Hypocoagulable Conditions

Hypocoagulable conditions, also known as bleeding disorders or bleeding diatheses, are a diverse group of diseases that result in abnormal hemostasis. Hemostasis is the innate, stepwise process resulting in bleeding cessation from a damaged blood vessel. Physiologic hemostasis is dependent on the integrity of endothelial cells and subendothelial matrix, platelets, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding.

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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

Formation of the temporary hemostatic plug:
The disrupted endothelial surface exposes von Willebrand Factor (vWF) to the passing blood. Platelets bind to the vWF via their GpIb receptors and are activated. Platelet activation triggers them to secrete adenosine diphosphate (ADP), which stimulates the expression of the GpIIb/IIIa receptors on the platelets. The GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing platelets to aggregate. As more platelets are bound to one another, the platelet plug is generated. As the coagulation cascade is activated, thrombin converts the weaker fibrinogen into the stronger fibrin, creating a much more stable clot.

Image by Lecturio.

Etiology

The following conditions can lead to a hypocoagulable state.

Table: Etiologies of hypocoagulable conditions
Inherited conditionsAcquired conditions
Vessel wall disorders
  • Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease)
  • Ehlers–Danlos syndrome
  • Age-related thinning of the skin
  • Chronic glucocorticoid use
  • Vitamin C deficiency
  • Henoch–Schönlein purpura
Platelet disorders
  • Wiskott–Aldrich syndrome
  • Fanconi anemia
  • Bernard–Soulier syndrome
  • Glanzmann thrombasthenia
  • Idiopathic thrombocytopenic purpura
  • Thrombotic thrombocytopenic purpura
  • Hemolytic uremic syndrome
  • Splenic sequestration
  • Aplastic anemia
  • Bone marrow infiltration
  • Myelosuppression: drug-induced, radiation-induced
  • Liver cirrhosis
  • Chronic kidney disease
  • Viral infections
  • Vitamin B12 and folate deficiencies
  • Pregnancy-associated conditions: gestational thrombocytopenia, HELLP syndrome
Coagulation disordersHemophilias A, B, and C
  • Development of clotting factor autoantibodies
  • Vitamin K deficiency
Mixed disordersVon Willebrand diseaseDisseminated intravascular coagulation
Medications
  • Antiplatelet drugs: aspirin, NSAIDs, clopidogrel, ticlopidine
  • Anticoagulants: warfarin, heparin
  • Factor inhibitors:
    • Argatroban (inhibits thrombin)
    • Rivaroxaban (inhibits factor Xa)
  • Myelosuppressive chemotherapeutic agents

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
Table: Usual clinical presentation according to the cause
Cutaneous bleedingMucosal bleedingInternal bleedingOnset of bleeding after trauma
Platelet disordersEarly (immediately)
Vessel disorders
Disorders of the coagulation cascadeLate (minutes to hours)

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.

Hereditary hemorrhagic telangiectasia

Image: “Clinical manifestations of HHT” by Latino et al. License: CC BY 4.0, cropped by Lecturio.

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

References

  1. Rajendran, P., Rengarajan, T., Thangavel, J., Nishigaki, Y., Sakthisekaran, D., Sethi, G., Nishigaki, I. (2013). The vascular endothelium and human diseases. International Journal of Biological Sciences 9(10):1057–1069. https://doi.org/10.7150/ijbs.7502
  2. Zehnder, J. (2020).  Clinical use of coagulation tests. Retrieved March 3, 2021, from https://www.uptodate.com/contents/clinical-use-of-coagulation-tests
  3. Ma, A. (2021). Approach to the adult with a suspected bleeding disorder. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved March 18, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-a-suspected-bleeding-disorder
  4. Longo, D., Fauci, A., Kasper, D., Hauser, S., Jameson, J., Loscalzo, J. (2012). Harrison’s Manual of Medicine, 18th ed. McGraw-Hill Professional, pages 2159–2178.
  5. Arnold, D.M., Cuker, A. (2021). Diagnostic approach to the adult with unexplained thrombocytopenia. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved March 30, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-with-unexplained-thrombocytopenia

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