Hypocoagulable Conditions

Overview

Definition

Hypocoagulable conditions, also known as bleeding disorders or bleeding diatheses, are a diverse group of diseases that result in abnormal hemostasis and increased bleeding risk.

Physiologic hemostasis is dependent on normal structure and function of: 

• Vessel walls, made up of:
  • Endothelial cells
  • Subendothelial matrix
  • Extravascular connective tissue 
• Platelets 
• Coagulation factors

Review of hemostasis

The following is a summary of the process:

• Constriction of the blood vessel limits blood flow to the area.
• Formation of the platelet plug: the initial, temporary plug formed via the following steps:
  • Adhesion: Exposed von Willebrand factor (VWF) binds to the glycoprotein (Gp) Ib receptors on platelets.
  • Aggregation: GpIIb/IIIa receptors on platelets bind fibrinogen.
  • Secretion: Substances are released that stimulate further platelet activation and aggregation and initiation of the coagulation cascade.
• Activation of the coagulation cascade: forms a more stable fibrin clot
  • Extrinsic pathway: 
    • Primarily responsible for initiation of the cascade
    • Involves (in order): tissue factor, factor VII, and factor X
  • Intrinsic pathway: 
    • Primarily involved in amplification of the cascade
    • Can also be directly activated by vessel injury
    • Involves (in order): factors XII, XI, IX, VIII, and X
  • Common pathway: 
    • The extrinsic and intrinsic pathways join together when factor X is activated to form the final common pathway.
    • Involves (in order): factors X, V, II (thrombin), I (fibrin), and XIII
• Inhibition of clotting and the fibrinolytic phase: 
  • Stops clotting and breaks down the clot once it is no longer necessary
  • Involves: 
    • Plasmin
    • Antithrombin
    • Proteins C and S

Etiology

The following conditions can lead to a hypocoagulable state.

Clinical Presentation

A hypocoagulable state may present in the following ways:

• Cutaneous bleeding:
  • Petechiae 
  • Purpura 
  • Ecchymosis and easy bruising  
• Mucosal bleeding: 
  • Gingival bleeding: with brushing, flossing, and/or dental procedures
  • GI mucosal bleeding: gross blood in stool or on fecal occult blood testing
  • Nasopharyngeal bleeding: prolonged or recurrent epistaxis 
  • Menstrual bleeding: prolonged or heavy periods 
  • Urinary tract bleeding: gross or microscopic hematuria
• Internal bleeding: 
  • Hemarthrosis 
  • Intramuscular hematoma
  • Intracranial hemorrhage 
  • Retroperitoneal hematoma 
• Iron deficiency anemia (if significant blood loss occurs):
  • Fatigue
  • Conjunctival pallor
  • Pica
• Genetic/inherited bleeding disorders:
  • Symptomatic bleeding early in infancy/childhood 
  • Other findings consistent with an inherited disorder

Disorders of the Vessel Wall

Overview

Bleeding disorders may stem from abnormalities of the vessel wall.

• Abnormalities may be in any component of the vessel walls, which are made up of:
  • Endothelial cells
  • Subendothelial matrix
  • Extravascular connective tissues
• Disorders may be inherited or acquired.
• Usually present with the spontaneous appearance of petechiae and ecchymoses in the skin and mucous membranes or after a minor trauma 
• Coagulation and bleeding studies are usually normal.

Inherited disorders of the vessel wall

Inherited disorders of the connective tissue matrix can cause vascular fragility, leading to frequent vessel injury.

• Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome):
  • Autosomal dominant mutation in endoglin (an integral collagen protein)
  • Presents with:
    • Telangiectasias in skin, mucous membranes, and internal organs
    • Epistaxis
    • GI bleeding
    • Iron deficiency anemia
    • Arteriovenous malformations in the lungs, liver, and brain
• Ehlers–Danlos syndrome:
  • A genetic disorder affecting the synthesis and/or processing of collagen 
  • Multiple phenotypes, but generally characterized by:
    • Skin hyperextensibility
    • Joint hypermobility
    • Tissue fragility
  • The vascular type in particular has ↑ risk for spontaneous vascular or visceral rupture with potentially life-threatening bleeding.

