CONTENTS

DIC (disseminated intravascular coagulation)

• Pathophysiology
• Symptoms
• Lab studies
• Causes
• Differential diagnosis
• Diagnostic criteria
• Sepsis-Induced Coagulopathy (SIC)
• Management

purpura fulminans

• Common causes
• Clinical findings
• Diagnostic tests
• Diagnosis
• Treatment
  • Antibiotics & source control
  • Heparin & heparin resistance
  • Protein C concentrates
  • Blood product replacement
  • Vitamin K supplementation
  • Vasodilators
  • Surgical debridement

hyperfibrinolysis

• Pathophysiology
• Causes
• Clinical manifestations
• Laboratory diagnosis
• Treatment

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pathophysiology

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the general concept of DIC

Normally, clots form locally at sites of vascular damage. These clots are subsequently degraded after tissue damage is repaired. The processes of clot formation and clot degradation (fibrinolysis) are localized and tightly regulated, based on a balance of counterregulatory proteins (procoagulants vs. anticoagulants regulate clot formation; fibrinolytics vs. antifibrinolytics regulate clot breakdown).

The fundamental pathophysiologic signature of DIC is widespread, uncontrolled clot formation. Clotting may be initiated by various factors (e.g., bacterial lipopolysaccharides, tissue factor released by monocytes or the placenta, or damage to the endothelial glycocalyx). The fine balance of procoagulation vs. anticoagulation is broken, leading to widespread disseminated clot formation. This clot burden places a massive strain on the fibrinolytic system, which is subsequently tasked with breaking down all of the clot. The fine balance of fibrinolysis vs. antifibrinolysis may subsequently become disrupted as numerous proteins are depleted.

DIC may cause a variety of life threats

1. Disseminated microvascular thrombosis may cause tissue hypoperfusion and tissue damage. This may be exacerbated by the depletion of fibrinolytic proteins, which prevents clots from undergoing thrombolysis (“fibrinolytic shutdown”).
2. Depletion of anticoagulant proteins may predispose patients to form macrovascular thromboses (e.g., deep vein thrombosis and pulmonary emboli).
3. Depletion of procoagulant proteins may lead to hemorrhage.

acute versus chronic DIC

• Acute DIC results from an acute coagulation trigger (e.g., sepsis). This leads to abrupt and exuberant depletion of coagulation factors, leading to hemostatic imbalances.
  • This chapter is predominantly about acute DIC – which is more immediately relevant to critical care medicine.
• Chronic DIC refers to chronic activation of coagulation, often due to disseminated adenocarcinomas. This causes gradual consumption of coagulation factors, which can be compensated by the production of additional clotting factors. Symptoms and laboratory abnormalities are consequently less notable (this is sometimes termed “chronic compensated DIC”).

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symptoms

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DIC may be asymptomatic, or it may cause bleeding and clotting. Symptoms may be dominated by either bleeding or clotting.

microvascular thrombosis causes organ failure

• Microvascular thromboses may be an occult cause of organ failures. With the exception of the skin, it is often difficult or impossible to tell that microvascular thrombosis is occurring. The most common manifestations are:
• (1) Renal failure.
• (2) ARDS (acute respiratory distress syndrome).
• (3) Brain involvement may cause delirium, coma, or seizure.
• (4) Adrenal failure (Waterhouse-Friedrichsen syndrome) may result from microvascular thromboses, followed by hemorrhagic transformation. The net result is adrenal failure, which can precipitate an adrenal crisis. 📖
• (5) Skin: purpura fulminans (occlusion of microvasculature in the skin potentially causing gangrene). This signifies an extreme form of DIC which requires aggressive management (more on this below: ⚡️)

macrovascular thrombosis

• DVT (deep vein thrombosis).
• PE (pulmonary emboli).

bleeding

• Petechiae and purpura may occur on the skin.
• Oozing may originate from intravenous catheters or mucus membranes.
• Life-threatening hemorrhage can result from gastrointestinal or intracranial hemorrhage. However, in most forms of DIC, severe bleeding is uncommon.

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laboratory studies

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DIC screening lab panel

• Complete blood count (CBC).
• INR and PTT.
• Fibrinogen.
• D-dimer.

D-dimer

• D-dimer is invariably elevated in DIC, often dramatically (e.g., >4,000 ng/mL).
• A normal D-dimer essentially excludes DIC.
• An elevated D-dimer is nonspecific. Serial measurement that reveals an acutely rising D-dimer might be more suggestive of active DIC. (38861325) However, advanced sepsis-induced DIC may impair fibrinolysis (“fibrinolytic shutdown”), which limits further increases in D-dimer.

thrombocytopenia

• Moderate thrombocytopenia is usually seen in DIC. Platelet counts of <30,000/uL are uncommon (25413378, 22735856, 26308340, 23159146, 19581801)
• Thrombocytopenia may be the most sensitive laboratory test for the detection of DIC. (30828800) A down-trending platelet count is often the first laboratory abnormality to be noted. (30634199) Of course, thrombocytopenia is not specific to DIC: thrombocytopenia is very common in the ICU due to various causes. 📖

INR and PTT abnormalities

• Elevations of INR and PTT support a diagnosis of DIC. However, they can be normal in over half of patients with DIC. (30634199)
• These abnormalities may not correspond to clinical hypocoagulability (they measure only clotting factors but do not reflect deficiencies that may be occurring in anticoagulant factors, such as protein C and protein S).
• In sepsis-induced DIC, PTT prolongation may lag behind PT prolongation as DIC develops. This occurs because the PTT is reduced by elevated factor VIII levels. (27578502)

fibrinogen

• Fibrinogen is the least sensitive marker of DIC, with a sensitivity of only 25%. (30634199) Low fibrinogen supports a diagnosis of DIC but usually isn't seen.
• Markedly low fibrinogen levels might raise the possibility of hyperfibrinolysis. ⚡️
• Sepsis increases fibrinogen levels so that sepsis-induced DIC may have elevated or normal levels of fibrinogen. Falling fibrinogen may suggest ongoing DIC with the consumption of fibrinogen.

