abnormal coagulation tests prompts a detailed investigation into the possible causes of their bleeding disorder. The clinical discussion in this case explores both acquired and congenital causes of coagulopathy, with a special focus on the liver’s role in clotting factor synthesis, the involvement of vitamin K, and the consideration of platelet dysfunction or genetic bleeding disorders like hemophilia and von Willebrand disease (vWD).

1. The Quick Test < 50%: A Sign of Impaired Coagulation

The Quick test, synonymous with Prothrombin Time (PT) in some countries, evaluates the extrinsic and common pathways of the coagulation cascade. A Quick value below 50% indicates that blood is taking significantly longer than normal to clot.

Main factors assessed:
Factor I (fibrinogen), II (prothrombin), V, VII, and X
Clinical implication:
A result <50% points to a serious coagulopathy, often involving liver dysfunction, vitamin K deficiency, or anticoagulant use (e.g., warfarin).

2. Vitamin K-Dependent Clotting Factors Are Low

Vitamin K is essential for post-translational γ-carboxylation of the following factors:

Factor II (prothrombin)
Factor VII
Factor IX
Factor X
As well as proteins C and S (natural anticoagulants)

In this case, the deficiency of these factors is likely due to liver dysfunction, not just dietary deficiency, because even with adequate vitamin K, a failing liver cannot produce them effectively.

3. The Liver: Central Factory for Coagulation

The liver produces most coagulation factors, including:

Factors I, II, V, VII, IX, X, XI
Regulatory proteins like antithrombin, protein C, protein S
Thrombopoietin, which regulates platelet production

Notably:

Factor VIII and von Willebrand factor (vWF) are produced primarily by endothelial cells and megakaryocytes, not hepatocytes.
Severe hepatitis, cirrhosis, or hepatic failure leads to reduced synthesis of both coagulation and anticoagulation proteins, resulting in complex bleeding and thrombotic risks.

4. Interferon to Reduce Viral Load

In viral hepatitis (e.g., Hepatitis B or C), liver inflammation and fibrosis impair synthetic function.

Interferon therapy (especially for HCV) aims to suppress viral replication.
Reducing viral load may slow or reverse liver damage, potentially restoring some coagulation function—but this is a long-term goal, not an immediate bleeding control measure.

5. Enormous Blood Loss Explained

Given the liver’s failure to produce sufficient clotting factors, the body lacks the tools to form stable clots. This leads to:

Uncontrolled bleeding during minor trauma, surgery, or spontaneously
Laboratory signs such as:
- Low Quick value
- Prolonged PT and PTT
- Low platelet count (if splenomegaly is present)
- Possibly elevated D-dimers (from secondary fibrinolysis)

6. Hemophilia Consideration

The differential diagnosis includes congenital bleeding disorders, particularly:

Hemophilia A: Factor VIII deficiency
Hemophilia B: Factor IX deficiency

Both cause prolonged aPTT, with normal PT and normal platelet count/function. These are typically X-linked recessive disorders, mainly affecting males, and present with:

Deep tissue bleeding
Joint hemorrhages (hemarthroses)
Prolonged bleeding after trauma or surgery

7. Platelet Dysfunction and Genetic Disorders

The dialogue then shifts to platelet-related causes of bleeding. Platelet disorders present differently from factor deficiencies:

a. Signs of Platelet Dysfunction

Petechiae (tiny skin hemorrhages)
Mucosal bleeding (nosebleeds, gum bleeding, heavy menstruation)
Prolonged bleeding time, but usually normal PT/PTT

b. Genetic Platelet Disorders

Glanzmann thrombasthenia: Defective GPIIb/IIIa → impaired aggregation
Bernard-Soulier syndrome: Defective GPIb → impaired adhesion
Both are rare autosomal recessive disorders

In the context of liver disease, acquired platelet dysfunction can occur due to:

Thrombocytopenia (from splenic sequestration)
Uremia
Alcohol toxicity

8. Delayed Platelet Activation & Prolonged PTT

The phrase "delayed platelet activation" alongside a prolonged PTT may reflect:

Hemophilia (due to Factor VIII or IX deficiency)
vWD Type 2 (see below), which can result in both platelet function defects and prolonged PTT

It's important to note:

PTT reflects deficiencies in Factors VIII, IX, XI, XII (intrinsic pathway)
Platelet function defects do not affect PTT but cause bleeding time prolongation

9. Coagulopathy is Congenital—And Rare

Congenital coagulopathies are far less common than acquired causes, especially in adults. They include:

Hemophilia A/B
von Willebrand Disease (vWD)
Factor V deficiency (Owren’s disease)
Prothrombin (Factor II) deficiency

Additional Focus: von Willebrand Factor, Factor V, and Factor II

🔹 von Willebrand Factor (vWF)

Essential for platelet adhesion to damaged endothelium
Binds and protects Factor VIII from degradation
Types:
- Type 1 (partial quantitative deficiency) – most common
- Type 2 (qualitative defect) – causes defective platelet function and sometimes prolonged PTT
- Type 3 (severe deficiency) – resembles hemophilia A
vWD can show:
- Mucosal bleeding, petechiae
- Prolonged bleeding time
- Prolonged PTT (if Factor VIII is low)

Factor II (Prothrombin)

Vitamin K-dependent
Converted to thrombin, which is central to the coagulation cascade
Deficiency leads to severe bleeding, but it’s extremely rare congenitally
Most often reduced in vitamin K deficiency or liver disease

Factor V

Acts as a cofactor for Factor X in converting prothrombin to thrombin
Synthesized in the liver, but not vitamin K-dependent
Deficiency can be inherited (rare, autosomal recessive) or acquired (e.g., liver disease, DIC)

Final Clinical Summary

The clinical picture described reflects a complex coagulopathy, most consistent with acquired liver failure, based on:

Low Quick/PT
Low vitamin K-dependent factors (II, VII, IX, X)
Possibly low Factor V
Prolonged PT and aPTT
Potential platelet abnormalities
Massive bleeding

While hemophilia and vWD Type 2 are considered, they are far less likely in this adult, unless there’s a known genetic history.

Takeaway Table: Comparing Key Bleeding Disorders

Feature	Liver Disease	Hemophilia A/B	vWD Type 2	Platelet Disorders
PT (Quick test)	↑ (prolonged)	Normal	Normal or slightly ↑	Normal
aPTT	↑	↑↑	↑	Normal
Platelet count	↓ (if splenomegaly)	Normal	Normal	↓ or normal
Bleeding time	Normal or ↑	Normal	↑	↑↑
Bleeding type	Mixed (mucosal + deep)	Deep (joints, muscles)	Mucosal, petechiae	Mucosal, petechiae
Cause	Acquired	Congenital (X-linked)	Congenital (usually dominant)	Congenital or acquired

Patients with coagulopathies—whether due to liver disease, vitamin K imbalance, or genetic conditions like vWD or hemophilia—should be mindful of certain foods that may worsen bleeding risk or interfere with treatment.

Foods and Substances to Avoid:

Alcohol
- Damages the liver further and impairs clotting factor production.
- Can cause gastric bleeding and worsen thrombocytopenia.
High-dose Garlic, Ginger, Ginkgo, Ginseng
- Natural blood thinners that can inhibit platelet function.
Cranberry juice and Grapefruit (in excess)
- Can interfere with the metabolism of medications, including anticoagulants.
Vitamin E supplements (high dose)
- Can have anticoagulant effects when taken in large amounts.
Raw or Undercooked Shellfish
- Risk of infection, especially Vibrio vulnificus, which can be fatal in liver disease.
Foods High in Vitamin K (only in patients on warfarin)
- Kale, spinach, broccoli, Brussels sprouts may counteract anticoagulant therapy.
- These are not harmful in liver disease per se but should be kept consistent if on warfarin or Marcumar.

Picture from the author (SWA) with vWF 2 & 5 on Heparin.
Heparin: Mode of action: Heparin inhibits blood clotting by reducing the activity of various clotting factors.

Search This Blog

Q and A: about health and research