Acquired disorders of the vessel wall

The following acquired conditions may lead to vascular fragility and increase vessel injury:

• Age-related thinning of the skin
• Long-term topical glucocorticoid use may cause atrophy of supporting connective tissue.
• Vitamin C deficiency (scurvy): 
  • Vitamin C is essential for collagen synthesis and integrity.
  • Presentation: 
    • Cutaneous signs: petechiae, perifollicular hemorrhage, and bruising
    • Gingivitis
    • Arthralgias
    • Impaired wound healing
• Henoch–Schönlein purpura: 
  • Postinfectious IgA-mediated small vessel vasculitis in children and young adults
  • Classical presentation:
    • Purpura on extensor surfaces
    • Arthralgias
    • Abdominal pain
    • Renal disease/hematuria

Platelet disorders

Overview

• Hypocoagulable platelet disorders may be due to: 
  • Decreased number (thrombocytopenia) 
    • Increased destruction/clearance
    • Decreased production
  • Abnormal function 
• Laboratory findings:
  • Bleeding time: prolonged
  • PT, INR, and PTT: not affected by pure platelet disorders

Thrombocytopenias

• Immune thrombocytopenic purpura (ITP):
  • IgG antibodies against platelets, leading to their destruction 
  • May be primary or secondary 
  • Secondary ITP may be caused by:
    • Viral infections (see below)
    • CLL
    • Systemic lupus erythematosus (SLE)
    • Antiphospholipid syndrome
    • Common variable immune deficiency (CVID)
• Thrombotic thrombocytopenic purpura (TTP):
  • Deficiency of ADAMTS13 metalloproteinase (congenital or autoimmune)
    • This protein is responsible for cleaving the large VWF multimers.
    • Deficiencies lead to large VWF multimers that strongly adhere to platelets and increase platelet aggregation.
    • These platelet plugs damage the flowing RBCs → hemolytic anemia
    • Limits blood flow to the brain and kidneys
  • Classic presentation (pentad): 
    • Thrombocytopenia 
    • Hemolytic anemia
    • Acute renal failure
    • Neurologic symptoms
    • Fever
  • Modern presentation (now often diagnosed prior to the classic presentation of more severe disease; fever, especially, is uncommon):
    • Fatigue, weakness
    • Bleeding, petechiae, or purpura
    • GI symptoms
    • Neurologic findings: stroke, seizure, headache, confusion
• Hemolytic uremic syndrome:
  • Primarily an acquired condition, typically in children
    • 90% occur after Shiga toxin–producing Escherichia coli infection.
    • Hereditary forms involving mutations in complement and coagulation pathway proteins are possible.
  • Classic presentation (triad): 
    • Thrombocytopenia
    • Hemolytic anemia
    • Acute renal failure 
  • Usually follows bloody diarrhea   
• Hypersplenism (splenic sequestration of platelets): 
  • Thrombocytopenia is typically mild.
  • Bleeding abnormalities are rare.
• Liver cirrhosis: 
  • Decreased liver production of thrombopoietin → ↓ platelet production
  • Portal hypertension →  splenomegaly  → splenic sequestration
• Viral infections:
  • Mechanisms:
    • Splenic sequestration
    • Viral infection → hepatitis → ↓ platelet production
    • Secondary ITP
    • Direct platelet destruction
  • Viruses most likely to cause thrombocytopenia:
    • HIV
    • Epstein–Barr virus
    • Cytomegalovirus
    • Rubella
    • Varicella
    • Mumps
    • Parvovirus
    • Hepatitis C
• Bone marrow suppression:
  • Aplastic anemia: 
    • A life-threatening failure of the bone marrow causing pancytopenia 
    • Due to injury of the multipotent hematopoietic stem cells
  • Fanconi anemia: 
    • An inherited type of aplastic anemia
    • Associated with an increased risk for malignancy, developmental delay, café-au-lait spots, and VACTERL (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association anomalies
  • Myelodysplasia
  • Drug-induced myelosuppression (e.g., chemotherapy)
  • Radiation-induced myelosuppression
  • Toxic chemicals (e.g., arsenic, benzene)
• Vitamin deficiencies: 
  • B₁₂
  • Folic acid 
• Conditions associated with pregnancy:
  • Gestational thrombocytopenia
  • HELLP syndrome