antithrombin-III levels

• Antithrombin-III is generally consumed in DIC. Reduced antithrombin-III levels may contribute to heparin resistance among patients with DIC.
• Reduced levels of antithrombin-III might be useful to identify early (nonovert) DIC since these levels often fall prior to the development of an obvious consumptive coagulopathy. (38861325)
• Other causes of reduced antithrombin levels include:
  • Exposure to devices (e.g., hemodialysis, ECMO, and possibly IABP).
  • Medications (especially unfractionated heparin infusion). (71399)
  • Cirrhosis.
  • Nephrotic syndrome.

microangiopathic hemolytic anemia (MAHA) can occur

• Microangiopathic hemolytic anemia can occur due to microthrombi in the capillaries. This causes intravascular hemolysis with the generation of schistocytes (fragmented RBCs).

role of thromboelastography (TEG) in DIC

• Patients with DIC often have reduced levels of both clotting factors and also endogenous anticoagulant proteins. This may create a situation where patients appear to be hypocoagulable based on traditional labs (e.g., platelet count and INR) – but they are actually hypercoagulable.
• TEG is a whole-blood integrative test that may help clarify the overall balance of coagulation.
• TEG often shows hypercoagulability early in the course of DIC (e.g., reduced R-time). Later on, during the course of fulminant DIC, TEG may show hypocoagulability.
• Reduction in the maximal amplitude (MA) may be the most common abnormality seen in DIC. (33682140)

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causes of DIC

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sepsis due to a wide variety of pathogens, most notably:

• Bacteria (thrombosis predominates):
  • Gram-negative bacteria.
  • Toxigenic organisms (e.g., group A streptococci).
• Viruses (e.g., viral hemorrhagic fevers).
• Malaria.

direct tissue damage

• Surgery.
• Trauma (especially involving traumatic brain injury).
• Thermal injury:
  • Burns or frostbite.
  • Heat stroke (thrombosis predominates).
• Fat emboli syndrome.
• Intravascular hemolysis:
  • Hemolytic transfusion reaction.
  • Malaria.

malignancy, especially:

• Acute promyelocytic leukemia (AML-M3) and monocytic leukemia (AML-M5) – Tend to cause DIC and hyperfibrinolysis, with prominent bleeding. 📖
• Adenocarcinoma (especially pancreas, prostate, lung, gastric, ovary). This is usually a chronic, compensated form of DIC with a tendency towards thrombosis.
• Chemotherapy.

obstetric catastrophe (hemorrhage & hyperfibrinolysis often predominate)

• Placental abruption.
• Amniotic fluid embolism.
• Preeclampsia, HELLP syndrome.
• Retained dead fetus.
• Maternal septic shock (e.g., chorioamnionitis, group A streptococcus infection).
• Acute fatty liver of pregnancy.

other

• Post-Cardiopulmonary Resuscitation (thrombosis predominates). (29255070)
• Severe collagen vascular disease, vasculitis.
• Drug-induced.
• Heparin-induced thrombocytopenia 📖 can cause DIC in ~10% of cases (although the two processes are usually separate).
• Severe hepatitis.
• Vascular malformations (e.g., giant hemangiomas or large aortic aneurysms; hemorrhage predominates).
• CAPS 📖 (catastrophic antiphospholipid antibody syndrome).
• HLH 📖 (hemophagocytic lymphohistiocytosis).

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common differential diagnostic considerations

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[1/5] DIC vs. sepsis-induced thrombocytopenia

• Sepsis may cause thrombocytopenia via a variety of mechanisms: (29255070)
  • Impaired platelet production.
  • Increased platelet consumption (sometimes due to hemophagocytosis).
  • Splenic sequestration of platelets.
• Septic patients often have thrombocytopenia without other abnormalities in their coagulation factors (e.g., normal INR and PTT). Such patients do not have DIC.

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[2/5] DIC vs. HIT 📖

• A useful feature to sort out HIT vs. DIC is chronicity. DIC usually occurs gradually, beginning around the time of admission. Alternatively, HIT tends to begin abruptly, more than five days after exposure to heparin. The 4-T score may be used to quantify the risk of HIT more precisely.
• Most patients with HIT do not have DIC. However, severe HIT may trigger DIC in ~10% of cases.
• HIT alone typically causes the following pattern of findings:
  • Platelet counts aren't profoundly reduced (e.g., platelets >20,000/uL).
  • INR and fibrinogen levels are normal.
• HIT complicated by DIC may cause the following pattern:
  • Platelets may be profoundly reduced (e.g., platelets <20,000/uL)
  • INR prolongation and hypofibrinogenemia may occur

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[3/5] cirrhosis vs. DIC vs. AICF (accelerated intravascular coagulation and fibrinolysis)

Cirrhosis is a risk factor for DIC because patients with cirrhosis often have reduced levels of coagulation factors and also anti-coagulant proteins (e.g., protein C and protein S). With lower levels of these proteins at baseline, patients with cirrhosis have a delicate balance of procoagulants vs. anticoagulants, which may be more easily disrupted by an acute insult. Thus, cirrhosis may often coexist with DIC. Patients with advanced cirrhosis are also at risk for primary hyperfibrinolysis (termed: accelerated intravascular coagulation and fibrinolysis).

• D-dimer:
  • Stable cirrhosis patients often have a mildly elevated D-dimer.
  • Markedly elevated D-dimer suggests DIC or AICF.
• Platelet count:
  • Cirrhosis can cause thrombocytopenia, but this is often stable.
  • A stable platelet count argues against DIC. (29255070)
• INR:
  • Cirrhosis often causes elevation of INR.
  • INR that is stable or close to its baseline argues against DIC. (29255070)
• Factor VIII:
  • In stable cirrhosis, factor VIII levels will remain normal or elevated (since this is produced by endothelial cells).
  • A low factor VIII level suggests DIC.
• TEG with elevated LY-30: If seen this would support hyperfibrinolysis (but it is very insensitive for ACLF).
• Antithrombin III: This may be reduced by cirrhosis and/or DIC.

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[4/5] DIC vs. other thrombotic microangiopathies (e.g., TTP)

• Both DIC and thrombotic microangiopathies may lead to anemia, schistocyte formation, and thrombocytopenia. However, schistocyte formation is considerably more exuberant in primary thrombotic microangiopathy compared to DIC.
• Patients with TTP, HUS, or drug-induced thrombotic microangiopathy should have normal coagulation factors (e.g., INR, PTT, fibrinogen) because clots are composed of platelets and don't involve coagulation system activation. Similarly, the D-dimer should be normal or only slightly elevated. (29255070)
• Further discussion on the approach to thrombotic microangiopathy: 📖

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[5/5] DIC vs. CAPS (catastrophic antiphospholipid antibody syndrome) 📖

• This can be challenging because CAPS causes DIC in ~25% of cases.
• Features that may suggest CAPS include:
  • A history of connective tissue disease (especially antiphospholipid antibody syndrome).
  • A history of pregnancy loss or illness onset during pregnancy.
  • Recent withdrawal of anticoagulation.
  • Skin manifestations (e.g., livedo reticularis or cutaneous necrosis).

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diagnostic criteria of DIC

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DIC is a clinical diagnosis

• No single lab test is diagnostic of DIC. Rather, the diagnosis of DIC rests roughly on three components:
• [1] Constellation of laboratory abnormalities, which is consistent with DIC.
• [2] Presence of an underlying disorder known to cause DIC (e.g., trauma, sepsis).
• [3] Exclusion of an alternative explanation for coagulation abnormalities (see the differential diagnosis section above).

DIC scoring systems

• Several DIC scoring systems exist. The ISTH (International Society of Thrombosis and Hemostasis) score below is the most widely utilized.
• Scoring systems help provide objectivity but aren't perfect.
• Early in the process of DIC, the patient may not quite reach a positive DIC score (sometimes called “non-overt DIC”). If there is ongoing concern regarding DIC, coagulation labs may be repeated in 12-24 hours to determine if the patient is developing DIC. Often, changes in serial labs may be more illuminating than a single set of labs (e.g., a fibrinogen that is actively falling from 300 mg/dL to 100 mg/dL is more worrisome than a fibrinogen that is stably low at 100 mg/dL).

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sepsis induced coagulopathy (SIC)

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what is sepsis-induced coagulopathy (SIC)?

• Sepsis-induced coagulopathy essentially refers to DIC caused by sepsis.
• Sepsis tends to cause a particular form of DIC with the following characteristics:
  • Hypercoagulability and microvascular thrombosis are usually the predominant problems.
  • Fibrinogen levels are generally within the normal range.
  • Fibrinolysis is suppressed, which may lead to impairment of the breakdown of microthrombi.
• The Sepsis-Induced Coagulopathy score is designed specifically to detect DIC in the context of sepsis (table below).
• For patients with sepsis, the Sepsis-Induced Coagulopathy score is more sensitive than the ISTH DIC criteria. For example, patients will generally meet sepsis-induced coagulopathy criteria before they deteriorate and meet ISTH DIC criteria. (31099127) However, patients with Sepsis-Induced Coagulopathy seem to have the same mortality as patients meeting the more stringent ISTH DIC criteria – suggesting that the increased sensitivity of the Sepsis-Induced Coagulopathy score may not come at the cost of impaired specificity. (31410983) Unfortunately, since there is no gold standard to diagnose DIC, it's impossible to definitively tell which scoring system is ideal.

how should sepsis-induced coagulopathy be used clinically?

• The utility of Sepsis-Induced Coagulopathy is unclear because, currently, there are no proven therapies for this. We are probably missing many septic patients with sepsis-induced coagulopathy, but does this actually matter?
• One way that Sepsis-Induced Coagulopathy could be used is as a screening tool for DIC among patients with sepsis (figure below). (31099127)
• It must be borne in mind that many disease processes can cause thrombocytopenia plus a mildly elevated INR. Therefore, patients meeting the criteria for sepsis-induced coagulopathy don't necessarily have DIC. Rather, these patients should be thoughtfully investigated with other differential diagnostic possibilities borne in mind (e.g., cirrhosis, heparin-induced thrombocytopenia).

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management

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some specific types of DIC require specific treatment:

1. DIC due to APL (acute promyelocytic leukemia): see 📖
2. Purpura fulminans: see 📖

treat the underlying disorder

• The most important principle of DIC management is to treat the underlying cause.
• DIC due to septic shock is perhaps the most notable example of this – treatment should overall focus on the basic tenets of sepsis care.