Disorders of platelet function

Inherited disorders:

• Bernard–Soulier syndrome:  
  • Autosomal recessive condition 
  • Abnormal platelet adhesion due to low GpIb
  • Large platelets on smear 
• Glanzmann thrombasthenia: 
  • Autosomal recessive condition 
  • Abnormal platelet aggregation due to low GpIIb/IIIa
  • Presents with mucocutaneous bleeding without thrombocytopenia 
• Wiskott–Aldrich syndrome (WAS): 
  • X-linked recessive disorder caused by mutations in the WAS protein
  • Presentation (classic triad): 
    • Immunodeficiency
    • Thrombocytopenia
    • Eczema
  • Mixed B- and T-cell deficiency results in immunodeficiency.
  • Abnormal platelet development causes:
    • Severely dysfunctional platelets
    • Thrombocytopenia
    • Abnormal bleeding

Acquired conditions:

• Uremic platelet dysfunction:
  • Chronic renal failure leads to abnormal platelets (mechanisms not fully understood).
  • Presentation: bruising, epistaxis, GI and genitourinary bleeding
• Myeloproliferative disorders:
  • Bleeding complications vary (incidence: 3%–59%).
  • Presentation: bruising, epistaxis, gingival hemorrhage, and GI bleeding 
• Use of antiplatelet agents: 
  • NSAIDs
  • Aspirin
  • Clopidogrel

Disorders of the Coagulation Cascade

Overview

• Hypocoagulable disorders may be due to: 
  • Decreased number of coagulation factors (referred to as “factor deficiency”)
  • Abnormal function of coagulation factors
• Laboratory findings:
  • PT and/or PTT will be prolonged by pure coagulation factor disorders.
  • Platelet count and bleeding time will not be affected.

Inherited conditions

• Hemophilia A:
  • X-linked recessive disorder 
  • Factor VIII deficiency 
  • Presents with:
    • Easy bleeding and bruising as an infant
    • Bleeding into the joints, muscles, and GI tract when older
  • Treated with prophylactic factor VIII infusions
• Hemophilia B:
  • X-linked recessive disorder 
  • Factor IX deficiency 
  • Less common
• Hemophilia C:
  • Autosomal recessive disorder 
  • Factor XI deficiency 
  • Less common

Acquired conditions

• Development of factor inhibitors (autoantibodies against specific clotting factors):
  • Manifests clinically as hemophilia 
  • Often difficult to treat
• Vitamin K deficiency: 
  • Malabsorption 
  • Malnutrition (e.g., alcohol abuse)
• Anticoagulation therapy:
  • Heparins: 
    • Bind to antithrombin and increase its activity 
    • Lead to faster inactivation of coagulation factors (thrombin, factor Xa)
  • Warfarin:
    • Inhibits the vitamin K epoxide reductase in the liver, which prevents gamma-carboxylation of the vitamin K–dependent coagulation factors
    • Vitamin K–dependent procoagulants: factors II (thrombin), VII, IX, and X 
    • Vitamin K–dependent anticoagulants: proteins C and S

Mixed Platelet and Coagulation Disorders

• Disseminated intravascular coagulation (DIC):
  • Cause: systemic thrombi formation throughout the microcirculation caused by systemic activation of coagulation due to:
    • Sepsis
    • Malignancy
    • Trauma
    • Obstetric complications: preeclampsia, postpartum hemorrhage, retained deceased fetus
    • Acute hemolytic transfusion reaction
  • Results: Platelets and coagulation factors are consumed, leading to bleeding diathesis. 
  • Presentation: spontaneous bleeding from mucous membranes
• Von Willebrand disease: 
  • The most common inherited bleeding disorder 
  • Autosomal dominant inheritance
  • Results from quantitative or qualitative deficiency of VWF
  • Functions of VWF:
    • VWF binds to and stabilizes factor VIII (affects the intrinsic pathway).
    • VWF is present on injured vessel walls and binds the GpIb receptor on platelets (initial adhesion of platelets).
  • Clinical presentations:
    • Asymptomatic 
    • Spontaneous bleeding from mucous membranes (e.g., epistaxis)
    • Menorrhagia 
    • Bleeding from wounds