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[1/2] anticoagulation for treatment of microthrombi or overt thrombosis

DVT prophylaxis

• DVT prophylaxis should be provided to all critically ill patients unless contraindicated. Contraindications may include:
  • Active bleeding.
  • Profound thrombocytopenia (e.g., platelet count <30,000/uL). (30828800)
  • Profound hypofibrinogenemia (e.g., fibrinogen <80 mg/dL).
  • Planned procedure with high concern regarding bleeding (e.g., neurosurgery, lumbar puncture).
• Subgroup analysis of the SCARLET and KYBERSEPT trials investigating antithrombin III and thrombomodulin anticoagulation suggest that these anticoagulants were potentially beneficial – but only among patients not taking concomitant heparin. This indirectly suggests that heparin could provide benefits analogous to more expensive anticoagulants. (31988789)

therapeutic heparin anticoagulation

• Rationale:
  • Theoretically, anticoagulation with heparin could impede ongoing thrombosis and thereby stop the primary abnormality of DIC (disseminated activation of coagulation).
  • Unfortunately, research into therapeutic heparin anticoagulation has generally been unimpressive. Thus, heparin anticoagulation isn't indicated in most cases of DIC.
• Potential indications for heparin anticoagulation:
  • [1] Clinical thrombosis (e.g., DVT or pulmonary embolism).
    • 💡 Have a low threshold to obtain DVT studies in this patient population if there is any potential concern for DVT.
  • [2] Purpura fulminans (this subset of DIC requires an entirely different treatment strategy: 📖).
  • [3] Severe digital ischemia might be an indication for considering anticoagulation. (33555051)
  • [4] If there is another indication for anticoagulation (e.g., atrial fibrillation), the presence of DIC could argue for anticoagulation.
• Heparin infusion may be preferred:
  • Patients with DIC often have heparin resistance due to low levels of antithrombin III. Consequently, higher doses of heparin may be required than usual. If low molecular weight heparin is administered in a weight-based fashion without measurement of anti-Xa levels, that could lead to subtherapeutic anticoagulation.
  • Heparin infusions should ideally be titrated using an anti-Xa level. Patients with DIC will often have an elevated PTT at baseline, which may confuse the use of PTT to monitor heparin dosing.
  • Further discussion on heparin resistance: 📖

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[2/2] blood product replacement (usually avoided)

platelet transfusion

• Platelet transfusion should generally be avoided unless:
  • Platelets <10,000/uL.
  • There is active bleeding.
  • There is a planned procedure with a substantial risk of bleeding.
• For patients with active bleeding or a pending procedure, transfusion to >30,000-50,000/uL may be reasonable. (29255070)
• Due to ongoing platelet consumption, results from platelet transfusion may be disappointing.

fibrinogen supplementation

• Profoundly low fibrinogen levels may increase the risk of bleeding, including intracranial hemorrhage.
• It may be reasonable to attempt to maintain fibrinogen levels above >~50-100 mg/dL (a target that may be personalized to some extent, depending on the risk of bleeding vs. thrombosis).
• For patients with active bleeding or a planned procedure, targeting a fibrinogen level >~150 mg/dL may be reasonable. Various sources recommend targets ranging from >100 mg/dL to >200 mg/dL, with little supporting evidence. The target may be individualized for a specific patient when considering the overall risks of hemorrhage and the state of coagulation (e.g., for patients with marked thrombocytopenia, a higher fibrinogen target may compensate for the thrombocytopenia to a certain degree).
• Fibrinogen levels may be supported using cryoprecipitate or fibrinogen concentrates.

coagulation factor replacement (e.g., fresh frozen plasma)

• This is confusing because traditional labs (e.g., INR) don't reflect the true coagulation tendency of the blood. INR measures only clotting factors (while ignoring endogenous anticoagulants such as protein C and protein S).
• Thromboelastography is likely a better tool to determine the true balance of coagulation. The use of thromboelastography for patients with DIC has not been specifically studied. However, thromboelastography has a proven track record for the management of patients with enormously complex coagulopathies in the operating room (e.g., hepatic transplantation, multiple trauma patients, cardiopulmonary bypass operations) – many of whom doubtless had DIC. Thus, it is a logical extension that thromboelastography could be used to tailor blood product selection in the intensive care unit.
• It may be better not to treat INR and PTT values when possible. However, in patients with active bleeding or planned procedures, factor replacement is indicated if thromboelastography reveals enzymatic coagulopathy (e.g., with prolonged R-time).
• Fresh frozen plasma (FFP) has traditionally been used for coagulation factor repletion. However, prothrombin complex concentrates may be another option (especially in patients with volume overload).

vitamin K administration

• It may be difficult to determine whether vitamin K deficiency exists (since INR prolongation results from DIC).
• If vitamin K deficiency is suspected, then vitamin K should be administered empirically (e.g., 10 mg intravenously infused over 30-60 minutes).

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purpura fulminans

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• Basics of Purpura Fulminans
• Pathophysiology
• Common causes
• Clinical findings
• Diagnostic tests
• Diagnosis
• Treatment
  • Antibiotics & source control
  • Heparin & heparin resistance
  • Protein C concentrates
  • Blood product replacement
  • Vitamin K supplementation
  • Vasodilators
  • Surgical debridement

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basics

• Purpura fulminans is an extreme thrombotic subtype of disseminated intravascular coagulation, marked by microvascular thrombosis causing skin necrosis (most typically involving the extremities and digits).
• In adults, purpura fulminans is most commonly caused by severe infection. However, the primary risk to life and limb is often the purpura fulminans (rather than the underlying infection). It's not uncommon for patients to lose digits or limbs to this disease.

types of purpura fulminans

• Three types:
  • (1) Congenital form (manifests shortly after birth due to congenital deficiency of protein C, protein S, or antithrombin III).
  • (2) Postinfectious form (extremely rare, caused by autoantibodies which deplete protein S activity).
  • (3) Acute infectious form (the most common form in adults, a complication of severe disseminated intravascular coagulation)
• The remainder of this section discusses the acute infectious form.

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pathophysiology

acquired protein C deficiency

• Purpura fulminans can be caused by either congenital or acquired protein C deficiency. In the context of septic shock, protein C deficiency is acquired.
• Causes of protein C deficiency include the following:(16635072)
  • Consumption of protein C due to overwhelming thrombin generation. (30396911)
  • Reduced hepatic synthesis due to liver dysfunction (purpura fulminans may be associated with shock liver).
  • Degradation of protein C by elastase released by white blood cells.
• Depletion of protein C leads to an imbalance in the coagulation systems, with inadequate safeguards to prevent excessive coagulation.

consequences of protein C deficiency

• Normally, protein C is activated by thrombin (IIa), an interaction that is facilitated by thrombomodulin (panel A above). Thrombin is generally procoagulant, but by activating protein C, thrombin participates in negative feedback inhibition of the coagulation system.
• Activated protein C has several effects to dampen coagulation:
  • Inactivation of factors Va and VIIIa (inhibiting enzymatic coagulation).
  • Inhibition of plasminogen-activator inhibitor-1 (PAI-1) – which overall will tend to favor fibrinolysis.
  • Cleavage of protease-activated receptor-1 (PAR-1), which sends anti-inflammatory and anti-apoptotic signals to the endothelial cell (thereby protecting it).
• Deficiency of protein C may lead to excess fibrin generation, as well as inadequate fibrinolysis. The result can be widespread fibrin deposition within the microvasculature, causing ischemic tissue damage.

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common causes of purpura fulminans

• Bacterial infections:
  • [#1] Neisseria meningitides (~20% of patients develop purpura fulminans, especially following treatment with eculizumab).
  • [#2] Streptococcus pneumoniae (especially asplenic or hypo-splenic patients). (34846563)
  • Streptococcus pyogenes.
  • Haemophilus influenzae.
  • Capnocytophaga canimorsus.
  • Staphylococcus aureus.
  • Gram-negatives (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis).
  • (Less common: Enterococcus faecalis, Leptospira, Rickettsia rickettsii, Vibrio parahaemolyticus)
• Viral infections:
  • Varicella zoster virus.
  • West Nile virus.
  • Rubeola virus.
• Plasmodium falciparum.
• Fungal infections:
  • Cryptococcus neoformans.
  • Aspergillus spp.
  • Fusarium spp.

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clinical findings

[1] initial skin findings

• Non-blanching, red, patchy macules on the skin with thin, lacy, irregular borders.
• Lesions are often most prominent on the extremities.
• Initially, the skin may be painful and indurated.
• These findings seem to represent the initial manifestation of microthrombi in small dermal vessels (29157918)

[2] rapid progression to skin necrosis within 24-48 hours

• Central necrosis occurs, leading to black necrotic lesions (with full-thickness necrosis of the skin). With necrosis, skin may become insensate.
• Necrosis may begin in the extremities and extend proximally.
• Hemorrhage into necrotic skin may lead to bullae formation.
• Eventually, hard eschars may form.

involvement of other organs

• Skin findings are most obvious, but thrombosis of small-medium vessels elsewhere in the body may cause failure of other organs. As such, purpura fulminans may be conceptualized as an occlusive, small-vessel vasculopathy.
• Adrenal hemorrhage (Waterhouse-Friderichsen syndrome):
  • This begins with infarction of small vessels within the adrenal glands, which subsequently leads to hemorrhagic transformation, with bleeding into the adrenal glands.
  • This may lead to adrenal insufficiency which precipitates adrenal crisis 📖.
• Renal failure due to glomerular thrombosis.

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diagnostic tests

laboratory studies

• Prolonged coagulation times:
  • INR may be normal or elevated (in a range of ~1-3). (32356378)
  • PTT is usually elevated (~1-3 times the upper limit of normal). (32356378)
• Fibrinogen:
  • This may be low, normal, or high. Infection tends to increase fibrinogen, whereas DIC may consume fibrinogen. Consequently, only a minority of patients have low fibrinogen levels.(32015972) Contrary to popular belief, a normal fibrinogen level excludes neither DIC nor purpura fulminans.
• D-dimer:
  • This is perhaps the most sensitive lab abnormality in purpura fulminans.
  • The D-dimer is generally very elevated (typically in the range of ~5,000-30,000 ng/mL).
• Platelet count: Thrombocytopenia is seen in most patients (e.g. in the range of roughly 25,000-150,000/uL).
• Reduced levels of protein C:
  • Levels will be reduced (e.g., below <40% of normal).
  • This is a send-out test at most hospitals that takes days to return. As such, it cannot contribute to acute patient management.
• (For a patient with high likelihood of having purpura fulminans, consider ordering: fibrinogen, D-dimer, protein C level, protein S level, antithrombin-III level, clotting factor levels including factors 2, 5, 7, 8, 9, 10).

skin biopsy

• Skin biopsy may be used to differentiate purpura fulminans from other conditions (e.g., vasculitis). In purpura fulminans, the biopsy will show dermal vessel thrombosis without vasculitis.
• Culturing the biopsy may reveal the underlying bacterial pathogen in patients with purpura fulminans due to Neisseria meningitidis. (34846563)
• Skin biopsy is usually unnecessary. In situations where the diagnosis of purpura fulminans is extremely likely based on clinical context, avoid delaying therapy while waiting for a skin biopsy.

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diagnosis

Diagnosis is often evident based on the observation of characteristic skin changes within a consistent clinical context (septic shock) and a consistent laboratory pattern. However, in situations where the diagnosis isn't clear, the following differential diagnosis should be considered: (29157918)

differential diagnosis

• Catastrophic antiphospholipid syndrome (CAPS) 📖
• Heparin-induced thrombocytopenia 📖
• Necrotizing fasciitis.
• Warfarin-induced skin necrosis.
• Vasculitis (e.g., Henoch-Schonlein purpura, cryoglobulinemic vasculitis).
• Thrombotic thrombocytopenic purpura (TTP).
• Cocaine/levamisole toxicity.

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treatment: antibiotics and source control

antibiotics

• Selection will depend on the clinical scenario.
• Consider the use of meningeal dosing if meningitis is possible (e.g., ceftriaxone 2 grams IV Q12).

stress-dose steroid

• Adrenal infarction may occur, which may require treatment with stress-dose steroids.
• Compared to septic shock in general 📖, there should be a somewhat lower threshold for steroid initiation. (27583208) 

vasopressors & inotropes

• Avoid vasoconstrictors as much as possible. Vasoconstrictors aren't the cause of tissue necrosis in purpura fulminans, but excess vasoconstrictors may nonetheless aggravate matters.
• Utilize agents that increase cardiac output, if possible (e.g., choosing epinephrine as a primary agent rather than norepinephrine).
• Avoid vasopressin since it may promote digital ischemia more than other agents do.

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treatment: heparin and heparin resistance

therapeutic unfractionated heparin infusion is generally recommended (if possible)

• Several studies have evaluated the use of heparin in septic shock. These studies have generally been negative. However, studies have included a wide variety of “septic” patients (most of whom did not have purpura fulminans).
• Given that purpura fulminans is a procoagulant form of DIC marked by clinical thrombus formation, guidelines, and expert opinion recommend the use of therapeutic anticoagulation with heparin.
• Thrombocytopenia is common but not necessarily a contraindication to heparin infusion. One center reported using therapeutic heparin infusions in patients with platelet counts >30,000/uL, which may be reasonable. (16635072) 

heparin administration: nuts and bolts

• Therapeutic anticoagulation with heparin is a bit complicated for the following reasons:
  • PTT will usually be elevated at baseline (making these labs unreliable in determining the heparin effect). Note that an elevated PTT is not necessarily a contraindication to heparin, as this may not correlate with true coagulation tendency within the context of DIC.
  • Patients are usually resistant to heparin due to a deficiency of antithrombin III, as well as the upregulation of heparin-binding proteins.
• ⚠️ Weight-based dosing of low molecular weight heparin is likely to fail in patients with purpura fulminans due to heparin resistance. Ideally, heparin should be provided as a continuous infusion of unfractionated heparin, titrated based on anti-Xa levels.
• Management of heparin resistance might include the following strategies:
  • [1] Use of higher doses of heparin (noting that there is no well-defined “maximal dose” of heparin). (29157918)
  • [2] Repletion of antithrombin III using antithrombin-III concentrates. Some centers will routinely administer antithrombin-III with the goal of maintaining levels >80% normal. (36485139) 
  • [3] Repletion of antithrombin III using blood products that contain antithrombin (e.g., Kcentra or fresh frozen plasma; see discussion of these products below).
  • Further discussion of heparin resistance: 📖

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treatment: protein C replacement +/- FFP

Deficiency of endogenous anticoagulant proteins is central to the pathophysiology of purpura fulminans (especially Protein C). Although high-level evidence is lacking for this rare condition, attempting to replace endogenous anticoagulants to re-balance hemostasis is rational. There are roughly four ways to do this, as described below. The selection of therapy will depend heavily on which products are available at your hospital and local regulations regarding their utilization (e.g., high doses of Kcentra are required, which may not receive pharmacy approval). Please note that purpura fulminans is a life- and limb-threatening disease. Although these treatments are expensive, they may still be cost-saving as compared to surgical amputation and debridement (see section below on surgical management).  

[1/3] Protein C concentrate (CEPROTIN) 💉

• Recombinant Protein C is a rational therapy for purpura fulminans, given that deficient protein C is a cornerstone of the pathophysiology of this entity. (27583208)
• Studies on protein C in purpura fulminans have not been adequately powered to prove any effect on mortality or such patient-centered outcomes as amputation. However, small studies in patients with purpura fulminans have demonstrated that protein C concentrates can improve hematologic endpoints, including (16635072)
  • Improved protein C activity (thus, there doesn't appear to be a need to use activated protein C).
  • Reduced D-dimer (implying successful braking of enzymatic coagulation).
  • Increasing levels of fibrinogen and antithrombin III.
  • Reduction of pathologically elevated plasminogen activator inhibitor-I (PAI-1). (10632475)
• Postmarketing surveillance and case series suggest that protein C replacement is safe. (20723255) In particular, protein C lacks the hemorrhage risk that was observed with activated protein C (XIGRIS).
• A reasonable dose might be a loading dose of ~100 units/kg, followed by ~50 units/kg q6hr until D-dimer shows a decreasing trend. (31449632, 12794428) If protein C levels can be measured with rapid turnaround time, the dose may also be titrated against protein C level. 

[2/3] Kcentra (four-factor PCC)

• Kcentra contains 840-1640 units of Protein C per 1,000 units of KCentra (roughly 1:1).
• Kcentra dosed at 100 U/kg would provide the following:
  • [1] ~100 units/kg of protein C.
  • [2] ~0.8-6 units/kg of Antithrombin III. For a 70-kg patient, this would be ~49-420 U  of antithrombin III. A typical loading dose of antithrombin III for the management of antithrombin deficiency is 500 mg. So, this might provide a meaningful dose of antithrombin III.
• Kcentra could be utilized if protein C concentrate isn't available. The optimal dose is unknown. To provide a standard replacement of protein C (100 U/kg) would require 1000 U/kg of Kcentra, which is an extremely large dose. It might be reasonable to cap the loading dose of Kcentra at 5,000 for this indication. Unfortunately, based on the short half-life of protein C, numerous doses of Kcentra would be required.

[3/3] FFP (fresh frozen plasma)

• FFP contains protein C and antithrombin III at roughly physiological concentrations (e.g., ~1 U/ml). It also contains additional anticoagulants, which might provide a more robust strategy for re-establishing hemostatic balance.
• The optimal dosing of FFP is not clear. Protein C has a very short half-life in the plasma, so repeated administration of FFP is needed (e.g., 2-4 units q6hrs).
• In the absence of more advanced blood products (Protein C concentrate or Kcentra), large volumes of FFP would be needed to re-establish a normal balance of coagulation. Targeting 100 U/kg replacement of protein C would probably be impossible with FFP since this would require a massive dose (100 cc/kg, which for a 70-kg patient is 7 liters of FFP). However, it's probable that a lower dose could provide some benefit. This will provide a substantial fluid load, so diuresis or CRRT might be required to avoid volume overload.
• In combination with protein C concentrates and antithrombin, less FFP would be required. Goshua G et al. describe an empiric regimen of 2 units FFP followed by 1 unit every four hours for the first three days, followed by 1 unit every six hours on days #4-5, and then 1 unit every 8 hours on days #6-7 in this context. (36485139)

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treatment: replacement of other blood products

general considerations in blood product replacement: 

• [1] Balance of hemostasis vs. thrombosis:
  • Overzealous replacement could theoretically aggravate thrombus formation.
  • However, allowing coagulation levels to fall extremely low could also be dangerous (particularly in patients who are receiving heparin infusions).
• [2] Concurrent use of heparin: For patients on therapeutic heparin, higher targets are often reasonable.
• [3] If FFP is utilized, note that one 250-ml unit of FFP contains roughly 750 mg of fibrinogen (~3 units/ml).

targets for product administration?

• Consider maintaining a fibrinogen level of >100 mg/dL.
• Consider maintaining a platelet level >~30,000/uL among patients on a therapeutic heparin infusion.  For patients who aren't receiving heparin, a usual platelet transfusion threshold might be appropriate (e.g., targeting >~10,000/uL). (16635072)

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treatment: vitamin K supplementation

administration of vitamin K

• A key pathophysiological problem in purpura fulminans is a deficiency of protein C. Synthesis of this protein depends on vitamin K.
• Replacement should be considered in patients with suspected or possible vitamin K deficiency. Some authors have suggested that vitamin K deficiency could contribute to a tendency towards developing purpura fulminans. (15186640)
  • Detection of vitamin K deficiency may be challenging because most patients will have an elevated INR due to disseminated intravascular coagulation.

avoidance of warfarin

• One of the first effects of warfarin is the depletion of protein C and protein S. This may lead to a transient hypercoagulable state (which is the pathophysiology underlying warfarin-induced skin necrosis).
• Initiation of warfarin in a patient with purpura fulminans would be illogical and potentially dangerous.

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treatment: vasodilators

For patients with digital ischemia and the threat of digital amputation, the following treatments may be attempted:

topical vasodilators

• Topical nitroglycerine for local vasodilation of hypoperfused extremities.

intravenous epoprostenol infusion

• Low-dose epoprostenol infusion has been described in case reports as improving distal perfusion and potentially reducing tissue loss (e.g., starting at a dose of 2 ng/kg/min). (21396502) Other case reports have used iloprost, a similar agent unavailable intravenously in the United States. (30871501)
• Evidence supporting epoprostenol consists solely of a few case reports. It is indirectly buttressed by evidence regarding epoprostenol in digital ischemia due to refractory Raynaud's phenomenon. (27465880)
• In patients with threatened perfusion of their digits who are at risk of amputation, a clinical trial of epoprostenol might be considered under close supervision.
• Epoprostenol can cause hypotension so that this therapy would be contraindicated in patients with severe hemodynamic instability. Other side effects are less serious (e.g., nausea, vomiting, abdominal pain, diarrhea).

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treatment: surgical debridement

general conceptualization as a burn wound

• Extensive skin necrosis due to purpura fulminans may mimic burns.
• Some authors have suggested that patients with extensive involvement should be treated in burn centers, but this is rarely done in practice. (32513908)

extremity compartment syndrome

• Pathophysiology:
  • (1) Aggressive fluid administration leads to tissue edema.
  • (2) Skin necrosis prevents the skin from stretching (especially if the skin is involved circumferentially with purpura fulminans).
• Extremity compartment syndrome may be a major driver for the need to amputate limbs. Although purpura fulminans involves the dermis, it usually spares the underlying tissue.
• Early surgical decompression with fasciotomy may potentially decrease the need for amputation. (31524150)
• Compartment syndrome often is not obvious (and in many cases, it may go entirely unrecognized). When in doubt, surgical consultants should be involved early.

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hyperfibrinolysis

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Similar to coagulation, there is a delicate balance between pro-fibrinolytic proteins (e.g., tPA, uPA, plasminogen) and anti-fibrinolytic proteins (e.g., TAFI, PAI-1, ⍺2AP). A relative deficiency of anti-fibrinolytic proteins will cause excessive fibrinolysis, which promotes clinical bleeding.

Hyperfibrinolysis may result from a primary abnormality of fibrinolysis (e.g., abnormality of one or more of the above proteins). Hyperfibrinolysis may also result as a secondary process due to DIC (i.e., the generation of large amounts of fibrin leads to an increase in fibrin breakdown). The following sections and discussion are directed at primary abnormalities of fibrinolysis.

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hyperfibrinolysis: causes

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[1] cirrhosis (termed AICF: accelerated intravascular coagulation and hyperfibrinolysis)

• Precise rates of AICF are unclear, but this is not uncommon in advanced cirrhosis. Correlates with AICF include:
  • [1] AICF may be more common among alcoholic cirrhosis, as opposed to nonalcoholic steatohepatitis. (33772480)
  • [2] AICF is more common among acute-on-chronic liver failure (ACLF). (33772480)
• ⚠️ AICF is often missed. Failure to diagnose AICF may lead to intractable hemorrhage that doesn't respond to usual treatment.
• Pathophysiology of AICF may involve:
  • [1] Normally, the endothelium releases tiny amounts of tissue plasminogen activator (tPA), which is subsequently cleared by the liver. Failure of the liver to metabolize endogenous tPA leads to increasing tPA levels.
  • [2] Decreased hepatic production of anti-fibrinolytic proteins (TAFI, PAI-1, and ⍺2AP).

[2] APM (acute promyelocytic leukemia)

• Discussed here: 📖

[3] other exposures

• Postpartum hemorrhage and placental disorders (release of plasminogen activators from the uterus and placenta).
• Trauma.
• Cardiopulmonary bypass.
• Thrombolytic therapy.

[4] congenital

• Alpha2-antiplasmin deficiency.
• Plasminogen activator inhibitor-1 deficiency.
• Quebec platelet disorder (overexpression of uPA in platelets).
• Hemophilia (enhanced lytic susceptibility of fibrin structure, impaired TAFI activation)
• FXIII deficiency (enhanced lytic susceptibility of fibrin structure, impaired alpha2-plasmin crosslinking to fibrin).
• Dysfibrinogenemias (abnormal fibrin structure increases susceptibility to lysis).

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hyperfibrinolysis: clinical manifestations

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Hyperfibrinolysis is difficult to diagnose due to its rarity. Some unusual clinical features may suggest the possibility of hyperfibrinolysis: 

• Delayed bleeding (clots form following trauma/surgery but subsequently break down).
• Intractable bleeding that fails to respond to usual therapy.
• Mucosal bleeding (areas with high fibrinolytic activity):
  • Menorrhagia.
  • Epistaxis.
  • Gastrointestinal hemorrhage (especially hyperfibrinolysis related to cirrhosis).
  • Gingival bleeding.
  • Urological.
• Continuous venous oozing from venipuncture or surgical sites.
• Spontaneous bleeding (e.g., intramuscular hematoma).

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hyperfibrinolysis: laboratory diagnosis

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general diagnosis of hyperfibrinolysis

• D-dimer elevation.
  • D-dimer is generally profoundly elevated.
  • Elevated D-dimer is the most sensitive finding for hyperfibrinolysis.
• Fibrinogen depletion.
  • Fibrinogen levels may respond initially to supplementation, but subsequently, fibrinogen levels continually drift downwards and require frequent repletion.
• Thromboelastography.
  • Thromboelastography is insensitive to hyperfibrinolysis because tPA rapidly becomes inactivated in vitro. (26049070) Therefore, a normal LY-30 doesn't exclude hyperfibrinolysis.
  • If seen, LY30 >3% suggests hyperfibrinolysis. (29363269)
• (Euglobulin clot lysis time is an assay for hyperfibrinolysis, but this usually isn't available.)

features that may support a diagnosis of hyperfibrinolysis rather than DIC

• Platelet count may be relatively stable over time.
• INR and PTT may be normal or close to baseline.
• Patients with hyperfibrinolysis may have normal/elevated levels of factor VIII (whereas factor VIII would be reduced in DIC). (21475134)
• Elevated LY-30 could be helpful (but this is rarely seen in practice, as discussed above).

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hyperfibrinolysis: treatment

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[1] restoration of fibrinogen levels

• For patients with hemorrhage, fibrinogen levels must be restored by transfusion of cryoprecipitate or fibrinogen concentrate.
• For intractable bleeding, targeting a relatively higher fibrinogen level (e.g., >150-200 mg/dL) could be helpful. Unfortunately, there is no high-level evidence regarding the optimal fibrinogen target.
• A combination of fibrinogen replacement with fibrinolysis inhibition is often required to maintain adequate fibrinogen levels over time.

[2] tranexamic acid or aminocaproic acid

• A fibrinolysis inhibitor is often required to maintain adequate fibrinogen levels and prevent excessive clot degradation.
• Tranexamic acid:
  • A starting dose may be 1 gram IV, followed by a continuous infusion of one gram over 8 hours repeatedly (i.e., 125 mg/hr infusion). (30986390) This is the standard dosing utilized in traumatology studies, such as the CRASH trials.
  • The optimal dose is unclear. In refractory cases of hyperfibrinolysis in cirrhosis, higher doses of tranexamic acid may be required (e.g., 200 mg/hour infusion). (31294331). The risk of seizure may increase at higher doses, so avoid using high-dose tranexamic acid in combination with other medications that reduce the seizure threshold.
  • After the bleeding has resolved, IV tranexamic acid may be converted to oral tranexamic acid (e.g., 1300 mg PO q6hr).
• Aminocaproic acid is discussed further here: 📖

[3] DDAVP is contraindicated

• DDAVP increases plasminogen activator activity, which may enhance fibrinolysis. Consequently, DDAVP is contraindicated in patients with hyperfibrinolysis. (34209949)
• By itself, DDAVP does not cause hyperfibrinolysis.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• When possible, try to avoid the use of blood products to “fix labs” in a patient with asymptomatic DIC (although this may be warranted for a profoundly low platelet count or fibrinogen level).
• Sepsis-associated DIC generally causes patients to be prothrombotic. Therefore, holding DVT prophylaxis for patients with mild-moderate thrombocytopenia (e.g., platelet count >30,000) may be inadvisable.
• Pitfalls on purpura fulminans:
  • Failure to involve surgical consultants early for patients who may require fasciotomy for compartment syndrome.
  • Failure to provide specific therapy for purpura fulminans (these patients will often respond poorly to usual sepsis care).
  • Excessive use of blood product replacement (e.g., fresh frozen plasma, platelets) in patients who are not bleeding.

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